Untitled

Alternative Medicines for
Diabetes Management
Apart from diet and exercise, the strategic use of different classes of prescribed or
non-prescribed xenobiotic compounds for the restoration of euglycaemic levels in
the body is well known. The ongoing rivalry between the recommended usage of
allopathic medicines versus Ayurvedic remedies has encouraged many researchers to
focus their studies on thoroughly isolating and characterizing extracts from different
parts of plants and then evaluating their relative activities via in vitro, in vivo, and, in
some cases, clinical studies.
Alternative Medicines for Diabetes Management: Advances in Pharmacognosy

and Medicinal Chemistry provides a holistic view of all oral therapies for diabetes
mellitus that are available to the public by removing the silos and stigmas associated
with both allopathic and Ayurvedic medicines.
Additional features include
• Highlights the potential role of dietary and medicinal plant materials in the
prevention, treatment, and control of diabetes and its complications.
• Educates readers on the benefts and shortcomings of the various current
and potential oral therapies for diabetes mellitus.
• Allows the quick identifcation and retrieval of material by researchers
learning the effcacy, associated dosage, and toxicity of each of the classes
of compounds.
• Presents the history, nomenclature, mechanisms of action, and shortcomings
of each of the various subclasses of allopathic therapeutants for diabetes
mellitus and then introduces Ayurvedic medicines.
• Chapter 4 discusses various metallopharmaceuticals and provides a holistic
view of all available and potential therapies for the disease.
Medicinal Plants and Natural Products for Human Health
Series Editor:
Christophe Wiart
We are at a point in history where the global population is increasingly interested

in medicinal plants, natural products and herbalism. This interest has accelerated
with COVID-19 and long COVID symptoms. Rediscovery of the connection between
plants and health is responsible for a new generation of botanical therapeutics that
include plant-derived pharmaceuticals, multicomponent botanical drugs, dietary sup-
plements, functional foods and plant-produced recombinant proteins. Many of these
products can complement conventional pharmaceuticals in the treatment, prevention
and diagnosis of diseases. This series is a critical reference for anyone involved in the
discovery of biopharmaceuticals for the improvement of human health.
Alternative Medicines for Diabetes Management: Advances in Pharmacognosy

and Medicinal Chemistry
Edited by: Varma H. Rambaran, Nalini K. Singh
Alternative Medicines for
Diabetes Management
Advances in Pharmacognosy
and Medicinal Chemistry
Varma H. Rambaran and Nalini K. Singh

University of Trinidad and Tobago, Tamana Campus,
Trinidad and Tobago
First edition published 2022
by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742
and by CRC Press

4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN
CRC Press is an imprint of Taylor & Francis Group, LLC
© 2023 Varma H. Rambaran, Nalini K. Singh
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Library of Congress Cataloging‑in‑Publication Data
Names: Rambaran, Varma H., author. | Singh, Nalini K., author.

Title: Alternative medicines for diabetes management : advances in
pharmacognosy and medicinal chemistry / Varma H. Rambaran, Nalini K.
Singh, University of Trinidad and Tobago, Tamana Campus, Trinidad and
Tobago.
Description: First edition. | Boca Raton, FL : CRC Press, 2023. | Includes
bibliographical references and index.
Identifers: LCCN 2022017667 (print) | LCCN 2022017668 (ebook) | ISBN
9781032344898 (hbk) | ISBN 9781032344973 (pbk) | ISBN 9781003322429
(ebk)
Subjects: LCSH: Diabetes--Alternative treatment. | Diabetes--Ayurvedic
treatment. | Materia medica, Vegetable--Therapeutic use. | Medicinal
plants--Therapeutic use. | Pharmacognosy.
Classifcation: LCC RC661.A47 R36 2023 (print) | LCC RC661.A47 (ebook) |
DDC 616.4/62--dc23/eng/20220716
LC record available at https://lccn.loc.gov/2022017667
LC ebook record available at https://lccn.loc.gov/2022017668
ISBN: 9781032344898 (hbk)

ISBN: 9781032344973 (pbk)
ISBN: 9781003322429 (ebk)
DOI: 10.1201/9781003322429
Typeset in Times
by Deanta Global Publishing Services, Chennai, India
For my mentors:
Dr Richard A. Fairman and Professor Alvin A. Holder
Thank you for your continued guidance and support
Varma
Contents
Preface.......................................................................................................................xi
Acknowledgements ................................................................................................ xiii
Authors..................................................................................................................... xv
Chapter 1 Etiology ................................................................................................1

1.1 Diabetes Mellitus (DM) ............................................................ 1
1.1.1 Type-1 Diabetes............................................................1
1.1.2 Type-2 Diabetes............................................................2
1.1.3 Hyperglycaemia in Pregnancy ..................................... 3
1.1.4 Other Types of Diabetes...............................................3
1.2 Insulin Transduction Pathway ................................................... 4
1.3 Our Goal....................................................................................5
Chapter 2 Allopathic Medicines ...........................................................................7

2.1 Introduction ............................................................................... 7
2.1.1 Overview and Signifcance...........................................7
2.1.2 History..........................................................................8
2.1.3 Downfalls .....................................................................8
2.2 Biguanides ................................................................................. 9
2.3 Sulfonylureas ........................................................................... 11
2.4 Meglitinides............................................................................. 14
2.5 Alpha-Glucosidase Inhibitors.................................................. 15
2.6 DPP-4 Inhibitors...................................................................... 18
2.7 Thiazolidinedione....................................................................20
2.8 SGLT-2 Inhibitors.................................................................... 22
Chapter 3 Ayurvedic Medicines: (Ethnopharmacological Treatments) ............. 39

3.1 Introduction ............................................................................. 39
3.1.1 Overview and Signifcance......................................... 39
3.1.2 History........................................................................40
3.1.2.1 Traditional Indian Medicine .......................40
3.1.2.2 Traditional Chinese Medicine .................... 41
3.1.2.3 Traditional Arabic and Islamic Medicine ..... 42
3.1.3 Downfalls ................................................................... 42
3.2 Abelmoschus esculentus Linn. (AE)........................................ 43
3.3 Ageratum conyzoides Linn. (AgC) .......................................... 45
3.4 Allium cepa Linn. (AC)............................................................ 47
3.5 Allium sativum Linn. (AS) ....................................................... 48
vii
viii Contents
3.6 Aloe barbadensis Mill. (ABM) ................................................ 50

3.7 Annona muricata Linn. (AM).................................................. 52
3.8 Apium graveolens Linn. (AG).................................................. 54
3.9 Azadirachta indica Linn. (AI) ................................................. 56
3.10 Bidens pilosa Linn. (BiP) ........................................................ 58
3.11 Bixa orellana Linn. (BO).........................................................60
3.12 Brassica juncea Linn. (BJ)...................................................... 61
3.13 Bryophyllum pinnatum Linn. (BP).......................................... 63
3.14 Capparis spinosa Linn. (CaS).................................................64
3.15 Carica papaya Linn. (CaP).....................................................66
3.16 Catharanthus roseus Linn. (CR) ............................................. 68
3.17 Cecropia obtusifolia Linn. (CeO) and Cecropia
peltata Linn. (CeP) .................................................................. 70
3.18 Centella asiatica Linn. (CeA).................................................. 72
3.19 Chromolaena odorata Linn. (CO) .......................................... 74
3.20 Citrus aurantiifolia Linn. (CiA) .............................................. 75
3.21 Citrus limon Linn. (Cil)........................................................... 77
3.22 Citrus paradisi Linn. (CiP) ..................................................... 78
3.23 Citrus sinensis Linn. (CiS) ...................................................... 81
3.24 Coriandrum sativum Linn. (CoS)............................................ 82
3.25 Crescentia cujete Linn. (CrC) .................................................84
3.26 Cucumis sativus Linn. (CS)..................................................... 86
3.27 Cucurbita fcifolia Linn. (CF) and Cucurbita
pepo Linn. (CP) ....................................................................... 88
3.28 Curcuma longa Linn. (CL) ...................................................... 89
3.29 Cymbopogon citratus Linn. (CC)............................................ 91
3.30 Euphorbia hirta Linn. (EH) .................................................... 93
3.31 Hibiscus rosa-sinensis Linn. (HRS) ........................................94
3.32 Justicia secunda Vahl (JS) ......................................................96
3.33 Lantana camara Linn. (LC)....................................................97
3.34 Leonotis nepetifolia Linn. (LN)............................................... 98
3.35 Mangifera indica Linn. (MI) ................................................. 100
3.36 Mentha................................................................................... 102
3.37 Mimosa pudica Linn. (MP) ................................................... 104
3.38 Momordica charantia Linn. (MC) ........................................ 105
3.39 Morinda citrifolia Linn. (MoC)............................................. 108
3.40 Moringa oleifera Linn. (MO) ................................................ 109
3.41 Murraya koenigii Linn. (MK)................................................ 111
3.42 Neurolaena lobata Linn. (NL)............................................... 114
3.43 Ocimum gratissimum Linn. (OG) and Ocimum
tenuiforum Linn. (OT) .......................................................... 117
3.44 Panax ginseng Linn. (PG) and Panax
quinquefolius Linn. (PQ)....................................................... 120
3.45 Parthenium hysterophorus Linn. (PaH) ............................... 122
3.46 Peperomia pellucida Linn. (PP)............................................ 123
Contents ix
3.47 Phyllanthus amarus Linn. (PA)............................................. 124

3.48 Scoparia dulcis Linn. (SD).................................................... 126
3.49 Senna italica Linn. (SI) ......................................................... 128
3.50 Stachytarpheta jamaicensis Linn. (SJ) ................................. 129
3.51 Syzygium cumini Linn. (SC) .................................................. 131
3.52 Tamarindus indica Linn. (TI)................................................ 134
3.53 Tournefortia hirsutissima Linn. (TH) ................................... 135
3.54 Urena lobata Linn. (UL) ....................................................... 136
3.55 Zingiber offcinale Linn. (ZO)............................................... 137
Chapter 4 Metallopharmaceuticals ................................................................... 153

4.1 Introduction ........................................................................... 153
4.1.1 Overview and Signifcance....................................... 153
4.1.2 The Challenge .......................................................... 154
4.1.3 The Future for Insulin-Enhancing Drugs? ............... 155
4.2 Vanadium............................................................................... 155
4.3 Chromium.............................................................................. 159
4.4 Zinc........................................................................................ 161
4.5 Cobalt..................................................................................... 164
4.6 Tungsten................................................................................. 166
4.7 Molybdenum.......................................................................... 169
Conclusion ............................................................................................................ 171

Bibliography ......................................................................................................... 173
Abbreviations .......................................................................................................207
Glossary ................................................................................................................ 211
Index...................................................................................................................... 215
Preface
Apart from diet and exercise, the strategic use of different classes of prescribed and
non-prescribed xenobiotic compounds for the restoration of euglycaemic levels in
the body is well known. The ongoing rivalry between the recommended usage of
allopathic medicines versus herbal remedies has encouraged many researchers to
focus their studies on thoroughly isolating and characterizing extracts from different
parts of plants, and then evaluating their relative activities via in vitro, in vivo, and, in
some cases, clinical studies. To further support this drive, the respective rich histories
of many countries with regard to both colonization and immigration have enabled a
wider selection of botanical sources to become more accessible to their inhabitants,
and it is observed that these plants are already integrated into their regular diets and
lifestyles.
Stepping aside from the aforementioned controversy between fact and folklore,
the emergence of a revolutionary class of therapeutics that belongs to a family of com-
pounds known as coordination complexes has also been reported. Fondly dubbed by
their developers as insulin mimetics or insulin enhancers, these metallo-drugs have
struggled for acceptance by the medical fraternity due to the divisive claims behind
them. However, perseverance driven by passion in this area has continued to yield
promising data, and this has stoked hope for their further development.
xi
Acknowledgements
The authors wish to thank the University of Trinidad and Tobago for all the assis-
tance given throughout the development of this book.
We also wish to thank our families and friends for their undying encouragement
and support throughout our endeavours.
Finally, we would like to give special thanks to Mrs Ashmini Motilal, Miss Pritivi
Narine, Miss Kajol Jagessar, Mr Dheeresh Ramcharan, and Mr Narendra Maharaj
for their invaluable contributions to the completion of this book.
xiii
Authors
Dr Varma H. Rambaran is currently employed as an
Associate Professor at the University of Trinidad and Tobago
(UTT), Offce of the Vice President of Research and Student
Affairs (VP-RASA). He graduated from the University of the
West Indies in 1999, with a Bachelor of Science in Chemistry,
and in 2005, obtained a Doctor of Philosophy degree in
Inorganic Chemistry. During his years as a post-graduate stu-
dent, he developed a keen interest in the behaviour of coor-
dination complexes in biological systems. However, it was
during his post-doctoral fellowship at the University of Southern Mississippi that
the ameliorative effects of vanadium-based complexes in diabetes therapy caught his
attention. Through the support of the International Centre for Genetic Engineering
and Biotechnology (ICGEB), he was able to successfully explore and develop his
idea of using a family of novel vanadyl complexes (PDOV and PYTOV) as insulin-
enhancing agents. The fndings from his studies were awarded a patent by the US
Patent and Trademark Offce in March 2021.
While working on his project, Dr Rambaran noticed a partiality to certain medi-
cines that were being prescribed to diabetic patients. The seemingly undying contro-
versy over the superiority of allopathic medicines, versus their ethno-pharmaceutical
counterparts has resulted in the polarization of many groups, due to their lack of
awareness and understanding of the different forms of therapies. To further com-
plicate matters, the majority of reference books on the market commonly lack the
supporting scientifc data of compound identity, mechanism of action, and safety
in use. Unfortunately, this has led to a bias against the use of herbal medicines by
insinuating that the claims being made are more witchcraft than science.
Inspired by this, Dr Rambaran saw a need to furnish a comprehensive book of
this nature, which would impartially and holistically educate its readers on the oral
therapeutic options that are available to them.
Nalini Kathleen Singh is currently employed at UTT as

a Research Assistant, under the Offce of VP-RASA. Ms
Singh’s research interests fall under the umbrella of non-
communicable diseases (NCDs), focusing mainly on the
epidemiology and etiology of hypothyroidism. Her extended
interest in natural medicines used in NCD-therapies has war-
ranted her invaluable contributions in this book.
Ms. Singh holds a Bachelor of Science in Chemical and
Process Engineering, which she obtained from the University
of the West Indies (UWI, St Augustine Campus) in 2013. She
also completed an Occupational Safety and Health Administration (OSHA) general
xv
xvi Authors
industry training course at the School of Business and Computer Science (SBSC) in
2014, and participates in short courses on a regular basis to improve her professional
skills. Since 2016, she has been an active member of the Association of Professional
Engineers of Trinidad and Tobago (APETT) in both the electrical and chemical divi-
sions, with her current grade being Associate Member. Ms Singh has also received
awards in leadership and good citizenship owing to her involvement in volunteer
programmes since 2002. Due to her positive attitude, her desire to learn, and her pas-
sion for scientifc research, Ms Nalini Singh continues to take steps to continuously
improve, both professionally and personally.
1 Etiology
1.1 DIABETES MELLITUS (DM)

Diabetes mellitus is ranked as one of the top four non-communicable diseases in the
world. According to its most recent release, the International Diabetes Federation
(IDF) has estimated a world population of 537 million people (aged 20–79 years)
who are living with the disease, which, if left unaddressed, will rise to a staggering
784 million by 2045! Within the North American and Caribbean region alone there
are 51 million adults, representing a regional prevalence of 9.5% (Figure 1.1); this
prevalence had an associated health expenditure of approximately US$415 billion
and accounted for 42.9% of total global diabetes-related health expenditure in 2021
(IDF Diabetes Atlas 2021: 10th Edition 2021).
DM’s diagnosis as a metabolic disease arises from either the pancreas’s inabil-
ity to produce suffcient quantities of insulin or the desensitization of the human
insulin receptor glycoprotein (INS-R) (due to the overproduction of the hormone).
Its etiology encompasses a range of factors that include genetics, viral infections,
autoimmunity, and obesity (Ramasamy and Schmidt 2014). Stemming from these
are its clinical manifestations, which include hyperglycaemia, glycosuria, insulin
resistance, fat and carbohydrate metabolism abnormalities, and chronic complica-
tions resulting from macro- and micro-vascular pathology. DM can be categorized
under two major classes: type-1 and type-2. However, the diagnosis of a patient with
DM and the classifcation under which type they suffer from, can vary according to
the individual. As such, it has been observed in recent times that endocrinologists
have further expanded the subclasses according to their contrasting occurrences and
symptoms. An example of this is a patient who was initially diagnosed with gesta-
tional diabetes (GDM) and continued to be hyperglycaemic even after delivery and,
as a consequence, was later diagnosed with type-2 diabetes mellitus (T2DM) (IDF
Diabetes Atlas 2021: 10th Edition 2021). To best understand this and other occur-
rences, a brief discussion of the various classifcations of the disease follows.
1.1.1 TYPE-1 DIABETES

Type-1 diabetes mellitus (T1DM) or “immune-mediated diabetes” was previously
classifed as “insulin-dependent diabetes” or “juvenile-onset diabetes.” It occurs as
a result of the cellular-mediated autoimmune destruction of the pancreatic β-cells,
which may be either genetically or environmentally infuenced. However, there has
been some suspicion of its occurrence due to toxic and some dietary factors (Sesti
2006, Nelson and Cox 2008). The rate of destruction of the β-cells has been observed
to vary from slow (occurring mainly in adults) to rapid (being highly peculiar to
infants and children). The condition can develop at any age, although it occurs most
frequently in children and young adults.
DOI: 10.1201/9781003322429-1 1
2 Alternative Medicines for Diabetes Management
FIGURE 1.1 International Diabetes Federation Diabetes Atlas (2021).
The incidence of T1DM is increasing worldwide, but there is considerable variation

by country with some regions of the world having much higher incidences than
others. The reasons for this are unclear, but the rapid increase over time is suspected
to be due to non-genetic factors, such as environmental and probably lifestyle-related
changes. Apart from this, proposals of an observed inverse relationship between the
decreasing incidence of infections in Western countries and the increasing incidence
of both autoimmune and allergic diseases have been put forward to justify the spike
(Okada, Kuhn and Feillet 2010).
Therapeutic treatments for people with T1DM include daily insulin injections,
which when complemented with regular blood glucose (BG) monitoring, education,
and support, allow the patient to live a relatively normal life.
1.1.2 TYPE-2 DIABETES

Previously classifed as “non-insulin-dependent diabetes” or “adult-onset diabetes,”
T2DM typically encompasses patients who either display a resistance to insulin or
have problems with secreting the hormone. During the state of insulin resistance, the
hormone is ineffective and in due course prompts an increase in insulin production.
Consequently, the β-cells become overworked and eventually cannot keep up with
the demand for the hormone.
Specifc etiologic factors for T2DM are unknown; however, β-cell destruction (as
in the case of T1DM) does not occur. This type predominantly occurs in adults and
children who are obese, which by itself is a contributing factor to insulin resistance.
Interestingly, individuals who may not be considered obese by the traditional criteria
of weight, tend to exhibit an increased percentage of body fat distribution, mostly to
the abdominal area (American Diabetes Association 2013).
Etiology 3
Globally, the prevalence of T2DM is high and rising across all regions. This rise
is driven by population ageing, economic development, and increasing urbanization
leading to more sedentary lifestyles and a greater consumption of unhealthy
foods linked to obesity (Sesti 2006). The cornerstone of T2DM management is
the promotion of a lifestyle that includes a healthy diet, regular physical activity,
smoking cessation, and maintenance of a healthy body weight. As a contribution
to improving the management of T2DM, in 2017 the IDF issued the IDF Clinical
Practice Recommendations for Managing T2DM in Primary Care (Aschner 2017).
If attempts at lifestyle changes are not suffcient to control blood glucose levels,
oral medication is usually initiated with biguanides (metformin) as the frst line
of therapy. Should this treatment prove to be inadequate or ineffcient, a range of
combination-therapy options, such as sulfonylureas, meglitinides, and dipeptidyl
peptidase-4 inhibitors are then considered for prescribed use. Finally, as a last resort,
if oral medications fail to control the hyperglycaemic levels, insulin injections may
be deemed necessary (IDF Diabetes Atlas 2021: 10th Edition 2021).
1.1.3 HYPERGLYCAEMIA IN PREGNANCY

Hyperglycaemia in pregnancy (HIP) can be classifed as either “gestational diabetes
mellitus” (GDM) or “diabetes in pregnancy” (DIP). It can occur anytime during
pregnancy, including the frst trimester; however, its occurrence is usually detected
during the third trimester. DIP classically applies to pregnant women who have
previously known diabetes or have hyperglycaemia that was frst diagnosed during
pregnancy and meets the World Health Organization’s (WHO) criteria of diabetes in
the non-pregnant state.
Due to hormone production by the placenta, GDM also arises in women with
an insuffcient insulin-secretory capacity to overcome insulin resistance. The risk
factors for GDM include older age (over 35 years), overweight and obesity, previous
cases of GDM, excessive weight gain during pregnancy, a family history of diabetes,
polycystic ovary syndrome, habitual smoking, and a history of stillbirth or giving
birth to an infant with a congenital abnormality (IDF Diabetes Atlas 2021: 10th
Edition 2021).
1.1.4 OTHER TYPES OF DIABETES

According to a recently published WHO report on the classifcation of diabetes
mellitus, there are a number of “other specifc types” of diabetes, including
“monogenic diabetes” and what was once termed “secondary diabetes.”
As the name implies, monogenic diabetes results from a single gene rather than
the contributions of multiple genes and environmental factors as seen in T1DM and
T2DM. With an occurrence of only 1.5%–2%, these cases are noted to be in the
minority; however, they include various manifestations that range from neonatal
diabetes mellitus (sometimes called “monogenic diabetes of infancy”), maturity
onset diabetes of the young (MODY), and rare diabetes-associated syndromic
diseases (IDF Diabetes Atlas 2021: 10th Edition 2021).
1.2 INSULIN TRANSDUCTION PATHWAY

The insulin transduction pathway refers to a self-regulating biochemical process in
which the hormone (insulin) infuences the uptake of glucose into the fat and muscle
cells or conversely reduces the synthesis of glucose in the liver.
The release of insulin from the pancreas is a consequence of spiked levels of
glucose in the blood. Identifed as the main contributor to normoglycaemic regulation,
the released insulin promotes the uptake of glucose by binding to its membrane-
embedded receptor and triggering a cascade of intracellular processes that promote
the usage and/or storage of glucose in the cell.
To better appreciate the action of insulin and its potential substitutes, a closer look
at its involvement in the insulin transduction pathway is necessary.
Spanning the cellular membrane is the insulin substrate receptor (INS-R). This
glycoprotein is composed of two extracellular α-subunits, which are linked to their
complementary β-subunits via disulphide bonds. The β-subunit itself comprises
three sections: the extracellular, transmembrane, and intracellular domains; the latter
section contains three main autophosphorylation sites: the juxtamembrane domain
(JM), the catalytic domain (TK), and the COOH-terminal phosphorylation domain
(CT) (Figure 1.2) (Sesti 2006).
As illustrated in Figure 1.3, after insulin enters the bloodstream it binds to the
α-subunits of the INS-R and forms a receptor–ligand complex (Step 1). This, in turn,
triggers the intracellular domain of the receptor’s β-subunit to undergo phosphoryla-
tion by adenosine triphosphate (ATP) (Step 2). Now decorated with the phosphate
groups, the INS-R becomes a suitable site for the transfer of these phosphate groups
FIGURE 1.2 Diagrammatic representation of the human insulin receptor glycoprotein

(INS-R).
Etiology 5
FIGURE 1.3 Schematic diagram of the insulin transduction pathway.
to other target proteins, such as the insulin receptor substrate (INR-S) (Step 3). The
phosphorylated INR-S is now a target for insulin receptor tyrosine kinase (IRTK),
which upon binding (Step 4) activates the enzyme phosphatidylinositol 3-kinase
(PI3K) (Step 5). This domino effect continues as the activated PI3K binds to the
membrane lipid, phosphatidylinositol (4,5)-bisphosphate (PIP2) (Step 6) and converts
it to phosphatidylinositol (3,4,5)-triphosphate (PIP3) (Step 7). Next in the sequence is
protein kinase-B (PKB/Akt), which binds to PIP3 via pleckstrin homology (Step 8).
PKB is then phosphorylated on a threonine residue by phosphoinositide-dependent
kinase-1 (PDK1) (Step 9), which in turn signals the translocation of the intracellular
vesicle glucose transporter type-4 (GLUT-4) to the cell membrane (Step 10). The
GLUT-4 fnally fuses with the cell membrane (Step 11) and creates a portal through
which glucose can enter (Step 12).
1.3 OUR GOAL

There is a large pool of reliable and compelling publications that are based on the
justifcation for using either an entire class of oral therapeutics or individual mem-
bers of that particular class. However, there does not exist any form of compiled
reference that impartially reports the benefts and shortcomings of all these forms
of therapy.
We were also concerned about the uncontrolled rise in cases of DM through-
out the world and the lack of availability of many prescription drugs, due to eco-
nomic factors. We believe that knowledge (backed by science) of alternative forms
of therapy for this disease would be welcomed by those who are unable to procure
such medication.
The authors hope that the information will serve to better educate the public, so
that more informed decisions can be made in selecting an appropriate and effective
form of therapy that best suits the patient’s lifestyle.
2 Allopathic Medicines
Despite the many confrmed and unconfrmed side effects, allopathic drugs are still peddled
as the safest form of therapy.
2.1 INTRODUCTION
2.1.1 OVERVIEW AND SIGNIFICANCE
Regarding allopathic medicines, drugs are strictly defned as chemical substances
that are used to prevent or heal diseases in humans, animals, and plants, and are
grouped according to the manner in which they are utilized. Of particular interest
to the medicinal chemist is the structure of the compound as well as its relative
pharmacological mechanism of action. However, other categories such as the nature
of the illness must also be considered.
In the case of diabetes mellitus (DM), there is a need for a multi-targeted strategy
for its effcient management. For example, postprandial hyperglycaemia (at the diges-
tive level) is controlled with α-glucosidase inhibitors such as acarbose, miglitol, and
voglibose, which are used to inhibit the degradation of carbohydrates. Alternatively,
to enhance glucose uptake by peripheral cells, biguanides such as metformin are
DOI: 10.1201/9781003322429-2 7
seen to be the therapeutant of choice, while insulinotropic sulfonylureas such as

glibenclamide serve as secretagogues for pancreatic cells (Nimesh, Tomar and
Dhiman 2019).
The structure–activity relationship (SAR) approach to drug discovery is based
on the observation that compounds with a structural resemblance to a known
pharmacologically active drug are often themselves similarly active. This activity
may be either comparable to that of the lead drug, with differences in potency and
toxicity, or may be completely different. Appreciatively, a study of the SARs between
a lead compound and its analogues may be used to determine the respective moieties
of the parent structure that are responsible for both its benefcial biological activity
and also its unwanted side effects. This information may be used to develop a new
drug that has improved activity and fewer unwanted side effects.
2.1.2 HISTORY
The term “allopathy” was coined by the inventor of “homeopathy,” the late Samuel
Hahnemann, and was used to describe the somewhat barbaric procedures that were
being performed by his colleagues at that time. Being an advocate of “observation
and experiment” versus “tradition and opinion,” Hahnemann condemned allopathic
practices, and used them as examples to point out how physicians, with conventional
training, were employing ineffective therapeutic techniques. He believed that if a
high dose of a therapeutic substance caused symptoms similar to those of a disease in
a normal person, then it may alleviate the symptoms of such a disease when given in
high dilution. As such, there can be an established relationship between the dilution
of the substance and its potency.
Despite Hahnemann’s rantings, allopathic techniques continued to be practiced.
Although critics of modern medicine in the 20th century implied that only
immunization was inconsistent with the singularity of allopathy and conventional
medicine, the practice was observed to increase in prevalence amongst main stream
physicians, possibly due to the interest in complementary and alternative remedies.
(Gundling 1998).
The continued interest in allopathic therapies led to the introduction of synthetic
compounds to be used as therapeutic drugs, in the late 19th century. This later spurred
the exploration of new remedies, which were less toxic than the naturally sourced
substances that were in use. The development was based on the modelling of novel
structures (analogues) that bore a physical resemblance to known pharmacologically
active compounds (leads), and then experimentally assessing their relative activities
and toxicities to gauge their superiority in action (Thomas 2007).
2.1.3 DOWNFALLS
Despite the many benefts of allopathic medicines, their defciencies must also
be deliberated. Firstly, we should consider holistically the associated toxicity
with this form of treatment. All drugs, both prescription and non-prescription,
are considered poisonous once taken in excess. For example, an overdose of the
Allopathic Medicines 9
over-the-counter drug paracetamol can cause coma and death. Additionally, drug
resistance must also be considered, as it affects the ability of the body to respond
to certain medicines.
Another point is that therapies developed along the principles of allopathy are
often limited in effcacy, and are often too costly, especially for developing coun-
tries like India (Nimesh, Tomar and Dhiman 2019). Finally, allopathic medicines
are known to carry the risk of having adverse events, and are generally prescribed
based on risk versus beneft for a particular disease and patient (Paudyal et al. 2019)
(Table 2.1).
2.2 BIGUANIDES
Biguanides, as exemplifed by one of its more popular members metformin
(Figure 2.1), refer to the family of insulin-enhancing drugs with the general formula:
HN(C(NH)NH2)2. In the early 1920s, guanidine was found to be the active compo-
nent of the plant Galega offcinalis Linn. The isolate was reported to exhibit remark-
able hypoglycaemic activity and was later used as the lead drug in the synthesis of
several antidiabetic compounds (Rena, Hardie and Pearson 2017, Bailey, Biguanides
and NIDDM 1992).
These compounds commonly improve insulin sensitivity by decreasing hepatic
glucose production, decreasing intestinal absorption of glucose, and increasing
peripheral glucose uptake and utilization. The multiple pathways through which
metformin affects liver metabolism have been described in detail by Rena et al.
(Rena, Hardie and Pearson 2017). However, due to the highly technical nature of
the overlapping pathways, more simplifed sites of action of the drug are presented
in Figure 2.2. In the frst instance (Step 1), the compound is catalytically taken into
the hepatocytes by the organic cation transporter-1 (OCT1). There, the drug accumu-
lates in the cells and further in the mitochondria, due to the similarity in membrane
potentials. Within the mitochondria, the drug inhibits Complex I, which initially
prevents mitochondrial adenosine triphosphate (ATP) production (Step 2). This inhi-
bition increases cytoplasmic [adenosine diphosphate (ADP) : ATP] and [adenosine
monophosphate (AMP) : ATP] ratios, which in turn activates AMP-activated pro-
tein kinase (AMPK) activity. The increased AMP : ATP ratios also result in multiple
indirect inhibitory effects, which include the suppression of fructose-1,6-bisphos-
phatase (FBPase) action (Step 3); a consequence of which is the acute inhibition
of gluconeogenesis. Another inhibitory effect, arising from the altered AMP : ATP
FIGURE 2.1 Structure of metformin.

FIGURE 2.2 Schematic diagram of the primary sites of action of biguanides in the liver
and the consequence of those actions. (The greyed areas of the diagram represent halted
processes due to precursor inhibition.)
ratio, is the restriction in production of the protein kinase-A (PKA) enzyme (Step 4).
PKA is known to be linked to both hepatic glucose production and the transcription
of the genes for phosphoenolpyruvate carboxykinase (PEPCK) (an enzyme in the
lyase family that is used in the metabolic pathway of gluconeogenesis) and glucose
6-phosphatase (G6Pase) (an enzyme that hydrolyzes glucose 6-phosphate, resulting
in the creation of a phosphate group and free glucose). Finally, the activated AMPK
phosphorylates the isoforms of acetyl CoA carboxylase (ACC) (ACC1 and ACC2),
thus inhibiting fat synthesis and promoting fat oxidation instead (Step 5) (Rena,
Hardie and Pearson 2017).
The use of biguanides comes with associated risks, as it was reported that contin-
ued use of metformin was associated with gastrointestinal (GI) side effects. However,
causation of the side effects remains inconclusive. Other common side effects that
have been reported from metformin use include nausea, diarrhoea, and weight loss
(Wang and Hoyte 2019).
Other examples of biguanides, such as phenformin (Figure 2.3a) and buformin
(Figure 2.3b), were marketed in the United States in the 1950s, subsequently becom-
ing available across Canada, the United Kingdom, and Australia. However, these
were removed from the market in the 1970s because of the toxic events that they
were associated with in the body (Bailey 1992, Wang and Hoyte 2019). Additionally,
metformin toxicity has also been known to lead to hyperlactatemia and metabolic
acidosis, though the level of incidence is very low due to its acceptable level of excre-
tion (Wang and Hoyte 2019).
FIGURE 2.3 Structures of examples of biguanides: (a) phenformin and (b) buformin.
In 2017, Abbas et al. formulated a new family of biguanide hydrochloride salts

that lowered blood glucose (BG) levels in hyperglycaemic rats (Abbas et al. 2017,
Basyouni et al. 2017). The antidiabetic activities of the novel salts were gauged
against that of metformin and showed comparable and signifcant decreases in the
elevated BG levels of the diabetic animals. As such, the results gave good justifca-
tion for the compounds to enter clinical studies to assess their relative potentials as
therapeutic agents in humans.
Finally, aside from their applications in DM therapy, in recent years scientists have
started exploring alternative applications for the use of biguanides. Interestingly,
great promise has been reported in their use as anticancer agents and this has encour-
aged further investigations in this area (Pollak 2013).
2.3 SULFONYLUREAS
Sulfonylureas are considered to be the “second-line treatment” after treatment fail-
ure with metformin (Douros, Dell’Aniello et al. 2018). Compounds belonging to this
class of antidiabetic therapeutants possess an S-arylsulfonylurea structure, with a
p-substituent on the phenyl ring (R1) and various groups terminating the urea N′ end
group (R2) (Figure 2.4).
The drugs function by stimulating the pancreas to release more insulin (Figure 2.5)
(Douros, Dell’Aniello et al. 2018, Sola et al. 2015, Östenson et al. 1986), but this
treatment is only effective if there is still residual pancreatic β-cell activity.
The intracellular mechanism of action in the pancreatic β-cells is initiated by
the binding of the sulfonylureas to the K ATP channels’ SUR-1 receptors (Step 1).
The binding causes the pancreatic ATP-sensitive potassium channels (KATP)
to close, resulting in an elevated electrical potential and the subsequent depo-
larization of the β-cell’s membrane (Step 2) (Douros, Dell’Aniello et al. 2018,
FIGURE 2.4 Structural formula of sulfonylureas.

FIGURE 2.5 Schematic diagram of the effect of sulfonylureas and meglitinides in the
pancreas.
Östenson et al. 1986). This depolarization leads to an infux of calcium ions (Ca 2+)
into the cell (Step 3) which, in turn, triggers the insulin vesicles to release granu-
lated insulin into the blood (Step 4). Apart from this, sulfonylureas have also been
found to suppress glucagon secretion which, when in conjunction with the gluca-
gon-like peptide-1 (GLP-1) (that is released from the small intestine), results in a
decreased BG concentration (Östenson et al. 1986).
Sulfonylureas are classified into two “generations.” First-generation drugs,
which possess small, polar, water-soluble substitutions and their second-gener-
ation cousins, which have large, non-polar, and more lipid-soluble substitutions.
The latter’s pendant groups allow for the easier penetration of cell membranes,
thus conferring a greater potency of insulin sensitivity and insulin secretion (R.
K. Campbell 1998). Currently, the second-generation sulfonylureas (glyburide
[glibenclamide: Figure 2.6a], glipizide [Figure 2.6b], glimepiride [Figure 2.6c],
and gliclazide [Diamicron: Figure 2.6d]) continue to be used, while the use of
first-generation sulfonylureas (tolbutamide: Figure 2.7a; chlorpropamide: Figure
2.7b; and tolazamide: Figure 2.7c) have been discontinued due to severe hypo-
glycaemic episodes. Apart from hypoglycaemia, the use of the first-generation
drugs has also led to disturbing cases of cholestatic jaundice, hepatitis, and
hepatic failure (Riddle 2017). Understandably, the shortcomings of the first-
generation drugs have raised concerns over the use of the second-generation
sulfonylureas due to a potential similar consequence arising from excessive
dosage.
FIGURE 2.6 Structural formulae of second-generation sulfonylureas: (a) glibenclamide;

(b) glipizide; (c) glimepiride, and (d) gliclazide.
The literature has shown that the use of tolbutamide has been associated with
increased mortality in its patients (Sola et al. 2015, Riddle 2017). Douros et al. com-
piled several clinical and research studies concerning the association of sulfonylureas
with the increased risk of cardiovascular events. They found that short-acting sulfo-
nylureas – gliclazide, glipizide, and tolbutamide – could increase the risk of adverse
cardiovascular events, compared to the long-acting sulfonylureas – glyburide and
FIGURE 2.7 Structural formulae of frst-generation sulfonylureas: (a) tolbutamide,

(b) chlorpropamide, and (c) tolazamide.
glimepiride (Douros, Yin et al. 2017). This greatly tarnished the reputation of sulfo-
nylureas and they were derided as the drugs associated with cardiovascular mortal-
ity, while their counterpart, metformin was known to mitigate that risk (Douros, Yin
et al. 2017).
Despite the negativities, patients still continue to use this class of drug because of
its relatively low cost, convenience in dosage to metformin, and reliability in action;
with as little as one dose per day, sulfonylureas can attenuate spiked BG levels, with
the only rare symptomatic side effects being hypoglycaemia and weight gain (Kalra,
Madhu and Bajaj 2015).
2.4 MEGLITINIDES
Meglitinides are short-acting antidiabetic agents and are often called “non-sul-
fonylurea secretagogues” or “glinides.” Meglitinides are the substrates of cyto-
chrome P450 (CYP) enzymes and the organic anion transporting polypeptides 1B1
(OATP1B1 transporter) (Wu et al. 2017). Like sulfonylureas, they increase insulin
secretion from the pancreas. However, their faster activity is compromised by their
much shorter duration of action, which is mainly due to their relatively short half-
lives. As illustrated in Figure 2.5, the mechanism of action of meglitinides is simi-
lar to that of sulfonylureas. Although seemingly identical, meglitinides differ from
sulfonylureas in two ways: (a) the discussed signal is mediated through a different
binding site on the SUR-1 receptor and (b) the differences in the drugs’ physical and
chemical characteristics.
In clinical practice, meglitinides possess a similar potency to metformin, and
could serve as an alternative to metformin when the latter’s side effects are intoler-
able (Wu et al. 2017, Diabetes Self-Management 2015). Like sulfonylureas, the most
common side effects of meglitinides are hypoglycaemia and weight gain. However,
the latter is still preferred due to its weaker binding to – and thus faster dissociation
from – the receptor.
FIGURE 2.8 Structural formulae of the main brands of meglitinides: (a) repaglinide
(Prandin) and (b) nateglinide (Starlix).
The main brands of this class of drugs are repaglinide (Figure 2.8a) and nateg-
linide (Figure 2.8b), both of which are metabolized in the liver, with <10% of repa-
glinide and most of nateglinide being excreted (Kawamori, Kaku et al. 2012).
Repaglinide was the frst of the two meglitinides that were developed and used
in adults with type-2 diabetes mellitus (T2DM) (Rosenstock et al. 2004). Like repa-
glinide, nateglinide also binds competitively to the sulfonylureas’ receptor however,
the pharmacodynamic properties of this molecule are unique in several aspects. Firstly,
in vitro studies have indicated that nateglinide inhibits the potassium ATP channels
faster than repaglinide and within a shorter duration of action (Guardado-Mendoza
et al. 2013)., and the half-life of nateglinide on the SUR-1 receptor is approximately 5
seconds compared to that of repaglinide, which is approximately 3 minutes.
It was found that the duration of binding showed good correlation with relatively
similar effcacy. In 2012, Kawamori et al. conducted a 16-week clinical trial aimed
at investigating the relative effcacy and safety of repaglinide and nateglinide on
130 Japanese patients with T2DM and glycated haemoglobin (HbA1c). During the
16-week study period, the patients were treated with repaglinide (0.5 mg) and nat-
eglinide (90 mg) three times a day together with diet and exercise. At the end of the
study, the group reported that repaglinide monotherapy had given greater glycae-
mic improvement than nateglinide monotherapy, by more effciently reducing both
HbA1c and fasting plasma glucose (PG) values (Kawamori, Kaku et al. 2012).
In another study by Rosenstock et al., 150 T2DM patients were randomized to
receive monotherapy of repaglinide (0.5 mg/meal, maximum dose 4 mg/meal) or
nateglinide (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Their report
showed that both repaglinide and nateglinide had similar postprandial glycaemic
effects on the patients, who were previously treated with diet and exercise. However,
repaglinide monotherapy was found to be signifcantly more effective than nateg-
linide monotherapy in reducing HbA1c and fasting blood glucose (FBG) values,
after 16 weeks of treatment (Rosenstock et al. 2004).
2.5 ALPHA-GLUCOSIDASE INHIBITORS

Alpha-glucosidase inhibitors (AGIs), such as acarbose (Glucobay) (Figure 2.9a),
miglitol (Figure 2.9b), and voglibose (Figure 2.9c), form a new class of “suppress-
ing-based” therapy that target the enzyme, α-glucosidase (AG). AG is an exo-type
FIGURE 2.9 Structural formulae of α-glucosidase inhibitors: (a) acarbose, (b) miglitol, and
(c) voglibose.
carbohydrase that is responsible for breaking down complex carbohydrates to glu-

cose in the upper gastrointestinal tract (Kumar, Narwal et al. 2011, Lebovitz 1998).
As such, the inhibition of the AG enzyme results in a decrease in complex carbohy-
drate catabolism, which as a consequence, retards the rise in postprandial BG levels
(Lebovitz 1998).
As illustrated in Figure 2.10, by brushing the borders of the small intestine, the
AG inhibitors competitively bind to the intestinal enzymes, thus hindering the for-
mation of the enzyme–substrate complexes (Step 1). This leads to the slow absorp-
tion of carbohydrates (Step 2), which results in a greater amount of undigested and
unabsorbed sugars (Step 3) (Dabhi, Bhatt and Shah 2013).
Acarbose is a pseudo-tetrasaccharide of microbial origin. Its chemical structure is
analogous to that of oligosaccharides obtained from starch digestion and this morpho-
logical similarity allows for its competitive inhibitory action along the small intestine,
up to the ileum (Rabasa-Lhoret and Chiasson 1998, Lin et al. 2003, Willms and Ruge
1999). Chiasson et al. reported on three in vivo studies that were conducted to compare
the effcacy of acarbose treatments versus that of sulfonylureas. Using 255 diabetic
patients, they found that the acarbose treatment resulted in an absolute reduction in
HbA1c of 0.66 percentage points ± 0.28, compared to 0.88 points ± 0.28 for sulfonyl-
urea treatment. This meant that acarbose was as effective as the sulfonylureas in the
normalization of glucose levels (Leroux‐Stewart, Rabasa‐Lhoret and Chiasson 2015).
FIGURE 2.10 Schematic diagram of the effect of α-glucosidase inhibitors in the small
intestine.
Miglitol is the frst pseudo-monosaccharide that comes from a 1-deoxynojirimy-

cin derivative (Kingma et al. 1992). It is excreted through the kidneys and unlike
sulfonylureas, does not cause an increase in body weight and excessive hypoglycae-
mia, when administered as monotherapy (Scott and Spencer 2000). Furthermore, it
is considered relatively safe, as it shows no signifcant effects on renal, cardiovascu-
lar, respiratory, or haematological parameters in long-term studies. Like acarbose, it
improves glycaemic control, which is refected in a reduced HbA1c level (Scott and
Spencer 2000). However, unlike acarbose, miglitol is almost completely absorbed in
the upper section of the small intestine.
Clinical trials conducted with the dosages of 50–100 mg of miglitol, three times a
day in patients with T2DM have shown signifcant improvements in glycaemic con-
trol during a 6 to 12 month period (Scott and Spencer 2000, Campbell, Baker and
Campbell 2000). Also, studies have shown that miglitol has a similar effcacy to that
of acarbose (but at lower doses), and compared to sulfonylureas, miglitol provides a
similar reduction in FBG and postprandial plasma glucose (PPG) levels (Kingma et al.
1992, Scott and Spencer 2000). As a common shortcoming however, both acarbose
and miglitol have been reported to cause fatulence, abdominal pain, and diarrhoea.
In 2000, Scott and Spencer compared clinical trials composed of 1783 patients
with T2DM, during a 6 to 12 month period. It was seen that some of the trials were
insuffciently controlled by diet alone or diet plus sulfonylurea agents. However, one
study using miglitol monotherapy of 50–100 mg, three times a day, resulted in a
signifcant improvement in glycaemic control and a decrease in postprandial serum
insulin levels (Kingma et al. 1992).
Finally, we look at voglibose, which is considered to be the most potent and toler-
able AGI than both acarbose and miglitol. While its competitive inhibitory action
is similar to those of acarbose and miglitol, it shows no inhibitory activity against
lactase. As such, it does not cause the digestive irregularities, that are associated with
its competing AGIs (Lybrate 2021).
In 2009, Kawamori et al. conducted a study to assess whether voglibose could
prevent T2DM from developing in high-risk Japanese subjects with impaired glu-
cose tolerance (IGT). Here, all 1780 eligible subjects received a standard diet and
exercise therapy, however out of the total number of patients, 897 were randomly
selected to receive voglibose treatment, while the remaining 883 were given a pla-
cebo. An interim analysis showed signifcant favour to treatment with voglibose and
notably, more subjects in that group achieved normoglycaemia when compared to
those given the placebo (Kawamori, Tajima et al. 2009).
As research progresses under this particular class of compounds, there have
been recent reports on nitrogen-containing heterocyclic compounds (without gly-
cosyl moieties), that exhibit potent α-glucosidase inhibiting activity. Some of these
drugs, classifed as triazoloquinazolines, have already undergone in vitro studies and
have shown comparable inhibitory activity to that of acarbose (Abuelizz et al. 2019).
These fndings have given support to the drugs being further studied in clinical tri-
als, for their potential use as novel AGIs.
2.6 DPP-4 INHIBITORS

Dipeptidyl-peptidase IV (DPP-4) inhibitors, such as sitagliptin (Januvia: Figure 2.11a)
and vildagliptin (Galvus: Figure 2.11b), are a new class of incretin-based therapies. Also
known as gliptins, they work by blocking the activity of DPP-4 enzymes, which are
known to break down the insulin-secreting and glucagon-inhibiting incretins: glucagon-
like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (Meier 2012).
Just like AG enzymes, DPP-4 enzymes are active in the small intestine. As illus-
trated in Figure 2.12, the DPP-4 inhibitor competitively binds to the DPP-4 enzymes
(Step 1) and suppresses the enzyme’s activity, thereby retarding the degradation rate
of the incretins (Meier 2012). The incretins are therefore allowed to be released into
the bloodstream (Step 2), where they act in the pancreas.
FIGURE 2.11 Structural formulae of dipeptidyl-peptidase IV (DPP-4) inhibitors:

(a) sitagliptin and (b) vildagliptin.
FIGURE 2.12 Schematic diagram of the effect of DPP-4 inhibitors in the small intestine.
Januvia was the frst DPP-4 inhibitor approved by the US Food and Drug
Administration (FDA) and marketed in the United States in 2006 for T2DM treat-
ment. In 2010, patients who used Januvia for T2DM treatment fled a lawsuit against
Merck & Co. with different law frms such as Morgan & Morgan, and The Drug Law
Centre in the United States, because it was alleged that Januvia was linked to pan-
creatic cancer and pancreatitis. Close to 90 cases were issued against Merck & Co.
On their website, Morgan & Morgan stated that Merck was facing several lawsuits,
claiming that Januvia was a fawed and defective product, and was alleged to be asso-
ciated with the risk of pancreatic cancer in its users. Further allegations stated that
the company knew about this information beforehand and withheld the information
from the public (Morgan & Morgan 2015). Despite this, the FDA chose to neither
publish any warning of the associated pancreatic cancer risk of the drug, nor order a
recall of Januvia from the market (Morgan & Morgan 2015, Drug Law Center 2017).
In a case study conducted by Charbonnel et al. in 2006, 701 patients with T2DM
were screened and randomized to assess the effcacy of sitagliptin with metformin
monotherapy. The patients, aged 19–78 years, had mild to moderate hyperglycaemia
(mean A1C 8.0%) and were given doses of 1500 mg/day of metformin alongside a
placebo or sitagliptin (100 mg once daily) in a 1 : 2 ratio for 24 weeks (Charbonnel
et al. 2006, Gallwitz 2007). This combination resulted in sitagliptin treatment show-
ing signifcant reductions compared with the placebo in A1C (–0.65%), FBG, and
2-hour post-meal glucose in some patients. A signifcantly greater proportion of the
patients achieved an A1C of 7% with sitagliptin (47.0%) when compared to those
receiving the placebo (18.3%), and did not experience any adverse effects from this
treatment or increased risk of hypoglycaemia. However, some patients experienced
body weight loss during the study. The investigating group concluded that combina-
tional therapy, using sitagliptin (at a dosage of 100 mg once daily) alongside metfor-
min, was effective and well-tolerated in patients with T2DM, who had inadequate
glycaemic control with metformin alone (Charbonnel et al. 2006). Coincidentally,
Janumet, which is presently being marketed by Merck and Co., carries a combination
dose of 50/1000 mg (sitagliptin/metformin).
2.7 THIAZOLIDINEDIONE
Thiazolidinediones (TZDs), such as rosiglitazone (Avandia: Figure 2.13a), pio-
glitazone (Actos: Figure 2.13b), and troglitazone (Rezulin: Figure 2.13c), serve by
promoting insulin sensitivity in the adipose tissue and muscles. They function by
stimulating the peroxisome proliferator-activated receptor (PPAR) gene, which
FIGURE 2.13 Structural formulae of thiazolidinediones: (a) rosiglitazone (Avandia),

(b) pioglitazone (Actos), and (c) troglitazone (Rezulin).
infuences insulin sensitization and enhances glucose metabolism. PPARs are ligand-
activated transcription factors of the nuclear hormone receptor superfamily that is
composed of the following three subtypes: PPARα, PPARγ, and PPARβ/δ (Tyagi
et al. 2011, Wafer, Tandon and Minchin 2017, Kahn, Chen and Cohen 2000). As
illustrated in Figure 2.14, TZDs enter the adipose tissue cell and activate the γ-gene
(Step 1). Along with ATP (produced from glycolysis), these ligands together with the
retinoid receptor X(RXR) form a nuclear receptor gene (Step 2), which undergoes
transcription to mRNA (Step 3). Finally, the mRNA is used to signal the formation
of vesicles for the purpose of insulin storage (Step 4) and transport across the tissue
(Step 5) (Kahn, Chen and Cohen 2000).
A major side effect of thiazolidinediones, as exemplifed by troglitazone (Rezulin),
is liver toxicity. In 1997, troglitazone was removed from the UK market by its distrib-
utor Glaxo, because it was associated with an increased risk of liver failure (Graham
et al. 2003). This later infuenced the decision of the FDA to have the manufacturer
remove the product from the US market for similar reasons. It was suggested that the
mitochondrial dysfunction induced by troglitazone caused cytotoxicity in the liver,
which led to liver failure and most times, death (Liao, Wang and Wong 2010).
In 2017, Wang et al. carried out a post-mortem comparison of several case stud-
ies investigating the effcacy and safety of thiazolidinediones in T2DM patients
(Wang et al. 2017). While it was noted that the effcacy of the drugs was undis-
puted, the group underscored the negativities that could arise from their long-term
use, citing that some trials reported hypoglycaemia and weight gain as adverse
side effects.
FIGURE 2.14 Schematic diagram of the effect of thiazolidinediones in adipose tissue.

2.8 SGLT-2 INHIBITORS

Recently, new treatments have emerged based on entirely new mechanisms. The
story of the naturally extracted glucoside, phlorizin (Figure 2.15), proves to be an
excellent case in point. In the 19th century, French chemists isolated the compound
from the bark of apple trees and initially used it in the treatment of fever and infec-
tious diseases (Nair and Wilding 2010). It was later found that its oral administra-
tion also led to the interference of carbohydrate absorption in the intestines, which
resulted in glycosuria (Riddle and Cefalu 2018, Wikipedia 2021).
While further studies using the extract in diabetic animal models provided use-
ful insights into the relationship between the reduction of hyperglycaemia and the
restoration of insulin sensitivity, the drug was considered unsuitable for human use
due to its undesirable side effects. However, its antidiabetic activity fuelled further
investigations into its mechanism, which was traced to its interactions with sodium–
glucose co-transporters (SGLTs) in the intestinal mucosa and the renal proximal
tubule. This fnding led to the development of newer drugs, which exhibited greater
nuanced effects on these transporters (especially SGLT-2) within the kidney (Riddle
and Cefalu 2018).
It is common knowledge to those in the feld that the kidney plays a major role
in glucose homeostasis through glomerular fltration and reabsorption of glucose
(VA Pharmacy Benefts Management Services; Medical Advisory Panel; VISN
Pharmacist Executives 2015). Glucose’s absorption/reabsorption in the renal tubules,
transport across the blood–brain barrier, and uptake and release by all cells in the
body are effected by two groups of transporters: glucose transporters (GLUTs) and
SGLTs. While GLUTs are facilitative or passive transporters that work along the
glucose gradient, SGLTs’ co-transport of sodium and glucose into cells is governed
by the sodium gradient that is generated by sodium/potassium ATPase pumps at
the basolateral cell membranes (Nair and Wilding 2010, VA Pharmacy Benefts
Management Services; Medical Advisory Panel; VISN Pharmacist Executives 2015).
FIGURE 2.15 Structural formula of phlorizin.

It is known that renal tubular reabsorption undergoes adaptations in uncontrolled

diabetes, particularly as it relates to the upregulation of renal GLUT vesicles. The
increase in extracellular glucose concentration in diabetes lowers its outward-
directed gradient from the tubular cells into the interstitium. As a natural response
to maintain homeostasis, an upregulation of SGLT-2 is stimulated in an attempt to
maintain renal tubular glucose reabsorption. This now manifests itself as a prob-
lem, as there is already a high BG level in the body. This situation (as illustrated
in Figure 2.16) now presents itself as the ideal stage for the action of the SGLT2
inhibitors (SGLTi), where the drug’s action results in the retardation of the rate of
glucose reabsorption, consequently leading to a drop in the hyperglycaemic state
(Nair and Wilding 2010).
Several specifc and potent SGLTi drugs have undergone preclinical testing,
most of which are glucosides that are structurally related to the lead drug: phlo-
rizin. O-glucosides, such as serglifozin etabonate (Figure 2.17a) and remogli-
fozin etabonate (Figure 2.17b), are strategically administered in the prodrug form
of the biologically active serglifozin A and remoglifozin to avoid degradation by
β-glucosidase in the small intestine (Nair and Wilding 2010).
The clinical effects of the newer SGLTi drugs on T2DM include modest reduc-
tions in plasma glucose, A1C, body weight, and blood pressure, and are mediated in
large part by glucosuria and sodium diuresis. These agents are taken once daily by
mouth and do not require dose titration.
FIGURE 2.16 Mechanism of action for the inhibition of SGLT-2 in the S1 segment of the
proximal convoluted tubule.
FIGURE 2.17 Structural formulae of O-glucosides: (a) serglifozin etabonate and

(b) remoglifozin etabonate.
Symptomatic side effects that include mostly urinary or genital irritation or

infections are common but tolerated by most patients. Importantly, the new SGLTi
drugs have highly desirable and somewhat unexpected cardiac and renal protective
effects, at least in selected cohorts. Large trials of empaglifozin (Figure 2.18a) and
canaglifozin (Invokana) (Figure 2.18b), aiming to demonstrate safety in patients
with T2DM and high cardiovascular risk, have shown favourable effects on heart
failure, cardiovascular death, and the progression of albuminuria. Unwanted side
effects, such as dehydration, lower extremity amputations, and diabetic ketoacido-
sis (DKA), have also been reported, but have been noted as very rare (Riddle and
Cefalu 2018).
FIGURE 2.18 Structural formulae of SGLTi drugs: (a) empaglifozin, (b) canaglifozin,
(c) dapaglifozin, and (d) ertuglifozin.
Although their underlying mechanisms are still not fully understood, the cardio-
vascular and renal benefts that have been achieved through the use of this class of
drugs have warranted the great enthusiasm for its increased clinical use (Riddle and
Cefalu 2018, Verma and McMurray 2018, Usman et al. 2018).
To date, SGLTi drugs present themselves as the new wonder drugs for T2DM
therapy and the newer forms: empaglifozin, dapaglifozin (Figure 2.18c), and ertug-
lifozin (Figure 2.18d), which are being marketed under the brand names “Jardiance,”
“Farxiga,” and “Steglatro,” respectively, offer a greatly improved balance of benefts
versus risks. Furthermore, ongoing studies aimed at assessing their effectiveness in
T1DM therapy add more hope for the use of these drugs by a greater population of
patients (Riddle and Cefalu 2018).
26
TABLE 2.1
Summary of Allopathic Preparations for T2DM Therapy, Mechanism of Actions, and Their Adverse Effects
Adverse Reactions
Class; Marketed Name; Therapeutic
Date of Entry Mechanism of Action Dosage (mg) Symptoms % Number of Patients
Biguanide: 2550 mg (n = 141)
Metformin (Glucophage) Decreases hepatic glucose 500 (twice Diarrhoea 53
(Bristol-Myers 1995) (DrugLib production and intestinal daily) or 850 Nausea/vomiting 26
.com 2009) absorption of glucose and (once daily) Flatulence 12
(First marketed in England in increases peripheral glucose Asthenia 9
1958; approved for use in uptake and utilization Indigestion 7
Canada in 1972; and fnally Abdominal discomfort 6
approved for use by the FDA in Headache 6
1994)
Warning: Lactic Acidosis
Post-marketing cases of metformin-associated lactic acidosis have resulted in
death, hypothermia, hypotension, and resistant brady arrhythmias. The onset
of metformin-associated lactic acidosis is often subtle, accompanied only by
non-specifc symptoms such as malaise, myalgias, respiratory distress,
somnolence, and abdominal pain.
Metformin-associated lactic acidosis was characterized by elevated blood
lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria
or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma
levels generally >5 mcg/mL).
Risk factors for metformin-associated lactic acidosis include renal impairment,
concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as
topiramate), age 65 years or greater, having a radiological study with contrast,
surgery and other procedures, hypoxic states (e.g. acute congestive heart
failure), excessive alcohol intake, and hepatic impairment.
(Continued)
Alternative Medicines for Diabetes Management
TABLE 2.1 (CONTINUED)
Adverse Reactions
Biguanide:
Allopathic Medicines
Phenformin (Information 2022) Decreases hepatic glucose 200 May cause metallic taste, nausea, anorexia, vomiting, diarrhoea, or cramps;
(Entered the market in the 1970s, production and intestinal weight loss sometimes occur.
but was withdrawn in 1976 due absorption of glucose and
to links to lactic acidosis) increases peripheral glucose
uptake and utilization
Sulfonylureas:
Glyburide (Glibenclamide) Stimulates the pancreas to produce 2.5–5 Gastrointestinal-related ailments 1.8
(Diabeta, Bagomet Plus, more insulin Dermatological reactions 1.5
Benimet, Glibomet, Gluconorm,
Glucored, Glucovance, Metglib)
(Sanof-Aventis,
DIABETA 2009)
(Entered the market in 1966, sold
under different trade names)
Sulfonylureas: (n = 702)
Glipizide (Glucotrol) (Pfzer- Stimulates the pancreas to produce 2.5–5 Combined observed ailments 11.8
Roerig 2008) more insulin
(Approved for use in 1971 and
fnally approved for use by the
FDA in 1984)
(Continued)
27
28

Adverse Reactions
Glimepiride (Amaryl) (Sanof- Stimulates the pancreas to produce 1, 2, and 4 Dizziness 13
Aventis, AMARYL 2013) more insulin Asthenia 12
(Approved for use by the FDA in Headache 11
February 1999) Nausea 8
Sulfonylureas: 30 mg (n = 728) 80 mg (n = 734)
Gliclazide (Diamicron) (Servier Stimulates the pancreas to produce 30 and 80 Resistance mechanism disorder 8.8 6.4
2018) more insulin Respiratory disorder 21.4 20.9
(Approved for medical use in Musculo-skeletal disorders 15.2 14.6
1972) Secondary term 4.3 4.5
Body as a whole 6 7.2
Cardiovascular disease 6.5 7.3
Urinary tract infection 2.6 3.0
Gastrointestinal disorders 8.6 7.3
Central peripheral nerve 3.4 3.0
disorders
Metabolic disorders 15.9 14.6
Dermatological disorders 5.5 4.8
Vision disorders 1.0 0.8
Psychiatric disorders 3.0 3.2
(Continued)
Adverse Reactions
Tolbutamide (Orinase) (L. Stimulates the pancreas to produce 500 Hypoglycaemia –

Anderson et al. 2021) more insulin Gastrointestinal disorders 1–10
(Entered the market in 1956, but Dermatological reactions –
was discontinued in the 1970s Haematological reactions 0.1
due to links to cardiovascular Metabolic reactions –
disease) Endocrinological reactions –
Hypersensitivity 0.1
Tolazamide (Tolinase) (L. A. Stimulates the pancreas to produce Metabolic reactions <0.01
Anderson et al. 2022) more insulin Gastrointestinal disorders 1–10
(Approved for use by the FDA in Hypersensitivity 0.4
December 1987) Nerve-related reactions 0.1–1
Hepatic reactions 0.1
Haematological reactions 0.1
(Continued)
29
30

Adverse Reactions
Meglitinide: (n = 352)
Repaglinide (Prandin) Stimulates the pancreas to produce 0.5, 1, and 2 Upper respiratory tract infection 16
(Nordisk 2017) more insulin Headache 11
(Approved for use by the FDA in Sinusitis 6
December 1997) Arthralgia 6
Nausea 5
Diarrhoea 5
Back pain 5
Rhinitis 3
Constipation 3
Vomiting 3
Paraesthesia 3
Chest pain 3
Bronchitis 2
Dyspepsia 2
Urinary tract infection 2
Tooth disorder 2
Allergy 2
(n = 1228)
Hypoglycaemia 31
Serious cardiovascular (CV) 4
events
Cardiac ischemic events 2
Deaths due to CV events 0.5
(Continued)
Adverse Reactions
Nateglinide (Starlix) Stimulates the pancreas to produce 60 and 120 Upper respiratory tract infection 16
(Cooperation 2017) more insulin Headache 11
(Approved for use by the FDA in Sinusitis 6
December 2000) Arthralgia 6
Nausea 5
Diarrhoea 5
Back pain 5
Rhinitis 3
Constipation 3
Vomiting 3
Paraesthesia 3
Chest pain 3
Bronchitis 2
Dyspepsia 2
Tooth disorder 2
Allergy 2
(n = 1228)
Hypoglycaemia 31
Serious cardiovascular (CV) 4
events
Cardiac ischemic events 2
Deaths due to CV events 0.5
31
(Continued)
32

Adverse Reactions
Nateglinide (Starlix) Stimulates the pancreas to produce 60 and 120 Upper respiratory infection 10.5
(Cooperation 2017) more insulin Back pain 4.0
(Approved for use by the FDA in Flu symptoms 3.6
December 2000) Dizziness 3.6
Arthropathy 3.3
Diarrhoea 3.2
Accidental trauma 2.9
Bronchitis 2.7
Coughing 2.4
Non-severe hypoglycaemia 2.4
Alpha‑glucosidase inhibitor: (n = 1255)
Acarbose (Precose) (B. H. Reduces the absorption of ingested 25, 50, and 100 Abdominal pain, diarrhoea, and 19, 31, and 74, respectively (at dosages of
Pharmaceuticals 2011) carbohydrates fatulence 50–300 mg)
(Approved for use by the FDA in
August 1999)
Alpha‑glucosidase inhibitor: (n = 962)

Miglitol (Glyset) (B. H. Reduces the absorption of ingested 25, 50, and 100 Abdominal pain, diarrhoea, and 11.7, 28.7, and 41.5, respectively (at
Pharmaceuticals 2012) carbohydrates fatulence dosages of 25 and 10 mg; three times
(Approved for use by the FDA in daily)
August 1999) Dermatological reactions 4.3
(Continued)
Adverse Reactions
Alpha‑glucosidase inhibitor:
Voglibose (Volicose) Reduces the absorption of ingested 0.2 and 0.3 Gastrointestinal adverse effects such as diarrhoea, loose stools, abdominal
(Biocon 2022) carbohydrates pain, constipation, anorexia, nausea, vomiting, or heartburn may occur with
(Unconfrmed date of approval the use of voglibose. Also abdominal distention, increased fatus, and
and entry into the market) intestinal obstruction–like symptoms due to an increase in intestinal gas.
DPP‑4 inhibitor: (n = 443) @ 100 mg

Sitagliptin (Januvia) Intensifes the effect of intestinal 25, 50, and 100 Nasopharyngitis 5.2
(Incorporated 2021) hormones (incretines) involved in (n = 179) @ 100 mg
(Approved for use by the FDA in the control of blood sugar Upper respiratory infection 5.1
October 2006) Headache 2.8
DPP‑4 inhibitor: (n = 1855)

Vildagliptin (Galvus) Intensifes the effect of intestinal 50 Infections and infestations Very rare (upper respiratory tract infection
(Panacea 2019) hormones (incretines) involved in and nasopharyngitis)
(Awaiting FDA approval) the control of blood sugar Metabolism and nutrition Uncommon (hypoglycaemia)
disorders
Nervous system disorders Common (dizziness)
Uncommon (headache)
Vascular disorders Uncommon (peripheral oedema)
Gastrointestinal disorders Uncommon (constipation)
Musculoskeletal and connective
tissue disorders
(Continued)
33
34

Adverse Reactions
Thiazolidinedione: (n = 2526)
Rosiglitazone (Avandia) Promotes insulin sensitivity in the 8 Upper respiratory tract infection 9.9
(GlaxoSmithKline 2007) adipose tissue and muscles Injury 7.6
(Approved for use by the FDA in Headache 5.9
May 1999) Back pain 4.0
Hyperglycaemia 3.9
Fatigue 3.6
Sinusitis 3.2
Diarrhoea 2.3
Hypoglycaemia 0.6
Pioglitazone (Actos) (Takeda Promotes insulin sensitivity in the 7.5, 15, 30, and Upper respiratory tract infection 13.2
Pharmaceuticals America 2011) adipose tissue and muscles 45 Sinusitis 6.3
(Approved for use by the FDA in Myalgia 5.4
July 1999) Tooth disorder 5.3
Headache 9.1
Pharyngitis 5.1
DM aggravated 5.1
(Continued)
Adverse Reactions
Troglitazone (Rezulin) Promotes insulin sensitivity in the 200 Infection 18

(Limited 1999) adipose tissue and muscles Pain 10
(Approved for use by the FDA in Back pain 6
September 1999, but withdrawn Dizziness 6
from the market in 2000, due to Asthenia 6
its connection to fve post- Headache 11
marketing cases of severe liver Nausea 6
disease that resulted in death or
liver transplantation)
Peripheral edema 5
Pharyngitis 5
Rhinitis 5
Backpain 6
*During all clinical studies in North America, a total of 48 of 2510 (1.9%)
Rezulin-treated patients and 3 of 475 (0.6%) placebo-treated patients had
alanine transaminase (ALT) levels greater than three times the upper limit of
normal (ULN).
Nineteen patients (0.8%) had ALT over 8 × ULN, fve patients (0.2%) had ALT
values over 30 × ULN.
Twenty of the Rezulin-treated and one of the placebo-treated patients were
withdrawn from treatment.
Two of the 20 Rezulin-treated patients developed reversible jaundice; one of
these patients had a liver biopsy which was consistent with an idiosyncratic
drug reaction. An additional Rezulin-treated patient had a liver biopsy which
35
was also consistent with an idiosyncratic drug reaction.

(Continued)
36

Adverse Reactions
Sodium glucose 100 mg (n = 833) 300 mg (n = 834)
co‑transporter‑2
(SGLT‑2) inhibitor:
Canaglifozin Helps the elimination of glucose 100 Urinary tract infections* 5.1 4.6
(Invokana) (Janssen via urine Increased urination** 2.9 3.8
Pharmaceuticals 2018) Thirst 2.8 2.4
(Approved for use by the FDA in Constipation 1.8 2.4
September 2019) Nausea 2.1 2.3
(n = 425) (n = 430)
Female genital mycotic 10.6 11.6
infections
Vulvovaginal pruritis 1.6 3.2
(n = 408) (n = 404)
Male genital mycotic 4.2 3.8
infections***
* Female genital mycotic infections include the following adverse reactions:
Vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis,
vaginal infection, vulvitis, and genital infection fungal.
**Increased urination includes the following adverse reactions: polyuria,
pollakiuria, urine output increased, micturition urgency, and nocturia.
*** Male genital mycotic infections include the following adverse reactions:
balanitis or balanoposthitis, balanitis candida, and genital fungal infections.
(Continued)
Adverse Reactions
Dapaglifozin (Farxiga) (A. Helps the elimination of glucose 10 Female genital mycotic 8.4 6.9
Pharmaceuticals 2020) via urine infections 6.6 6.3
(Approved for use by the FDA in Nasopharyngitis
January 2014) Urinary tract infections 5.7 4.3
Back pain 3.4 4.2
Increased urination 2.9 3.8
Male genital mycotic infections 2.8 2.7
Nausea 2.8 2.5
Infuenza 2.7 2.3
Dyslipidaemia 2.1 2.5
Constipation 2.2 1.9
Discomfort with urination 1.6 2.1
Pain in extremity 2.0 1.7
(Continued)
37
38

Adverse Reactions
co‑transporter‑2 (SGLT‑2)
inhibitor:
Empaglifozin (Jardiance) (l. B. Helps the elimination of glucose 10 and 25 Urinary tract infections 9.3 7.6
Pharmaceuticals 2022) via urine Female genital mycotic 5.4 6.4
(Approved for use by the FDA in infections
August 2014) Upper respiratory tract infections 3.1 4.0
Dyslipidaemia 3.9 2.9
Arthralgia 2.4 2.3
Male genital mycotic infections 3.1 1.6
Nausea 2.3 1.1
Ertuglifozin (Steglatro) Helps the elimination of glucose 5 and 15 Female genital mycotic infections 9.1 12.2
(Inc. 2021) via urine Male genital mycotic infections 3.7 4.2
(Approved for use by the FDA in Urinary tract infections 4.0 4.1
December 2017) Headache 3.5 2.9
Vaginal puritis 2.7 2.4
Nasopharyngitis 2.5 2.0
Back pain 1.7 2.5
Weight decrease 1.2 2.4
Thirst 2.7 1.4
3 (Ethnopharmacological
Ayurvedic Medicines
Treatments)
Modern science has tested the many claims of ethnomedicine and the majority of studies
have shown them to be true. However, the possibility of drug–drug interactions or the occur-
rence of cytotoxic events due to wrongful dosages remain a concern. Thankfully, progressive
research continues to churn out the solutions to these apprehensions.
3.1 INTRODUCTION
Apart from the commonly recognized allopathic drugs that are used in the treatment
of diseases, a greatly regarded source of medicine throughout human history is natu-
ral herbs, and their worldwide popularity in present medicinal therapies indicates
that they have grown in acceptance in modern medicine. Correspondingly, the use of
herbal remedies is gaining more signifcance owing to the drawbacks and limitations
noted with many allopathic drugs (Table 3.1).
DOI: 10.1201/9781003322429-3 39
Esteemed researchers in the feld of ethnomedicine such as Associate Professor,

Dr Amala Soumyanath (Wright et al. 2022), as well as corporations such as Shaman
Pharmaceuticals Inc. (Reed and Scribner 1999, Oubré et al. 1997) have added to
creating a stable foundation for further Ayurvedic medicines to be investigated and
accepted.
3.1.2 HISTORY
Traditional medicine is a bank of knowledge, skills, and practices that, whether jus-
tifable or not, is used in the prevention, diagnosis, and treatment of both physical
and mental illnesses. When referring to traditional medicine outside its regular cul-
ture it is often referred to as “complementary” or “alternative” medicine. The three
major traditional medicines that are globally recognized are Ayurveda or Traditional
Indian Medicine (TIM) in India, Traditional Chinese Medicine (TCM) in China,
and Traditional Arabic and Islamic Medicine (TAIM) in the Middle East.
India and China, whose traditional therapies are highly complementary, have
historical origins of mutual learning and development, from medical theory to
drugs used. The exchange of traditional medicines between China and India began
in the Qin and Han dynasties (221 BC–220 AD), prospered in the Tang dynasty
(618–907 AD), and declined after the Song dynasty (960–1279 AD) (Wu, Chen
and Wang 2021).
TCM intellectuals are yet to gain a thorough understanding of the origin and
historical development of TIM, but it is this understanding that will allow the joint
promotion of traditional medicines from both countries.
3.1.2.1 Traditional Indian Medicine

In India, it is common medicinal practice for practitioners to formulate and dispense
their own plant-based concoctions, using medicinal plants that have been tradition-
ally used for over 1000 years. Prior to 1970, it was estimated that approximately 70%
of the Indian population relied on Ayurvedic medicine since the national healthcare
structure at the time could only provide for about 30% of the 1.38 billion population
(Shi, Zhang and Li 2021).
During the Vedic period (10th century BC) in ancient India, one of the oldest
medical systems (the Ayurvedic system) was developed into a comprehensive medi-
cal structure, which is now recognized as the AYUSH system. AYUSH has become a
popular acronym that is used to describe TIM; it stands for Ayurveda, yoga and natu-
ropathy, Unani, siddha, Sowa Rigpa, and homoeopathy (Wu, Chen and Wang 2021).
India attaches great importance to the management of, education in, and industry
of traditional medicine, and has made various efforts to protect intellectual property
(IP) rights. As such, it established the Ministry of AYUSH of the Government of
India, which is responsible for traditional medicine in the country. Furthermore, a
“Traditional Knowledge Digital Library” and special investment foundation were
formed to archive traditional medical knowledge and to promote the industrial-
ization of TIM. Regarding the IP rights, the National Biodiversity Authority must
grant consent for research based on Indian biological resources or related traditional
Ayurvedic Medicines 41
knowledge (Wu, Chen and Wang 2021). Additionally, the Indian Pharmacopoeia
Committee and the Indian Laboratory Committee execute the standardization and
modernization of Indian medicine, and specifcally organize the preparation and
printing of publications such as the Traditional Indian Pharmacopoeia (Shi, Zhang
and Li 2021).
In 2002, the state introduced policies on the Indian medical system, with the main
objectives to (1) use Ayurveda to promote good health and to promote healthcare for
the local people (mainly those who cannot afford or do not have access to modern
medical facilities) by means of prevention, promotion, mitigation, and treatment; (2)
provide affordable, safe, and effective Ayurvedic services and medicines; (3) ensure
that the supply, and authentic products of active pharmaceutical ingredients (APIs)
meet the pharmacopoeia standard requirements, to help improve the quality of drugs
for domestic use and/or export; (4) integrate Ayurveda into the medical service sys-
tem and national planning, and ensure the maximum possible use of the huge infra-
structure of hospitals, pharmacies, and doctors; and (5) provide full opportunities
for the expansion and development of Indian pharmaceutical systems (ISM), utilize
their potential, and revive their glory (Shi, Zhang and Li 2021).
3.1.2.2 Traditional Chinese Medicine

Traditional Chinese medicine is a broad range of medicine practices that share com-
mon concepts, and an integrated theory system. It has progressed through over 3000
years of clinical and pharmacological trials, as one of the longest medical prac-
tices in China and the Asia-Pacifc areas. In China, TCM is considered equal to
that of Western medicine, and there has been an integration between these two in
the Chinese healthcare systems. However, TCM still lacks international recognition
because of the scarcity of systemic research and evidenced investigation.
TCM has strong associations with yin-yang theory; fve elements theory; the con-
cept of qi; internal organ systems; and other vital systems such as blood, essence,
and fuids. TCM also includes ethnic medicine (e.g. Tibetan medicine) and religious
medicine (e.g. Buddhist medicine). It further and more specifcally includes various
forms of acupuncture, dietary therapy, herbal medicine, moxibustion, and physical
exercise, which collectively predate to the birth of Chinese civilization (Wu, Chen
and Wang 2021, W. Wang 2016).
Similar to the Ministry of AYUSH of the Government of India, the State
Administration of Traditional Chinese Medicine oversees traditional medicine in
the country. By the end of 2018, there were 60,700 Chinese medicine, medical, and
health institutions with over 1.2 million beds, 715,000 personnel, over 1 billion peo-
ple diagnosed and treated, and an estimated 36 million discharged. The progress of
TCM can further be seen by the number of TCM pharmaceutical enterprises, col-
leges and universities of TCM, and non-Chinese medicine colleges and universities
offering TCM, with a high student intake (Wu, Chen and Wang 2021).
In 2016, it was reported that the market scale of the TCM health industry totalled
1.75 trillion yuan; in 2018, the import and export volume of TCM products was
reported at over 36 billion yuan; and in 2017, the annual trade volume of the indus-
try was almost 500 billion yuan. Furthermore, there are more than 300,000 TCM
clinics worldwide, and approximately 4 billion people use Chinese herbal medicine
products (Wu, Chen and Wang 2021).
3.1.2.3 Traditional Arabic and Islamic Medicine

Herbal medicine has also been found as part of modern healing in the Middle
East. More specifically referred to as Traditional Arabic and Islamic Medicine,
it has grown in acceptance, interest, and respect by many of those in the herbal
and scientific communities. TAIM refers to healing practices, beliefs, and phi-
losophy incorporating herbal medicines, spiritual therapies, dietary practices,
mind–body practices, and manual techniques, which may be applied singularly
or in combination to treat, diagnose, and prevent illnesses and/or maintain well-
being (Al Rawi et al. 2017).
TAIM came into existence hundreds of years ago, and investigations into its asso-
ciated herbs have been conducted in many Arab countries such as Syria, Morocco,
Yemen, and Egypt. The most recent survey conducted to investigate the possible uses
of Mediterranean plants recorded many plant species belonging to different families
still in use; however, the number is actually less than the over 700 known species of
plants that were previously recorded as medicinal plants because of several factors
endangering plant diversity or even causing the eradication of these herbs (Al Rawi
et al. 2017, Azaizeh et al. 2010).
TAIM is the frst choice for many in dealing with ailments such as infertility, epi-
lepsy, psychosomatic troubles, and depression, and has been found to be quite suc-
cessful in treating both acute and chronic diseases. Typically, a decoction is prepared
by boiling plant parts in hot water, infusing in water or oil, or inhaling essential oils.
It is also taken as juice, syrup, roasted material, fresh salad or fruit, macerated plant
parts, oil, milky sap, poultice, or paste. TAIM treatments have been tested in coop-
eration with physicians and are now routinely prescribed to patients in Europe and in
Mediterranean countries (Azaizeh et al. 2010).
Similar to TIM and TCM, it is well documented that TAIM has signifcantly
impacted the development of modern medicine in Europe and remains one of the
closest forms of original European medicine. Also, studies indicate that the eastern
region of the Mediterranean has been identifed as having a rich inventory of natural
medicinal herbs. In recent times, the Galilee Society Research and Development
Center, in cooperation with different institutes, collected data, which indicated that
200–250 herbs are still used in human treatment, and are commercialized regionally
and internationally (Azaizeh et al. 2010, Masic et al. 2017).
3.1.3 DOWNFALLS
Although the advantages of ethnopharmacological and other natural treatments are
signifcant, particularly from an economic perspective as well as their availability
on a global scale, it is vital to also acknowledge the possible shortcomings of these
forms of therapies.
Paudyal et al. recognized the importance of highlighting the possible adverse
effects arising from the proclivities of Ayurvedic medicines, possibly due to adul-
teration or inherent constituents such as alkaloids. As such, proper advising by health
professionals is crucial in minimizing harm (Paudyal et al. 2019). Additionally, it
should be taken into consideration that there exists the common misconception that
alternative treatments are harmless because they are natural and are sometimes
promoted as completely safe; however, natural does not equate to harmless. Since
allopathic medicines are known to have adverse effects and are prescribed based on
a risk versus beneft basis, many persons assume that these remedies are devoid of
adverse effects because similar information, regarding alternative treatments, is not
as readily available to them.
3.2 ABELMOSCHUS ESCULENTUS LINN. (AE)

Common names: Bindi, Lady Fingers, Ochro, Okra, Okro (Figure 3.1)
A. esculentus is a perennial plant that is often cultivated as an annual in temperate
climates. As a member of the Malvaceae family, it is related to species such as cot-
ton, cocoa, and hibiscus. Its leaves are 10–20 cm long and broad, palmately lobed,
with fve to seven lobes. Its fowers are 4–8 cm in diameter, with fve white to yellow
petals, often with a red or purple spot at the base of each petal. Its fruit is a capsule
up to 18 cm long (however other species are known to grow to over 30 cm), with a
pentagonal cross section, containing numerous seeds (Wikipedia 2021).
It was initially proposed that the antidiabetic effect of AE be attributed to its high
mucilage content, which was thought to delay the absorption of glucose into the
bloodstream. However, this idea was debunked as it was later demonstrated that the
FIGURE 3.1 Illustration of Abelmoschus esculentus.

FIGURE 3.2 Structural formulae of isolated compounds from Abelmoschus esculentus: (a)
isoquercetin and (b) quercetin-3-O-β- glucopyranosyl-(1→6)-glucoside.
mucilage yield, glucose entrapping capability, and α-glucosidase inhibitory potential

of the aqueous fruit extract were relatively low. Interestingly, in vivo studies showed
that it was the seeds of the fruit that actually conferred the plant’s antidiabetic activity.
A report suggested that the hypoglycaemic effect observed in rats, that were fed AE
seed extract, was due to the inhibition of the intestinal α-glucosidase enzymes by two
isolated favonols: isoquercetin (Figure 3.2a) and quercetin-3-O-β-glucopyranosyl-
(1→6)-glucoside (Figure 3.2b) (Thanakosai and Phuwapraisirisan 2013).
Another study by Sabitha and coworkers, investigated the antidiabetic and anti-
hyperlipidemic potential of the peel (AEP) and seed (AES) powders in streptozoto-
cin (STZ)-induced diabetic rats. Acute toxicity assays on both powders showed no
signs of toxicity-related illnesses or death, at doses as high as 2000 mg/kg. From
this, suitable therapeutic doses of AEP (100 mg/kg.bw) and AES (200 mg/kg.bw)
were administered to the diabetic rats. The results showed a signifcant reduction
in blood glucose (BG) levels and a simultaneous increase in the body weight of
the treated subjects, relative to their untreated diabetic counterparts (Sabitha et al.
2011).
Alternatively, Herowati et al. used both aqueous and fractionated organic extracts
of the AE fruit to assess its hypoglycaemic activity in insulin-resistant rats. It was
reported that while the extract and its fractions showed antihyperglycaemic effects,
they were still lower than that of the control standard, metformin. Additionally, the
group observed and reported differences in the mechanisms of action due to the dif-
ference in the nature of the extracts. The presence of the water-favoured favonols
(isoquercetin and quercetin-3-O-β-glucopyranosyl-glucoside) acted as α-glucosidase
inhibitors (AGI) and thus inhibited the absorption of maltase and sucrose in the
intestine. However, the non-polar hexane fractions (containing non-polar compounds
such as phytosterols and fatty acids) delayed the rate of gastric emptying, while the
ethyl acetate fractions (containing alkaloids, terpenoids, and many favonoids) posi-
tively infuenced the translocation of the glucose transporter type-4 (GLUT-4) vesi-
cles (Herowati et al. 2020).
In this next instance, Ramachandran et al. tested the antihyperglycaemic activity
of the AE fruit extract in alloxan-induced diabetic rats. Here, 100 and 400 mg/kg
.bw doses of extract were administered to both diabetic and non-diabetic subjects
over a 15-day period. Subsequently, they observed a return to normoglycaemic levels
for the treated diabetic subjects, suggesting that the constituent compounds were in
some way either infuencing an increase in glucose uptake or potentiating the secre-
tion of insulin by the pancreas. The group further reported that continued treatment
until Day 21 showed sustained control over the elevated BG levels of the diabetic
rats, but not over the levels of the normal rats (Ramachandran et al. 2010).
In an interesting report by Khatun et al., aqueous AE fruit fractions were co-
administered alongside metformin in an attempt to compare the effects of the
absorption of orally administered glucose in Long–Evans rats. As expected,
it was found that the extract signifcantly reduced the absorption of glucose in
both 24-hour fasting rats and alloxan-induced diabetic rats. However, it was
reported that the co-administration of the extract alongside metformin resulted
in a drug–drug interaction that resulted in the near-complete loss of metformin’s
antihyperglycaemic activity. Little change was observed in the BG levels of the
“double-treated” rats (33.5–32.2 mmol/L at 4 hours) in relation to the animals
that received only the metformin therapy (a drop to 14.9 mmol/L within 4 hours)
(Khatun et al. 2011).
Finally, Uraku et al. demonstrated the restorative potential of the AE fruit extract
on several liver enzymatic activities. Using alloxan-induced diabetic rats, the group
reported that elevated levels of alkaline phosphatase (ALP), aspartate aminotrans-
ferase (AST), and alanine aminotransferase (ALT) activities were attenuated in a
dose-dependent manner, when the diabetic rats were treated with varying concentra-
tions of the extract (Uraku et al. 2011).
3.3 AGERATUM CONYZOIDES LINN. (AgC)

Common names: Billygoat-weed, Tropical Whiteweed, Zeb-a-fam (Figure 3.3)
A. conyzoides is an annual herb that belongs to the Asteraceae family. It is
mostly grown in Asia, temperate Brazil, and areas that are hot and humid. It can
be identifed by its shallow fbrous roots and colourful fowers, which can be either
FIGURE 3.3 Illustration of Ageratum conyzoides.

FIGURE 3.4 General structural formula of favonoids (polyphenolic compounds).
purple, blue, or white (The Environmental Weeds of Australia n.d.). Its leaves,
juices, and extracted essential oil (containing alkaloids, cardenolides, tannins,
saponins, and favonoids [Figure 3.4]) (Egunyomi, Gbadamosi and Animashahun
2011) are known to possess anti-infammatory properties, as well as display anti-
bacterial and antidiarrhoeal effects. However, studies have also shown it to exhibit
antidiabetic activity.
Egunyomi et al. investigated the hypoglycaemic activity of an ethanolic extract
of AgC shoots on alloxan-induced diabetic rats. The rats were divided into six
groups: Group 1: negative control (healthy and untreated); Group 2: positive control
(alloxan induced, untreated); Group 3: alloxan-induced diabetic rats (treated with
100 mg/kg.bw of the ethanol extract); Group 4: alloxan-induced diabetic rats (treated
with 200 mg/kg.bw of the extract); Group 5: alloxan-induced diabetic rats (treated
with 400 mg/kg.bw of the extract); and Group 6: normoglycaemic rats (healthy, but
administered 400 mg/kg.bw of the extract). Appreciatively, it was reported that there
was a signifcant decrease in fasting blood glucose (FBG) levels in Groups 3, 4, and
5 after the 2-week study period. In Group 3, the FBG levels decreased from 390.6
to 90.2 mg/dL; in Group 4, from 590.4 to 45.8 mg/dL; and in Group 5, from 466.2
to 42.4 mg/dL. Interestingly, in Group 6, the FBG levels only decreased in the last 2
days, from 55.0 to 49.3 mg/dL. Based on the in vivo experiment and phytochemical
screenings results, the team was able to confrm the hypoglycaemic activity of AgC
and thus its potential use as a phytomedicine for type-2 diabetes mellitus (T2DM)
(Egunyomi, Gbadamosi and Animashahun 2011).
Nyunaï et al. also investigated the antihyperglycaemic properties of AgC in STZ-
induced diabetic rats. Compared to Egunyomi et al.’s study, the present group used
an aqueous extract from the leaves and administered three different doses, 100, 200,
and 300 mg/kg.bw, for up to 8 hours. It was reported that both the 200 and 300 mg/
kg.bw doses produced a signifcant reduction in the BG levels of the rats after 1.5
hours, up to the 8-hour stop time (Nyunaï, Njikam et al. 2009). Furthermore, the
300 mg/kg.bw dose of the extract produced the maximum reduction in the BG lev-
els (36.85%), while 200 mg/kg.bw reduced the levels by 33% and 100 mg/kg.bw by
20.3% at the end of the 8-hour period. At the end, the group awarded greatest eff-
cacy to the 200 mg/kg.bw dose, because of its consistency throughout the 8 hours.
In another report, Nyunaï and coworkers performed further studies, adminis-
tering aqueous extract fractions: F1a, F1b, and F1c to STZ-induced diabetic rats
at doses of 16 mg/kg.bw of F1a, 16 mg/kg.bw of F1b, and 88 mg/kg.bw of F1c.

Although all the subfractions (F1a, F1b, and F1c) were found to be active against
increases in BG, it was the F1c subfraction that had a signifcant effect. The group
also indicated that the F1c fraction was more potent than the others because it
showed similar activity compared to the control standard, glibenclamide (Nyunaï,
Manguelle-Dicoum et al. 2010).
Finally, Agunbiade et al. investigated the hypoglycaemic effect of the aqueous
leaf extract on alloxan-induced diabetic rats. Using a similar protocol to Nynai,
they administered 500 mg/kg.bw of the AgC aqueous extract to the rats and com-
pared it to the same dose of the commercial drug, glibenclamide. After treatment,
the group reported a satisfactory reduction (by 39.1%) in the FBG levels of the rats;
from a starting level of 309.6 mg/dL and then dropping to a level of 195.8 mg/dL
(Agunbiade et al. 2012).
3.4 ALLIUM CEPA LINN. (AC)

Common names: Bulb Onion, Common Onion (Figure 3.5)
A. cepa, a member of the garlic family, is also known as the bulb onion or com-
mon onion, a vegetable that is the most widely cultivated species of the genus Allium.
It has long been used as dietary supplements for the traditional treatment of diabetes
in Asia, Europe, and the Middle East (Bailey and Day 1989). Allyl propyl disulphide
(APDS) (Figure 3.6a) and diallyl disulphide (Figure 3.6b) have been identifed in
the onion to be the active components in hyperglycaemic attenuation (Dey, Attele
FIGURE 3.5 Illustration of Allium cepa.

FIGURE 3.6 Structural formulae of isolated compounds from Allium cepa: (a) allyl propyl
disulphide, (b) diallyl disulphide, and (c) S-methyl cysteine sulphoxide.
and Yuan 2002); however, their excessive intake has been known to have detrimen-
tal effects on hepatic metabolism (Augusti and Benaim 1975, Jain and Vyas 1974).
Researchers have postulated that APDS functions as a competitive inhibitor to insu-
lin for insulin-inactivating sites in the liver, thereby increasing the concentration of
free insulin in the body.
Other studies using concentrated extracts from the plant organs have reported
weak hypoglycaemic effects in healthy and alloxan-induced diabetic animals and
healthy human subjects (Augusti and Benaim 1975, Jain and Vyas 1974, Jain, Vyas
and Mahatma 1973, Day and Bailey 1986, Mathew and Augusti 1975).
Kumari et al. reported another isolate (S-methyl cysteine sulphoxide [SMCS]
[Figure 3.6c]) that also showed antidiabetic activity. The administration of SMCS
isolate at 200 mg/kg.bw for 45 days to “alloxanized” rats signifcantly controlled
BG and lipids in serum and tissues and normalized the activities of liver hexokinase,
glucose 6-phosphatase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)
reductase. The effect of this hyperglycaemic attenuation was notably comparable to
that of glibenclamide and insulin (Kumari, Mathew and Augusti 1995).
Finally, a clinical study by Sharma et al. showed that the oral administration of
aqueous onion extracts (at 25, 50, 100, and 200 g) to overnight-fasted healthy vol-
unteers (30 minutes before, after, or simultaneously giving 50 g of an oral glucose
supplement) signifcantly increased glucose tolerance in a dose-dependent manner.
The effect was noted to be comparable to that of their control standard drug, tolbu-
tamide (K. K. Sharma et al. 1977).
3.5 ALLIUM SATIVUM LINN. (AS)

Common names: Garlic, Lahasun (Figure 3.7)
A. sativum is a species in the onion genus, Allium. Its close relatives include the
onion, shallot, leek, chive, and Chinese onion. Native to Central Asia and north-
eastern Iran, it has long been used as a common seasoning worldwide, with a history
of several thousand years of human consumption and use.
Many studies have been undertaken to evaluate the hyperglycaemic attenuating
capability of AS extracts via oral administration. Jain et al. reported that the oral
administration of its organic extract (at 0.25 g/kg.bw) caused a maximum reduction
FIGURE 3.7 Illustration of Allium sativum.
FIGURE 3.8 Structural formulae of isolated compounds from Allium sativum: (a) allicin
and (b) alliin.
in BG levels by 26.2%, in alloxan-induced diabetic rabbits (Jain and Vyas 1975). In

another study, the oral administration of allicin (isolated from AS) (Figure 3.8a) at
0.25 g/kg.bw exhibited hypoglycaemic effects that were comparable to tolbutamide
in mildly diabetic rabbits (BG ranging from 180 to 300 mg%); however, there was no
such effect in severely diabetic animals (BG >350 mg%) (Mathew and Augusti 1973).
The Zacharias group later demonstrated that the oral administration of an aque-
ous homogenate of garlic (10 mL/kg.bw/day) to sucrose-fed rabbits had signifcant
ameliorative effects on FBG, protein levels, and triglyceride levels in serum, liver,
and aorta, while increasing hepatic glycogen (HG) and free amino acid contents
(Zacharias et al. 1980).
Other studies have also shown that the oral administration of 1 mL/kg.bw gar-
lic juice extract was able to effect a 68% reduction in elevated PG levels in dia-
betic rats (El-Gamal and El-Khedr 2017). With similar fndings being reported by
El-Demerdash et al., there is further support for the inclusion of raw garlic in a
regular diet for the purpose of BG regulation (El-Demerdash, Yousef and El-Naga
2005).
The Kasuga group reported that the oral pretreatment of stress-induced hypergly-
caemic mice with aged garlic extracts (AGE) (5 and 10 mL/kg.bw) prevented adre-
nal hypertrophy and hyperglycaemia and the elevation of cortisone without altering
serum insulin levels. Interestingly, the effcacy of AGE was the same as that of diaz-
epam (5 mg/kg.bw). This supported that AGE may prevent the stress-induced risk of
DM and its progression. Furthermore, daily oral feeding of garlic extract (100 mg/
kg.bw) increased the cardiovascular functions in STZ rats, prevented abnormality in
the lipid profle, and increased fbrinolytic activities with decreased platelet aggre-
gation. Notably, there was an increase in plasma insulin levels with a concomitant
decrease in PG levels. Of equal interest, the group reported that, daily oral feeding of
the same dose for 16 weeks showed anti-atherosclerotic effects in their STZ diabetic
rats (Patumraj, Tewit et al. 2000).
Sheela et al. reported that the administration of alliin (an analogue to allicin) (Figure
3.8b) at a dosage of 200 mg/kg.bw signifcantly decreased the concentration of serum
lipids and BG, and the activities of serum enzymes such as alkaline phosphatase, acid
phosphatase, lactate dehydrogenase, and liver glucose-6-phosphatase. It also signif-
cantly increased liver and intestinal HMG-CoA reductase activity and liver hexokinase
activity (Sheela and Augusti 1992). In a later study, the oral administration of alliin to
alloxan-induced diabetic rats for 1 month showed similarity in improvements to their
glucose intolerance, weight loss, and the depletion of liver glycogen, when compared to
other groups treated with glibenclamide and insulin (Sheela, Kumud and Augusti 1995).
Finally, another AS extract isolate, S-allyl cysteine sulphoxide (SACS), was also
shown to control lipid peroxidation (LPO) better than glibenclamide and insulin, and
ameliorated the diabetic condition almost to the same extent as the allopathic thera-
peutics did. Furthermore, it was found that SACS was able to signifcantly stimulate
in vitro insulin secretion from β-cells that were isolated from normal rats (Augusti
and Sheela 1996).
3.6 ALOE BARBADENSIS MILL. (ABM)

Common names: Aloe, Aloe vera, Alovis, Sabila (Figure 3.9)
A. barbadensis is a short-stemmed succulent perennial herb of the Liliaceae fam-
ily that can grow to a height of 3–4 m through its central axis or stem. Different
species can be identifed by variations in their leaf size and fower colour (I. A. Ross
2003, Pamplona-Roger 2005). Native to North Africa, the Mediterranean region of
southern Europe, and the Canary Islands, it is now cultivated throughout tropical
regions including the West Indies (I. A. Ross 2003).
For centuries, many aloe species have been used to treat several conditions due
to their laxative, anti-infammatory, immunostimulant, antiseptic wound- and burn-
healing, antiulcer, antitumour, and antidiabetic activities (Okyar et al. 2001). ABM
is claimed to contain several polysaccharides, whose biological interactions result in
hypoglycaemic effects (Bailey and Day 1989, Ghannam et al. 1986). Several research-
ers have isolated some of these compounds (β-sitosterol Figure 3.10a], campesterol
[Figure 3.10b] (Verma et al. 2018), lophenol [4-methylcholest-7-en-3-ol] [Figure
FIGURE 3.9 Illustration of Aloe barbadensis.
FIGURE 3.10 Structural formulae of isolated compounds from Aloe barbadensis Miller:
(a) β-sitosterol, (b) campesterol, (c) lophenol (4-methylcholest-7-en-3-ol), and (d) cycloartenol
(9,19-cyclolanostan-3-ol).
3.10c], and cycloartenol [9,19-cyclolanostan-3-ol] [Figure 3.10d] [Shakib et al. 2019,

Pothuraju et al. 2016], 24-methyl-lophenol, 24-ethyl-lophenol, and 24-methylene-
cycloartanol [Pothuraju et al. 2016]) from the ABM plant, and tested for their relative
activities and toxicities.
Two independent groups led by Okyar and Ghannam, respectively, investigated
the impact of leaf pulp and leaf gel extracts of ABM on non-diabetic, T1DM, and
T2DM rats. While both groups reported confrmed hypoglycaemic activity in their
diabetic subjects, using the pulp extracts, the Okyar group in particular, observed an
enhanced effect for the ABM-treated T2DM subjects, in comparison to their glib-
enclamide-treated controls. Interestingly, it was found that ABM was ineffective in
lowering the BG level in non-diabetic rats, contrary to the effect of glibenclamide
(Okyar et al. 2001, Ghannam et al. 1986).
Similarly, a study conducted by Rajasekaran et al. demonstrated the hypoglycae-

mic activity of alcoholic extracts of ABM gel. The extract was found to maintain
glucose homeostasis by controlling the activity of the carbohydrate metabolizing
enzymes. It was observed that the effect of the gel extract in this study was similar to
that of Okyar et al., where the effect of the ABM gel extract on the BG levels of non-
diabetic rats was not deemed signifcant (Shakib et al. 2019, Rajasekaran et al. 2004).
It was further proposed that the potentiation of insulin from the β-cells of the islets
of Langerhans, or its release from its bound form, may be the possible mechanism by
which ABM brings about its hypoglycaemic action (Rajasekaran et al. 2004).
3.7 ANNONA MURICATA LINN. (AM)

Common names: Soursop, Prickly Custard Apple, Graviola, Guanabana (Figure 3.11)
A. muricata is a tropical plant species that belongs to the family: Annonaceae, and
is known for its many ethnomedicinal uses. All parts of Annona are used in natural
medicine due to its unique phytochemical composition and, as such, it is considered
a good source of natural antioxidants for various diseases. Traditionally, the leaf
extracts are used to treat headaches, insomnia, cystitis, antitumor, anti-infammatory
liver problems, and, of course, diabetes (Agu et al. 2019, Saleem et al. 2017, Adeyemi
et al. 2009, Florence et al. 2014).
Agbai et al. studied the effect of AM seed extract on the anti-atherogenic proper-
ties in STZ-induced diabetic rats for 30 days. The results showed that treatment with
a high dose of the extract (750 mg/kg.bw) signifcantly increased the anti-atherogenic
percentage by 70.7% and low-density lipoprotein-cholesterol (LDL-C). Furthermore,
after treatment with 600 and 800 mg/kg.bw of the extract, there was an observed
reduction in the total cholesterol (TC), low-density lipoprotein-cholesterol, triglyc-
erides (TG), and malondialdehyde of the subjects (Agbai, Mounmbegna et al. 2015).
In another study, the Agbai-led group used STZ-induced diabetic rats (with repeated
exposure to 20 mg/kg.bw of clozapine) to investigate the effects of 600 and 750 mg/kg
.bw doses of AM seed extract on BG levels, along with the total and differential white
cell count. From their analysis of the data, the group concluded that the seed extract
FIGURE 3.11 Illustration of Annona muricata.

successfully exerted a hypoglycaemic effect on the clozapine-treated rats, without

improving the decreased total and white cell count (Agbai, Njoku et al. 2015).
Adewole et al. then looked at the effects of the aqueous leaf extract on the mor-
phology of pancreatic β-cells and oxidative stress induced in STZ- induced diabetic
rats. The fndings of the study not only indicated that AM treatment had ameliora-
tive effects on pancreatic tissues, which were subjected to STZ-induced oxidative
stress, but also showed the protection and preservation of pancreatic β-cell integrity
(Adewole and Ojewole 2009).
Alternatively, studies have revealed that FOXO1 protein inactivation in the
nucleus is one of the targets in the treatment of DM. Considering this, through an
in silico study, Dini et al. aimed at predicting the inhibition of the FOXO1 protein
by AM’s active compounds. Their results showed that the compounds contained in
AM: xylopine (Figure 3.12a), anonaine (Figure 3.12b), isolaureline (Figure 3.12c),
FIGURE 3.12 Structural formulae of isolated compounds from Annona muricata: (a)
xylopine, (b) anonaine, (c) isolaureline, (d) kaempferol 3-O-rutinoside, (e) rutin, and (f)
muricatocin.
kaempferol 3-O-rutinoside (Figure 3.12d), rutin (Figure 3.12e), and muricatocin

(Figure 3.12f) had the ability to strongly and spontaneously bind with the active
side of the FOXO1 protein, and consequently inhibit its activity (Damayanti, Utomo
and Kusuma 2017).
3.8 APIUM GRAVEOLENS LINN. (AG)

Common names: Ajmod, Celeriac, Celery, Leaf celery, Root celery, Wild celery
(Figure 3.13)
A. graveolens is an erect, annual or perennial herb of the Apiaceae or Umbelliferae
family (Gauri, Ali and Khan 2015). It is usually located in Europe, temperate and sub-
tropical parts of Africa and Asia (Gauri, Ali and Khan 2015, AlMalaak, Almansour
and Hussein 2018, Kooti et al. 2014), and North America (Kooti et al. 2014). The
whole plant is known for its specifc taste and aromatic smell, especially the roots
and leaves (Al-Sa’aidi and Al-Shihmani 2013). Various forms of AG, such as the
leaves, stalk, seeds, oil, and oleoresin, are used for favouring foods and for medici-
nal purposes (Gauri, Ali and Khan 2015, Kooti et al. 2014, Hedayati et al. 2019,
Gutierrez et al. 2014). When used as a therapeutic agent for T2DM, the literature has
FIGURE 3.13 Illustration of Apium graveolens.

shown AG to stimulate the pancreatic secretion of insulin and, as such, reduce BG

levels (Kooti et al. 2014).
Mans and Aburjai investigated the hypoglycaemic effects of AG on diabetic rats.
They found that the AG seed extract (at a dose of 425 mg/kg.bw) led to a signifcant
decrease in BG levels and also infuenced the increase in serum insulin levels. It was
equally interesting to note that for the duration of the experiment, the group reported
that the rats displayed minimal toxicity – associated symptoms (Mans and Aburjai
2019).
Our research into the bioactive components of the AG plant, which are respon-
sible for its ameliorative effects in DM therapy, revealed the compounds: luteolin
(Figure 3.14a), apigenin (Figure 3.14b) (Hedayati et al. 2019, Niaz, Gull and Zia
2013, Yusni et al. 2018), and 3-n-butylphthalide (Figure 3.14c) (Hedayati et al. 2019).
We found that the outcomes from the application of such therapy included a reversal
of the catabolic features of insulin defciency, a decrease in the release of glucagon,
or an increase in the release of insulin (Al-Sa’aidi and Al-Shihmani 2013, Mans and
Aburjai 2019, Niaz, Gull and Zia 2013). Furthermore, reports have been made of the
direct stimulation of glycolysis in peripheral tissues, an increase in the removal of
BG (Mans and Aburjai 2019, Niaz, Gull and Zia 2013), or a reduction in the absorp-
tion of glucose from the gastrointestinal tract (Mans and Aburjai 2019).
As reported by Al-Sa’aidi et al., the “drenching” of STZ-induced diabetic rats
with a 60 mg/kg.bw dose of n-butanol AG seed extract resulted in a reduction in
the BG levels and also infuenced the regeneration of damaged pancreatic islets
(Al-Sa’aidi and Al-Shihmani 2013). In support of this, another study revealed that
AG seed extract caused a signifcant decrease in serum glucose levels and the
FIGURE 3.14 Structural formulae of isolated compounds from Apium graveolens: (a) luteo-
lin, (b) apigenin, (c) 3-n-butylphthalide, and (d) vitamin C.
induction of insulin release from the pancreatic islets (Hedayati et al. 2019, Niaz,
Gull and Zia 2013). However, Wasf and AL-kabi claimed that the effect of the
AG extract may take a long time to show (possibly due to its low metabolism) and
suggested that the extract lowers BG levels by affecting the absorption of glucose
in the intestine and not by stimulating the production of insulin by the pancreas
(Wasf and AL-kabi 2019).
Apart from the seeds, the leaf extracts from the AG plant also exhibit hypogly-
caemic activity (Gutierrez et al. 2014, Abozid, El-Rahman and Mohamed 2018).
Stemming from their study, Abozid et al. proposed that the glucose-lowering effect
of AG leaf extracts can be attributed to the presence of a high content mixture of phe-
nolic compounds, vitamin C (Figure 3.14d), and favonoids (Figure 3.4), all of which
have been associated with antidiabetic activity in other botanical sources (Abozid,
El-Rahman and Mohamed 2018).
3.9 AZADIRACHTA INDICA LINN. (AI)

Common names: Dogoyaro, Indian lilac, Margosa tree, Neem, Nimtree (Figure 3.15)
A. indica, popularly known as Neem, is a member of the mahogany family:
Meliaceae. It is a fast-growing tropical evergreen tree that grows to 20 m in height.
It was originally cultivated in the Asian subcontinents, and later introduced to the
Caribbean and South and Central America. Different parts of the tree (such as the
FIGURE 3.15 Illustration of Azadirachta indica.

leaves, bark, and fowers) have been studied for its use in phytomedicinal therapy.
Stemming from these studies, supportive evidence has come forward for its thera-
peutic use in the treatment of diabetes, infertility, bacterial infection, skin disease,
oral care, and scalp disorders. The literature has also revealed the nature and effcacy
of its active compound: azadirachitin (Figure 3.16), and has shown that alongside
other active constituents, has been able to confer the antidiabetic activity of the plant
(Pandey 2020).
Shravan et al. showed that a single dose of AI aqueous leaf extract (250 mg/kg.bw)
was able to reduce elevated BG levels in diabetic rats after 24 hours, and this effect
was observed to continue until the end of the 14-day study period (Dholi et al. 2011).
In another study, Bhat et al. compared the effects of chloroform extracts of AI
against those of aqueous/methanolic extracts of Bougainvillea spectabilis Linn. (a
fowering plant), using STZ-induced diabetic mice. At the end of the 21-day study,
the group reported a signifcant increase in glucose-6-phosphate dehydrogenase
activity as well as hepatic and skeletal muscle glycogen content. In their immunohis-
tochemical analysis, they observed that treatment with both extracts resulted in the
regeneration of the insulin-producing cells and there was a corresponding increase
in the plasma insulin and c-peptide levels. From their analysis, it was concluded that
both sources were good candidates for the development of new nutraceutical treat-
ments for diabetes (Bhat et al. 2011).
Finally, Satyanarayana et al. administered dehydrated aqueous leaf-extracts
(400 mg/kg.bw) to STZ-induced diabetic rats for 30 days. The group reported that
the animals receiving the therapeutic dose of the extract showed a normalization
in the altered levels of BG, serum insulin, lipid profle, and insulin signalling mol-
ecules, as well as GLUT-4 proteins (Satyanarayana et al. 2015).
FIGURE 3.16 Structural formula of azadirachitin.

3.10 BIDENS PILOSA LINN. (BiP)

Common names: Black Jack, Cobbler’s pegs, Farmers friend, Hairy beggarticks,
Needle bush, Spanish needle, Sticky beaks (Figure 3.17)
B. pilosa is an erect, perennial herb with serrated, lobed, or in a dissected form
of green opposite leaves, white or yellow fowers, and long, narrow, ribbed, black
seeds. It is believed to have originated in South America, before spreading to other
parts of the world. Regarding its pharmacological actions, its antidiabetic polyynes
have been reported to be an effective treatment for both T1DM and T2DM. Yang
et al. used the “bioactivity-directed isolation and identifcation” approach to identify
three active polyynes: 3-β -D-glucopyranosyl-1-hydroxy-6(E)-tridecene-8,10,12-
triyne (Figure 3.18a), 2-β -D-glucopyranosyloxy-1-hydroxy-5(E)-tridecene-7,9,11-tr
iyne (Figure 3.18b), and 2-β -D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tet
rayne (cytopiloyne) (Figure 3.18c), as well as three index compounds: 4,5-di-O-
caffeoylquinic acid (Figure 3.18d), 3,5-di-O-caffeoylquinic acid (Figure 3.18e), and
3,4-di-O-caffeoylquinic acid (Figure 3.18f), from the butanolic extract (BE) of the
BP plant (W.-C. Yang 2014).
An animal study by Hsu et al. assessed the hypoglycaemic activity of aqueous
whole plant extract (BiPWE) using a population of C57BL/KsJ-db/db mice. An eval-
uation of the attenuating effects was determined through analysis of the BG levels,
serum insulin, HbA1c, glucose tolerance, and islet structure. The results showed that
after the 28-day study period, treatment with BiPWE (50–250 mg/kg.bw) signifcantly
improved glucose tolerance, decreased HbA1c levels, and protected the islet structure
in the diabetic mice. The investigating team proposed that the extract’s mechanism
of action was similar to that of the control standard, glimepiride. However, unlike
the prescription drug, which is incapable of either restoring or protecting the pancre-
atic cells, the BiPWE showed capability for such action. The fndings of the group
supported further studies being done on the plant, and also gave encouragement to
attempt human studies due to the lack of observed side effects (Hsu et al. 2009).
A clinical study performed by Lai et al. gave promise of the potential use of BiP
extract therapy for T2DM patients. Fourteen diabetic volunteers, whose FBG levels
were more than 126 mg/dL and/or whose 2-hour postprandial plasma glucose (PPG)
levels were more than 200 mg/dL, were recruited. The human subjects were divided
FIGURE 3.17 Illustration of Bidens pilosa.

FIGURE 3.18 Structural formulae of isolated compounds from Bidens pilosa: (a) 3-β -D-gl
ucopyranosyl-1-hydroxy-6(E)-tridecene-8,10,12-triyne, (b) 2-β -D-glucopyranosyloxy-1-hy
droxy-5(E)-tridecene-7,9,11-triyne, (c) 2-β -D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,1
1-tetrayne, (d) 4,5-di-O-caffeoylquinic acid, (e) 3,5-di-O-caffeoylquinic acid, and (f) 3,4-di-
O-caffeoylquinic acid.
into two groups: Group 1 consisted of six diabetics, who were prescribed 400 mg
oral doses of the BiP formulation for 3–7 months, while Group 2 comprised the
remaining eight diabetics, who were allowed to continue their regular antidiabetic
drug regimen in addition to prescribed doses of the BiP formulation. It was found
that both groups displayed noticeable decreases in their hyperglycaemic levels by
following their respective treatments. However, the subjects that took the antidia-
betic drugs along with the BiP formulation showed better recovery and control than
the stand-alone regimen. Furthermore, there were no reported illnesses in either
group, which supports the extract’s safety in use and gives motivation for further
similar studies to be undertaken (Lai et al. 2015)
3.11 BIXA ORELLANA LINN. (BO)

Common names: Achiote, Annatto, Ookoo plant, Roucou (Figure 3.19)
B. orellana belongs to the Bixaceae family and can be identifed as a small
shrub bearing vibrant orange-red fruits with prickly seed–containing pods. In the
Caribbean, its seeds are popular in the culinary industry, for use as both a natu-
ral food colouring and a favour-enhancing agent. However, what may not be well
known is that the BO plant also has great medicinal properties. Apart from its BG
lowering capabilities, we have found that the seed extract can be used as an anti-
venom therapy in cases of snakebites, and the leaf extract can also be used as an
antiseptic for wounds (Peter 2012).
Bixin (Figure 3.20), a carotenoid that constitutes 80% of the pigments found in
BO, has been suggested as the responsible constituent for the observed hypoglycae-
mic activity in animal models. Teles et al. conducted a 14-day study on the hyper-
glycaemic lowering effect of BO extracts in diabetic rats with BG levels above 500
mg/dL. Here, the rats were separated into three groups: non-diabetic control group
(CN); diabetic group (not treated with BO) (DM); and diabetic group (treated with
BO, with a daily dose of 540 mg/kg.bw) (DMa). Appreciatively, analysis of the data
revealed that relative to the DM group, there was a noticeable but modest drop in BG
levels in the rats from the DMa group (423 ± 18 to 380 ± 43 mg/dL) (Teles et al. 2014).
Russell et al. also investigated the hypoglycaemic effect of BO, but this time using
diabetic dogs. In the study, extract doses of 80 mg/kg.bw were given daily to the dogs
for a week. The group reported hypoglycaemic episodes as early as 1 hour after the
administration of the extract in the treated animals, when compared with the control
(<5.50 mmol/L). Furthermore, there was an interesting increase in the percentage of
FIGURE 3.19 Illustration of Bixa orellana.

FIGURE 3.20 Structural formula of bixin.
insulin levels of the extract-treated dogs (>55 μlU/mL) when compared to those of
the control subjects (Russell, Morrison and Ragoobirsingh 2005).
The results from both studies show supporting evidence for the antidiabetic activ-
ity of BO extracts. However, more studies are encouraged to confrm the potency
and possible associated toxicity, if the plant is to be used as a viable form of T2DM
therapy.
3.12 BRASSICA JUNCEA LINN. (BJ)

Common names: Brown mustard, Mustard greens, Chinese mustard, Leaf mustard,
Rai (Figure 3.21)
B. juncea is a member of the Cruciferae family and is native to parts of Asia
and the Middle East. However, it is now also cultivated worldwide in regions such
as America, Russia, and parts of Africa (Kumar et al. 2011). Its leaves, roots, and
shoots are known as vegetables, while its seeds were initially used as a condiment or
a source of oil (Szollosi 2011). It is interesting to note that the climatic zones in which
the plant has now spread to, have been seen to infuence the phytochemical content
of the seeds. This, in turn, has extended its use as a source of natural medicine in
various cultures. Although there is information suggesting that BJ-derived products
have therapeutic potential against diabetes, no defnitive statements on the nature of
the phytoconstituents involved can yet be made (Kumar et al. 2011).
One of the active constituents of the BJ seed extract has been suggested to be
sulphoraphane (Figure 3.22a), which is thought to increase the activity of glyco-
gen synthetase (Verma et al. 2018). That aside, Yokozawa et al. also investigated
the effect of isorhamnetin 3,7-diglucoside (Figure 3.22b) (the main compound in
BJ), which has also been confrmed to exhibit antidiabetic activity (Yokozawa et al.
2002).
Other studies have been carried out, aimed at demonstrating the BG-lowering
activity of the AG aqueous seed extracts, using alloxan-induced diabetic rats with
doses of 250, 350, and 450 mg/kg.bw extract, over both short-term and long-term
periods (Verma et al. 2018, Kumar et al. 2011, Thirumalai et al. 2011). It was
FIGURE 3.21 Illustration of Brassica juncea.
FIGURE 3.22 Structural formulae of isolated compounds from Brassica juncea: (a) sulpho-
raphane and (b) isorhamnetin 3,7-diglucoside.
observed that the insulin serum augmenting effect was dose dependent, with the
highest therapeutic dose being 450 mg/kg.bw (Thirumalai et al. 2011).
Additionally, the results of the study carried out by Yadav et al. confrmed that BJ
can play a role in the management of the prediabetic state of insulin resistance and
its use in higher quantities as a food ingredient should be encouraged for those prone
to diabetes (S. P. Yadav et al. 2004).
In summary, although extracts or parts of BJ are not recommended as a stand-
alone therapy for the control of severe diabetes and may not be benefcial in insulin-
dependent diabetes, it can be used as a safe dietary supplement in the management
of a prediabetic or a moderately diabetic state. Its safety in use can be supported by
the fact that it has been consumed over centuries by people without effect and, more
recently, effcacy studies using rodent subjects have reported no adverse effects on
food intake and various haematological parameters (Grover, Yadav and Vats 2002).
3.13 BRYOPHYLLUM PINNATUM LINN. (BP)

Common names: Good Luck, Resurrection plant, Wonder of the World (Figure 3.23)
B. pinnate is a crassulaceant herb of about 1 metre in height, with opposing gla-
brous leaves (each having three to fve deeply crenulated, feshy leafets). Its use as a
form of herbal remedy for an array of human disorders, including hypertension, dia-
betes mellitus, bruises, wounds, boils, abscesses, insect bites, arthritis, rheumatism,
joint pains, headaches, and body pains, is ubiquitous throughout the world. Its range
of therapeutic applications can be justifed by its large number of active compounds
(such as favonoids [Figure 3.4], glycosides, steroids, bufadienolides, and organic
acids).
A study carried out by Aransiola et al., using a population of 25 diabetic rats, demon-
strated the glucose-lowering ability of its ethanolic extract. In an effort to highlight the
extract’s potency, the activity was gauged against that of glibenclamide. The animals
were divided into fve groups and made diabetic by injecting them with Glucose-D at
a dose of 3 g/kg.bw. Groups 2–4 were then administered varying doses of the extract,
with Group 5 being administered the glibenclamide drug and Group 1 remaining as
the untreated control. At the end of the experiment, the results showed good correlation
in the activities of the extracts, with the glibenclamide standard; the highest perfor-
mance observed was at the dosage of 200 mg/kg.bw (Aransiola et al. 2014).
FIGURE 3.23 Illustration of Bryophyllum pinnate.

In another study by Ojewole, the glucose-lowering effect of the aqueous extracts

of BP leaves was weighted against that of another commercial antidiabetic drug,
chlorpropamide. Using a population of 24 young, adult Wistar rats, the animals were
randomly divided into two groups (Group A: test and Group B: control). Diabetes
was induced in the Group A rodents by intraperitoneal injections of STZ, while
Group B rats were treated with a placebo (distilled water). The Group A subjects
were then orally treated with either varying doses of the BP extract (ranging from
25 to 800 mg/kg.bw) or chlorpropamide (250 mg/kg.bw). Arising from this, Ojewole
reported that when compared with Group B, the pretreated rats of Group A showed
signifcant reductions in their BG levels. The hypoglycaemic effect of the plant
extract was signifcant at 1–2 hours following oral administration, reaching the peak
of its hypoglycaemic effect at 2–4 hours after administration, and remaining stable
for a further 8 hours (Ojewole 2005).
3.14 CAPPARIS SPINOSA LINN. (CaS)

Common names: Alaf-e-Mar, Alcaparro, Caper bush, Cappero, Kebbar, Wild
Watermelon (Figure 3.24)
C. spinosa is a deep-rooted, spiny, perennial shrub that can grow up to 10 m in
height. It is native to, and widely distributed throughout the Middle East, but is now
cultivated worldwide in tropical and subtropical zones (Nabavi et al. 2016, Zhang
and Ma 2018, Vahid, Rakhshandeh and Ghorbani 2017).
The wide range of pharmacological applications of CaS can be justifed by its well-
known history as an antifungal, antileishmanial, antihepatotoxic, anti-inflammatory,
and antidiabetic agent (Eddouks, Lemhadri and Michel 2004). Regarding the latter,
studies have shown that the root, seeds, and aerial components contain compounds
that exhibit hypoglycaemic effects (Zhang and Ma 2018, Vahid, Rakhshandeh and
Ghorbani 2017, Okur et al. 2018). As a matter of fact, the pickled forms of the CaS
fruits and fower buds are consumed by diabetic patients in the Middle East because
of the belief that it possesses BG-lowering and hypolipidaemic properties (Huseini
et al. 2013).
FIGURE 3.24 Illustration of Capparis spinosa.

FIGURE 3.25 Structural formulae of isolated compounds from Capparis spinosa: (a) caf-
feic acid, (b) catechin, (c) chlorogenic acid, (d) coumarin, (e) ferulic acid, (f) kaempferol, (g)
quercetin, (h) resveratrol, (i) syringic acid, and (j) vanillic acid.
The main constituents of CaS have been demonstrated to be flavonoids

(Figure 3.4), alkaloids, lipids, and glucosinolates (Eddouks, Lemhadri and
Michel 2004). More specifcally, some of the isolated flavonoids and phenolic
compounds that have displayed antidiabetic activity have been identifed as caf-
feic acid (Figure 3.25a), catechin (Figure 3.25b), chlorogenic acid (Figure 3.25c),
coumarin (Figure 3.25d), ferulic acid (Figure 3.25e), kaempferol (Figure 3.25f),
luteolin (Figure 3.14a), quercetin (Figure 3.25g), resveratrol (Figure 3.25h),
rutin (Figure 3.12e), syringic acid (Figure 3.25i), and vanillic acid (Figure 3.25j)
(Vahid, Rakhshandeh and Ghorbani 2017).
However, it is important to note that although these CaS compounds were identi-
fed, a limitation exists as to which are with certainty the active constituent(s) that
directly or indirectly affect glucose or insulin metabolism (Huseini et al. 2013).
A study suggested that the mechanisms involved in antihyperglycaemic effects
include the reduction of carbohydrate absorption in the small intestine, the inhibition
of gluconeogenesis in the liver, the enhancement of the uptake of glucose by tis-
sues, and β-cell conservation. Conservatively, 11 animal model studies and 1 clinical
trial in T2DM patients have confrmed the antihyperglycaemic effects of aqueous and
hydro-alcoholic extracts of CaS (Vahid, Rakhshandeh and Ghorbani 2017). However,
there is ongoing controversy whether or not CaS only affects the serum insulin level
in the hyperglycaemic state, as suggested by differences in experimental fndings.
Eddouks et al. reported that the aqueous extracts of caper fruits (20 mg/kg.bw)
had signifcant and potent antihyperglycaemic activity, which was independent of
insulin secretion in STZ-induced diabetic rats. It was further suggested that this
activity was due to hepatic glucose production and/or stimulation of glucose utiliza-
tion by peripheral tissues, particularly muscle and adipose tissue (Zhang and Ma
2018, Eddouks, Lemhadri and Michel 2004).
Currently, there is limited information on the adverse effects of CaS on the human
body. However, independent toxicity studies performed by Zhang et al. and Huseini
et al. reported no signs of hepatotoxicity, nephrotoxicity, or any other adverse effects
(Zhang and Ma 2018, Huseini et al. 2013).
3.15 CARICA PAPAYA LINN. (CaP)

Common names: Aanabahe-hindi, Buah papaya, Papaw, Papaya, Pawpaw (Figure 3.26)
C. papaya is a member of the Caricaceae family. It is popularly known as paw-
paw in the West Indies, and is one of the most popular tropical fruits, cultivated in
tropical and subtropical areas across the world. It is a small, fast-growing evergreen
tree, that can grow as high as 10 m. The tree’s leaves, fruits, stem, and latex have
been used for a variety of medicinal therapies for ailments including diabetes, gas-
trointestinal disorders, and wound healing (as an anti-infammatory or antimicrobial
agent) (I. A. Ross 2003). Although there are few in vivo clinical trials aimed at
investigating the antidiabetic effects of this plant, it is known that the edible fruit
contains high levels of vitamin A (Figure 3.27a), vitamin C (Figure 3.14d), and the
phytochemical compound β-cryptoxanthin (Figure 3.27b), which can regulate BG
levels through diet (Venkateshwarlu et al. 2013).
FIGURE 3.26 Illustration of Carica papaya.
FIGURE 3.27 Structural formulae of isolated compounds from Carica papaya: (a) vitamin
A and (b) β-cryptoxanthin.
Papaya is one of the many fruits ranked low on the glycaemic index and, as such,
diabetics can consume it safely in small portions, thus reducing the risk of complica-
tions associated with the disease (Ismawanti, Suparyatmo and Wiboworini 2019).
As a matter of fact, the results from a clinical study showed that the consumption of
as much as 438 g of the unripened fruit maintained normoglycaemic levels in a test
group of diabetic patients (Fatema et al. 2011).
In addition to the previously mentioned components, favonoid compounds
(Figure 3.4) have also been isolated in papaya. These favonoids are able to control
glucose levels by regenerating pancreatic β-cells, which in turn increases the produc-
tion of insulin in the body (Akhlaghi and Foshati 2017).
Furthermore, favonoids also inhibit the GLUT-2 transporter (in the intestinal
mucosa) and the α-glucosidase enzyme (in the small intestine). They have also
been reported to reduce glucose absorption and prevent carbohydrate breakdown,
which would ultimately result in reduced BG levels (Ismawanti, Suparyatmo and
Wiboworini 2019).
Maniyar and Bhixavatimath experimented with CaP leaf extracts on alloxan-
induced diabetic rats and found that, at a dose of 400 mg/kg.bw, the aqueous extract
was effective in reducing the BG levels of the diabetic animals (Maniyar and
Bhixavatimath 2012). Similarly, Airaodion et al. also investigated the antidiabetic
activity of the compounds contained in papaya leaves. In their study, they gauged the
effcacy of the compounds against that of the commercial drug, glibenclamide. The
group reported that due to the comparable activity with the commercial drug, the
use of papaya leaf extracts could be a viable alternative in the treatment of diabetes
(Airaodion et al. 2019).
To complete our story, we report on the interesting fndings of Venkateshwarlu
et al., who directed their investigations towards the aqueous extract of the CaP seeds.
The group found that a therapeutic dose of 200 mg/kg.bw of the extract resulted
in a signifcant reduction in BG levels in STZ/nicotinamide-induced diabetic rats
(Venkateshwarlu et al. 2013). In support of this study, Juárez-Rojop et al. confrmed
that both the seeds and ethanolic extract from the leaves (3 g/100 mL) exhibited
hypoglycaemic effects on STZ-induced diabetic rats. Not only did the extracts lower
the BG levels in the subjects, but they also decreased their cholesterol and triacylg-
lycerol blood levels (Juárez-Rojop et al. 2012). Similarly, Dhawan et al. also inves-
tigated the hypoglycaemic activity of CaP in rats, where a dosage of 250 mg/kg.bw
was able to bring about a 30% drop in their BG level over a study period of 10 days
(Dhawan et al. 1977).
3.16 CATHARANTHUS ROSEUS LINN. (CR)

Common names: Bright eyes, Cape periwinkle, Graveyard plant, Madagascar peri-
winkle, Old maid, Pink periwinkle, Rose periwinkle (Figure 3.28)
C. roseus, also known as Vinca rosea Linn., is an ornamental sub-shrub that is
cultivated mainly for its alkaloids: vinblastine (Figure 3.29a), vincristine (Figure
3.29b), and ajmalicine (Figure 3.29c). Reports have shown that these isolated com-
pounds display both anticancer and hypotensive activity; however, there are records
of it also being used for DM therapy (Jaleel et al. 2006, Council of Scientifc &
Industrial Research 1992, Kulkarni et al. 1999). Furthermore, the CR plant is known
to produce more than 100 monoterpenoids and indole alkaloids, which claim to have
ameliorative effects in different organs (Jordan, Thrower and Wilson 1991).
Although Watt and Breyer-Brandwijk considered that most investigations
into the claim of hypoglycaemic activity have shown negative results and that
any advantage obtained can be ascribed to weak digitalis and purgative action
(Watt and Breyer-Brandwijk 1932), the plant still enjoys a widespread reputation
FIGURE 3.28 Illustration of Catharanthus roseus.
FIGURE 3.29 Structural formulae of isolated compounds from Catharanthus roseus:

(a) vinblastine, (b) vincristine, and (c) ajmalicine.
for its antihyperglycaemic action in the treatment of diabetes (Watt and Breyer-
Brandwijk 1932, Pillay, Nair and Santi Kumari 1959, Nammi et al. 2003, Singh
et al. 2001). It is proposed that the mechanism of action of CR is mediated either
through the enhancement of insulin secretion from the β-cells of Langerhans or
through an extra-pancreatic mechanism (Rahimi 2015, Nammi et al. 2003). Using
a population of healthy rats in their frst study, Chattopadhyay et al. reported that
the oral administration of varying dosages of water-soluble fractions of the eth-
anolic extract of CR leaves (100, 250, 500, and 1000 mg/kg.bw) showed a sig-
nifcant dose-dependent reduction in BG at 4 hours by 26.22%, 31.39%, 35.57%,
and 33.37%, respectively. Furthermore, the oral administration of CR extract (at
500 mg/kg.bw), 3.5 hours before an oral glucose tolerance test (OGTT) (10 g/kg.
bw) and 72 hours after STZ administration (50 mg/kg.bw) in rats showed a signif-
cant antihyperglycaemic effect (Chattopadhyay et al. 1991).
In yet another study it was reported that the oral administration of the leaf and
twig extract (500 mg/kg.bw) was benefcial to animals by lowering their elevated BG
levels (Malvi et al. 2011). Finally, histopathological studies carried out by Ahmed
et al. showed the effective reversal of the alloxan-induced changes in the BG level
and the β-cell population in the pancreas. These fndings support previous stud-
ies and encourage more research on the therapeutic benefts of CR in DM therapy
(Ahmed et al. 2010).
3.17 CECROPIA OBTUSIFOLIA LINN. (CeO) AND

CECROPIA PELTATA LINN. (CeP)
Common names: Cecropia obtusifolia: Trumpet tree, Pop-a-gun, Tree-of-laziness,
Snakewood tree (Figure 3.30a);
Cecropia peltata: Bacano, Bois Cano, Trumpet Tree, Snakewood, Congo pump,
Wild pawpaw, Pop-a-gun (Figure 3.30b)
Cecropia is a neotropical genus, composed of 61 recognized species, with a
highly distinctive lineage of dioecious trees. The genus consists of pioneer trees in
the relatively humid parts of the neotropics, with the majority of the species exhibit-
ing a symbiotic relationship with ants. Out of the 61 species, C. obtusifolia and C.
peltata are of particular interest due to their associated hypoglycaemic activity. Both
CeO and CeP can be found in the Central American regions; however, the peltata
species are limited to some West Indian countries, Guyana, Trinidad, and Jamaica.
The hypoglycaemic effects of methanol extracts of CeO and CeP have been linked
to their respective chlorogenic acid (Figure 3.25c) and isoorientin (Figure 3.31) con-
tent. Studies have suggested a linear correlation between the hypoglycaemic activity
and chlorogenic acid content in the species; however, discrepancies in indepen-
dent studies have failed to confrm which of the two species is more potent (Costa,
Schenkel and Reginatto 2011).
The mechanism of the antidiabetic activity of the genus was investigated by
evaluating the inhibitory effect of the butanolic extract of CeO on α-glycosidase.
In vitro studies confrmed the inhibitory activity of the extract on α-glycosidase,
while the results from the in vivo experiment showed that the extract was able to
reduce the PG levels as early as 90 minutes after administration. Another investiga-
tion into the mechanism of action, demonstrated an increase in in vitro glucose reup-
take (in both insulin-sensitive and insulin-resistant adipocytes), when treated with an
aqueous extract of CeO, and with chlorogenic acid (Costa, Schenkel and Reginatto
2011). Recently, it was reported that the oral administration of both aqueous and
FIGURE 3.30 Illustrations of Cecropia species: (a) Cecropia obtusifolia and (b) Cecropia
peltata.
FIGURE 3.31 Structural formula of isoorientin.

butanolic extracts of CeO and CeP was able to reduce hepatic glucose production
in vivo and inhibit the activity of glucose-6-phosphatase during the process of glu-
coneogenesis. The study brought to light the attractive BG-lowering effciency of the
Cecropia extracts in relation to the commercial drug, metformin (Andrade-Cetto
and Cárdenas-Vázquez 2010).
Studies on human patients are described only for CeO. The daily intake of aque-
ous leaf extracts by 22 patients (with a history of poor responses to conventional
allopathic treatments) resulted in a signifcant reduction in glucose levels. In another
study that lasted 32 weeks, 12 patients who were diagnosed with T2DM, showed a
signifcant and sustained hypoglycaemic effect over a treatment period of 18 weeks;
this effect was maintained for a further 4 weeks after the treatment ended (Costa,
Schenkel and Reginatto 2011).
Finally, having established the hypoglycaemic activity of the Cecropia extracts,
the Andrade-Cetto group set out to gauge the relative potencies of both aqueous
and butanolic extracts of CeP against that of glibenclamide. The group was able to
report a good correlation in activity between the commercial drug and both extracts,
with the greater potency observed for the butanolic extracts versus the aqueous type
(Andrade-Cetto, Cárdenas and Ramírez-Reyes 2007).
3.18 CENTELLA ASIATICA LINN. (CeA)

Common name: Gotu Kola, Asiatic Pennywort, Spade leaf (Figure 3.32)
With its origins traced back to Asia, C. asiatica can now be found fourishing
in swampy areas and ditches of the Caribbean. Research on the plant has led to the
isolation of a large variety of biomolecules, which include favonoids (Figure 3.4),
tannins, phytosterols, saponins, amino acids, and sugars, each of which commands
various ethnopharmacological applications inclusive of DM therapy (Dewi and
Maryani 2015).
In an attempt to elucidate the active compounds and the mechanism of action
responsible for the antidiabetic activity in CeA, Dewi et al. tailored an in vitro exper-
iment that investigated the suspected α-glucosidase inhibiting action of its extracts.
FIGURE 3.32 Illustration of Centella asiatica.

The group was successful in isolating two compounds from the organic extracts:
kaempferol (Figure 3.25f) and quercetin (Figure 3.25g).
Furthermore, based on observed increased insulin levels and the results from pan-
creatic histopathology studies of diabetic models, the antidiabetic activity of those
samples was believed to occur by stimulating the non-damaged pancreatic β-cells by
another isolate: Asiaticoside (Figure 3.33), to produce more insulin (Fitrianda et al.
2017).
Another group aimed to examine the effect of dosage variations of whole plant
extracts on STZ/nicotinamide-induced diabetic rats. The results confrmed the anti-
diabetic effect of CeA extract dosages of 1200 mg/kg.bw/day and reported a simi-
larity in activity with that of the control standard, metformin (at 45 mg/kg.bw/day)
(Muhlishoh, Wasita and Nuhriawangsa 2018).
Finally, in a study using alloxan-induced diabetic male Wistar rats, Emran et al.
confrmed both the glucose and total cholesterol-lowering ability of CeA extracts at
a dosage of 50 mg/kg.bw. Equally interesting was their observation that the plant
extracts showed no toxic effects on the treated rats. This fnding suggested that
FIGURE 3.33 Structural formula of asiaticoside.

unlike insulin and other common antidiabetic agents, overdose of the drug may not
result in hypoglycaemia (Emran et al. 2015).
3.19 CHROMOLAENA ODORATA LINN. (CO)

Common names: Siam weed, Christmas bush, Jack in the Box, Devil Weed,
Communist Pacha, Common Floss Flower, Rompe Saragüey (Figure 3.34)
C. odorata (also classifed as Eupatorium odoratum Linn.) is a fowering shrub of
the Astereaceae family that is considered one of the world’s worst weeds (Omonije,
Saidu and Muhammad 2019, Oguntibeju 2019, Amaliah et al. 2019). It is a fast-grow-
ing, densely tangled bush, with a height range of 2–10 m (Oguntibeju 2019, Ijioma
et al. 2014, Ogugua et al. 2013). The CO plant can be found thriving in all parts of
the United States, Mexico, West Africa, the Caribbean (Oguntibeju 2019), and other
tropical countries (Asomugha et al. 2013).
Many studies in the past, focused on the antidiabetic properties of CO extracts.
Justifably, we have found that greater attention was placed on the CO leaves than
its roots (Omonije, Saidu and Muhammad 2019) due to the presence of the bioac-
tive components: quercetin (Figure 3.25g), kaempferol (Figure 3.25f), tamarixetin
(Figure 3.35a), and kaemferide (Figure 3.35b) (Onkaramurthy et al. 2013).
The frst study by Selvanathan and Sundaresan compared the possible improve-
ment of elevated BG levels and damaged pancreatic β-cells through the administration
FIGURE 3.34 Illustration of Chromolaena odorata.
FIGURE 3.35 Structural formulae of isolated compounds from Chromolaena odorata: (a)
tamarixetin and (b) kaempferide.
of ethanolic leaf extracts to diabetic albino rats. The results showed that on the ninth
day of treatment, doses of 200 and 400 mg/kg.bw led to lowered serum glucose lev-
els (from 258.2 ± 8.5 and 259.9 ± 10.9 to 204.9 ± 9.2 and 191.2 ± 8.4 mg/dL, respec-
tively) (Selvanathan and Sundaresan 2020). Another investigating team reported that
infused CO leaf extract caused a reduction in the BG levels of male mice, with the
most effective dosage being at a concentration of 20% (Amaliah et al. 2019).
In a fnal study, Omonije et al. examined the BG levels of diabetic rats when
treated with methanolic root extracts of CO. The group reported a BG level reduc-
tion of 49.86% and 68.3% at doses of 300 and 600 mg/kg.bw, respectively, thus again
supporting the potential therapeutic use of CO in DM therapy (Omonije, Saidu and
Muhammad 2019).
It should be noted that CO contains carcinogenic pyrrolizidine alkaloids (Ogugua
et al. 2013). Although acute toxicity studies revealed that CO methanolic root extracts
and ethanolic leaf extracts did not produce signifcant changes in animal behaviour
in doses up to 5000 mg/kg.bw (Omonije, Saidu and Muhammad 2019, Ijioma et al.
2014), the fnding was not supported by Asomugha et al., who observed a 43% mor-
tality rate in their test rats after oral administration of the aqueous leaf extract, at
a dose of 1077 mg/kg.bw (Asomugha et al. 2013). The conficting reports clearly
underscores the need for further toxicity and safety-in-use studies for this plant.
3.20 CITRUS AURANTIIFOLIA LINN. (CiA)

Common names: Lime, Key Lime, Mexican Lime, Mexican Thornless Key Lime
(Figure 3.36)
FIGURE 3.36 Illustration of Citrus aurantiifolia.

C. aurantiifolia is a short, densely branched evergreen tree that is popular for

its edible fruit. It is mainly grown in tropical and subtropical regions, such as the
Caribbean, Mexico, Florida, and Southeast Asia. Belonging to the Rutaceae fam-
ily, the fruit is known for its vibrant green and yellow exterior (peel) and the zesty,
acidic taste of its juice. Like its cousin, the lemon (CiL), CiA shares a wide array of
applications in both the culinary and medical felds. Regarding the latter, the leaves,
fruit, peel, and essential oils are used because of their confrmed astringent, antibac-
terial, and anti-infammatory properties (Fern n.d.). While it is common knowledge
that this citrus family is packed full of powerful antioxidants, such as vitamin C
(Figure 3.14d), much research has been carried out to confrm the effectiveness of
the other constituent chemicals as a natural diabetic treatment.
One study conducted by Mawatri et al. focused on evaluating the synergistic
effects of mixtures of CiA extracts with that of Cinnamomum burmannii Linn. (CB;
cinnamon) to treat hyperglycaemic levels in diabetic rats. Twenty-fve STZ-induced
rats were divided into fve groups and administered different doses of the extracts
for 30 days: Group 1: negative control, standard diet; Group 2: positive control, high-
cholesterol diet; Group 3: high-cholesterol diet + CiA extract (100 mg/kg.bw/day)
and CB extract (200 mg/kg.bw/day); Group 4: high-cholesterol diet + CiA extract
(300 mg/kg.bw/day) and CB extract (400 mg/kg.bw/day); and Group 5: high-cho-
lesterol diet + CiA extract (500 mg/kg.bw/day) and CB extract (800 mg/kg.bw/day).
The results showed that both extracts had a signifcant effect on the BG in Groups
2, 3, and 5, decreasing their levels by 53.2% overall. Also, the levels of superoxide
dismutase (SOD) increased in Group 4 indicating higher anti-infammatory agents in
the body. They concluded that, when used in conjunction with CB extracts, CiA can
be an effective therapy in the management of diabetic complications in hyperglycae-
mic patients (Mawarti, Khotimah and Rajin 2018).
In another study, Karmi and Nasab compared the antidiabetic effect of varying
concentrations of CiA juice against that of a combination of garlic extract (AS) and
CiA juice. Gauging their results against metformin (as a control standard), it was
found that a 50% dilution of the CiA juice was able to comparably, but temporarily,
reduce the BG levels in diabetic rats. Furthermore, they reported that the combina-
tion of CiA juice (50%) and garlic (250 mg/100 g.bw) also signifcantly lowered the
BG levels in the diabetic subjects (Karimi and Nasab 2014).
Ibrahim et al. experimented with the essential oil from the CiA leaf on alloxan-
induced diabetic rats for 14 days. They conducted a chemical analysis of the oil and
identifed the main constituent as D-limonene (Figure 3.37) (57.84%), which accord-
ing to the literature, has confrmed anti-infammatory and antimicrobial properties.
FIGURE 3.37 Structural formula of D-limonene.

The essential oil was hydro-distilled and administered to the rats daily, at doses
of 25, 50, 100, and 200 mg/kg.bw. From this, the group reported that the oil (at
100 mg/kg.bw) showed a signifcant reduction in and normalization of the FBG and
hepatic glucose during the 14-day study, as compared to the other doses (Ibrahim
et al. 2019).
3.21 CITRUS LIMON LINN. (CiL)

Common name: Lemon (Figure 3.38)
C. limon belongs to the Rutaceae family alongside lime, grapefruit, and orange.
It is grown in tropical and semi-tropical climates and is recognized as an oval citrus
fruit with either a smooth porous or rough skin. Its high content of ascorbic acid
(vitamin C), potassium, and citric acid makes them very popular in the West for
treating the common cold and sore throat, detoxifying the body, and weight loss. The
leaves, stems, juices, pulp, and peel from the fruit contain vitamins that have anti-
infammatory and antioxidant properties. Furthermore, the high content of polyphe-
nols present in the fruit and the peel of CiL confers an appreciable hypoglycaemic
effect (Rafque et al. 2020).
Lv et al. investigated the antihyperglycaemic activity of CiL using the hydro-
alcoholic extract found in its peel. Using a population of STZ-induced diabetic rats,
the subjects were divided into four groups: normal control, diabetic control, dia-
betic + low dose of the peel extract, and diabetic + high dose of the peel extract. The
rats were then administered 250–500 mg/kg.bw of the extract daily for 35 days.
After the 35-day period, both groups that were treated with the low and high dosage
of the peel extract, showed a signifcant decrease in FBG levels and a reduction in
FIGURE 3.38 Illustration of Citrus limon.

FIGURE 3.39 Structural formula of naringin.
insulin resistance. Interestingly, there was an increase in body weight in the treated
diabetic rats, while oxidative stress was alleviated and antioxidant activities in the
liver were restored (Lv et al. 2018).
Another group demonstrated the ameliorative effects of CiL and pomegranate
juices on the BG and plasma insulin levels in alloxan-induced diabetic rats. The
rodents were administered three doses of CiL juice: 0.2, 0.4, and 0.6 mL/kg.bw over
a 6-week period, after which a signifcant decrease in the BG levels was noted. It was
proposed that the antihyperglycaemic effect was due to the high content of vitamin C
(Figure 3.14d), favonoids (Figure 3.4), and naringin (Figure 3.39) (Riaz, Khan and
Ahmed 2013).
Naim et al. also investigated the antidiabetic activity of CiL peel on alloxan-
induced diabetic rats using a hexane extract and compared its effect against the com-
mercial drug, glimepiride. The rats were separated into three groups: Group 1 (treated
with normal saline), Group 2 (treated with 15 μg/kg.bw glimepiride), and Group 3
(treated with 10 mg/kg.bw hexane extract from CiL peel). After 1 week, the results
indicated that the hexane extract reduced the BG levels by 44.57%, 75.96%, 95.43%,
and 98.08% in 24, 48, 72, and 96 hours, respectively. The investigating team found
that the effcacy of the extract showed good correlation with that of glimepiride and
was able to confrm its therapeutic potential in DM treatment (Naim et al. 2012).
3.22 CITRUS PARADISI LINN. (CiP)

Common names: Grapefruit, Paradise Citrus (Figure 3.40)
The citrus fruit C. paradisi was developed in the West Indies in the early 1700s as
a cross-breed between an orange and a shaddock. It is consumed worldwide, not only
because of its taste and nutritional value, but also because of its accredited medicinal
FIGURE 3.40 Illustration of Citrus paradisi.
properties (Owira and Ojewole 2009). Evergreen grapefruit trees have an average
height of 5–6 m, but can grow as tall as 13–15 m. The tree has long, thin, glossy,
dark-green leaves, and produces white, four-petaled fowers that are approximately 5
cm wide. The spheroidal fruit is usually yellow skinned, with an average diameter of
10–15 cm (Wikipedia 2021), and the fruit pulp is either yellow, pink, or white in colour.
Since the 1930s, CiP has been a constituent of many diets (as an anti-obesity
ingredient). Such an inclusion therefore suggests that consumption of grapefruit
or grapefruit juice may be benefcial to T2DM patients. Modern research has con-
frmed its effectiveness in infuencing an improvement in glucose tolerance as well
as plasma lipid (PL), TC, LDL, and TG levels (Hayanga et al. 2015). Drawing from
these studies, it would be expected that the fruit and its extracts would top the list
of herbal therapeutants for the disease. However, research has uncovered that the
consumption of CiP juice is connected to unfavourable increases in the plasma con-
centrations of orally administered drugs, due to the inhibition of the activity of the
metabolizing enzyme, cytochrome P450IIIA4 (CYP3A4) (Owira and Ojewole 2009,
Lundahl et al. 1997, Saito et al. 2005, Zaidenstein et al. 1998). As such, although only
a few cases of life-threatening effects have been reported, the use of CiP juice as a
viable T2DM therapeutant has since been avoided (Hayanga et al. 2015).
The components in CiP juice that are responsible for CYP3A4 inhibition have
not been fully determined. However, in vitro studies have confrmed the CYP3A4
inhibitory action of some CiP juice isolates, such as bergamottin (Figure 3.41a) and
6′,7′-dihydroxy-bergamottin (Figure 3.41b) (Christensen et al. 2002).
Despite all the aforementioned negativities, researchers continue to explore
the potential of its use in DM therapy. A study by Hayanga et al. demonstrated an
FIGURE 3.41 Structural formulae of isolated compounds from Citrus paradisi: (a) berga-
mottin, (b) 6′,7′-dihydroxy-bergamottin, and (c) hesperidin.
improvement in the glucose intolerance of STZ-induced diabetic rats, using CiP juice
therapy. The group reported an improvement in the weight of the treated rats as well
as more normalized FBG and fasting plasma insulin (FPI) levels, when compared
to the control animals. This observation suggested that the juice therapy may have
inhibited protein and lipid catabolism, which is associated with insulin defciency.
Furthermore, the untreated diabetic rats showed signifcantly reduced hepatic glyco-
gen content compared to the non-diabetic controls. Interestingly, treatment with either
the CiP juice alone or in combination with insulin signifcantly increased the hepatic
glycogen content in relation to the untreated group. However, it was observed that the
juice had no effect on pancreatic insulin secretion, which confrmed that the bioactive
constituents of CiP are neither insulinotropic nor did they promote pancreatic β-cell
regeneration. Finally, the group noted that the effects of CiP juice appeared to be
enhanced by insulin. As such, it was speculated that the juice, like metformin, could
be upregulating adenosine monophosphate–activated protein kinase (AMPK), which
is known to activate glucokinase and simultaneously deactivate G6Pase and PEPCK,
respectively (refer to the actions of biguanides in Chapter 2) (Hayanga et al. 2015).
In another study, Jung et al. investigated the effect of the contained biofavonoids
(hesperidin [Figure 3.41c] and naringin [Figure 3.39]) on the BG levels, hepatic glu-
cose-regulating (HGR) enzyme activity, hepatic glycogen concentration, and plasma
insulin levels of genetically raised diabetic mice (C57BL/KsJ-db/db). Test animals
were fed an AIN-76 control diet (standard diet formulation proposed by the American
Institute of Nutrition) supplemented with hesperidin (0.2 g/kg.bw diet) or naringin
(0.2 g/kg.bw diet). It was found that the treated animals showed a signifcant reduc-
tion in BG levels, but elevated HG activity and HG concentrations, when compared
with the control group. The results of the experiment gave good support to both
hesperidin’s and naringin’s important roles in preventing the progression of hypergly-

caemia, partly by increasing hepatic glycolysis and glycogen concentration and/or by
lowering hepatic gluconeogenesis (Jung et al. 2004).
While the ameliorative effects of CiP juice seem to be promising for T2DM mod-
els, its juice contents have been proven ineffective in T1DM subjects. The metformin-
like mechanism of action, which was proposed by Hayanga, can be corroborated with
the fndings of Xulu’s group, which confrmed that although naringin showed signs
of anti-atherogenic activity, it was ineffective in antihyperglycaemic action (Xulu and
Owira 2012).
3.23 CITRUS SINENSIS LINN. (CiS)

Common names: Orange, Sweet orange (Figure 3.42)
Along with lemon, C. sinensis belongs to the Rutaceae family. CiS is a small,
evergreen, aromatic tree that is grown in both tropical and subtropical regions. It is
more round in shape compared to CiL and comes in various colours and sizes. It is
popular for its fruit’s juices and essential oils, which are good sources of vitamin C
and antioxidants. These components carry powerful medicinal properties that can
be used in the treatment of the common cold. However, besides the common cold,
studies have shown that the extracts from the plant (juices, peels, and bark) exhibit
antihyperglycaemic activity, and can be applied to T2DM therapy.
Parmar and Kar investigated the antidiabetic effect of the peel extract in alloxan-
induced diabetic mice over a period of 10 days. Four different concentrations of the
extract, ranging between 12.5, 25, 50, and 100 mg/kg.bw, were administered daily to
FIGURE 3.42 Illustration of Citrus sinensis.

FIGURE 3.43 General structural formula of favonols.
the subjects, which resulted in a dose responsive arrest of the hepatic lipid peroxidation,
as well as a signifcant decrease in serum glucose (Parmar and Kar 2007). From this,
the study group suggested that the medley of compounds present in the CiS extract,
such as favonols (Figure 3.43), hesperidin (Figure 3.41c), and naringin (Figure 3.39),
were responsible for its antidiabetic and antiperoxidative activity (Parmar and Kar 2007,
2008).
Next, Sathiyabama et al. investigated the antidiabetic effect of the methanolic fruit
peel extract in STZ insulin-resistant diabetic rats over a 30-day period. The rodents
were divided into fve groups: Group 1: normal control rats; Group 2: diabetic con-
trol; Group 3: diabetic (treated with 50 mg/kg.bw of CiS methanol extract); Group 4:
diabetic (treated with 100 mg/kg.bw of CiS methanol extract); and Group 5: diabetic
(treated with 100 mg/kg.bw of metformin). The group reported that the diabetic rats
(receiving both 50 and 100 mg/kg.bw of methanol extract) showed decreased BG levels
at 60 and 120 minutes after glucose administration. Additionally, the peroxisome pro-
liferator-activated receptor gamma (PPARγ), GLUT-4, and insulin receptor messenger
ribonucleic acid (IR-mRNA) expression levels in CiS methanol extract–treated diabetic
groups were signifcantly higher than those in the diabetic control group. These results
thus infuenced the team’s proposal that the observed activity was due to the presence
of polyphenols, which were abundant in the methanolic elixir (Sathiyabama et al. 2018).
In an independent study, Boris et al. experimented with three different forms of
CiS stem bark extracts. Analysis of each extract for polyphenolic content revealed
the ethanolic solution to have a higher concentration of polyphenols, relative to those
of the other aqueous and hydro-ethanolic samples. However, it was interesting to
later learn that after the 10-day study period, the aqueous extracts (at doses of 400
mg/kg.bw) signifcantly decreased the BG compared to the others. In the end, the
group was able to confrm the ability of the extract to interfere with both starch
and sucrose digestion and recommended that the source be further explored for its
potential in the treatment of DM and other metabolic disorders (Boris et al. 2017).
3.24 CORIANDRUM SATIVUM LINN. (CoS)

Common names: Cilantro, Coriander, Coriandre, Dhania (Figure 3.44)
C. sativum is a herbaceous plant of the Apiaceae or Umbelliferae family and can
grow to a height of 0.2–0.6 m. CoS is native to eastern Mediterranean countries, but
FIGURE 3.44 Illustration of Coriandrum sativum.
is now cultivated across Europe and America (Pamplona-Roger 2005). The fruit,
fresh leaves, and cooked root can be used for various culinary purposes (Waheed
et al. 2006); however, its most popular use is as a spice in various food items (Verma
et al. 2018). Findings have suggested that only its ripe fruit should be used and never
the green parts. Furthermore, the essence of CoS should be consumed in modera-
tion, as high doses could lead to seizures (Pamplona-Roger 2005).
CoS seeds have been shown to reduce the rate of development and the extent of
hyperglycaemia in STZ-induced diabetic mice (Bailey and Day 1989). Two constitu-
ents of its seed extract that have shown antidiabetic activity have been identifed as
p-cymene (Figure 3.45a) and linalool (Figure 3.45b) (Bailey and Day 1989, Rahimi
2015, Verma et al. 2018).
A clinical investigation by Waheed et al. compared the effects of powdered, aque-
ous, and alcoholic extracts of CoS on 20 diabetic patients, half of whom had a con-
frmed history of unsuccessful therapy using prescribed antidiabetic medication. The
study group reported that the administration of any of the three forms had resulted
in signifcant decreases in the mean concentrations of PG in the patients and also
highlighted the ameliorative effects of the extracts in patients who were previously
FIGURE 3.45 Structural formulae of isolated compounds from Coriandrum sativum:

(a) p-cymene and (b) linalool.
using allopathic drug therapy, but were unable to control their elevated sugar levels
with the prescribed medication (Waheed et al. 2006).
In another study, Eidi et al. experimented with the CoS ethanolic seed extract in
a population of STZ-induced diabetic rats. The team reported that a 200 mg/kg.bw
dose was able to signifcantly increase the activity of the pancreatic β-cells and lower
the serum glucose levels in the treated diabetic rats, in comparison to their untreated
counterparts (Verma et al. 2018, Rahimi 2015, Eidi et al. 2009).
As an alternative mechanism, Das et al. showed that an aqueous extract of the
CoS seeds enhanced glucose transport, glucose oxidation, and glycogenesis to an
extent that was comparable to 10 –8 M insulin (Gray and Flatt 1999). However, it was
noted that the action of CoS greatly differed from that of metformin (which is still
deemed a more potent antidiabetic agent in comparison to the aqueous CoS seed
extract), due to its effects on glucose transport via insulin-mediated peripheral glu-
cose uptake (Das et al. 2019).
An in vivo study by Aligita et al. showed that the administration of 200, 400,
and 800 mg/kg.bw leaf extract doses to different groups of alloxan-induced dia-
betic mice showed appreciable hyperglycaemic attenuation in comparison to gliben-
clamide (0.65 mg/kg.bw) over a 14-day period. Interestingly, the group receiving the
200 mg dose showed closer correlation in effcacy to the prescription drug over the
other higher doses. The group also performed an in vitro study to assess the inhibit-
ing activity of the CoS extract on the AG enzyme (see Chapter 2.5). Based on the
experiment’s IC50 value, the CoS extract showed stronger inhibition of the enzyme
(at 32.376 ppm) in relation to the standard drug, acarbose (at 82.272 ppm) (Aligita
et al. 2018).
3.25 CRESCENTIA CUJETE LINN. (CrC)

Common names: Calabacero, Calabash, Kalbas, Miracle fruit, Rum tree, Totumo
(Figure 3.46)
Cr. cujete (commonly known as calabash) is a species of fruiting plant that is
ubiquitous to Africa, Central America, South America, extreme southern Florida,
FIGURE 3.46 Illustration of Crescentia cujete.
and the West Indies. It is dicotyledonous, with simple leaves that are either alternate
or clustered on short shoots. In the Caribbean, the calabash fruit is mainly grown for
decorative and crockery purposes. However, the revelation of its use in Philippine
folk medicine as a treatment for many diseases, including diabetes, warranted its
inclusion in this book. The phytochemical composition of CrC has been documented
to include alkaloids, iridoids, sterols, triterpenes, peptides (insulin), proteins (bix-
ine), cyanhydric acid (hydrogen cyanide), allicine (Figure 3.8a), pectin (Figure 3.47a),
tartaric acid (Figure 3.47b), citric acid (Figure 3.47c), nerolidol (Figure 3.47d), and
malic acid (Figure 3.47e), all of which are believed to possess antidiabetic properties.
In particular, cyanhydric acid was found to stimulate insulin release, while the alka-
loids of CrC were noted to be involved in glycogenesis (Koff, Édouard and Kouassi
2009). In addition, contained iridoids were noted to reverse high glucose levels and
obesity-induced β-cell dysfunction in the pancreas (Zhang et al. 2006), and also
stimulate insulin secretion (Sundaram, Shanthi and Sachdanandam 2013). Pectin
was shown to increase the activity of glycogen synthase, increase hepatic glyco-
gen, and decrease BG levels (Gomathy, Vijayalekshmi and Kurup 1990, Buchanan,
Gruissem and Jones 2000). Furthermore, the presence of citrate (Figure 3.47f) (from
citric acid) is found to inhibit phosphofructokinase, which helps regulate glycolysis
and, eventually, the citric acid cycle (Murray et al. 2009).
In a study carried out by Uhon et al., the antidiabetic activity of crude ethanolic
extracts (CCE) of air-dried CrC leaves was studied. It was reported that the extracts
were able to normalize the BG level in a population of 27 alloxan-induced diabetic
mice (Mus musculus, MM). Furthermore, using ethyl acetate extracts, it was able
to mitigate hyperglycaemia in pre-orally treated MM mice. Noteworthy, the team
underscored an observed likeness in the effect of the extracts (at concentrations of
10,000 and 5,000 ppm) to that of metformin (Uhon and Billacura 2018).
Similarly, Billacura et al. also gauged the hypoglycaemic activity and protective
potential of the CrC fruit against those of metformin. In vitro (α-amylase inhibi-
tion activity) and in vivo screening methods (utilizing MM mice) were performed
FIGURE 3.47 Structural formulae of isolated compounds from Crescentia cujete: (a) pec-
tin, (b) tartaric acid, (c) citric acid, (d) nerolidol, (e) malic acid, and (f) citrate.
using fresh, decocted, hexane, aqueous, and crude ethanolic extracts. Alpha-amylase
inhibitory assays revealed that 10,000 ppm hexane extracts were most effcacious in
inhibiting the enzyme activity, followed by similar doses of the aqueous and crude
ethanolic extracts, respectively. The in vivo experiments that followed suggested that
the fresh extract and the three solvent extracts (10,000 ppm hexane, 10,000 ppm
aqueous, and 10,000 ppm crude ethanolic extract) were also equally capable of low-
ering elevated BG levels in the diabetic animals. Finally, the group demonstrated that
normoglycaemic levels could be maintained in healthy subjects by dietary supple-
mentation with any of the extract forms: fresh (1 : 1 [m/v ratio of the sample : water]),
decocted, solvent (hexane [10,000ppm]), aqueous (10,000 ppm), or CCE (5000 or
1000 ppm) (Billacura and Alansado 2017).
3.26 CUCUMIS SATIVUS LINN. (CS)

Common names: Cucumber (Figure 3.48)
C. sativus belongs to the family Cucurbitaceae and is cultivated on vines that root
in the ground, and grow on supporting frames. The leaves are usually large, with the
fruit varying in size, shape, and texture. It has been reported that the plant has anti-
diabetic properties and scientists have performed several confrmatory studies using
animal models, such as rabbits and rats (I. A. Ross 2003).
Sharmin et al. assessed the activity of the aqueous fruit extract on the FBG lev-
els of diabetic rats using a single intraperitoneal injection of the cucumber extract
FIGURE 3.48 Illustration of Cucumis sativus.
(200 mg/kg.bw). The research group reported good correlation in the extract’s activ-
ity, by demonstrating a reduction in the rats’ FBG levels to 81.02%, 58.65%, and
32.61% at 4, 8, and 12 hours, respectively, in relation to the metformin standard,
which showed a reduction of 69.20%, 44.95%, and 25.44% within the same time
period (Sharmin et al. 2013).
Ebirien et al. experimented with CS fruit juice on 50 healthy human subjects
(aged 18–29 years). The individuals were separated into fve groups: Group 1: receiv-
ing 200 g CS juice only; Group 2: receiving 200 g CS juice and 200 g rice meal;
Group 3: receiving 400 g CS juice only; Group 4: receiving 400 g CS juice and 400
g rice meal; and Group 5: receiving 400 g rice meal only. They discovered that when
compared to Groups 1 and 2, Groups 3, 4, and 5 showed a signifcant difference in
PG values between the baseline (pretreatment) individuals and the 2-hour postpran-
dial individuals. From their results, they concluded that the cucumber supplement
was able to effect hypoglycaemic activity on the PG levels, since an intake of an
increased dose or at concentrations of 400 g caused a signifcant change in the BG
concentration (Bartimaeus, Echeonwu and Ken-Ezihuo 2016).
In another study, Karthiyayini et al. looked at the ethanolic extracts of CS fruit to
assess the effectiveness of hyperglycaemic attenuation and hypolipidaemic activity
in both healthy glucose-loaded and STZ-induced diabetic rats. To underscore the
validity of their study, they included the commercial drug glibenclamide for refer-
ence purposes. The group reported that when extracts of 200 and 400 mg/kg.bw of
CS were administered to the glucose-loaded healthy rats for 18 hours, a signifcant
reduction in PG levels was observed after 30 minutes. The effect was observed to
continue until normal levels were recorded at 90 minutes from the point of adminis-
tration. They then turned to their diabetic subjects, where they reported that hyper-
glycaemia was signifcantly lowered through the administration of 200 and 400 mg/
kg.bw of both the CS extract and glibenclamide. Noteworthy was their observation
that at 400 mg/kg.bw, the CS extract showed similar activity to that of the commer-
cial drug (Karthiyayini et al. 2009).
Finally, it was found that not only does CS exhibit antihyperglycaemic activity,
but it also has the potential to mitigate oxidative and carbonyl stress (which is typi-
cally observed in diabetes). In this fnal study, Heidari et al. used an aqueous extract
of CS (40 μg/mL) on freshly isolated rat hepatocytes and proved that the extract had
a favourable infuence on the cytotoxicity markers of both the oxidative and car-
bonyl stress models, including those for cell lysis and reactive oxygen species (ROS)
(Heidari et al. 2016).
3.27 CUCURBITA FICIFOLIA LINN. (CF) AND

CUCURBITA PEPO LINN. (CP)
Common names: C. fcifolia: Fig-leaf gourd, Malabar gourd, Black seed squash,
Cidra (Figure 3.49a);
C. pepo: Pumpkin, Field pumpkin, Ozark melon, Texas gourd (Figure 3.4b)
The wide variety of pumpkins and squash belong to the Cucurbitaceae family. It
is an edible plant that is prepared and consumed in various dishes around the world.
Pumpkins are mainly cultivated in temperate, tropical areas and are found grow-
ing on vines that trail over the ground or on supporting fences. Its fruits, leaves,
seeds, and oil contain active constituents such as alkaloids and favonoids, which
FIGURE 3.49 Illustrations of Cucurbita species: (a) Cucurbita fcifolia and (b) Cucurbita
pepo.
have proven medicinal properties and can be used for antidiabetic, antioxidant, and
anti-infammatory treatments (I. A. Ross 2003).
Xia and Wang demonstrated the similarity in the hypoglycaemic activity of CF
with that of the commercial drug tolbutamide, using both healthy animals (with tem-
porary hyperglycaemia) and mildly diabetic animals. Extracts from the pumpkin
fruits (300 mg/kg.bw) were administered daily (over a period of 30 days) to STZ-
induced diabetic rats, during which the BG levels of the subjects were routinely
monitored. The results indicated that feeding with the fruit extract caused reductions
in STZ-induced hyperglycaemia, while simultaneously increasing the plasma insu-
lin levels and markedly reducing the STZ-induced lipid peroxidation in the pan-
creas. There was also a signifcant increase in the number of pancreatic β-cells in the
CF-treated animals when compared to the untreated diabetics. However, it should
be noted that the degree of β-cell restoration of the CF-treated rats was not as high
as that of the healthy rats, thus hinting the degree of potency of the CF fruit extract
(Xia and Wang 2007).
In another study, Kwon et al. investigated the antidiabetic and antihypertensive
potentials of the phenolic phytochemicals contained in CP. Interestingly, the study
revealed that there was a variation in the bio-active phenol concentrations in rela-
tion to the species of pumpkin tested. Among the varieties of pumpkin extracts
evaluated, round/orange and spotted orange/green had the highest content of total
phenolics and exhibited moderate antioxidant activity, coupled with moderate to
high glucosidase and angiotensin I-converting enzyme (ACE) inhibitory effects
(Kwon et al. 2007).
Finally, Makni et al. looked at the ameliorative effects of the compounds con-
tained in a powdered seed mixture of pumpkin (CP) and fax seeds (Linum usitatis-
simum Linn.) on a test group of alloxan-induced diabetic rats. Here, they found that
upon administration of the seed mixture, there was an observed decrease in the BG
concentration in the treated rats. Furthermore, continued administration of the feed
mixture until day-1 resulted in a 63% increase in plasma insulin concentration, as
well as an increase in antioxidant effects.
3.28 CURCUMA LONGA LINN. (CL)

Common names: Curcuma, Haldi, Hardi, West Indian saffron, Saffower, Turmeric,
Yellow Ginger (Figure 3.50)
The spice turmeric that is derived from the root of the plant C. longa has been
described as a treatment for diabetes in Ayurvedic medicine for thousands of years
(Aggarwal et al. 2007). In a very comprehensive review carried out by Zhang et al.,
the many studies and benefts of CL were discussed and summarized (Zhang et al.
2013). Curcumin (Figure 3.51) has been identifed as the predominant active compo-
nent of turmeric and has caught the attention of the scientifc community as a poten-
tial therapeutic agent in both the direct treatment of diabetes and the treatment of its
associated complications (Pérez-Torres et al. 2013). This popularity is well-deserved
because of its effectiveness in reducing hyperglycaemia and hyperlipidaemia in
rodent models and, of equal importance, its relatively low cost and low toxicity
FIGURE 3.50 Illustration of Curcuma longa.
FIGURE 3.51 Structural formulae of enol and keto forms of curcumin.
(Goel, Kunnumakkara and Aggarwal 2008, Shehzad et al. 2011, Chuengsamarn
et al. 2012, Sahebkar 2013, Evangelopoulos et al. 2014).
In diabetes-induced rat models (Pari and Murugan 2007), the oral administration
of various dosages of curcumin (ranging from 80 to 300 mg/kg.bw, during a 2 to
8-week period) (Pari and Murugan 2007, Arun and Nalini 2002, Murugan and Pari
2007, Soetikno, Watanabe et al. 2011, Xavier et al. 2012, Na et al. 2011, Patumraj,
Wongeakin et al. 2006, Soetikno, Sari et al. 2011, Jain et al. 2009) was able to pre-
vent body weight loss, reduce the levels of glucose, haemoglobin (Hb), and HbA1c
in blood (Arun and Nalini 2002), and improve insulin sensitivity (Murugan and Pari
2007). Additionally, the oral administration of turmeric aqueous extract (300 mg/kg.
bw) (Hussain 2002) or curcumin (30 mg/kg.bw) for 56 days (Mahesh, Balasubashini
and Menon 2004) resulted in a signifcant reduction in the BG in STZ-induced dia-
betic rat models. In high-fat diet (HFD)-induced insulin resistance and T2DM mod-
els in rats, the oral administration of curcumin (80 mg/kg.bw) for 15 and 60 days,
respectively, showed an antihyperglycaemic effect and improved insulin sensitivity
(El-Moselhy et al. 2011). Dietary curcumin (0.5% in diet) was also effective in ame-
liorating the increased levels of FBG, urine sugar, and urine volume in STZ-induced
diabetic rats (Chougala et al. 2012). Unfortunately, despite all these and many more
studies that support the effectiveness of CF therapy, the data is still criticized for
not being “high-quality clinical evidence” for its use in treating any disease (Nelson
et al. 2017)
3.29 CYMBOPOGON CITRATUS LINN. (CC)

Common names: Citron grass, Citronela, Citronella grass, Fever grass, Lemon grass
(Figure 3.52)
Cy. citratus (also known as Andropogon citratus Linn.) is a perennial plant of
the Poaceae or Gramineae family (Shah et al. 2011). It is cultivated in temperate
and tropical regions and is native to Asia, Africa, and America (Garba et al. 2020,
Machraoui et al. 2018, Oladeji et al. 2019). It is a grass-like plant that can grow
up to 2 m in height, with a plant width of approximately 1.2 m (Oguntibeju 2019,
Machraoui et al. 2018).
Various reports have shown the extracts of CC to exhibit desirable hypoglycaemic
effects (Shah et al. 2011, Garba et al. 2020, Machraoui et al. 2018, Abbas et al. 2018).
FIGURE 3.52 Illustration of Cymbopogon citratus.

Analysis of these extracts have revealed an assemblage of different bioactive com-

pounds, which when purifed have yielded the most effcacious isolates: citral (exist-
ing as two isomers: gerenial and neral) (Figure 3.53a) and β-myrcene (Figure 3.53b)
(Mishra et al. 2019, Omari et al. 2007). It is important to note that although the aque-
ous extract of the leaves is more commonly used, similar extracts from the roots and
fowers were observed to display greater antidiabetic activity than its co-candidate
source (Abbas et al. 2018).
Oguntibeju et al., Adeneye et al., and Sharma et al. independently explored the
effects of CC leaf extracts on diabetic rats, and unanimously confrmed their effcacy
in attenuating the elevated BG levels in the subjects (Oguntibeju 2019, Adeneye and
Agbaje 2007, Sharma and Gupta 2017). Another study by Ademuyiwa et al., was
undertaken to investigate the effect of different forms of extracts on the blood sugar
level, lipid profles, and hormonal profles of normal rats. Reports showed that the
oral administration of the ethanolic and aqueous forms (200 mg/kg.bw for 30 days)
caused a signifcant reduction in BG levels. Furthermore, the thyroid-stimulating
hormone (TSH), triiodothyronine (T3), and thyroxine (T4) hormonal levels were
found to be desirably higher in all the administered groups, while the lipid profle
levels were observed to be lowered in the treated rats (Ademuyiwa, Olamide and
Oluwatosin 2015).
Alternatively, Bharti et al. experimented with the essential oil of CC and found
that it signifcantly lowered the insulin resistance of diabetic rats (evaluated by the
homeostatic model assessment for insulin resistance [HOMA-IR] index). The group
observed a dose-response effect to the therapy, as the drop in insulin resistance was
FIGURE 3.53 Structural formulae of isolated compounds from Cymbopogon citratus: (a)
citral and (b) β-myrcene.
more evident in the diabetic rats, which were treated with doses of 800 mg/kg.bw
compared to those treated with 400 mg/kg.bw (Oladeji et al. 2019, Bharti et al. 2013).
Similarly, the Buaduo-led group reported satisfactory α-glucosidase and α-amylase
inhibitory effects of CC extracts, thus confrming its use as a potent regulator in
glucose metabolism (Boaduo et al. 2014).
While promising in its effcacy, toxicity studies on the extracts of CC have pro-
duced quite conficting results. Formigoni et al. found that the administration of high-
level doses of an infusion of CC leaves to rats was deemed non-toxic (Formigoni
et al. 1986). However, another study revealed that at higher doses of 1500 mg/kg.bw,
CC oils caused signifcant functional damage to the stomach and liver of Wistar rats,
and at a dose of 2000 mg/kg.bw, tea from CC dried leaves also caused similar dam-
age (Fandohan et al. 2008). This again underscores the need for more robust toxicity
studies to be performed on this and other biologically active plant extracts to gauge
their safety in use.
3.30 EUPHORBIA HIRTA LINN. (EH)

Common names: Asthma plant, Asthma weed, Soro Soro, Garden spurge, Snakeweed
(Figure 3.54)
E. hirta (also known as E. pilulifera Linn.) is a small, erect plant of the
Euphorbiaceae family that reaches an approximate height of 0.5 m (Al-Snaf 2017).
It is native to India and Australia but is now widely found in both tropical and sub-
tropical countries (N’Guessan Bra Fofe et al. 2013).
The presence of numerous chief chemical constituents in EH, including quercitrin
(Figure 3.55a), polyphenolic favonoids, and palmitic acid (Figure 3.55b), has sup-
ported its potential use in T2DM therapy (Sharma et al. 2018, Le et al. 2018).
In this frst study, Kumar et al. reported on the effects of ethanolic and petroleum-
ether extracts of the stems and concluded that the respective extracts had impactful
antihyperglycaemic activity (Kumar, Rashmi and Kumar 2010, Kumar, Malhotra
FIGURE 3.54 Illustration of Euphorbia hirta.

FIGURE 3.55 Structural formulae of isolated compounds from Euphorbia hirta: (a) quer-
citrin and (b) palmitic acid.
and Kumar 2010). Supplementary explorations showed that not only the stem but
also the ethanolic extracts of the leaf, fower, and root had therapeutic effects on
elevated BG levels (Al-Snaf 2017, Kumar, Rashmi and Kumar 2010).
The investigating teams also determined that the antidiabetic mechanism of both
ethanolic and ethyl acetate extracts followed an α-glucosidase inhibitory pathway
(Al-Snaf 2017, Sharma et al. 2018, Widharna et al. 2010). Alternatively, a study
carried out by Subramanian et al. suggested that the antidiabetic activity of the
EH plant extract was due to an insulin stimulatory effect from remnant β-cells
(Subramanian, Bhuvaneshwari and Prasath 2011). In yet another direction, in vitro
investigations performed by Shilpa et al. (using the methanolic extract of the whole
plant) proposed another mechanism of action, in which the active compounds served
as inhibitors to α-amylase activity (Shilpa et al. 2020). Adding to this, independent
investigations using similar extract forms showed that doses of 200 and 400 mg/kg
.bw infuenced striking decreases in the BG levels, and also gave some protection
and recovery from dyslipidaemia and oxidative stress in STZ-induced diabetic rats
(Devi and Kumar 2017).
Regarding its associated toxicity, it was indeed encouraging to note that com-
plimentary to its reported desirable activities, (Al-Snaf 2017, Sharma et al. 2018,
Subramanian, Bhuvaneshwari and Prasath 2011, Uppal, Nigam and Kumar 2012,
Maurya et al. 2012), no cytotoxic events were observed (in doses up to 500 mg/kg.bw)
(Uppal, Nigam and Kumar 2012) and no mortalities (in doses up to 2000 mg/kg.bw).
3.31 HIBISCUS ROSA-SINENSIS LINN. (HRS)

Common names: Hibiscus, Rose mallow, Shoe black plant, Shoe fower plant,
Tulipan (Figure 3.56)
H. rosa-sinesis is a perennial, ornamental, glabrous shrub of the Malvaceae fam-
ily (Upadhyay and Upadhyay 2011, Bhaskar and Gopalakrishnan 2012) which is
native to Southeast Asia, but is now mainly grown in tropical regions (I. A. Ross
2003). Due to their observed hypoglycaemic effect, extracts of both the fowers
(Upadhyay and Upadhyay 2011, Pillai and Mini 2016, Venkatesh, Thilagavathi and
Shyam sundar 2008, Ghosh and Dutta 2017) and the leaves (I. A. Ross 2003, Ghosh
FIGURE 3.56 Illustration of Hibiscus rosa-sinesis.
and Dutta 2017, Sachdewa and Khemani 2003, Mamun et al. 2013) of the plant have
been commonly considered for diabetes treatment (Moqbel et al. 2011). Additionally,
a few recent studies have suggested that the root extract can also be used as a viable
therapeutant (Kumar et al. 2013).
Several studies have demonstrated the glucose-lowering effect of the ethanolic
fower extracts (at common doses of 250 and 500 mg/kg.bw) in diabetic rats (Bhaskar
and Gopalakrishnan 2012, Venkatesh, Thilagavathi and Shyam sundar 2008, Ghosh
and Dutta 2017). Adding to this, Ghosh and Dutta observed a boost in the insulin
levels of their test animals, when extracts of a similar nature were used in their study
(Ghosh and Dutta 2017). Of particular importance, Sachdewa and Khemani found
that the fower extracts infuenced a significant and comparable BG attenuating
effect to that of the commercial drug, glibenclamide (Bhaskar and Gopalakrishnan
2012, Sachdewa and Khemani 2003).
Alternatively, there were also signifcant improvements in the ability to utilize
the external glucose load, when the alcoholic leaf extract was orally administered
to rats at a dose of 250 mg/kg.bw daily for 7 days (I. A. Ross 2003). Moqbel et al.
reported that the oral administration of the fractionated ethanolic leaf extract (at a
dose of 200 mg/kg.bw) to non-obese diabetic mice, exhibited the greatest ameliora-
tive insulinotropic effect in relation to the other retrieved fractions (Moqbel et al.
2011). Sachdewa et al. also investigated the effect of the aqueous leaf extract and
found good correlation with the control standard, tolbutamide (Sachdewa, Nigam
and Khemani 2001).
Regarding its toxicity or its infuence on the occurrence of toxic events, we
found that the intraperitoneal administration of a 70% ethanolic leaf extract to mice
exhibited an LD50 of 1.533 g/kg.bw. Similarly, additional rodent studies showed that
the intraperitoneal administration of an ethanolic extract solution of the aerial parts
of the plant showed an LD50 of 1 g/kg.bw (I. A. Ross 2003). From these studies, we
have noted that the effective doses that were used in the aforementioned studies were
well below the reported lethal doses and as such, the use of the HRS extract can be
deemed a relatively safe form of therapy.
3.32 JUSTICIA SECUNDA VAHL (JS)

Common names: Saint John’s bush (Figure 3.57)
J. secunda is a vibrant red fowering plant belonging to the Acanthaceae family
that grows in the tropical and subtropical zones of Africa, Asia, Madagascar, and
the Caribbean (Mea et al. 2017). In Caribbean traditional medicine, herbal tea is
made from the plant that is consumed for menstrual pain (Useful Tropical Plants
n.d.). The leaves and stems are used in the treatment of anaemia, coughs, colds,
fevers, and amenorrhoea, while (Useful Tropical Plants n.d., DeFilipps, Maina and
Crepin 2004) in African pharmacopoeia, JS is used for its antidiabetic properties
(Mea et al. 2017).
Mea et al. investigated the possible hypoglycaemic effects of JS on diabetic rats.
In their study, 2.5 and 3 g/kg.bw of an aqueous extract of JS leaves were adminis-
tered to the test animals. After the treatment, they found that both doses signifcantly
decreased BG levels over time; however, a lower reduction was observed at the 3 g/
kg.bw dose (Mea et al. 2017).
In another study, Theiler et al. proposed that the compounds contained in the
JS leaf extract possessed α-glucosidase-inhibiting capabilities, which as a conse-
quence, could infuence a decrease in patient BG levels. From their investigations,
not only was the group able to confrm the enzyme inhibiting effcacy of the extracts,
but it was also successful in isolating and characterizing two novel compounds that
seemed to be responsible for the activity: Compound 1 (Figure 3.58a) and Compound
2 (Figure 3.58b) (Theiler et al. 2016).
FIGURE 3.57 Illustration of Justicia secunda.

FIGURE 3.58 Structural formulae of isolated compounds from Justicia secunda:

(a) Compound 1 and (b) Compound 2.
3.33 LANTANA CAMARA LINN. (LC)

Common names: Common Lantana, Lantana, Red Sage, Shrub Verbena, Yellow
Sage, Caraquite, Cariaquito, West Indian lantana (Figure 3.59).
L. camara is an erect, hairy, aromatic shrub that grows to an approximate height
of 3 m. The plant belongs to the Verbenaceae family, and can be found in tropical
and subtropical regions, such as parts of the Americas, Asia, and Africa. LC con-
tains signifcant amounts of essential oils, with higher concentrations found in the
fowers and leaves rather than other parts, such as the roots and stem (Nawaz et al.
2016, Kalita et al. 2012).
Qualitative screening and subsequent antidiabetic evaluations have been done on the
phytochemicals contained in the foliar extract of LC. It was reported that the presence
of common phenols and favonoids was responsible for its α-amylase inhibiting activity,
in a dose-dependent manner (Bhowmick, Bartariya and Kumar 2018). Furthermore,
two triterpenoid compounds (urs-12-en-3β-ol-28-oic acid [a stearoyl glucoside of
ursolic acid] [Figure 3.60a] and urs-12-en-3β-ol-28-oic acid 3β-D-glucopyranosyl-4′-
octadecanoate [Figure 3.60b]) have been isolated and identifed to be predominantly
responsible for the plant’s antidiabetic activity (Nawaz et al. 2016, Kazmi et al. 2012).
Supporting this, Jawonisi and Adoga provided independent evidence of the antidiabetic
FIGURE 3.59 Illustration of Lantana camara.

FIGURE 3.60 Structural formulae of isolated compounds from Lantana camara: (a) Urs-
12-en-3β-ol-28-oic acid and (b) urs-12-en-3β-ol-28-oic acid 3β-D-glucopyranosyl-4′-octade
canoate.
activity of the LC leaf extract constituents and underscored the therapeutic potential of
this class of natural products (Jawonisi and Adoga 2015).
Additionally, it was observed that the methanolic extracts of LC leaves and
fruits also showed antihyperglycaemic activity (Kalita et al. 2012, Pramanik and
Giri 2018, Sangeetha, Mahendran and Ushadevi 2015). Complementary to this,
Venkatachalam et al. administered oral doses of 100 and 200 mg/kg.bw (methano-
lic fruit extract) to STZ-induced diabetic rats, and confrmed its antihyperglycae-
mic effects (Venkatachalam et al. 2011). Another investigating team confrmed the
antidiabetic activity of the plant, using 200 and 400 mg/kg.bw doses (aqueous leaf
extract) on alloxan-induced hyperglycaemic rats (Dash, Suresh and Ganapaty 2001).
We found comparable results in other studies, where the methanolic extracts (at the
same doses) were administered to both STZ-induced (Loganathan and Bhadauria
2019), and alloxan-induced diabetic rats (Ganesh et al. 2010). Khatoon et al. support-
ively showed that there was similar normalization of BG levels, using the ethanolic
leaf extract, at doses of 250 and 500 mg/kg.bw (Khatoon et al. 2013).
Before concluding, it is very important to note that LC is considered one of the
most toxic plants (Kalita et al. 2012, Dash, Suresh and Ganapaty 2001) however, the
occurrence of toxic events has only been reported following a high consumption of
the plant material (Kalita et al. 2012). Encouragingly, Venkatachalam et al. stated
that their acute toxicity studies revealed that the methanolic extract of the LC fruits
was non-toxic (Venkatachalam et al. 2011), and Khatoon et al. claimed that in their
study, the diabetic rats treated with the ethanolic leaf extract (at a dose of 2000 mg/
kg.bw) did not exhibit any toxicity-associated side effects (Khatoon et al. 2013).
3.34 LEONOTIS NEPETIFOLIA LINN. (LN)

Common names: Klip dagga, Christmas candlestick, Lion’s ear, Chandilay bush
(Figure 3.61)
FIGURE 3.61 Illustration of Leonotis nepetifolia.
L. nepetifolia is a plant belonging to the Lamiaceae family and is found in tropi-

cal and subtropical regions such as Africa, Asia, and the Caribbean. Although they
are not traditionally eaten as food, all parts of the plant are known to possess medic-
inal properties, due to their wide spectrum of chemical constituents (Gungurthy
et al. 2013). In Trinidad, it is used as a traditional medicine (infusion) against fever,
coughs, and malaria (Gungurthy et al. 2013, Mendes 1986, TROPILAB® INC. n.d.);
however, little research has been done to evaluate its antidiabetic activity.
We were able to fnd a study that was conducted by Gungurthy et al., which showed
promise for the plant to be used in this aspect. Preliminary phytochemical analysis
indicated the presence of glycosides, favonoids (quercetin: Figure 3.25) and alka-
loids, carbohydrates, steroids and terpenoids, proteins, fxed oils and volatile oils, and
phenolics and tannin, all of which have been previously discussed as being responsi-
ble for the potent hypoglycaemic effects in other botanical sources (I. A. Ross 2003).
Results from their oral glucose tolerance test (OGTT), which was done to assess
the effect of varying concentrations of the extract and also to gauge their respec-
tive effcacies and potencies against the control standard: glibenclamide, showed an
appreciable and steady decrease in the BG levels, with the most comparative to the
control drug being the ethanolic extract, at 500 mg/kg.bw (Gungurthy et al. 2013).
In their in vivo studies,. Twenty-four alloxan-induced diabetic rats were equally
divided into four groups (Groups B–E). Treatment of the groups was as follows: nor-
mal saline solution was administered to Groups A (healthy rats) and B (diabetic con-
trol), while LN ethanolic extracts (500 and 250 mg/kg.bw) were orally administered
to Groups D and E, respectively. Finally, Group C animals received the reference
drug glibenclamide (10 mg/kg.bw) and used as the control standard. Blood samples
were then collected from the rat tail vein and BG levels were estimated using a One
Touch® glucometer on Days 1, 7, 14, and 21. At the end, it was observed that the
BG levels of the rats belonging to Groups D and E had dropped from their initial
hyperglycaemic level of ≥250 mg/dL. However, the greatest degree of reduction was
observed for the subjects of Group D (Gungurthy et al. 2013).
While the results of this study seem very promising, further research is necessary
to frstly properly isolate and identify the effcacious compounds, and secondly, to
properly evaluate the relative toxicities of their respective dosages.
3.35 MANGIFERA INDICA LINN. (MI)

Common names: Aam, Manako, Mango (Figure 3.62)
M. indica is one of the oldest cultivated plants in the world, having been grown
in India for over 4000 years, and subsequently introduced to the Caribbean during
the colonization of the Western world. Belonging to the family: Anacardiaceae, the
use of some 30 different species of mangoes goes well beyond its original purpose of
food. Different parts of the fruiting tree have been found to possess medicinal prop-
erties that can be used for antidiabetic, antioxidant, and anti-infammatory applica-
tions (Verma et al. 2018).
Shah et al. investigated the antidiabetic activity of the constituent compounds
found in mango leaves and was able to confrm the hypoglycaemic activity of the
isolated compound: mangiferin (Figure 3.63a) (Shah et al. 2010).
Furthermore, studies have found that α-carotene (Figure 3.63b) and β-carotene
(Figure 3.63c) are converted to vitamin A (Figure 3.27a), which, in turn, stimulates
the insulin secretion of the β-cells in the pancreas (Verma et al. 2018, Perry et al.
2009). These active constituents promote a reduction in the intestinal absorption of
glucose in the small intestine, which leads to hypoglycaemic activity in the blood.
FIGURE 3.62 Illustration of Mangifera indica.

FIGURE 3.63 Structural formulae of isolated compounds from Mangifera indica: (a) man-
giferin, (b) α-carotene, and (c) β-carotene.
Bhowmik et al. compared the antihyperglycaemic effect of ethanolic extracts of

the MI stem, barks, and leaves on T2DM model rats. The group reported that both
extracts exhibited signifcant antihyperglycaemic activity in the subjects, when fed
simultaneously with a glucose load. Noteworthy was the observation that the etha-
nolic extract showed superior effcacy to the aqueous extract (being able to signif-
cantly reduce BG levels, when administered 30 minutes prior to the glucose load)
(Bhowmik et al. 2009).
In another study, Sánchez et al. reported that an administered dose of 1 mg/
kg.bw aqueous extract (60 minutes before glucose loading) was able to attenuate
hyperglycaemic levels in rats (Sánchez et al. 2000). Other studies also revealed
that the ethanolic extract from the MI bark was also found to display appreciable
α-glucosidase inhibitory activity, thus enabling postprandial glucose regulation
(Prashanth et al. 2001).
Additional investigations, conducted by Adedosu et al. (Adedosu et al. 2018) and
Mohammed et al. (Luka and Mohammed 2012) have furnished further supportive
evidence of the antidiabetic activity displayed by MI extracts. Despite all the sup-
portive data however, it should be noted that the respective mechanisms of action of
the plant extract are yet to be confrmed.
3.36 MENTHA
Common names: Mentha aquatica Linn.(MeAq): Water mint (Figure 3.64a);
Mentha arvenisis Linn. (MeAr): Wild mint (Figure 3.64b);
Mentha spicata Linn. (MeS): Pudina, Spearmint (Figure 3.64c);
Mentha peperita Linn. (MeP): Peppermint (Figure 3.64d)
In the Caribbean, the name “mint” covers a wide range of plant species belonging
to the genus Mentha. As such, without knowing the botanical name, it is necessary
to view the source plant to differentiate one from the other. While the various plants
have different appearances, they equally share popularity in culinary preparations
as well as pharmacological applications that include the treatment of depression and
age-related illnesses, colds and respiratory problems, gastrointestinal-associated
ailments, and hepatic-associated diseases. Considering this, we found it necessary
to present the common studies that have tried to confrm their uses as antidiabetic
agents.
M. aquatica is a perennial plant that is easily recognizable by the scent of its
volatile oil, which is highly favoured for its favour, fragrance, and pharmaceutical
FIGURE 3.64 Illustrations of Mentha species: (a) Mentha aquatica, (b) Mentha arvensis,
(c) Mentha spicata, and (d) Mentha piperita.
applications. Regarding the latter application, the plant was reported to exhibit lipid
peroxidative, antimicrobial, antioxidant, and anti-infammatory activities. Konda
et al. proposed to evaluate the antidiabetic and nephron-protective activities of
MeAq in STZ-induced diabetic rats. The results showed that the oral administration
of its aqueous leaf extract (at a dose of 100 mg/kg.bw/day for 90 days) signifcantly
decreased the level of FBG, HbA1c, TC, TG, plasma urea, creatinine, urine albu-
min, and LPO. Furthermore, the rats were observed to have increased body weight,
insulin, high-density lipoprotein (HDL) cholesterol, plasma albumin, urinary urea,
urinary creatinine, and antioxidant enzyme activities. In conclusion, the antidiabetic
and nephron-protective potential activities of the extract were attributed to the pres-
ence of the plant’s phytoconstituents and their synergistic effects (Konda et al. 2020).
Next, we look at the antidiabetic activity of M. arvensis. Agawane et al. used the
methanolic extract of the MeAr leaves to evaluate its antioxidant and antiglycation
potential, through both in vitro and in vivo studies. Here, 50 mg/kg.bw (methanolic
whole plant extract) showed remarkable inhibitory effects on the key enzymes:α-
amylase and α-glucosidase(which are linked to T2DM), and infuenced a signifcant
reduction in postprandial hyperglycaemia in starch-induced diabetic Wistar rats.
From the study, it was suggested that the tested extract had the potential to emerge as
a means of treating postprandial hyperglycaemia (Agawane et al. 2017).
M. spicata is a rhizomatous, perennial plant with a height range of 30–100 cm. It
has square-shaped, hairy stems and foliage and a wide-spreading feshy underground
rhizome. The leaves are 5–9 cm long and 1.5–3 cm broad, with a serrated margin.
Like its related members within the genus, MS owes its broad pharmacological uses
to the favonoids (Figure 3.4), terpenoids, and phenols that have been isolated from
its different extracts.
In a study by Bayani et al., the hypoglycaemic activity of MeS was gauged against
that of the sulfonylurea, glibenclamide (2 mg/kg.bw). Initially, diabetes was induced
in male rats by a single intraperitoneal injection of alloxan monohydrate (150 mg/kg
.bw). Therapy then followed, with the oral administration of the aqueous extract (at a
dose of 300 mg/kg.bw) over a period of 21 days. The results revealed that the extract
displayed similar effcacies to those of the commercially marketed drug and was able
to produce a signifcant reduction in FBG, TC, TG, LDL, and serum malondialde-
hyde (Bayani, Ahmadi-hamedani and Javan 2017).
M. piperita (peppermint) is known to be a hybrid species, arising from a cross
between water mint and spearmint. Its antidiabetic activity was studied by two inde-
pendent research groups, led by Angel and Barbalho, respectively. In the frst study,
the oral administration of peppermint juice (over a 21-day period at an extracted con-
centration of 100 g/L) produced a signifcant decrease in the BG level of 30 alloxan-
induced diabetic rats (Angel, Sai Sailesh and Mukkadan 2013). Such results were
mirrored by the Barbalho-led team, who although using similar extract concentra-
tions as the Angel group, performed their study on an F1 population of male inbred
Wistar rats. The results showed that the offspring of the treated diabetic females
exhibited signifcantly reduced levels of glucose, cholesterol, LDL, and triglycerides,
and also displayed a signifcant increase in their HDL levels. In their conclusion,
it was the group’s opinion that the use of MeP juice was a culturally appropriate
strategy to aid in the prevention of DM, dyslipidaemia, and its associated complica-
tions (Barbalho et al. 2011).
3.37 MIMOSA PUDICA LINN. (MP)

Common names: Chhui-mui, Humble plant, Lajja, Laajvanti, Teemarie, Ti-Marie,
Touch-me-not plant, Sensitive plant, Shameful plant (Figure 3.65)
M. pudica is recognized as a creeping annual or perennial plant, belonging to the
Fabaceae family. Descended from parts of Central and South America and southern
India, this prickly plant has quite a uniqueness: specifcally its bending movement,
giving it its curiosity status (Ahmad et al. 2012). It responds to environmental stim-
uli, hence one of its names “Touch-me-not.” Two well-known movements exhibited
by MP are a very rapid movement of the leaves when it is stimulated by touch, heat,
etc., and a very slow movement of the leaves controlled by a biological clock (Ueda
and Yamamura 1999). MP is known to possess anti-asthmatic, antidepressant, tonic,
and sedative properties due to the presence of alkaloids, favonoids, and tannins
(Ahmad et al. 2012). In India, the use of MP as a natural treatment for T2DM has
also been noted.
Tunna et al. conducted a study on the antidiabetic potential and inhibitory activi-
ties of its methanolic extract. The mentioned crude extract underwent sequential
fractionation with hexane, ethyl acetate, acetone, and methanol successively, thus
furnishing the purer, more soluble components. Using in-depth chemical profling
(gas chromatography and quadrupole time of fight mass spectrometry to assess
the phenolic compounds), it was determined that both the methanol and acetone
fractions had the highest inhibitory activities against α-amylase and α-glucosidase
enzymes (Tunna et al. 2015).
Sutar et al. also compared the antidiabetic activity of the leaf extract of MP in
alloxan-induced albino diabetic rats against that of the commercial drug, metfor-
min. The rodents were divided into four different groups: Group 1: control group;
FIGURE 3.65 Illustration of Mimosa pudica.

Group 2: diabetic rats (treated with metformin [500 mg/kg.bw/day]); Group 3:

diabetic rats (treated with a suspension of petroleum ether extract [600 mg/kg.bw
/day]); and Group 4: diabetic rats (treated with a suspension of ethanolic extract
[600 mg/kg.bw/day]). The subjects were then administered the extracts and refer-
ence drug daily, for a total of 7 days. On the frst day, the ethanolic extract showed
a signifcant decrease in serum glucose level to 32.46% as compared to metformin,
which was 43.57% at the ffth hour. This trend continued to Day 7, when the etha-
nolic extract further reduced serum glucose to 50.35% as compared to metformin
(62.44%). Unfortunately, the petroleum ether extract did not show any signifcant
reduction in the serum glucose level. From the results, the group was able to con-
frm that the active constituents responsible for the plant’s antidiabetic properties
were selectively present in the ethanolic extract and could be isolated in such a man-
ner (Sutar, Sutar and Behera 2009).
Sundaresan and Radhiga also studied the effect of MP leaf extract on high fructose
diet–induced T2DM rats. The rats were divided into four groups: Group 1: normal
untreated rats; Group 2: normal rats (administered MP at a dose of 100 mg/kg.bw
orally twice a day, over a period of 2 weeks); Group 3: fructose-induced diabetic rats;
and Group 4: fructose-induced diabetic rats (administered MP at a dose of 100 mg/kg.
bw orally twice a day, over a period of 2 weeks). It was reported that MP extracts were
able to attenuate both PG levels and the observed case of hyperinsulinemia, while
glycogen levels (liver and skeletal muscle) were signifcantly increased in the Group 4
rats. Additionally, it was reported that the extract was able to signifcantly reduce the
body weight of the treated rats of Group 4 (Sundaresan and Radhiga 2015).
In another report, Rajendiran et al. aimed at evaluating the antidiabetic effect
of the MP leaf extract in STZ-induced diabetic rats over a 30-day period. Like the
Sutar-led group, the effcacy of the extract on the diabetic rats was gauged against
that of the commercial drug, metformin. It was found that oral treatment of the rats,
with 300 mg/kg.bw of ethanolic extract, resulted in signifcant decreases in their
BG and HbA1c levels, when compared to metformin. Similar to the fndings of
Sudaresan et al., the study group also reported a decrease in the body weight of their
MP-treated subjects (Rajendiran et al. 2017).
Apart from the leaves, seeds have also been reported to possess antidiabetic
properties. Kumar, Sunday, and Obuotor investigated the potential antidiabetic and
antioxidant effects of MP seeds in STZ-induced diabetic Wistar rats. They used
the ethanolic extract from the seeds and further fractionated it using three solvents:
butanol, ethyl acetate, and hexane. The group reported that both the ethanolic extract
and the associated extract fractions caused a signifcant reduction in the FBG levels,
with the ethyl acetate fraction having the maximum effect. Furthermore, they found
that all extracts were able to signifcantly increase serum insulin (Kumar, Sunday
and Obuotor 2019).
3.38 MOMORDICA CHARANTIA LINN. (MC)

Common names: Bitter Melon, Bitter Gourd, Bitter Squash, Balsam-pear, Karela,
Carailla, Carille Cerasee, Coraillie (Figure 3.66).
FIGURE 3.66 Illustration of Momordica charantia.
M. charantia is a slender-stemmed tendril climber of the Cucurbitaceae family.

Its older stems are often fattened and futed to 6 m or longer, and its fruits are 8–15
cm long with a distinctly bumpy exterior (I. A. Ross 2003). Originally found only
in the tropics of the Old World, the plant now grows in the tropical regions of the
Americas and the Caribbean (Dey, Attele and Yuan 2002, I. A. Ross 2003). MC
is not only considered a food source but is also used traditionally as a medicine
in developing countries due to its therapeutic properties, including anticancer, anti-
infammation, antivirus, cholesterol-lowering, and antidiabetic action. The antidia-
betic effects of the MC fruit, as well as the hypoglycaemic effects of the entire plant,
have been widely investigated in both experimental and clinical studies.
The main constituents of MC that have been proposed to be responsible for its
BG-lowering capabilities are triterpenes, proteins steroids, alkaloids, lipids, and
inorganic and phenolic compounds. However, the most effcacious compounds from
its extracts were found to be charantin (Figure 3.67a), vicine (Figure 3.67b) (Joseph
and Jini 2013), polypeptide-p (Dey, Attele and Yuan 2002, Joseph and Jini 2013),
and the non-protein, lectin. It was further noted that MC contains other biologically
active compounds such as momordicin I (Figure 3.67c), momordicin II (Figure 3.67d),
cucurbitacin B (Figure 3.67e) (Kim et al. 2018, Joseph and Jini 2013), glycosides
(momordin, charantin, charantosides, and goyaglycosides), terpenoid compounds
(momordicinin, momordicilin, and momordol), and the cytotoxic protein (momor-
charin) which also contribute to its antidiabetic activity (Khan et al. 2014).
Sarkar et al. investigated the hypoglycaemic effect of alcoholic fruit extracts (500
mg/kg.bw) from the MC fruit in both healthy and STZ-induced diabetic rats. It was
found that the extract depressed the PG levels in non-diabetic subjects by 10%–16%
FIGURE 3.67 Structural formulae of isolated compounds from Momordica charantia: (a)
charantin (β-sitosteryl glucoside), (b) vicine, (c) momordicin I, (d) momordicin II, and (e)
cucurbatacin B.
at 1 hour and a further 6% at 2 hours. In comparison, their control standard: tolbu-

tamide (100 mg/kg.bw), caused a 40%–44% reduction in PG at both time intervals
and under similar conditions. When compared to the STZ-induced diabetic rats, MC
reduced PG levels by 26% at 3.5 hours in comparison to the 40%–50% reduction of
PG levels by metformin under similar conditions (Sarkar, Pranava and Marita 1996).
In another study, Virdi et al. compared the results of three types of extracts from
MC using methanol, chloroform, and water. The most successful of the three was
reported to be the dehydrated aqueous extract from fresh unripe whole fruits, at a
dose of 20 mg/kg.bw. This dose was able to reduce the FBG by 48%, which was
comparable to that of glibenclamide. A point to note is that at higher doses, the MC
was deemed to be not only ineffective but also toxic! (Virdi et al. 2003)
Yet, despite the reported shortcomings, researchers such as Srivastava et al. still
believe in the therapeutic use of the MC extracts due to their modest ameliorative
effects. In support of this, their studies reported the effectiveness of the aqueous
extract of the MC fruit versus the powdered version of the dried fruit (Srivastava,
Venkatakrishna-Bhatt et al. 1993). This underscored a very valid point across the
board, that the effcacy of a dose is greatly dependent on the form in which it is iso-
lated and administered (Dey, Attele and Yuan 2002, Mozersky 1999).
3.39 MORINDA CITRIFOLIA LINN. (MoC)

Common names: Ach, Achi, Awltree, Bo-aal, Cheese Fruit, Hog apple, Indian mul-
berry, Noni, Nono, Nonu (Figure 3.68)
M. citrifolia, commonly known as hog apple in Trinidad, is a tropical evergreen
shrub or a small tree with a conical crown belonging to the Rubiaceae family. Its
height varies between 3 and 6 m with a straight trunk, and its leaves are relatively
broad and glossy. Commonly found in Hawaii and known as Noni, it can now be
easily identifed in both tropical and subregions. The juices from the MoC fruit and
leaf extracts have been faunted as having healing properties and have been used as a
therapy for gout, cancer, ageing, arthritis, blood pressure, and diabetes. Although the
identity of the compounds responsible for the antidiabetic activity remains unknown,
suffcient reports have confrmed that the fermented juice of the MoC fruit, when
administered as a dietary supplement, can infuence a decrease in the BG levels of
diabetic animal models (Lee et al. 2012, Nayak et al. 2011, Horsfall et al. 2008).
Stemming from this, Nayak et al. experimented with the fermented fruit juice
on STZ-induced diabetic male rats. The group reported that a dose of 2 mL/kg.
bw (twice daily) was able to restore normoglycaemic levels in the test subjects and
showed similar effcacy to the reference standard: glibenclamide. Furthermore, it
was reported that there was an increase in animal body mass by the end of the
20-day study period (Nayak et al. 2011).
In another study, Horsfall et al. investigated the synergistic effects of Noni juice
with insulin (humilin 70/30), using alloxan-induced diabetic rats. Interestingly, the
results of their experiments showed that at the end of the 4-week study period, the
mean FBG level of the rats that received the combination therapy of juice and insu-
lin was lower than that of either therapies, when administered by itself (Horsfall
et al. 2008).
FIGURE 3.68 Illustration of Morinda citrifolia.

3.40 MORINGA OLEIFERA LINN. (MO)

Common names: Drumstick tree, Horseradish tree, Moringa, Mother’s best friend,
Saijan, West Indian ben (Figure 3.69)
M. oleifera is a fast-growing, drought-resistant tree of the family: Moringaceae
that was originally native to the Himalayas, but is currently cultivated in many tropi-
cal and subtropical regions around the world. Having such a rich history of its use in
Ayurvedic medicine, all parts of the plant (the leaves, fruits, fowers, bark, and roots)
are now being thoroughly explored using modern techniques to confrm their thera-
peutic applications to various diseases (Ahmad, Khan and Blundell 2019, Vargas-
Sánchez, Garay-Jaramillo and González-Reyes 2019, Tang et al. 2017, Jaiswal et al.
2009, Latif et al. 2014).
Regarding its applications to DM therapy, several mechanisms have been pro-
posed that address the possible and plausible interactions of the bioactive isolates.
These are represented by the relationship chart in Figure 3.70 (Ahmad, Khan and
Blundell 2019). However, as new isolates are reported, we can expect that further
mechanism bubbles will be added in the future.
The leaves of MO were found to be rich in proteins, vitamins, minerals,
β-carotene, and other biologically active compounds that include dietary fbre, fa-
vonoids, phenolic acids, alkaloids, carotenoids, isothiocyanates, glucosinolates,
tannins, saponins, oxalates, and phytates. From the list of bioactive compounds
isolated, 4-hydroxyphenylacetonitrite (Figure 3.71a), fuoropyrazine (Figure 3.71b),
methyl-4-hydroxybenzoate (Figure 3.71c), and vanillin (Figure 3.71d) have been
isolated from its leaves and have been shown to infuence both a signifcant glu-
cose-dependent insulin release (at a stimulatory glucose concentration of 16.7 mM),
FIGURE 3.69 Illustration of Moringa oleifera.

FIGURE 3.70 Summary of the possible mechanisms of hypoglycaemic action of MO leaf

extracts.
and a dose-dependent release of insulin (at a dose of 200 μM) (Ahmad, Khan and
Blundell 2019).
Further to the aforementioned isolates, other researchers have reported the dis-
covery of several polyphenols in MO extracts. Among the most important are the
favonoids: kaempferol (Figure 3.25f) and quercetin (Figure 3.25g), and the phe-
nolic acids: chlorogenic acid (Figure 3.25c) and caffeoylquinic acid (Figure 3.71e),
which exhibit antihyperglycaemic properties by acting as competitive inhibitors of
the sodium-glucose linked transporter type 1 (SGLT1) in the mucosa of the small
intestine. Interestingly, their mechanisms of action seems to mimic those of both the
allopathic SLGTi and the AG inhibitors (see Chapter 1.5 and 1.7) (Vargas-Sánchez,
Garay-Jaramillo and González-Reyes 2019).
The potency of yet another plant isolate was demonstrated by the Waterman
group, who showed that the oral administration of a 5% moringa concentrate (con-
taining an estimated 66 mg/kg.bw of the biologically active moringa isothiocyanate
[MIC]: moringin Figure 3.71f]) to obese-C57BL/6L mice led to a signifcant reduc-
tion in the accumulated fat mass and an improvement in glucose tolerance and insu-
lin signalling (Waterman et al. 2015).
Although the following fnal report may be argued to not belong here because
of the nature of the administration, we believed that it was still worthy of mention,
due to the link between the active compound and its botanical source. Paula et al.
FIGURE 3.71 Structural formulae of isolated compounds from Moringa oleifera: (a)
4-hydroxyphenylacetonitrite, (b) fuoropyrazine, (c) methyl-4-hydroxybenzoate, (d) vanillin,
(e) caffeoylquinic acid, and (f) moringin (4-(α-L-rhamnosyloxy)benzyl isothiocyanate).
confrmed the antidiabetic activity of the leaf isolate (M. oleifera leaf protein isolate
[MO-LPI]) by giving a single intraperitoneal dose of the compound (at 300 or 500
mg/kg.bw) to diabetic mice. The group reported that a more pronounced effect was
observed when the higher dose of 500 mg/kg.bw was used, resulting in drops in
the BG levels by 34.3%, 60.9%, and 66.4% after 1, 3, and 5 hours, respectively. The
sustained BG-lowering potential of MO-LPI was also evidenced when the intra-
peritoneal administration of the higher dose for 1 week resulted in a reduction in
the mice’s BG levels by 56.2%. As in the case with many other plant extracts, with
such promising results, one may expect that concerns would be raised regarding the
associated compound toxicity. However, it was indeed eye-catching to learn that
there were no reported adverse effects, even at an extreme dose of 2500 mg/kg.bw
(Paula et al. 2017).
3.41 MURRAYA KOENIGII LINN. (MK)

Common names: Caripeelay, Carypoulay, Curry leaf, Curry patta, Kaddi patta
(Figure 3.72)
M. koenigii is a small, tropical to subtropical tree or shrub with an average height
of 4–6 m and a trunk up to 40 cm in diameter. The aromatic leaves are pinnate, with
11–21 leafets, each leafet 2–4 cm long and 1–2 cm broad. The plant produces small
white fowers that can self-pollinate to produce small shiny-black drupes containing
FIGURE 3.72 Illustration of Murraya koenigii.
a single, large viable seed, and berry pulp, which is edible, with a sweet favour
(Wikipedia 2021). This tree is native to moist forests in India and Sri Lanka, but was
introduced to the West Indies during the colonization period.
The MK plant is highly reputed for its stimulant, stomachic, antidysenteric (Wang
et al. 2003), and antidiabetic properties (Husna et al. 2018, Kesari et al. 2007, Vinuthan
et al. 2004), which are owed to the wide variety of biological substances, such alka-
loids, favonoids, terpenoids, tannins, glycosides, and phenolics that are contained
within. Preliminary phytochemical screening by Husna et al. showed the presence
of the bioactive compounds: 1,8-cineol (Figure 3.73a), β-caryophyllen (Figure 3.73b),
hexadecen-1-ol (Figure 3.73c), α-matrine (Figure 3.73d), benzo[a]naphtacene
(Figure 3.73e), γ-sitosterol (Figure 3.73f), and vitamin E (Figure 3.73g) (Husna et al.
2018). Furthermore, 1-formyl-3-methoxy-6-methylcarbazole (Figure 3.73h) and
6,7-dimethoxy-1-hydroxy-3methylcarbazole (Figure 3.73i) were later isolated by the
Chowdhury group (Wang et al. 2003).
Yadav et al. investigated the effcacy of feeding MK leaves as a dietary con-
stituent to control hyperglycaemia in alloxan-induced rats. It was found that the
supplement did not show any profound hypoglycaemic effects in the 7-day study.
However, the potential therapeutic effects were not dismissed due to the probability
that the period of time for the effect to be noticeable may have been longer than the
study period. That aside, the group also noticed an unusual outcome from the MK
FIGURE 3.73 Structural formulae of Murraya koenigii: (a) 1,8-cineol, (b) β-caryophyllen,
(c) hexadecen-1-ol, (d) α-matrine, (e) benzo[a]naphtacene, (f) γ-sitosterol, (g) vitamin E, (h)
1-formyl-3-methoxy-6-methylcarbazole, (i) 6,7-dimethoxy-1-hydroxy-3-methylcarbazole, (j)
mahanine, (k) mahanimbine, (l) cadinene, and (m) dipentene.
supplementation, which they coined an “anti-alloxan” effect. Alloxan and STZ are
chemicals known to produce hyperglycaemia through selective cytotoxic effects on
the pancreatic β-cells; one of the intracellular phenomena for their cytotoxicity was
discovered to be the generation of free radicals that target the pancreas. It was sug-
gested in the past, that MK possibly prevented the destruction of β-cells through
possible antioxidant or free radical scavenger properties, which was previously

reported by other researchers (Tachibana et al. 2001, Khan, Abraham and Leelamma
1997). As such, it was concluded that while the use of MK therapy may not be effec-
tive for chronic T2DM or T1DM therapy, it can play a role in the management of a
prediabetic state or mild diabetes (S. Yadav et al. 2002).
The antioxidant activity of the bioactive compounds contained in MK was further
explored by Arulselvan et al. From their investigations, the group reported that there
was recovery of the altered levels of glucose, glycosylated haemoglobin, insulin, and
other metabolic-related biomolecules. There was further supportive evidence of the
protective nature of the MK extract in the pancreas, when there was an observed
increase in the amount of secretory vesicles in the pancreatic β-cells, and also with
the restoration of the normal architecture of the nuclei (Arulselvan and Subramanian
2007). Similarly, the therapeutic stimulation of damaged β-cells was again observed
by Vinuthan et al., where the insulin levels of extract-treated, alloxan-induced dia-
betic rats were monitored over an 8-week study period. It was suggested that the
increased insulin secretion in the diabetic groups could have been effected through
the presence of carbohydrates, alanine, leucine, niacin, iron, and calcium in the
aqueous extract and various constituents in the methanolic extract, such as mahanine
(Figure 3.73j), mahanimbine (Figure 3.73k), cadinene (Figure 3.73l), and dipentene
(Figure 3.73m) (Vinuthan et al. 2004).
Another report by Kesari et al. examined the effect of the oral administration of
MK aqueous leaf extract (at a dose of 300 mg/kg.bw) to normal and STZ-induced
diabetic rats, over a 1-month period. In the case of the treated diabetic animals,
FBG levels were reduced by almost half, along with signifcant decreases in TC
and TG levels in both normal and treated rats (Kesari et al. 2007). Appreciatively,
results from this investigation were later corroborated with those published by the
Husna group. In their 4-week study, 200 and 400 mg/kg.bw doses of MK ethanolic
leaf extract were administered to STZ-induced diabetic rats, alongside the control
standard, glibenclamide (1 mg/kg.bw). The results showed that both doses were able
to infuence signifcant reductions in the BG levels, through the actions of-, or a
combination of the plethora of bioactive compounds contained within it (Husna et al.
2018). Furthermore, acute toxicity studies showed that all doses did not produce
any drug-induced physical signs of toxicity and no death was observed up to 14
days, indicating that MK was non-toxic in rats up to an oral dose of 5000 mg/kg.bw
(Khan, Abraham and Leelamma 1997).
3.42 NEUROLAENA LOBATA LINN. (NL)

Common names: Herbe á pic, Jackass Bitters, Zeb-a-pique (Figure 3.74)
N. lobata is a herb or bush (Andrade-Cetto, Cruz et al. 2019) of the Asteraceae or
Compositae family that inhabits warm and semi-warm climates. It stands erect with
stems up to 3 m high (Cruz and Andrade-Cetto 2015, Gupta et al. 1984, Morales et al.
2001), and with long, slender leaves when young, but typically having three points
when mature. The leaves of the NL plant are considered to exhibit hypoglycaemic
properties (Gupta et al. 1984, Morales et al. 2001) and to date, although several
FIGURE 3.74 Illustration of Neurolaena lobata.
FIGURE 3.75 Structural formulae of Neurolaena lobata: (a) lobatin-B and (b) neurolenin-B.
isolates have been proposed to be responsible for this desirable action, there seems to
be some agreement that the compounds, lobatin-B (Figure 3.75a) and neurolenin-B
(Figure 3.75b), are the most effcacious.
While there have been no reported cases of clinical studies performed using the
NL plant, a study by Andrews et al. looked at its history of use, along with other herbal
remedies in the rural areas of Guatemala. It was heartening to learn of the objec-
tive of the authors, such that although traditional healers were not the main source
of diabetic treatment, they recognized that many patients still relied on medicinal
plants to control their blood sugar, due to a lack of access to allopathic medicines.
As such, documenting the medicinal plants used to treat diabetes was essential to
improving diabetic care in the area. Since a large proportion of people with diabetes
in these communities use medicinal plants, it was important for healthcare providers,
including health promoters and traditional healers, to understand their proper use
and potential interactions (Andrews, Wyne and Svenson 2018).
In this frst instance, a study was carried out to compare the hypoglycaemic effect
of four plants (Hamelia patens Linn. [HP], N. lobata, Solanum americanum Linn.
[SA], and the cortex of Croton guatemalensis Linn. [CG]), all of which were native
to Guatemala. The study group’s frst experiment aimed at gauging the plants’ rela-
tive antidiabetic activities under normal conditions (without a sugar load) and then
under a maltose- and sucrose-loaded condition. In agreement with the traditional
usage of the plants, in normal conditions, the extracts produced a statistically sig-
nifcant hypoglycaemic effect, similar to the control drug, glibenclamide. However,
when the sugar was sucrose, both CG and HP produced a statistically signifcant
effect at 30 minutes, compared to the control group, while SA did so at 60 minutes,
and NL was slowest in activity (at 90 minutes) (Andrade-Cetto, Cruz et al. 2019).
In their next study, the inhibitory potential of α-glucosidase enzymes, which were
taken from either yeast or rat intestines, was investigated. These assays showed that
the extracts were able to inhibit the enzyme retrieved from the yeast but not from the
animal. A plausible explanation for this interesting activity was that the yeast and
mammalian enzymes belonged to two different families that differed in their amino
acid sequences. As such, the abilities of the compounds to act on different substrates
would obviously have varied. In conclusion, the group stated that none of the tested
plants displayed antihyperglycaemic activity and the observed hypoglycaemic effect
was possibly produced by the stimulation of insulin release. Their theory was based
on the short time to produce the hypoglycaemic effect in their frst experiment and
the fact that the effect was similar to their control standard, glibenclamide. The
group did acknowledge that their explanation was not concrete and further confrma-
tory studies on their mechanism of action were defnitely recommended (Andrade-
Cetto, Cruz et al. 2019).
However, in the next study, Gupta et al. proudly supported the popular folk use of
the NL plant, by his experiments with its leaf extract. His group evaluated the plant’s
hypoglycaemic activity, by administering ethanolic leaf extracts to a population of
12 alloxan-induced diabetic mice. The results of this study showed that the extracts
(at doses of 250 and 500 mg/kg.bw) were able to lower elevated BG levels in the
tested nomoglycaemic and hyperglycaemic mice, respectively, within a space of 4
hours (Gupta et al. 1984)
Apart from its direct antidiabetic potential, the plant has also been proposed to
have ameliorative effects in diabetes-related illnesses. Regarding this, Morales et al.
aimed at evaluating the infuence of several popular native plants of Guatemala on
the occurrence of toxic events in the central nervous system of Swiss albino mice.
Aqueous and organic extracts from the areal parts of Tridax procumbens Linn. (TP),
N. lobata (NL), Byrsonima crassifolia Linn. (BC), and Gliricidia sepium Linn.
(GS), and of the root and leaves of Petieria alliacea Linn. (PA) were used. Their
report confrmed that the aqueous leaf-extract of NL was able to modestly decrease
the spontaneous motor activity and muscle tone and also mice-exhibited diuresis.
However, the authors concluded that in relation to the other plants screened, the NL
plant showed relatively little or no effect on behavioural, neurological, and auto-

nomic signs (Morales et al. 2001).
3.43 OCIMUM GRATISSIMUM LINN. (OG) AND

OCIMUM TENUIFLORUM LINN. (OT)
Common names: Ocimum gratissimum: Clove basil, African basil, Wild basil
(Figure 3.76a);
Ocimum tenuiforum: East Indian basil, Holy basil, Krishna Toolsie, Tulasi, Tulsi
(Figure 3.76b)
Among all the medicinal plants, those under the genus of Ocimum (belonging
to family Lamiaceae) have strong therapeutic potentials. These herbs are com-
monly found in the tropical regions of Asia, Africa, and all of the Americas. Several
Ocimum species exhibit strong antihyperglycaemic effects (Antora and Salleh 2017);
FIGURE 3.76 Illustrations of Ocimum species: (a) Ocimum gratissimum and (b) Ocimum
tenuiforum.
however, two species (O. gratissimum and O. tenuiforum) are of particular interest
due to their relative ubiquity in the North American and Caribbean (NAC) region.
The extracted essential oil from the OG plant has shown high concentrations
of eugenol (1-hydroxy-2-methoxy-4-allybenzene) (Figure 3.77a) and chicoric acid
(Figure 3.77b), which have been attributed to its prowess in the attenuation of hyper-
glycaemia (Antora and Salleh 2017).
FIGURE 3.77 Structural formulae of isolated compounds from Ocimum gratissimum

and Ocimum tenuiforum: (a) eugenol, (b) chicoric acid, (c) ursolic acid, (d) carvacrol, (e)
estragole, (f) rosmarinic acid, and (g) cirsimaritin.
Reports have shown that the aqueous leaf extract of the OG plant can drasti-
cally reduce postprandial hyperglycaemia in T2DM model rats, but without the risk
of hypoglycaemia (Oguanobi, Chijioke and Ghasi 2012). Supporting studies by the
Ekaiko group, have also revealed that the elevated BG levels in diabetic rats were
reduced, using doses of 200 and 400 mg/kg.bw of aqueous leaf extracts (Ekaiko
et al. 2016).
Another investigating team showed that intraperitoneal treatment with the metha-
nolic extract of the OG leaves (400 mg/kg.bw) reduced the BG levels in both nor-
mal and diabetic rats (Aguiyi et al. 2000). Furthermore, the team led by Okoduwa
demonstrated that the daily administration of n-hexane, chloroform, ethyl acetate,
n-butanol, and the aqueous fractions of the OG leaf resulted in lowered BG levels
in a T2DM animal model (Okoduwa et al. 2017). It was also confrmed that at equal
doses, the aqueous extracts of OG leaves, led to greater drops in BG levels than the
ethanolic extracts (Antora and Salleh 2017).
We have also stumbled upon the suggestion that the OG leaf extracts can stimu-
late surviving β-cells to release more insulin in T2DM subjects (Oguanobi, Chijioke
and Ghasi 2012, Okoduwa et al. 2017) and that the hypoglycaemic effcacy of OG
was higher than that of insulin! (Okon and Umoren 2017).
Regarding OT (formerly known as Ocimum sanctum Linn.), this species is par-
ticularly sacred in India, and its fresh leaves are commonly used in the treatment of
coughs, colds, abdominal pain, skin diseases, arthritis, painful eye diseases, mea-
sles, and diarrhoea. Furthermore, the preclinical evaluation of various extracts of
different parts of OT showed antifertility, anticancer, antifungal, cardioprotective,
hepatoprotective, and antidiabetic actions.
In this frst instance, Parasuraman et al. reported that the hydro-alcoholic extract
of OT exhibited signifcant antidiabetic activity at doses of 250 and 500 mg/kg.bw,
in STZ- and NIC--induced diabetic rats, and was comparable to that of gliben-
clamide. Some phytoconstituents identifed as infuential to its effcacy were euge-
nol (Figure 3.77a), ursolic acid (Figure 3.77c), carvacrol (Figure 3.77d), linalool
(Figure 3.45b), estragole (Figure 3.77e), rosmarinic acid (Figure 3.77f), apigenin
(Figure 3.14b), and cirsimaritin (Figure 3.77g) (Parasuraman et al. 2015).
Another study that focused on the phytochemical qualitative assay of aqueous
crude extract and aqueous fractions reported that the active methanolic crude extract
and its active fractions (ethyl acetate and butanol) showed the presence of poly-
phenolic active constituents (3,4-dimethoxycinnamic acid, caffeic acid, diosmetin,
luteolin, kaempferol, and genistein), which are all well known to exhibit antidiabetic
activity (Mousavi, Salleh and Murugaiyah 2018).
It was unusual to also fnd a study that was aimed at evaluating the effect of the
OT aqueous leaf extract in hyperglycaemic tilapia (Oreochromis niloticus Linn.).
Interestingly, the group also confrmed the extract’s antihyperglycaemic activity in
this form of animal! (Arenal et al. 2012).
Regarding toxicity, one study showed that a dose of 300 mg/kg.bw of OG leaf
extract (both aqueous and ethanolic) appeared to have no adverse effects on the
organs of the test subjects (Oguanobi, Chijioke and Ghasl et al. 2019). It was also
indicated that a dose of 350 mg/kg.bw of combined aqueous leaf- extracts of OG and
G. latifolium Linn. showed no toxicity (Eyo and Chukwu 2016) with the lethal dose
estimated as ≥5000 mg/kg.bw (Eyo and Chukwu 2016, Lawal et al. 2019). Adding
to this, another acute toxicity study reported that a single oral administration of
combined extracts of OG and V. amygdalina Linn. (at doses from 10 to 5000 mg/kg.
bw) did not produce any apparent toxic symptoms or mortality after a 24-hour period
(Okoduwa et al. 2017, Abdulazeez et al. 2013). Despite these promising revelations,
caution has still be placed on its use, as studies have suggested that the constituent
compounds in OG may worsen diabetes-induced renal injury (Onaolapo, Onaolapo
and Adewole 2012).
With respect to OT, a study carried out by Mousavi et al. concluded that based
on the histological analysis of tissues, there were no adverse changes in the liver,
kidneys, and pancreas of the test subjects in comparison to the control group
(Mousavi, Salleh and Murugaiyah 2018). Similarly, the previously discussed study
by Parasuraman et al., using the hydro-alcoholic extract of OT, did not show any
harmful effects and also showed no mortality up to 2000 mg/kg.bw, when given as a
single oral administration (Parasuraman et al. 2015).
3.44 PANAX GINSENG LINN. (PG) AND PANAX

QUINQUEFOLIUS LINN. (PQ)
Common names: Panax ginseng: Asian Ginseng, Chinese Ginseng, Guigai, Jiln
Ginseng, Korean Ginseng, Ninjin, Oriental Ginseng, Panax schinseng, Red Ginseng
(Figure 3.78); Panax quinquefolius: American ginseng, Canadian ginseng, Ginseng
Of the different types of ginseng, P. ginseng and P. quinquefolius are the
most commonly used for medicinal purposes. The perennial herb PG is consid-
ered native to countries in the Oriental region, such as Korea, Siberia, and China,
and has also been found growing wild and cultivated in North America. It has
feshy, pale-yellow, multi-branched roots with an average stem height of 0.6–0.8 m
(Schulz et al. 2004).
Most of the active ingredients found in the ginseng species are ginsenosides, poly-
saccharides, peptides, polyacetylenic alcohols, phenolic compounds, and fatty acids
(Dey, Attele and Yuan 2002, Kim et al. 2016). However, the ginsenosides (bearing
protopanaxadiol or protopanaxatriol groups) (Figure 3.79) have been found to be
the most pharmacologically active components (Dey, Attele and Yuan 2002, Lim
et al. 2009) and this has warranted their therapeutic use in the treatment of T2DM
(Rahimi 2015).
Extracts of both ginseng species show antihyperglycaemic activity (Lim et al.
2009) and are more specifcally associated with increased PPAR-γ expression and
AMP-activated protein kinase phosphorylation in the liver and muscle (Lim et al.
2009, Rahimi 2015). Additional biochemical interactions, as stated by Rosalie and
Ekpe, include a decreased carbohydrate absorption rate into the hepatic portal cir-
culatory system, increased glucose transport and uptake (mediated by nitric oxide),
increased glycogen storage, and the modulation of insulin secretion (Dey, Attele
and Yuan 2002, Vuksan et al. 2000, Rosalie and Ekpe 2016, Verma et al. 2018).
Furthermore, Lim et al. suggested that ginsam (a vinegar extract from PG) has
FIGURE 3.78 Illustrations of Panax species: (a) Panax ginseng and (b) Panax quinquefolius.
FIGURE 3.79 Structural formulae of common Panax ginseng and Panax quinquefolius
ginsenosides.
distinct benefcial effects on glucose metabolism (Lim et al. 2009). As such, it was
deemed possible to be an adjuvant therapy for treating diabetic patients with insulin
resistance (Rahimi 2015).
Sotaniemi et al. demonstrated a reduction in both FBG and A1C (HbA1c) levels in
persons with T2DM when treated with a 100 and 200 mg dose of the extracts, respec-
tively (Dey, Attele and Yuan 2002, Vuksan et al. 2000, Sotaniemi, Haapakoski and
Rautio 1995). However, Schulz et al. suggested that a more reliable therapeutic effect
could be achieved with a dosage of 1–2 g (crude) or 200–600 mg of extract (Dey,
Attele and Yuan 2002, Schulz et al. 2004).
It should be noted as a precautionary measure, that consistent use of ginseng
can consequently affect the central nervous system (Dey, Attele and Yuan 2002,
Bailey and Day 1989), therefore it is important that the dosage should be moni-
tored and reduced if necessary. As such, some researchers strongly recommend
that there should be a 3-month limit on the period of treatment (Dey, Attele and
Yuan 2002).
3.45 PARTHENIUM HYSTEROPHORUS LINN. (PaH)

Common names: Santa-Maria, Santa Maria feverfew, Whitetop weed, Famine weed,
Whitehead broom (Figure 3.80)
Belonging to the Asteraceae family, P. hysterophorus is a short fowering plant
that is mainly located in Asia, Africa, the Americas, and the Caribbean. It is easily
identifed as ground weeds found along roadsides and in backyards. In traditional
medicine, reports have revealed that PaH is used in a wide range of therapies due to
its antiviral, antifungal, antibacterial, anti-helminthic, anti-infammatory, and anti-
diabetic properties (Joshi et al. 2016, Mew et al. 1982).
FIGURE 3.80 Illustration of Parthenium hysterophorus.

Patel et al. investigated the hypoglycaemic effects of PaH in alloxan-induced

diabetic rats with BG levels in the range of 280–310 mg/dL. The rats were divided
into three groups and administered the following solutions via oral gavage: control
(only solvent); positive control (0.5 mg/kg.bw glibenclamide + solvent); and test
(100 mg/kg.bw PaH aqueous fower extract + solvent). In relation to the positive
control, the results showed a signifcant reduction in the BG levels after 2 hours
(<240 mg/dL) and also a signifcant decrease in the FBG levels in the treated rats
(Patel et al. 2008).
Arya et al. also investigated the hypoglycaemic effects of PaH in diabetic rats,
using fresh-leaf extract (Arya et al. 2012). However, when compared to the previ-
ously discussed study group, we found that the attenuation of the BG levels was
slightly less appreciable (Arya et al. 2012, Sahrawat et al. 2018). As promising as the
results from both studies were, concurrently run toxicity evaluations have revealed
a precautionary toxic nature of PaH (Arya et al. 2012). Supporting this, additional
studies have shown that regular exposure to the chemicals contained within the
extracts may lead to dermatitis and respiratory problems (Khaket et al. 2015, Towers
and Subba Rao 1992, McFadyen 1992).
3.46 PEPEROMIA PELLUCIDA LINN. (PP)

Common names: Pepper elder, Silverbush, Rat-ear, Shining bush plant, Man to Man
(Figure 3.81)
P. pellucida is a member of the Piperaceae family and is an annual common
weed that is delicate, feshy, and glabrous. It usually grows to a length of 15–45 cm
with translucent, erect, pale-green stems with internodes usually 3–8 cm long. PP is
native to tropical North and South America (Amarathunga and Kankanamge 2017,
Raghavendra and Prashith Kekuda 2018), but is now widely distributed throughout
the tropics (Amarathunga and Kankanamge 2017, N et al. 2018). Several studies
(using alloxan-induced diabetic rodent models) have been published that confrm the
FIGURE 3.81 Illustration of Peperomia pellucida.

FIGURE 3.82 Structural formulae of isolated compounds from Peperomia pellucida: (a)
yohimbine and (b) 8,9-dimethoxyellagic acid.
plant’s hypoglycaemic activity (Hamzah et al. 2012, N et al. 2018, Kanedi, Sutyarso
et al. 2019, Kanedi, Sutyarso et al. 2019).
An interesting report by Hamzah et al. demonstrated that feeding diabetic rats
with diets, enriched with 10% w/w and 20% w/w dried-leaf powder, resulted in a
reduction in the BG levels as well as the TC, TG, and LDL levels, compared to their
untreated diabetic counterparts. Furthermore, treatment with glibenclamide and PP
(10% w/w and 20% w/w) led to the increased activities of SOD, catalase activities
(CAT), and glutathione (GSH), respectively (Hamzah et al. 2012).
A paper by Sheikh et al. suggested that the plant’s ability to stimulate or regener-
ate the pancreatic β-cells was attributed to its high content of the biologically active
alkaloids, saponins, and favonoids (Figure 3.4) (Sheikh et al. 2013). Apart from this,
while screening the activity of the PP extracts against the receptor protein aldose
reductase, Akila et al. was able to confrm the outstanding potency of one of the
plant’s most active constituents, yohimbine (Figure 3.82a), against the standard com-
pound, quercetin (Figure 3.25g) (Akhila, Aleykutty and Manju 2012).
Adding to this, Susilawati et al. further isolated the compound 8,9-dimethoxy-
ellagic acid (Figure 3.82b) from PP and determined that a dose of 100 mg/kg.bw
was able to yield signifcant antidiabetic effects in alloxan-induced diabetic mice
(Susilawati et al. 2017).
In this fnal report, Oyolede et al. performed acute brine shrimp toxicity stud-
ies (using various extracts of the PP leaves). The group recounted that the fractions
with low-polarity solvents (hexane and ethyl acetate) were found to be toxic, while
the most polar fractions, which contained butanol and water, were deemed safe. In
the three assays used for antioxidant screening, the extracts were most effective in
the hydrogen peroxide assay: giving a percentage inhibition of over 98% scavenging
activity. This high effcacy (at low concentration) supports its use in the treatment
of a wide range of ailments that are associated with oxidative stress. However, the
authors highly recommended that the use of such toxic chemical compounds (at high
doses) should be properly monitored (Oloyede, Onocha and Olaniran 2011).
3.47 PHYLLANTHUS AMARUS LINN. (PA)

Common names: Gale of the wind, Stonebreaker, Seed-under-leaf (Figure 3.83)
Ph. amarus is a small, erect, annual herb of the family Euphorbiaceae that grows
to 30–60 cm, in height. It is believed to be native to the Caribbean, but is now located
FIGURE 3.83 Illustration of Phyllanthus amarus.
in both tropical and subtropical parts of the world (Meena, Sharma and Rolania
2018). Clinical studies have shown that extracts of PA exhibited signifcant hypo-
glycaemic effects in animals, due to its rich content of alkaloids, tannins, saponins,
anthraquinones, cardiac glycosides, and favonoids (A. A. Adeneye 2012, Adeneye,
Amole and Adeneye 2006, Joseph and Raj 2011, Moshi et al. 2001, Meena, Sharma
and Rolania 2018, Adedapo, Ofuegbe and Oguntibeju 2014).
Raphael et al. reported that the methanolic extract of PA was found to have poten-
tial anti-oxidant activity, as it could inhibit lipid peroxidation and scavenge hydroxyl
and superoxide radicals in vitro. Furthermore, 4 hours after administration, the
extract (at doses of 200 and 1000 mg/kg.bw) was found to reduce the BG levels in
alloxan-induced diabetic rats by 6% and 18.7%, respectively. It was further reported
that the rats treated with the 1000 mg/kg.bw dose, displayed normoglycaemic BG
levels on Day-18, after alloxan administration (Raphael, Sabu and Kuttan 2002).
Similar doses were used by Lawson-Evi et al. when the group investigated the
antidiabetic effect of aqueous and hydro-alcoholic extracts of PA on similarly diabet-
ized rats. However, in this study the group reported a restoration of euglycaemic lev-
els after 15 days of administration (Lawson-Evi et al. 2011). Interestingly, we found
lower but equally therapeutic doses being used by another group. In that study, the
oral administration of the ethanolic leaf extract (400 mg/kg.bw) for 45 days to dia-
betic mice, resulted in a signifcant decline in the BG levels (from 310.2 to 141.0 mg/
dL) and a signifcant recovery in body weight. There was also an observed alteration
in the activity levels of the liver enzymes, whereby there was a signifcant decrease
in glucose-6-phosphatase and fructose-1-6-disphosphatase action, and a simultane-
ous increase in the activity of glucokinase (Shetti, Sanakal and Kaliwal 2012).
In a clinical study, Moshi et al. reported that there was no effect on non-insulin-
dependent diabetes mellitus (NIDDM) patients who underwent PA extract therapy.
In their experiment, 21 NIDDM patients (who were currently undergoing allopathic
treatment) were asked to switch to PA herbal therapy for 1 week, following a 1 week
“wash-out” period (a period where no form of T2DM therapy would be taken). It was
noted that after 1 week of herbal treatment, no hypoglycaemic activity was observed.
As such, the researchers concluded that a 1-week treatment with the aqueous PA
extract was incapable of lowering both the FBG and PBG levels in untreated NIDDM
patients (Moshi et al. 2001). However, the results can be considered debatable, due to
the relatively short study time in relation to other previously discussed study periods.
Regarding its safety in use, a dose-response study was performed by Adedapo
et al., using random groups of male Wistar rats. Graded doses of the plant’s extract
(100, 200, 400, 800, and 1600 mg/kg.bw) were orally administered to the subjects
in each of the groups, after which they were allowed free access to food and water
and monitored for any signs of toxic-related events over a 48-hour period. At the
end, all the rats appeared to be normal and none of them showed any visible signs
of illness. Appreciatively, it was noted than even at the extreme dose of 1600 mg/kg
.bw, the extract from the plant still appeared to be safe for medicinal use (Adedapo,
Ofuegbe and Oguntibeju 2014).
3.48 SCOPARIA DULCIS LINN. (SD)

Common names: Licorice weed, Goatweed, Scoparia-weed, Sweet-broom
(Figure 3.84)
S. dulcis is an erect, annual herb that can reach a height of 0.5 m at maturity. It
belongs to the family Scrophulariaceae, and is widely distributed in tropical and sub-
tropical regions. The plant is known to be a rich source of favones, terpenes, and ste-
roids and its leaves (in both fresh and wet forms) are traditionally used as remedies
for DM in India (Mishra, Behera et al. 2011). However, we have noted cases in which
the entire plant (inclusive of the roots) has been used (Pamunuwa, Karunaratne and
Waisundara 2016).
FIGURE 3.84 Illustration of Scoparia dulcis.

Studies on the phytochemical and pharmacological profle of the SD plant have

presented ammeline (Figure 3.85a) and scoparic acid D (Figure 3.85b), which along
with other diterpenes, triterpenes, and favonoids (Figure 3.4) also contribute to the
plant’s ability to control elevated BG levels (Sarkar et al. 2020, Mishra, Mishra et al.
2013, Paul, Vasudevan and Krishnaja 2017). Furthermore, in their review, Mishra
et al. identifed the bioactive compounds cirsimarin/cirsitakaoside (Figure 3.85c),
cynaroside (Figure 3.85d), and stigmasterol (Figure 3.85e) as contributors to the
plant’s antidiabetic activity (Mishra, Behera et al. 2011). They further suggested
that the compounds glutinol (Figure 3.85f) and coixol (Figure 3.85g), obtained from
the aqueous decoctions, were found to be potent and active in insulin secretagogue
activity (Pamunuwa, Karunaratne and Waisundara 2016, Sarkar et al. 2020).
The hypoglycaemic activity of the methanolic extract of the SD plant was inves-
tigated by Mishra et al., using both in vitro and in vivo models. Their in vitro experi-
ments, which were aimed at studying the inhibitory effects of the methanolic extract
on the two intestinal enzymes: α-amylase and α-glycosidase, confrmed its effective-
ness in controlling PBG levels, while the results from their in vivo studies, using
STZ-induced diabetic rats, revealed a signifcant arrest and decrease in the BG levels
(at an extract dosage of 400 mg/kg.bw). This activity was found to be comparable to
that of the control standard, glibenclamide (Mishra, Mishra et al. 2013).
FIGURE 3.85 Structural formulae of isolated compounds from Scoparia dulcis: (a) amme-
line, (b) scoparic acid D, (c) cirsimarin/cirsitakaoside, (d) cynaroside, (e) stigmasterol, (f)
glutinol, and (g) coixol.
Pari and Latha investigated the effect of SD whole-plant extracts (aqueous, etha-
nolic, and chloroform) on key hepatic metabolic enzymes that have been identifed
in carbohydrate metabolism. The group reported that the aqueous extract showed
superior antihyperglycaemic activity, in comparison to its organic extract competi-
tors in the treated STZ-induced diabetic rodent subjects (Murti et al. 2012, Pari and
Latha 2004). In a following study, Pari et al. demonstrated the ability of the SD plant
extract to attenuate hyperglycaemia and also maintain optimal GSH levels in STZ-
induced diabetic rats, by reducing the infux of glucose through the polyol pathway
(Murti et al. 2012, Latha and Pari 2004). Adding to this, Latha et al. further pre-
sented the insulin secretagogue potential of the SD plant, when a 10 g/mL dose was
able to stimulate a 6.0 fold secretion of insulin from isolated mouse pancreatic tissue.
Additionally, it was reported that the extract protected against STZ-mediated cyto-
toxicity (88%) and nitric oxide production, in the rat insulinoma cell lines (RINm5F)
(Latha, Pari and Sitasawad et al. 2004).
Like all other potential botanical sources of therapy, concerns have been voiced
regarding the plant’s toxicity and safety in use. Two independent reviews have
shown that SD extract therapy can be considered relatively safe (Sarkar et al. 2020,
Paul, Vasudevan and Krishnaja 2017) as its aqueous extract did not produce any
mortality up to the excessive oral dose level of 8 g/kg.bw in mice. Furthermore, the
group reported that continued daily administration of the extract for a total of 30
days resulted in no occurrences of gross toxicological symptoms or deaths (Paul,
Vasudevan and Krishnaja 2017).
3.49 SENNA ITALICA LINN. (SI)

Common names: Senne, Senna (Figure 3.86)
S. italica, with the synonyms Cassia italica Linn. and Acacia obovata Linn.,
belongs to the family Caeslpinaceae. It is a perennial shrub, whose leaves and fruit/
pulp are used as stimulants and substitutes for tea and coffee. Senna species have
been of extreme interest in phytochemical and pharmacological research due to their
excellent medicinal values. They are well known in folk medicine for their laxa-
tive and purgative effects, and have also been found to exhibit anti-infammatory,
antioxidant, hypoglycaemic, antiplasmodial, larvicidal, antimutagenic, and antican-
cer activities. The wide range of SI applications can be attributed to the various
families of biomolecules that have been isolated from the plant, including alkaloids,
carotenoids, favonoids (Figure 3.4), glycosides, phenols, saponins, and tannins
(Malematja et al. 2018, Nadro and Onoagbe 2014).
More specifcally, Nadro et al. was able to confrm the presence of sodium, zinc,
iron, potassium, manganese, calcium, and magnesium. The presence of magnesium
in SI is indeed interesting because, while it may be associated with its applications
as a laxative, it also gives consideration to its confrmed importance in the mitigation
of insulin resistance (Nadro and Onoagbe 2014).
A study by Malematja et al. evaluated the in vitro effects of SI’s acetone leaf
extracts on GLUT-4 translocation, expression, and adipogenesis in 3T3-L1 pre-adi-
pocyte cells. The results showed a high anti-glycation effect attained at 10 mg/mL,
FIGURE 3.86 Illustration of Senna italic.
while at 25–200 g/mL, there was no discerning increase in adipogenesis and lipoly-
sis. Interestingly, the extract (at 100 g/mL) was linked to the decrease in the expres-
sion levels of various adipokines, but had minimal effect on glucose uptake at 50–100
g/mL, when used in combination with insulin. However, the combinatory and syn-
ergistic effect (using the aforementioned extract dose range along with insulin) was
noted to infuence both GLUT-4 translocation and its increase in expression. Of equal
importance, toxicity studies revealed that the extract had no adverse effect on the cells’
viability, which emphasized the plant’s safety in use. In the end, the group was able to
confrm the safe and potential use of SI as a viable agent for both the anti-glycation and
the down-regulation of obesity-associated adipokines (Malematja et al. 2018).
3.50 STACHYTARPHETA JAMAICENSIS LINN. (SJ)

Common names: Blue porterweed, Blue snake weed, Bastard vervain, Brazilian tea,
Jamaica vervain, Light-blue snakeweed (Figure 3.87)
S. jamaicensis is a member of the Verbenaceae family. It is a weedy, herbaceous
plant, and has an average height of 60–120 cm. The plant is found mainly in the
tropical regions of the Americas, as well as in the subtropical forests of Africa, Asia,
Oceania, and the Caribbean (Liew and Yong 2016, Ezenwa, Igbe and Idu 2015,
Estella, Obodoike and Esua 2020).
Estella et al. evaluated the antidiabetic activity in different organic fractions of
the SJ leaves, using protocoled in vitro and in vivo experiments. They reported that
the extract showed signifcant dose-dependent hypoglycaemic activity in both of
their acute and chronic in vivo studies, yielding respective reductions in the BG lev-
els by (25.40% and 55.80%) against glibenclamide (12.60% and 51.40%) in normal
rats, and the BG levels by (22.00% and 86.90%) against glibenclamide (19.37% and
85.50%) in diabetic rats (Estella, Obodoike and Esua 2020).
FIGURE 3.87 Illustration of Stachytarpheta jamaicensis.
Another study by Ezenwa et al. showed that although the total reduction in BG
levels using glibenclamide (at 10 mg/kg.bw) was higher than that of the plant extract
at different time points of the experiment, the overall hypoglycaemic effect of the
extract (at 400 mg/kg.bw) was comparable to that of the control standard (Ezenwa,
Igbe and Idu 2015).
Similar therapeutic doses were described by Egharevba et al., who reported that
daily oral administration of the methanolic and ethyl acetate leaf extracts (at 200 and
400 mg/kg.bw) signifcantly decreased the BG levels of STZ-induced diabetic rats,
as compared to the untreated diabetic animals (Egharevba et al. 2019). Supportively,
Rozianoor et al. demonstrated the ameliorative effect of the ethanolic leaf extract by
showing its ability to attenuate the spiked BG levels in a population of male diabetic
rats. The group proposed that the observed therapeutic effect was possibly due to the
presence of the contained bioactive compounds: genipin (Figure 3.88a) and linolenic
acid (Figure 3.88b) (Ma et al. 2013, Rozianoor, Eizzatie and Nurdiana 2014).
FIGURE 3.88 Structural formulae of isolated compounds from Stachytarpheta jamaicen-

sis: (a) genipin and (b) linolenic acid.
Finally, results from various independent toxicity studies showed that even at high
doses, the SJ leaf extracts infuenced little or no observed abnormalities in the sub-
jects’ health and, as such, it was deemed safe for therapeutic use (Liew and Yong
2016, Ezenwa, Igbe and Idu 2015). It was noteworthy that in the acute toxicity and
lethality tests that were performed by the Estella group, the LD50 was established
to be >5000 mg/kg.bw, thereby underscoring the relative non-toxic nature of the SJ
plant (Estella, Obodoike and Esua 2020).
3.51 SYZYGIUM CUMINI LINN. (SC)

Common names: Black plum, Goolab Jamun, Jambolan, Jamun, Java plum, Malabar
plum (Figure 3.89)
S. cumini is a rapidly growing species that can reach heights of up to 30 m and can
live more than 100 years. Its dense foliage provides shade and was initially grown for
its ornamental value. At the base of the tree, the bark is rough and dark grey, becom-
ing lighter grey and smoother higher up. The wood can be used to make furniture
and other construction-related applications due to its water-resistant nature. Its leaves
are pinkish when young and change to a leathery, glossy dark green with a yellow
midrib, as they mature. The trees start fowering from March to April, and their fow-
ers are fragrant and small (about 5 mm in diameter). The oblong fruits that develop
resemble large berries and change from green to crimson red as they mature. Their
taste has a combination of sweet and mildly sour favours and they tend to discolour
the tongue when eaten (Wikipedia 2021).
While in most other cases there is only anecdotal evidence for the antidiabetic
properties of traditionally used medicinal plants, the SC plant has been exten-
sively studied for its astringent, antidiarrhoeal, antidiabetic (Helmstädter 2008),
FIGURE 3.89 Illustration of Syzygium cumini.

antilipidemic (Jagetia 2018, Zulcafi et al. 2020), and antioxidant (Sharma et al.
2012) properties. Different parts of the jambolan tree, especially its fruits, seeds,
and stem-bark exhibit promising activity against DM. These properties have been
confrmed by several supporting experimental and clinical studies that we shall now
further discuss. Tea prepared from SC leaves was reported to have antihyperglycae-
mic effects, while the stem-bark of the plant was found to induce the appearance of
positive insulin-staining cells (in the epithelia of the pancreatic duct of treated ani-
mals) and infuence a signifcant decrease in the BG levels, in treated mice (Ayyanar
and Subash-Babu 2012).
Additionally, a study was carried out by Kumar et al. with the aim to isolate and
characterize the putative antidiabetic compound from the SC seed. The group was
successful in identifying the glucosamine, mycaminose (Figure 3.90a), which was then
studied for its glucose-lowering effcacy in a population of STZ-induced diabetic rats.
Here, the group reported that a dose of 50 mg/kg.bw (seed extract) was able to effect
a signifcant reduction in the BG levels of the treated rats, which interestingly was
similar to that of the control standard, glibenclamide (1.25 mg/kg.bw). Because of
the known mechanism of action of the control standard, it was hypothesized that
mycaminose followed a similar action pathway in stimulating insulin secretion from
pancreatic β-cells (Kumar et al. 2008).
The ambiguity of the mechanism underlying SC’s ameliorative action inspired
Sharma and coworkers to investigate whether its aqueous seed extract (100, 200, or
400 mg/kg.bw) had any benefcial effects on insulin resistance, serum lipid profle,
antioxidant status, and/or pancreatic β-cell damage in high-fat diet/STZ–induced
diabetic rats. Sharma proudly demonstrated (through in vivo and cytology studies)
that SC therapy (at a dose of 400 mg/kg.bw) was able to restore altered pathological
FIGURE 3.90 Structural formulae of isolated compounds from Syzygium cumini: (a) myca-
minose, (b) oleic acid, (c) myricetin, and (d) myricitrin.
changes to pancreatic islets and β-cells and also infuence an increase in PPARγ
and PPARα protein expressions in hepatic tissue. In their discussion of the results,
Sharma cited work by Anandharajan et al., who proposed that SC augments glucose
uptake by upregulating the glucose transporter-4, PPARγ, and phosphatidylinositol
3-kinase in L6 myotubes. The increased levels of PPARγ were shown to infuence
both hypoglycaemic and hypolipidemic activity and also insulin-sensitizing actions
in mild and severe diabetic rats. Another interesting observation by the group was
that SC treatment in diabetic rats caused a signifcant decrease in serum tumour
necrosis factor-alpha (TNF-α), which further supported its therapeutic role in T2DM.
Sharma went on to justify their observations regarding the effects on PPARα activity,
by attributing the attenuation of dyslipidaemia to the receptor’s increased expres-
sion. In conclusion, they noted that single action or combinations of the phytochemi-
cals (contained in SC seed extract), such as triterpenoids, anthocyanins, oleic acid
(Figure 3.90b), essential oils, glycosides, saponins, and several members of the fa-
vonoids (e.g. rutin [Figure 3.12e], quercetin [Figure 3.25g), myricetin (Figure 3.90c),
and myricitrin (Figure 3.90d) were responsible for the plant’s DM therapeutic action
(Sharma et al. 2012).
In his review entitled “Syzygium cumini (L.) Skeels (Myrtaceae) against
Diabetes – 125 Years of Research,” Helmstaedter presented the controversial effects
of SC therapy in clinical studies, as they were reported by independent research
(Helmstädter 2008). Using the report from Sepaha and Bose (1956), he highlighted
their observation that less than 50% of their test patients showed a positive response
to SC therapy (Bose and Sepaha 1956). Unfortunately, these fndings were further
corroborated by studies carried out in India and Brazil and, as such, did not meet
the modern criteria for clinical studies to be performed. However, Shrivastava and
coworkers treated 28 “severely diabetic patients” with 4–24 g SC seed powder (in
gelatine capsules) and reported a signifcant reduction in mean fasting (–18%) and
postprandial (–32%) blood sugar levels. Unfortunately, several adverse drug-related
reactions were reported in less than 20% of the patients, which included nausea,
diarrhoea, and epigastric pain (Srivastava, Venkatarishna-Bhatt et al. 1983).
Similarly, another dissuading study by Teixeira et al. reported randomized
patients (with T2DM) being treated with a tea that was prepared from SC leaves and
its effect being gauged against that of the standard control drug, glyburide. It was
found that FBG levels decreased signifcantly in participants who were treated with
the allopathic drug, but showed no changes in those who were treated with either
the SC tea or combinations with placebos. In the end, the researchers adamantly
concluded that SC therapy was ineffective in treating complications related to T2DM
(Teixeira et al. 2005).
Due to the opposing data being published on SC therapy, it is understand-
ably confusing whether or not this form of therapy is effective. A closer look at
Helmstaedater’s reports revealed that the SC studies were dose responsive and time
related, such that investigations that used the extracts at higher doses and for longer
periods of time appeared to get more desirable responses than the low-dose, short-
term experiments. This idea was well supported by Kohli and Singh, who reported a
study on 30 patients with “uncomplicated” NIDDM. In their investigations, patients
received 12 g SC seed powder in three divided doses for 3 months. An oral glucose
tolerance test was performed every month and subjective parameters were moni-
tored. There was a considerable and progressively increasing relief of symptoms
such as polyuria, polyphagia, weakness, and weight loss. The results of the glucose
tolerance test were signifcantly improved after 3 months of treatment. One- and
two-hour values were reduced by up to 30% after 2 months of treatment compared to
their control (chlorpropamide). Furthermore, they reported that the seed powder did
not show any side effects to patient-health during their study (Kohli and Singh 1993)
3.52 TAMARINDUS INDICA LINN. (TI)

Common names: Tamarind, Tambran (Figure 3.91)
T. indica belongs to the Fabaceae family and is a long-lived fruit tree that bears
fragrant fowers and fruit (Useful Tropical Plants n.d.). The fruit is easily recognized
by its brittle exterior (fruit shell) and chewy, but sour pulp that is commonly used
in the food industry (in the form of condiments, sauces, and as processed confec-
tionaries). The tree and its edibles have been found to contain tannins, saponins,
glycosides, favonoids (Figure 3.4), and polyphenols (Bhadoriya et al. 2018) that are
all well known for their associated medicinal properties, which range from anti-
infammatory, antioxidant, natural laxative, and antihyperglycaemic activity.
Bhadoriya et al. conducted a study on the antidiabetic potential of the TI seed
coat in alloxan-induced diabetic rats. They used a hydro-ethanolic extract from the
seed coat and administered doses of 100 and 250 mg/kg.bw to the diabetic rats daily
for 14 days. After the treatment, their results indicated that both doses signifcantly
FIGURE 3.91 Illustration of Tamarindus indica.

reduced the BG levels in normoglycaemic and alloxan-induced hyperglycaemic rats,

in relation to the control group (Bhadoriya et al. 2018). In glucose-loaded hypergly-
caemic rats, both doses showed similar effcacy by signifcantly attenuating the BG
levels as well. Complementary to these results was the observation that the body
weight of the rodents had decreased during the administration of the extract.
While the results from the Bhadoriya research group seemed promising, results
from two other groups were found to be quite contradicting (perhaps due to the seed
coat being used in the aforementioned study and the seeds by themselves being used
in the proceeding reports). Maiti et al. conducted a study on the antidiabetic effect of
the aqueous extract of the TI seed on STZ-induced diabetic rats, over a period of 7
and 14 days. Unfortunately, the group reported that there were no observed changes
in the FBG levels when daily doses of 80 mg/0.5 mL distilled water/100 g.bw were
administered to the diabetic subjects (Maiti et al. 2004). Similarly in another study,
Parvin et al. administered a seed powder mixture of 1.25 g/kg.bw/10 mL of water
to STZ-induced diabetic rats for 24 hours. They too observed relatively paltry activ-
ity, whereby the serum glucose level was reduced by only 2.43% at 60 minutes and
7.68% at 120 minutes (Parvin et al. 2013).
It can be gathered that the potency of the seed extract when used as a form of diabe-
tes therapy is inconclusive. However, further studies are encouraged to either support
or refute the idea of its use as an alternative means of BG regulation. Additionally,
due to the lack of available information, studies that explore the antidiabetic activity
of the extracts from its leaves and bark should also be encouraged.
3.53 TOURNEFORTIA HIRSUTISSIMA LINN. (TH)

Common names: Chiggery grapes, Jigger Bush (Figure 3.92)
T. hirsutissima, of the Boraginaceae family, is a woody vine, with cylindrical
pubescent stems, and bisexual fowers that are white or yellow to greenish and may
produce fve lobulated fruit. Its applications in ethnomedicine include the treatment
of rheumatic, urinary, and also hyperglycaemic-related complications (Andrade-
Cetto, Revilla-Monsalve and Wiedenfeld 2007).
FIGURE 3.92 Illustration of Tournefortia hirsutissima.

A study by Andrade-Cetto et al. compared the antidiabetic activities of the buta-

nolic extracts (BE) and dehydrated aqueous extracts (WE) of TH, against those of
glibenclamide. Using a population of 77 adult Wistar rats, the animals were equally
divided into seven groups. Group 1 (non-diabetic control), received 1.5 mL of physi-
ological NaCl solution, while Group 2 (diabetic control) also received the same vol-
ume of the physiological saline solution. The subjects of Group 3 were orally treated
with glibenclamide (at a dose of 3 mg/kg.bw) and used as a standard control. For the
remaining Groups 4–7, the test compounds were administered at increasing doses, in
accordance with their method of extraction: Groups 4 and 5 received WE (20 and 80
mg/kg.bw) and Groups 6 and 7 received BE (8 and 80 mg/kg.bw), respectively. The
results revealed that the effect of the administered extract was dose dependent, with
the greatest effcacy observed using a dose of 80 mg/kg.bw. Appreciatively, it was
found that at 80 mg/kg.bw, the extract activity was similar to the control-standard
group (Andrade-Cetto, Revilla-Monsalve and Wiedenfeld 2007, Andrade-Cetto,
Cabello-Hernández and Cárdenas-Vázquez 2015).
3.54 URENA LOBATA LINN. (UL)

Common names: Caesarweed, Congo jute, Cooze mahot, Kuze maho, Pink
Chineseburr (Figure 3.93)
U. lobata is a member of the family: Malvaceae, and is traditionally used to treat
several ailments including diabetes. It is a sub-shrub that has an average height of
0.6–3 m and a basal diameter of 0.7 m (Omonkhua and Onoagbe 2007), and is usu-
ally grown as annuals in tropical and temperate regions of Asia, Africa, and the
Americas (Babu, Madhuri and Ali 2016).
Research showed that methanolic, ethanolic, and hot aqueous leaf extracts of UL
exhibited DPP-4 inhibitory activity, thus supporting their effective use as diabetic
therapeutic agents. Owing to these ameliorative effects, are the isolated compounds:
β-sitosterol (Figure 3.10a), mangiferin (Figure 3.63a), and stigmasterol (Figure 3.85e)
FIGURE 3.93 Illustration of Urena lobata.

(Islam and Uddin 2017, Y. Purnomo, D. W. Soeatmadji et al. 2015, Y. Purnomo, D.

W. Soeatmadji et al. 2015). It was further noted, by the Purnomo-led group, that the
ethanolic extract showed stronger DPP-4 inhibitory effects than the aqueous extracts
in vitro, ) however, the opposite was observed when the studies were performed in
vivo. The difference in activity was attributed to the greater solubility of the active
compounds in the more polar medium, which also infuenced better absorption
within the gastrointestinal system (Y. Purnomo, D. W. Soeatmadji et al. 2015, Y.
Purnomo, D. W. Soeatmadji et al. 2018).
In the same study by Purnomo et al., the oral administration of UL at doses of
250, 500, and 1000 mg/kg.bw to diabetic rats prevented degradation of GLP-1 by
inhibiting DPP-4 activity (Y. Purnomo, D. W. Soeatmadji et al. 2015). Later, the
group reported an increase in GLP-1 bioavailability through UL administration, and
suggested that the therapy could lead to an improvement in the structure and func-
tion of the islet β-cells (Y. Purnomo et al. 2017). Other groups have successfully
demonstrated the comparable therapeutic effects of the UL root extracts versus leaf
extracts in diabetic animal models, and have shown that the extracts from the roots
also exhibited potent antidiabetic/hypoglycaemic effects in their test subjects (Babu,
Madhuri and Ali 2016, Islam and Uddin 2017, Omonkhua and Onoagbe 2017, Y.
Purnomo, D. W. Soeatmadji et al. 2015, Y. Purnomo, D. W. Soeatmadji et al. 2018,
Wahyuningsih and Purnomo 2018).
Finally, Omonkhua and Onoagbe investigated the occurrence of any possible toxic
events that could be associated with UL therapy in healthy rabbits. They found that
although there was an initial ill response on the rabbits’ hepatocytes as well as pre-
liminary bile obstruction, the effects were not sustained (Omonkhua and Onoagbe
2011). Furthermore, the UL extracts did not appear to exert any form of oxidative
damage to normal (healthy) rabbits, with respect to the liver and pancreatic MDA
levels; as a matter of fact, they even seemed to be protective against lipid peroxida-
tion (Omonkhua and Onoagbe 2007, Omonkhua and Onoagbe 2012).
3.55 ZINGIBER OFFICINALE LINN. (ZO)

Common names: Halia, Common Ginger, Canton Ginger, Stem Ginger, Ginger
(Figure 3.94)
Z. offcinale belongs to the Zingiberaceae family, along with its relative C. longa
(turmeric). It is popularly known as ginger in the Caribbean and is a perennial plant
that grows below or on the surface of the soil. In the Caribbean, ZO is consumed as
a drink (tea or soft drink), and used as a seasoning for meats and foods or as a spice
for desserts. More importantly, ZO is popularly known to have strong medicinal
properties, used to reduce arthritis, migraines, abdominal pain, and nausea (I. A.
Ross 2005). Furthermore, in vitro studies on the isolated active compounds gingerol
(Figure 3.95a) and shogaol (Figure 3.95b) have confrmed their antidiabetic activity,
thus making the rhizome a good option for the maintenance of normoglycaemic
levels (Rani et al. 2011).
In our searches, we have found several animal and human studies that aimed to
confrm the hypoglycaemic activity of the plant. In a clinical study, Mahabir and
FIGURE 3.94 Illustration of Zingiber offcinale.
FIGURE 3.95 Structural formulae of isolated compounds from Zingiber offcinale: (a) gin-
gerol and (b) shogaol.
Gulliford, for example, used a group of 264 diabetic individuals to evaluate the
diabetic activity of ginger and other herbal medicines. They concluded that ginger,
among other herbs used, was able to restore euglycaemic levels in individuals who
had diabetes, and were consuming the hot water extract (ginger tea) as a form of
therapy (Mahabir and Gulliford 1997).
Alternatively, in 2006, Al-Amin et al. studied the hypoglycaemic potentials of
ZO in STZ-induced diabetic rats. A 500 mg/kg.bw dose of an aqueous extract of
raw ginger was administered to these rats daily for 7 weeks. After the 7-week treat-
ment period, the results showed that the therapeutic dose produced a signifcant
reduction in both the BG levels, as well as the urine protein levels in the diabetic
rats (Al-Amin et al. 2006).
In this fnal report, we saw the ethanolic extract of the rhizome being admin-
istered to diabetic rabbits, at a dose of 100 mg/kg.bw over 3 weeks. The research
group reported that the therapy resulted in a signifcant reduction in the BG levels,
when compared to the untreated animals, and thus confrmed the potential use of the
ZO extract as a viable and relatively safe means to attenuate hyperglycaemia in DM
subjects (Mascolo et al. 1989).
140
TABLE 3.1
Summary of the Medicinal Plants with Their Respective Dosages and Mechanisms of Action
Extract Type and Mechanism of Antidiabetic Observed Degree of
Common Name Scientifc Name Therapeutic Dose Action (in Animal Models) Antidiabetic Activity
Aam, Manako, Mango Mangifera indica Leaf and stem bark extract: 1) Reduction in glucose absorption, in the Good effcacy when
(250 mg/kg.bw) GI tract. compared to glibenclamide.
2) Stimulation of β-cell release of insulin.
Aanabahe-hindi, Buah Carica papaya Leaf extract: (400 and 1) Enhanced secretion of insulin from the Dose dependent with very
papaya, Papaw, Papaya, 200–600 mg/kg.bw) pancreatic β-cells. good correlation with
Pawpaw 2) Alpha-amylase inhibitory activity. gibenclamide, at the highest
dosages.
Ach, Achi, Awltree, Bo-aal, Morinda citrifolia Fruit juice (2 mL/kg.bw) Promotes insulin sensitivity in adipose Good effcacy when
Cheese Fruit, Hog apple, tissue and muscles. compared to glibenclamide.
Indian mulberry, Noni,
Nono, Nonu
Achiote, Annatto, Ookoo Bixa orellana Seed extract: Inconclusive mechanism. Moderate.
plant, Roucou (80 and 540 mg/kg.bw)
Ajmod, Celeriac, Celery, Apium graveolens Seed extract: (425 mg/kg.bw) Direct stimulation of glycolysis in Satisfactory reduction in BG
Leaf celery, Root celery, Leaf extract: (150 mg/kg.bw) peripheral tissues, and a reduction in the levels relative to untreated
Wild celery absorption of glucose from the rodent groups.
gastrointestinal tract.
Alaf-e-Mar, Alcaparro, Capparis spinosa Fruit extract: (20 mg/kg.bw) 1) Reduction of carbohydrate absorption Good correlation with
Caper bush, Cappero, in the small intestine; inhibition of sodium vanadate.
Kebbar, Wild Watermelon gluconeogenesis in the liver.
2) Enhancement of the uptake of glucose
by tissues and β-cell conservation.
(Continued)
Aloe, Aloe vera, Alovis, Aloe barbadensis Leaf pulp extract: Control of carbohydrate metabolizing Good effcacy when
Sabila (500 mg/kg) enzyme activity. compared to glibenclamide.
Ayurvedic Medicines
Leaf gel extract: (10 mL/kg)

Asian Ginseng, Chinese Panax ginseng Root extract: (100–600 mg) 1) Increased PPAR-γ expression and Satisfactory reduction in BG
Ginseng, Guigai, Jiln Panax quinquefolius AMP-activated protein kinase levels, relative to untreated
Ginseng, Korean Ginseng, phosphorylation in liver and muscle. patients.
Ninjin, Oriental Ginseng, 2) Decrease in carbohydrate absorption
Panax schinseng, Red rate into the portal hepatic circulatory
Ginseng, American system.
ginseng, Canadian 3) Increased glucose transport and uptake.
ginseng, Ginseng 4) Increased glycogen storage.
5) Modulation of insulin secretion.
Asthma plant, Asthma Euphorbia hirta Leaf and stem extract: 1) Stimulation of insulin effects from Good effcacy when
weed, Soro, Garden (200–400 mg/kg.bw) remnant β-cells. compared to glibenclamide.
spurge, Snakeweed 2) Inhibition of α-amylase activity.
Billygoat-weed, Tropical Ageratum Shoot extract: 1) Inhibition of the GLUT-2 transporter (in Good effcacy when
Whiteweed, Zeb-a-fam conyzoides (100–400 mg/kg.bw) the intestinal mucosa), and the compared to glibenclamide.
Leaf extract: α-glucosidase enzyme (in the small
(100–500 mg/kg.bw) intestine).
Fractionated leaf extract: 2) Proposed reduction in glucose
(88 mg/kg.bw) absorption and prevention of
carbohydrate breakdown.
(Continued)
141
142

Bindi, Lady Fingers, Ochro, Abelmoschus Powdered peel: Exhibits α-glucosidase-inhibiting activity. Good effcacy when
Okra, Okro esculentus (100 mg/kg.bw) compared to metformin.
Powdered seed:
(200 mg/kg.bw)
Fruit extract:
(100–400 mg/kg.bw)
Bitter Melon, Bitter Gourd, Momordica Wet fruit extract: 1) Stimulation of insulin release. Good effcacy when
Bitter Squash, Balsam- charantia (500 mg/kg.bw) 2) Stimulation of peripheral and skeletal compared to metformin,
pear, Karela, Carailla, Dehydrated fruit extract: muscle glucose utilization. and tolbutamide.
Carille Cerasee, Coraillie (20 mg/kg.bw) 3) Inhibition of intestinal glucose uptake. Good effcacy when
4) Inhibition of adipocyte differentiation. compared to glibenclamide.
5) Suppression of key gluconeogenic
enzymes.
6) Stimulation of key enzyme of HMP
pathway.
7) Preservation of islet β-cells and their
functions.
8) Regulation of AMP-activated protein
kinase α and glucagon-like peptide-1
via bitter taste receptor signalling.
(Continued)
Black Jack, Cobbler’s pegs, Bidens pilosa Whole plant extract: 1) Stimulation of insulin secretion from Good effcacy when
Farmers friend, Hairy (50–400 mg/kg.bw) pancreatic β-cells. compared to glibenclamide.
Ayurvedic Medicines
beggarticks, Needle bush, 2) Additional benefts of restoration or

Spanish needle, Sticky protection of the pancreatic cells.
beaks
Black plum, Goolab Jamun, Syzygium cumini Seed extract: 1) Stimulation of insulin secretion from Good effcacy when
Jambolan, Jamun, Java (50–400 mg/kg.bw) pancreatic β-cells. compared to glibenclamide
plum, Malabar plum 2) Infuences an increase in PPARγ and and chlorpropamide.
PPARα protein expressions in hepatic
tissue.
Blue porterweed, Blue Stachytarpheta Leaf extract: Activates IRS-1, PI3-K, and downstream Good effcacy when
snake weed, Bastard jamaicensis (200–400 mg/kg.bw) signalling pathway and increases compared to glibenclamide.
vervain, Brazilian tea, concentrations of calcium, resulting in
Jamaica vervain, GLUT4 translocation and glucose uptake
Light-blue snakeweed increase.
Bright eyes, Cape Catharanthus roseus Leaf extract: Enhancement of insulin secretion from the Dose dependent with 500
periwinkle, Graveyard (100–1000 mg/kg.bw) β-cells of Langerhans. mg/kg.bw being most
plant, Madagascar effcient.
periwinkle, Old maid, Pink
periwinkle, Rose
periwinkle
(Continued)
143
144

Brown mustard, Mustard Brassica juncea Seed extract: 1) Increases the activity of glycogen Dose dependent with very
greens, Chinese mustard, (250–450 mg/kg.bw) synthetase. good results at the higher
Leaf mustard, Rai 2) Stimulation of insulin secretion from dosages.
pancreatic β-cells.
Bulb Onion, Common Allium cepa Bulb extract: (25–200 g) Increasing the concentration of free insulin Good effcacy when
Onion in the body. compared to tolbutamide.
Caesarweed, Congo jute, Urena lobata Leaf extract: Exhibits DPP-4 inhibitory activity. Good effcacy when
Cooze mahot, Kuze maho, (250–1000 mg/kg.bw) compared to the control.
Pink Chineseburr
Calabacero, Calabash, Crescentia cujete Fruit extract: Stimulation of insulin secretion from Good effcacy when
Kalbas, Miracle fruit, Rum (10,000 ppm = 10 mg/L) pancreatic β-cells. compared to glibenclamide.
tree, Totumo
Caripeelay, Carypoulay, Murraya koenigii Leaf extract: Preservation of pancreatic β-cells. Good effcacy when
Curry leaf, Curry patta, (200–400 mg/kg.bw) compared to glibenclamide.
Kaddi patta
Chhui-mui, Humble plant, Mimosa pudica Leaf extract: Exhibits inhibitory action against Good effcacy when
Lajja, Laajvanti, Teemarie, (300–600 mg/kg.bw) α-amylase and α-glucosidase enzymes. compared to metformin.
Ti-Marie, Touch-me-not Seed extract: Good effcacy when
plant, Sensitive plant, (100–400 mg/kg.bw) compared to glibenclamide.
Shameful plant
(Continued)
Chiggery grapes, Jigger Tournefortia Stem extract: Inconclusive mechanism. Dose dependent with very
Bush hirsutissima (8–80 mg/kg.bw) good correlation with
Ayurvedic Medicines
gibenclamide at the highest

dosages.
Cilantro, Coriander, Coriandrum sativum Seed extract: (200 mg/kg.bw) 1) Infuences enhanced glucose transport, Good effcacy when
Coriandre, Dhania Leaf extract: glucose oxidation, and glycogenesis. compared to glibenclamide.
(200–800 mg/kg.bw) 2) Exhibits inhibitory action against
α-glucosidase enzymes.
Citron grass, Citronela, Cymbopogon Leaf extract: 1) Exhibits inhibitory action against
Citronella grass, Fever citratus (125–500 mg/kg.bw) α-glucosidase and α-amylase enzymes.
grass, Lemon grass Essential oil: (800 mg/kg.bw) 2) Observed improvement in insulin
resistance.
Clove basil, African basil, Ocimum Leaf extract: Stimulation of insulin secretion from Good effcacy when
Wild basil gratissimum (200–400 mg/kg.bw) pancreatic β-cells. compared to the group that
East Indian basil, Holy Ocimum tenuiforum Leaf extract: Stimulation of insulin secretion from was treated with insulin.
basil, Krishna Toolsie, (250–500 mg/kg.bw) pancreatic β-cells. Good effcacy when
Tulasi, Tulsi compared to glibenclamide.
Common Lantana, Lantana Lantana camara Fruit extract: Exhibits inhibitory action against Good effcacy when
Red Sage Shrub, Verbena (100–200 mg/kg.bw) α-amylase enzymes. compared to glibenclamide.
Yellow Sage, Caraquite, Leaf extract:
Cariaquito, West Indian (200–500 mg/kg.bw)
lantana
145
(Continued)
146

Cucumber Cucumis sativus Fruit juice: (400 g Inconclusive mechanism. Good effcacy with the juice
supplement) alone.
Fruit extract: (400 mg/kg.bw) Good effcacy when
compared to glibenclamide.
Curcuma, Haldi, Hardi, Curcuma longa Root extract: 1) Infuences an increase in PPARγ Satisfactory reduction in BG
West Indian saffron, (80–300 mg/kg.bw) activity. levels relative to untreated
Saffower, Turmeric, 2) Inhibition of infammatory cytokines, rodent groups.
Yellow Ginger such as MCP and TNF-α along with the
induction of AMPK through the
inhibition of MAPK.
Dogoyaro, Indian lilac, Azadirachta indica Leaf extract: 1) Infuences increase in glucose-6- Satisfactory reduction in BG
Margosa tree, Neem, (250–400 mg/kg.bw) phosphate dehydrogenase activity as levels relative to untreated
Nimtree well as hepatic and skeletal muscle rodent groups.
glycogen content.
2) Proposed to infuence the regeneration
of damaged pancreatic β-cells.
(Continued)
Drumstick tree, Horseradish Moringa oleifera Leaf extract: (66 mg/kg.bw) 1) Decreased gluconeogenesis in the liver. Good effcacy when
tree, Moringa, Mother’s 2) Increased insulin sensitivity and compared to metformin.
Ayurvedic Medicines
best friend, Saijan, West secretion.

Indian ben 3) Increased insulin sensitivity and
secretion.
4) Inhibition of glucose uptake in the liver.
5) Increased glucose uptake in the liver
and muscles.
Fig-leaf gourd, Malabar Cucurbita fcifolia Fruit extract: (300 mg/kg.bw) Proposed to infuence the regeneration of Good effcacy when
gourd, Black seed squash, Cucurbita pepo Seed powder (mixed with fax damaged pancreatic β-cells and increase compared to tolbutamide.
Cidra seed powder): (2–3 g/kg.bw) plasma insulin levels. Good effcacy when
Pumpkin, Field pumpkin, compared to tolbutamide.
Ozark melon, Texas gourd
Gale of the wind, Phyllanthus amarus Leaf and stem extract: Infuence a decrease in glucose-6- Good effcacy when
Stonebreaker, (200–1000 mg/kg.bw) phosphatase and fructose-1-6- compared to the control.
Seed-under-leaf disphosphatase action and a simultaneous
increase in the activity of glucokinase.
Garlic, Lahasun Allium sativum Bulb extract: Improve plasma lipid metabolism and Similar effcacy when
(1–10 mL/kg.bw) plasma antioxidant activity. compared to diazepam and
glibenclamide.
(Continued)
147
148

Good Luck, Resurrection Bryophyllum Leaf extract: Exhibits α-glucosidase inhibiting activity. Good effcacy when
plant, Wonder of the World pinnate (200 and 25–800 mg/kg.bw) compared to glibenclamide
and chlorpropamide
respectively.
Gotu Kola, Asiatic Centella asiatica Whole plant extract: Exhibits α-glucosidase inhibiting activity. Good correlation with
Pennywort, Spade leaf (1200 mg/kg.bw) metformin.
Grapefruit, Paradise Citrus Citrus paradisi Pure juice: (3.0 mL/kg.bw) Infuences the inhibition of protein and Good effcacy in T2DM
lipid catabolism, which is associated with models but not in T1DM.
insulin defciency and increases hepatic
glycogen content.
Halia, Common Ginger, Zingiber offcinale Root extract: Associated with increased production of Good effcacy when
Canton Ginger, Stem (100–500 mg/kg.bw) insulin. compared to tolbutamide.
Ginger, Ginger
Herbe á pic, Jackass Bitters, Neurolaena lobata Whole plant extract: Inconclusive mechanism. Good effcacy when
Zeb-a-pique (5000 mg/kg.bw) compared to the control.
Hibiscus Rose mallow, Shoe Hibiscus Flower extract: Associated with increased production of Good effcacy when
black plant, Shoe fower rosa-sinesis (200–500 mg/kg.bw) insulin. compared to glibenclamide.
plant, Tulipan
Klip dagga, Christmas Leonotis nepetifolia Leaf extract: Associated with increased production of Good effcacy when
candlestick, Lion’s ear, (250–500 mg/kg.bw) insulin. compared to glibenclamide.
Chandilay bush
(Continued)
Lemon Citrus limon Pure juice: (0.2– Amelioration of diabetes-associated Good effcacy when
0.6 mL/kg.bw) conditions in insulin-resistant models. compared to glibenclamide.
Ayurvedic Medicines
Peel extract:
(250–500 mg/kg.bw)
Licorice weed, Goatweed, Scoparia dulcis Leaf and stem extract: 1) Exhibits inhibitory action against Good effcacy when
Scoparia-weed, (200–400 mg/kg.bw) α-glucosidase and α-amylase enzymes. compared to glibenclamide.
Sweet-broom 2) Infuences insulin secretagogue activity.
Lime, Key Lime, Mexican Citrus aurantiifolia Pure juice: (50% dilution, 1) Inhibition in the activities of Excellent correlation with
Lime, Mexican Thornless 5 mL/kg.bw) gluconeogenic enzymes: glucose metformin.
Key Lime Leaf essential oil: 6-phosphatase and
(100 mg/kg.bw) fructose-1,6-bisphosphatase.
2) Increase in the activity of glucokinase.
Orange, Sweet orange Citrus sinensis Peel extract: Amelioration of diabetes-associated Good effcacy when
(12.5–100 mg/kg.bw) conditions in insulin-resistant models. compared to glibenclamide.
Bark extract: (400 mg/kg.bw)
Pepper elder, Silverbush, Peperomia pellucida Dried leaf powder: (10%– Enhanced secretion of insulin from the Good effcacy when
Rat-ear, Shining bush 20% w:w food supplement) pancreatic β-cells. compared to glibenclamide.
plant, Man to Man
Saint John’s bush Justicia secunda Leaf extract: (2.5–3 g/kg.bw) Exhibits inhibitory action against Good effcacy when
α-glucosidase enzymes. compared to glibenclamide.
(Continued)
149
150

Santa-Maria, Santa Maria Parthenium Flower extract: Inconclusive mechanism. Good effcacy when
feverfew, Whitetop weed, hysterophorus (100 mg/kg.bw) compared to glibenclamide.
Famine weed, Whitehead
broom
Senne, Senna Senna italica Leaf extract (only found in in Proposed to infuence both GLUT-4
vitro studies: translocation and its increase in
10–200 g/mL) expression.
Siam weed, Christmas bush, Chromolaena Leaf extract: 1) Reduction of carbohydrate absorption Dose dependent with very
Jack in the Box, Devil odorata (200–400 mg/kg.bw) in the small intestine; inhibition of good correlation with
Weed, Communist Pacha, Root extract: gluconeogenesis in the liver. gibenclamide at the highest
Common Floss Flower, (300–600 mg/kg.bw) 2) Enhancement of the uptake of glucose dosages.
Rompe Saragüey by tissues and β-cell conservation.
Soursop, Prickly Custard Annona muricata Seed extract: 1) Protection and preservation of Satisfactory reduction in BG
Apple, Graviola, (600 and 800 mg/kg.bw) pancreatic β-cell integrity. levels relative to untreated
Guanabana 2) Exhibits inhibitory action against rodent groups.
FOXO1 protein.
Tamarind, Tambran Tamarindus indica Seed coat extract: (100 and Exhibits α-glucosidase inhibiting activity. Good effcacy, when
250 mg/kg.bw) compared to glipizide.
(Continued)
Trumpet tree, Pop-a-gun, Cecropia obtusifolia Leaf extract: (150 mg/kg.bw) Exhibits α-glucosidase and glucose-6- Dose dependent with very
Tree-of-laziness, Cecropia peltata Leaf extract: (200 mg/kg.bw) phosphatase inhibiting activity. good correlation with
Ayurvedic Medicines
Snakewood tree glibenclamide at the highest

Bacano, Bois Cano, dosages.
Trumpet Tree, Snakewood,
Congo pump, Wild
pawpaw, Pop-a-gun
Water mint Mentha aquatica Whole plant extract: Inconclusive mechanism; however, it is Good effcacy when
Wild mint Mentha arvenisis (100 mg/kg.bw) thought to exhibit α-glucosidase compared to glibenclamide.
Pudina, Spearmint Mentha spicata Whole plant extract: inhibiting activity as one of its Good effcacy when
Peppermint Mentha peperita (50 mg/kg.bw) mechanisms of action. compared to acarbose.
Whole plant extract: Good effcacy when
(300 mg/kg.bw) compared to glibenclamide.
Whole plant extract: Good effcacy when
(290 mg/kg.bw) compared to the control.
151
4 Metallopharmaceuticals
The failures to understand and follow the progress of the research behind many coordination
complexes have led to very harsh and unfounded criticisms against chemists, especially by
those in the medical feld. Yet, in what could be considered hypocrisy, the coordination com-
plex, cisplatin, is still recognized as one of the most successful and widely used medicines
of this day.
4.1 INTRODUCTION
Metallopharmaceuticals or “metallo-drugs” fall under the umbrella of “alternative
medicines” and show promise in the prevention, diagnosis, and treatment of an
extensive range of ailments. Metal complexes exhibit pharmacological effects by
reacting with biological molecules in a cell, with proteins and nucleic acids being
the main targets for these agents. The interest in these relatively novel therapeutants
has been justifed by their demonstrated superiority in action over non-chelated
compounds, which promise to serve the same purpose.
DOI: 10.1201/9781003322429-4 153

4.1.2 THE CHALLENGE

Nature has developed effcient defense mechanisms for mitigating the effects of
metallo-drugs, by either sequestering and eliminating the toxic metal ion or repairing
the damage done to critical targets such as DNA. Noting that the human body has
tens of thousands of different proteins, involved in a variety of different catalytic,
transport, and structural roles, if a metallo-drug complex were to attach itself to a part
of an enzyme that is critical for catalytic function, the activity of the enzyme could
be impaired. Further to this, other proteins have metal ions in parts of their structure
that are important for maintaining protein structure and conformation. Again, if one
or more of these metal ions is replaced with a metal ion supplied by a drug molecule
having a coordination geometry that is different from the naturally occurring metal
ion, the protein could lose its function due to this allosteric change (Dabrowiak 2017).
From the standpoint of coordination chemistry, only 7 of the 20 common amino
acids found in proteins have donor atoms in their side chains that present them as
potential targets for metallo-drugs. Unlike purely organic-based drugs, metal com-
plexes that are used for treating and diagnosing diseases are exposed to different
physiological environments in the body that could cause changes in their chemical
composition as they travel from the site of administration to target molecules in a
cell (Dabrowiak 2017).
The road from the laboratory bench to the clinic for all new drugs is marked with
many pitfalls. Only a tiny fraction of new compounds makes it over the regulatory
hurdles and is approved by the respective agencies such as the European Agency for
the Evaluation of Medicinal Products (in Europe), the Food and Drug Administation
(FDA; in the United States), and the Ministry of Health, Labor, and Welfare (in
Japan). The approval process is a justifably thorough one and, as a result, is known
to be quite lengthy. Unfortunately, this has been a major deterrent to many scientists,
due to fear of failure and wasted time.
Understandably, researchers have looked to the library of natural products and
chosen suitable ligands that, by themselves, have exhibited desirable activities
against particular diseases, and strategically mixed them with metals of interest.
Although there is no guarantee that the result will be favourable, there have been
instances where the resulting metal complex displayed higher levels of effcacy
and lower levels of toxicity due to the nature of the ligand (Dabrowiak 2017, Crans
et al. 2019, Adachi, Yoshida et al. 2004). Furthermore, many more metal-centred
compounds have been synthesized by redesigning the existing chemical structure
through ligand modifcation or building an entirely new compound with an enhanced
safety and cytotoxic profle (Thompson and Orvig 2006, Rambaran et al. 2020).
However, because of the increased emphasis on the clinical relevance of metal-based
complexes, only a few of these drugs have made it to clinical trials and many more
are awaiting ethical approval to join them.
With regard to the development of antidiabetic compounds, we have found that
much work has been done using natural product isolates, such as allixin (Figure 4.1a),
dipicolinic acid (Figure 4.1b), and maltol (Figure 4.1c), due to their known benefcial
activities in various metabolic pathways (Dabrowiak 2017).
Metallopharmaceuticals 155
FIGURE 4.1 Structural formulae of natural product isolates: (a) allixin, (b) dipicolinic acid,
and (c) maltol.
Fondly dubbed by their developers as “insulin mimetics” or “insulin enhancers,”

these metallo-drugs are known to effect the hypoglycaemic action in diabetic condi-
tions through multiple intracellular pathways. Among them, vanadium has garnered
much attention due to its ability to attenuate elevated blood sugar levels in both human
and animal type-1 diabetes mellitus (T1DM) and type-2 diabetes mellitus (T2DM)
subjects. Yet, like natural products, these drugs have also struggled for acceptance
among the medical fraternity, due to incomplete research behind them. Pioneering
work done by the Sakurai-led group and the Crans/Willsky and Orvig/McNeill
teams continue to encourage and empower researchers to not give up, despite the
many detracting opinions that may be directed at them. The McNeill/Orvig group
inspired many with their development of the lead compound: bis(ethylmaltolato)
oxovanadium(IV) (BEOV), which was successfully taken through Phases 1 and 2
clinical trials. Unfortunate rumours of the drug failing in the trials followed its shock-
ing discontinuation into Phase 3 studies. However, it was revealed that a soon-to-be
expired patent was the true cause for its withdrawal, due to there being no potential for
generating revenue on these otherwise promising antidiabetic therapeutants.
4.1.3 THE FUTURE FOR INSULIN-ENHANCING DRUGS?

Because there are large differences between having a compound being board
approved as a drug and being licensed as a nutritional additive, metallopharmaceu-
ticals have been allowed into the market as supplements, where the requirements for
such are much less strict. Currently, several metals such as vanadium, chromium,
and zinc exist as nutritional additives in either their salt or complex forms, and
despite their mechanisms remaining obscure, are marketed as proponents for diabe-
tes management and weight loss (Staff 2018). In instances like these, where available
information on their respective formulations is limited, researchers must examine
the publications reporting human and animal studies, as well as draw from the many
commercial forms of the compound (Crans et al. 2019).
4.2 VANADIUM
The element vanadium is classifed as a frst-row transition metal, with the symbol
V and atomic number 23 (Figure 4.2). It has a low natural abundance and can exist
FIGURE 4.2 Periodic table highlighting the position, physical appearance, and atomic
properties of vanadium.
in several oxidation states. However, once artifcially isolated, the subsequent forma-
tion of an oxide layer (passivation) somewhat stabilizes the free metal against further
reactivity and allows for its use in various applications.
In vitro and in vivo studies have demonstrated the potential of many vanadium
compounds as insulin-mimetic (or insulin-enhancing) agents. Of particular interest
was the observation that among those demonstrated to be effective in normalizing
serum glucose and fatty acid levels in streptozotocin (STZ)-induced diabetics rat were
complexes bearing ligands that were obtained from or modeled after natural sources,
namely: bis(maltolato)oxovanadium(IV) (BMOV) (Figure 4.3a), bis(ethylmaltolato)
oxovanadium(IV) (BEOV) (Figure 4.3b), diaqua(dipicolinato)oxovanadium(IV)
(Figure 4.3c), and bis(allixinato)oxovanadium(IV) (Figure 4.3d) (D. C. Crans 2005,
Adachi, Yoshida et al. 2006). Despite many attempts to explain how exactly vana-
dium compounds act in biological systems, only vague explanations persist. The
problem is exacerbated by the fact that observations in tissue cultures do not always
accurately refect responses in animals. The enigma is rooted in their inconclusive
mechanisms of action, uncertain dosage regimes, and speculated cytotoxicities
(Thompson and Orvig 2006). Although vanadium has been taunted for its promiscu-
ity, when it comes to intracellular protein binding, thus far it has been confrmed to
contribute to dual ameliorative actions in the insulin transduction pathway. In the
frst mechanism (Mechanism 1), the vanadate ion directly binds to and activates the
insulin receptor tyrosine kinase (IRTK) (Figure 4.4), thereby bypassing the need
for the triggering effect of insulin. In its second mode of action (Mechanism 2),
FIGURE 4.3 Structural formulae of vanadium complexes: (a) bis(maltolato)

oxovanadium(IV): BMOV; (b) bis(ethylmaltolato)oxovanadium(IV): BEOV; (c)
diaqua(dipicolinato)oxovanadium(IV); (d) bis(allixinato)oxovanadium(IV); and (e) [V(IV)
O(2,6-pyridine diacetatato)(H2O)2]: PDOV.
FIGURE 4.4 Mechanism of action of vanadium in the insulin transduction pathway.

the vanadate ion can bind to and inhibit protein tyrosine phosphatase (PTP-1B),
which prevents the shutdown of the glucose entry portals and enables the continued
entry of sugar into the cells. Controversially, the role of PTP-1B as the key player
in glucose regulation has not been generally accepted. This leaves unanswered the
question about the true target biomolecule(s) for the insulin-like effects of the vana-
dium complexes.
The foundation for the insulin-mimetic effects of vanadium salts can be gauged
by two criteria: (1) the enhancement of glucose utilization; and (2) its storage, after
entering the cells. Certain key metabolic enzymes in glucose utilization and stor-
age are located in the liver, muscle tissue, or adipocytes. Some are blocked by
vanadate(V), while vanadyl(IV) acts on the membranes of the cell plasma facilitat-
ing the cell permeation of glucose and possibly inhibiting lipolysis (Scior et al. 2016).
Efforts to identify a particular “best” vanadium-based, insulin-enhancing agent are
unlikely to yield a unique candidate, as biomolecular transformation in vivo is a nec-
essary feature of vanadium’s modus operandi.
That said, one can still aim to choose better ligands for vanadyl complexation
such that premature redox conversion is inhibited, stronger binding is favoured, the
safety of the dissociated ligand is assured, and synergistic effects are taken advan-
tage of, where possible (Thompson and Orvig 2006).
As mentioned earlier, much research has been devoted to vanadium-centred
coordination complexes, with one in particular making it as far as Phase 2 clini-
cal trials (Thompson and Orvig 2006, Mohammadi et al. 2005, Thompson,
Liboiron et al. 2003, Thompson, Lichter et al. 2009). Most recently, Rambaran
et al. reported a unique glucose-lowering response to a novel complex [V(IV)
O(2,6-pyridine diacetatato)(H2O)2] (PDOV) (Figure 4.3e). In that study, over a
90-day period, intraperitoneal administration of PDOV (at a dose of 75 mg/kg.bw)
and oral administration of PDOV (at a dose of 100 mg/kg.bw) were effective in
suppressing the hyperglycaemic state in STZ-induced diabetic subjects. Exposure
to PDOV was found to have little impact on the insulin levels of diabetics; how-
ever, improved urea, creatinine, aspartate transaminase (AST), and alanine trans-
aminase (ALT) levels were noted (Rambaran et al. 2020). From the outstanding
behaviour of the drug, the group was successful in their patent application in the
United States (Rambaran and Mani 2021) and, following in the footsteps of the
Orvig/McNeill group, have now embarked on protocol studies, with the hope of
entering human trials.
As we present the supporting research for the potential use of this form of therapy,
the associated toxicity of vanadium should also be discussed. Although the metal is
less toxic to humans than rodents, adverse effects reported in clinical studies were
primarily gastrointestinal disorders, including cramping, diarrhoea, and loose stools.
Owing to matrix effects, the vanadium content of a basal diet cannot be determined.
However, human dietary intake is normally in the range of 5–20 μg V/day, with an
upper tolerable level (UL) established at 1.8 mg/day (about 100 times the average
intake). As such, the amount of vanadium used in diabetes studies is far in excess
of the UL, which is allowable for clinical studies with careful safety monitoring
(Vincent 2018).
4.3 CHROMIUM
Chromium is represented by the symbol Cr and atomic number 24 (Figure 4.5). It
is debatably an essential element that is required for glucose and lipid metabolism
and is further respected for its improvement of insulin sensitivity, by enhanc-
ing intracellular signalling. Despite its cons, supplemental trivalent chromium
appears to be a useful tool in the world’s fght against epidemic-like manifes-
tations of metabolic syndromes, namely obesity and diabetes. Laboratory and
clinical studies indicate that certain forms of trivalent chromium have various
capabilities such as overcoming insulin resistance, ameliorating diabetes, sup-
pressing free-radical formations, and decreasing systolic blood pressure (Peng
and Yang 2015).
The intracellular action of chromium is still ungrounded, but studies have
shown plausible evidence that, like vanadium, it binds to both IRTK and PTP-1B
(Mechanisms 1 and 2) (R. A. Anderson 1998). Other studies have shown that it also
assists in the promotion of insulin-induced glucose uptake via amplifying the activa-
tion of Akt (Mechanism 3) (Figure 4.6) (Peng and Yang 2015).
Chromium(III)picolinate (CrPic) (Figure 4.7) is the most extensively studied
antidiabetic and anti-obese chromium complex. It has been reported that CrPic
treatment is able to protect from hepatocellular injury and also shows enhanced Cr
properties of chromium.
FIGURE 4.6 Mechanism of action of chromium in the insulin transduction pathway.
FIGURE 4.7 Structure of tris(picolinate)chromium(III) (CrPic).
translocation through the adenosine monophosphate (AMP)-activated protein kinase

pathway, in 3T3-L1 adipocytes. Similarly, another study reported that the adminis-
tration of the CrPic complex to insulin-resistant 3T3-L1 adipocytes led to improved
glucose uptake via the activation of the P38 pathway (Peng and Yang 2015).
Clinical studies have used considerably lower doses (μg-Cr/kg.bw) than rodent-
involved experiments and tend to be negative or, at best, ambiguous. In response to a
request from a nutraceutical company, the FDA examined the relationship between
Cr and insulin resistance, cardiovascular disease (CVD), T2DM, and other conditions
related to elevated glucose levels. The FDA issued a letter of enforcement discretion
allowing only one qualifed health claim for the labelling of dietary supplements:
One small study suggests that chromium picolinate may reduce the risk of insulin
resistance, and therefore possibly may reduce the risk of T2DM. FDA concludes, how-
ever, that the existence of such a relationship between chromium picolinate and either
insulin resistance or T2DM is highly uncertain.
(Vincent 2018)
Not limiting its treatment to the classic cases of diabetes, we report here a study
carried out by Janovic et al. In this study, chromium therapy was administered to
a group of 30 women, who were diagnosed with gestational diabetes (20–24 ges-
tational weeks). The study group was divided into three subgroups and given 0, 4,
and 8 g-Cr/kg.bw doses (in the form of CrPic) for 8 weeks. It was reported that
chromium supplementation improved glucose intolerance and lowered hyperglycae-
mia in the treated patients. It was further noted that the group that received the 8
g of supplement showed a higher degree of improvement relative to that of the
group that received the 4 g treatment. These results led the authors to conclude that
“chromium picolinate supplementation may be an adjunctive therapy when dietary
strategies are not suffcient to achieve normoglycaemia in women with gestational
diabetes” (Jovanovic, Gutierrez and Peterson 1999).
It would be remiss of us if we did not also present the alleged shortcomings from
the usage of CrPic. Questions arose about the safety in use of the complex as a
dietary supplement, as Stearns et al. reported that the compound caused chromo-
somal cleavage in Chinese-hamster ovary (CHO) cells and was also mutagenic at the
hypoxanthine phosphoribosyltransferase locus in CHO cells. However, the data was
found to have been misrepresented as the studies used high, non-physiological con-
centrations of Cr (0.05–1 mM). Similarly, Bagchi et al. subsequently observed DNA
fragmentation in another type of cultured cell treated with CrPic, although the Cr
concentrations were also non-physiological. Apart from these extreme but debatable
cases, there have been confrmed isolated incidents of the deleterious effects of the
compound supplementation in humans, which include weight loss, anaemia, renal
failure, and hypoglycaemia (Vincent 2003).
4.4 ZINC
Zinc is represented by the symbol Zn and atomic number 30 (Figure 4.8). Like chro-
mium, it is considered an essential element and plays an important role in the main-
tenance of several tissue functions including the synthesis, storage, and release of
insulin. The metal plays an important role in glucose metabolism and has been found
to enhance the effectiveness of insulin in vitro. Further, it has been suggested that its
defciency may aggravate insulin resistance in non-insulin-dependent diabetes mel-
litus (NIDDM) (Devi et al. 2016).
The infuence of zinc on the translocation of the glucose transporter type-4
(GLUT-4) vesicle to the plasma membrane has been proposed to be in the form of
properties of zinc.
a post-insulin receptor mechanism. Supporting evidence has shown that the metal
potentiates insulin-induced glucose transport and also increases glucose transport
into cells by binding to key enzymes within the insulin signalling pathway.
The extent of zinc’s interactions with the various intracellular proteins of the insu-
lin transduction pathway is summarized in Figure 4.9. In the frst instance, the metal
ion infuences the phosphorylation of the β-subunit of the insulin substrate receptor
(INS-R) (Mechanism 1) and also the inhibition of the PTP-1B enzyme (Mechanism
2). Further to this, Akt is activated by zinc in a phosphatidylinositol 3-kinase (PI3K)-
dependent way (Mechanism 3) and in a similar action to insulin, it also inhibits
glycogen synthase kinase-3 (GSK-3) (Mechanism 4). Finally, the metal is also known
to play a role in glucose transport, since it is part of the insulin-responsive aminopep-
tidase (IRAP) enzyme (a molecule required for the maintenance of normal GLUT
levels) (Mechanism 5) (Jansen, Karges and Rink 2009).
Generally, it is accepted that upon binding with organic compounds, the asso-
ciated toxicity of metal ions tends to decrease, while their relative bioavailability
tends to increase. Supportively, an in vitro study by Sakurai et al. presented a series
of Zn(II) complexes with maltol, picolinic acid, and amino acid ligands that had
higher insulin-mimetic activity than zinc sulphate. In addition, the supplementation
of KK-Ay mice (a T2DM model subject) with the Zn(II) complexes was found to
maintain normoglycaemic levels (Ueda et al. 2002).
FIGURE 4.9 Mechanism of action of zinc in the insulin transduction pathway.
In another study, the Sakurai group used the potent complex: bis(maltolato)zinc(II)
(Figure 4.10a) as the lead compound in their investigations of the structure–activity
relationships (SARs) of its family of complexes. The in vitro insulin-mimetic activi-
ties of these complexes were determined by the inhibition of free fatty acid release
and the enhancement of glucose uptake in isolated rat adipocytes treated with epi-
nephrine. The group reported that the new Zn(II) complex, Zn(alx)2 (Figure 4.10b),
which was created from the allixin isolate (from garlic) exhibited the highest insulin-
mimetic activity among all the complexes analyzed (Adachi, Yoshida et al. 2004).
Continuing with their investigations, Sakurai then showed that further modifca-
tion of the “Zn(alx)2” complex led to another novel Zn(II) compound, Zn(II)–thioal-
lixin-N-methyl (Zn(tanm)2) (Figure 4.10c). The results from this study showed that
daily oral administration of Zn(tanm)2 for 4 weeks in KKAy mice was able to sig-
nifcantly improve hyperglycaemia, glucose intolerance, insulin resistance, hyper-
leptinemia, obesity, and hypertension. In conclusion, the group proposed that their
Zn(tanm)2 complex could be used as a viable therapeutic option for obesity-linked
T2DM and metabolic syndromes (Adachi, Yoshida et al. 2006, Adachi, Yoshikawa
et al. 2006).
While caution taking zinc and its associated complexes is not as forewarned as
vanadium and chromium, supplements should be taken responsibly and not exces-
sively. According to the Offce of Dietary Supplements (ODS), an excessive intake of
zinc can lead to zinc toxicity, which can cause gastrointestinal discomfort, and when
chronic, may also disrupt the balance of other chemicals in the body, including cop-
per and iron (Galan 2019, National Institutes of Health 2021).
FIGURE 4.10 Structural formulae of zinc complexes: (a) bis(maltolato)zinc(II) complex;

(b) bis(allixinato)Zn(II) complex: Zn(alx)2; and (c) Zn(II)-thioallixin-N-methyl: Zn(tanm)2 .
4.5 COBALT
Cobalt is represented by the symbol Co and atomic number 30 (Figure 4.11). It is
considered essential to the metabolism of all animals and is a key constituent of
cobalamin (also known as vitamin B12) (Yamada 2013).
The literature has shown that under hypoxic conditions there is a responsive
increase in GLUT-1 gene expression, which in turn leads to an increase in tissue
glucose uptake. Interestingly, Beigi et al. reported that under normoxic conditions,
the effect of hypoxia-induced GLUT-1 expression can be mimicked by the adminis-
tration of Co in the form of cobalt chloride [Co(II)Cl2] (Figure 4.12a) (Mechanism
1) (Ybarra et al. 1997).
This fnding spurred the group’s curiosity to investigate other glycaemic regu-
lating mechanisms that can be stimulated by Co supplementation. In a following
paper, they reported that the administration of 2 mM CoCl2 in the drinking water
of Sprague-Dawley rats led to a decrease in the production of phosphoenolpyruvate
carboxykinase (PEPCK) mRNA (a rate-determining enzyme in the gluconeogenic
pathway) (Figure 4.12b) (Mechanism 2). The decreased production of PEPCK had a
consequential decrease in the production of hepatic glucose and thus presented itself
as another mechanism in normoglycaemic regulation (Saker et al. 1998).
To further investigate the ameliorative effects of cobalt, McNeill et al. fed a popu-
lation of both normal and diabetic rats a solution of 3.5 mM CoCl2 (ad libitum) for
3 weeks, followed by a 4 mM solution for 4 weeks. Body weight and fuid consump-
tion were monitored daily, while food intake was recorded twice every week. Prior
to termination, an oral glucose tolerance test was performed on the animals. The
properties of cobalt.
FIGURE 4.12 Illustration of (a) the role of Co(II) in the production of the GLUT-4 vesicle and
(b) the inhibition of the production of PEPK, which forms part of the insulin transduction pathway.
FIGURE 4.13 Structural formulae of cobalt complexes: (a) [Co(II)(H2dipic)(dipic)] 3H2O

and (b) [Co(II)(dipic)( -dipic)Co(II)(H2O)5] 2H2O.
results showed that by the fourth week, the co-solution was able to achieve a moder-
ate reduction in plasma glucose (PG) levels; however, it was unable to fully restore
euglycaemic levels in the diabetic subjects. Although the group concluded that cobalt
treatment decreases PG levels in STZ-diabetic rats and improves tolerance to glu-
cose, they noted that the majority of the results obtained from relatively short-term
studies continued to refect mediocre blood glucose (BG) attenuation. The fact that
at higher concentrations the results have been shrouded by toxic events the benefcial
effect of this form of therapy has been found to be controversial (Vasudevan and
McNeill 2007).
Yet, similar to vanadium research, studies continue in the hope of fnding a per-
fectly stable complex, such as those illustrated in Figure 4.13, that will be able to
produce the desirable glucose-lowering effect without the associated cytotoxicity
(Yang et al. 2002).
In line with this trend of thought, Talba et al. reported the effects of a glucosa-
minic acid-cobalt chelate on a population of STZ-induced diabetic mice. Daily oral
administration of the chelate solution (0.4 mL at various concentrations [0.32–0.4 g/
mL]) led to a peculiar reduction in water intake by the diabetic mice within the frst
5 days of treatment and a subsequent reduction in BG levels 2 weeks later. In conclu-
sion, they found that the complex was an effective antidiabetic agent and it exhibited
much less toxicity compared to cobalt alone (Talba et al. 2011).
4.6 TUNGSTEN
Tungsten is classifed as a third-row transition metal with the symbol W and atomic
number 74 (Figure 4.14). It has a wide array of applications in the feld of material
science; however, there have been reports of its experimental use as a therapeutic
agent in the regulation of hyperglycaemia (Wikipedia 2021). Although tungsten and
vanadium exhibit different physical and chemical characteristics, their behaviours as
insulin mimetic/enhancing agents bear great similarity to each other.
properties of tungsten.
FIGURE 4.15 Structure of tungstate ion.
In recent years, a number of studies have demonstrated the antidiabetic effects

of oral tungstate (WO42–) (Figure 4.15) in diabetic animal models, and it has been
touted as a more promising drug candidate than vanadium because of its rela-
tively lower toxicity. Despite this slight edge over its competitor, the fear of the
occurrence of cytotoxic events due to poor clearance is still a cause for concern
(Domingo 2002).
Under diabetic conditions, there is a consequential increase in L-lactate (Jenei
et al. 2019) and CO production (Paredi et al. 1999) and a decrease in glucose-6-phos-
phate levels (Aiston, Andersen and Agius 2003). Biological studies (using rat hepa-
tocytes) have revealed that like vanadate, tungstate inactivates glycogen synthase (a
FIGURE 4.16 Mechanism of action of tungsten in the liver.
key enzyme in the conversion of glucose into glycogen) by a mechanism independent

of Ca2+ (Mechanism 1). It is also seen to activate glycogen phosphorylase (an enzyme
that catalyzes the rate-limiting step in glycogenolysis) by a Ca2+-dependent pathway
(Mechanism 2). The actions of the second mechanism consequently increase fruc-
tose 2,6-bisphosphate levels and counteract the decrease in this metabolite induced
by glucagon. Although these effectors do not directly modify 6-phosphofructo-2-ki-
nase activity, they partially inhibit its inactivation that was infuenced by glucagon
(Fillat, Rodriguez-Gil and Guinovart 1992) (Figure 4.16).
In January 1997, the patent application “Tungsten (VI) Compositions for the
Oral Treatment of Diabetes Mellitus” by Guinovart et al. was approved by the US
Patent and Trademark Offce (USPTO). The invention laid claims to formulations of
a tungstate-based, insulin-mimetic compound that was capable of attenuating hyper-
glycaemic levels in mammalian models through oral administration. Unfortunately,
no further records were found on the advancement of the invention to the stage of
human clinical trials, perhaps due to the looming fear of its toxicity (Agency for
Toxic Substances and Disease Registry, Division of Toxicology and Human Health
Sciences 2005).
Despite the understandable fears surrounding its use, studies on the toxic effects
of tungstate remain very scant. It is therefore imperative that due to the continued
interest in tungstate as a potential DM therapeutant, greater focus should be placed
on the in vitro and in vivo evaluation of its toxicity (Guinovart Cirera, Barbera Lluis
and Rodriguez-Gil 1997).
4.7 MOLYBDENUM
Molybdenum is classifed as a second-row transition metal with the symbol Mo
and atomic number 42 (Figure 4.17). It is an essential mineral that is found in high
concentrations in legumes, grains, and organ meats, and is considered essential for
human life (Rowles 2017). Like the tungstate ion, molybdate is a compound contain-
ing an oxo-anion with Mo in its highest oxidation state of 6 (Figure 4.18).
The insulin-like effects of Mo were studied in rat adipocytes and compared
to the actions of vanadium. Other than being less potent, the molybdate’s activi-
ties resembled those of the vanadate ion, in stimulating lipogenesis, activating
properties of molybdenum.
FIGURE 4.18 Structure of molybdate.

glucose oxidation, enhancing the rate of hexose uptake, and inhibiting lipolysis
(Li et al. 1995).
Recently, evidence has been presented that Mo also infuences carbohydrate
metabolism in vitro. The metallo-oxo anion was observed to stimulate both gly-
colysis and accelerated glycogen degradation in isolated hepatocytes and was also
seen to infuence increased insulin receptor autophosphorylation, phosphorylation of
insulin receptor 160-kDa substrate, and augmented glucose transport in adipocytes
(Ozcelilkay et al. 1996).
A study by Ozcelilkay et al. reported the insulin-like action of molybdate in a pop-
ulation of STZ-induced diabetic rats. The oral administration of the metal to the rats
resulted in a 75% decrease in hyperglycaemic and glucosuric levels. Appreciatively,
the rats’ tolerance to glucose loads was also improved and glycogen stores were
replenished. In the liver, the ion effected the restoration of blunted mRNA and nor-
malized the activities of glucokinase, pyruvate kinase, and phosphoenolpyruvate
carboxykinase. Finally, it was reported that the therapeutant totally reversed the low
expression and activity of acetyl-CoA carboxylase and fatty acid synthase in the
liver, but not in the white adipose tissue (Ozcelilkay et al. 1996).
In another study (using molybdate-treated diabetic rats), a reduction in the lev-
els of cholesterol, triglycerides, phospholipids, and lipid peroxidation was reported.
There was also an observed increase in the activity of antioxidants such as superox-
ide dismutase, catalase, and glutathione peroxidase, and a reduction in glutathione.
Stemming from this, the group was convinced that the Mo ion was responsible for
the recorded biological activity and suggested its use as a form of prevention or early
treatment for DM (Panneerselvam and Govindasamy 2004).
Finally, an investigation by Liu et al. demonstrated the infuence of molybdate
treatment on the increase in cellular-insulin content and the enhancement of basal
insulin release, by clonal BRIN BD11 cells. Further to this, the team reported a
desirable improvement in the responsiveness to glucose and a wide range of other
secretagogues (Liu et al. 2004).
Conclusion
Board-approved antidiabetic drugs continue to be the most popular form of oral therapy
for diabetes mellitus (DM), owing to the protocolled number of pharmacokinetic and
pharmacodynamic studies carried out on them. However, infuenced by both custom
and cost, ethnopharmacological therapies also remain equally popular among patients
with the disease. Apart from these allopathic and Ayurvedic medicines, ongoing
research into insulin-mimetic coordination complexes has continued to generate
great interest due to their respective improved effcacies and lower cytotoxicities.
Although these medications may be controversially better than their Food and Drug
Administration (FDA)-approved counterparts, their respective safety and effcacy
standards need to be further evaluated by well-designed, controlled clinical studies.
171
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Abbreviations
A1C Glycated haemoglobin (HbA1c)
ADP Adenosine diphosphate
AG Alpha glucosidase
AGE Aged garlic extract
AMP Adenosine monophosphate
AMPK AMP-activated protein kinase
APDS Allyl propyl disulphide
ATP Adenosine triphosphate
BG Blood glucose
CAT Catalase activities
CVD Cardiovascular disease
CYP Cytochrome P450 enzymes
DIP Diabetes in pregnancy
DM Diabetes mellitus
DPP‑4 Dipeptidyl peptidase-4
FBG Fasting blood glucose
FDA US Food and Drug Administration
FPI Fasting plasma insulin
GDM Gestational diabetes mellitus
GI Gastrointestinal
GIP Glucose-dependent insulinotropic peptide
GLP‑1 Glucagon-like peptide-1
GLUT‑4 Glucose transporter type-4
Hb Haemoglobin
HbA1c Glycated haemoglobin (A1C)
HDL High density lipoprotein
HFD High-fat diet
HG Hepatic glycogen
HIP Hyperglycaemia in pregnancy
HMG‑CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A
HOMA‑IR Homeostatic model assessment for insulin resistance
HTC Hepatic total cholesterol
IP Intraperitoneal
IC50 Half maximal inhibitory concentration
IDF International Diabetes Federation
INS‑R Insulin substrate receptor
IR‑mRNA Insulin receptor messenger ribonucleic acid
207
208 Abbreviations
K ATP ATP-sensitive potassium channel

LD50 The amount of a material, given all at once, which causes the death
of 50% (one half) of a group of test animals. The LD50 is one way
to measure the short-term poisoning potential (acute toxicity) of a
material.
LDL Low density lipoprotein
LPO Lipid peroxidation
mg Milligrams
mg/kg.bw Milligrams per kilogram of body weight
ml/kg.bw Millilitres per kilogram of body weight
mmol/L Millimoles per litre
MODY Maturity onset diabetes of the young
mRNA Messenger ribonucleic acid
NAC North American and Caribbean
NIC Nicotinamide
NIDDM Non-insulin-dependent diabetes mellitus
OATP1B1 Organic anion transporting polypeptide 1B1 transporter
OGT Oral glucose tolerance
PBG Postprandial blood glucose
PDK1 Phosphoinositide-dependent kinase 1
PG Plasma glucose
PH Pleckstrin homology
PI3K Phosphatidylinositol 3-kinase
PIP2 Phosphatidylinositol (4,5)-bisphosphate
PIP3 Phosphatidylinositol (3,4,5)-triphosphate
PKB Protein kinase-B; Akt
PL Plasma lipid
po Per oral
PPAR Peroxisome proliferator-activated receptor
PPG Postprandial plasma glucose
ROS Reactive oxygen species
SGLT Sodium–glucose cotransporters
SOD Superoxide dismutase
STZ Streptozotocin
SUR‑1 Sulfonylureas receptor
T1DM Type-1 diabetes mellitus; type-1 diabetes; type-1 diabetic
T2DM Type-2 diabetes mellitus; type-2 diabetes; type-2 diabetic
T3 hormone Triiodothyronine (affects almost every physiological process in the
body, including growth and development, metabolism, body tem-
perature, and heart rate)
T4 hormone Regulates metabolism and plays a crucial role in digestion, muscle
function, and bone health
TAIM Traditional Arabic and Islamic medicine
TC Total cholesterol
TCM Traditional Chinese medicine
Abbreviations 209
TG Triglycerides
TIM Traditional Indian medicine
TSH Thyroid-stimulating hormone
TZD Thiazolidinediones
WHO World Health Organization
Glossary
Adipogenesis: The formation of adipocytes (fat cells) from stem cells.
Alkaloids: Any of a class of naturally occurring organic compounds of nitrogen-
containing bases.
Allopathic medicine: Pharmaceutical drugs.
Alloxan: An acidic compound obtained by the oxidation of uric acid and isolated
as an efforescent crystalline hydrate. It is known to kill islet cells in the
pancreas and induce a diabetic state due to the lack of insulin.
Anthelmintic: Used to destroy parasitic worms.
Antiatherosclerotic: That which counters the effect of atherosclerosis (a disease of
the arteries characterized by the deposition of plaques of fatty material on
their inner walls).
Antibodies: A protein produced by the immune system to defend the host body from
a foreign substance.
Apoptosis: A form of programmed cell death.
Atomic number: Represented by the symbol Z, it is the number of protons in the
nucleus of an atom of a particular element.
Ayurvedic medicine: Use of herbs, fruits, and vegetables for medicinal purposes; it
may also be extended to include animal, metal, or mineral material.
Curcumin: The main chemical substance of the Curcuma longa plant (turmeric).
This gives turmeric its bright yellow colour.
Cytokines: Proteins used for cell signalling and communications between cells.
Cytotoxic: Toxic to living cells.
Digitalis: A fowering plant belonging to the family Scrophulariaceae.
Effcacy: The ability to produce a desired or intended result.
Enzymes: Specialized proteins that act as catalysts that help speed up chemical
reactions.
Et al. (et alibi): And others.
Ethnomedicine: The study or comparison of traditional medicine based on bioactive
compounds in plants and animals and practiced by various ethnic groups.
Etiology: The cause, set of causes, or manner of causation of a disease or condition.
Euglycaemia: A normal blood glucose concentration.
Flavonoids: A group of plant chemicals (phytonutrients) found in the majority of
fruit and vegetables.
Gavage: The administration of food or drugs by force, especially to an animal, typi-
cally through a tube leading down the throat to the stomach.
Gene: Physical and functional unit of heredity.
Glucose: Monosaccharide (simple sugar) comes from food and provides energy to
the body.
Glycaemic index: A number representing the carbohydrates in foods according to
how they affect the blood glucose level.
211
212 Glossary
Glycogenesis: Anabolic pathway by which glycogen synthesis occurs from a simpler

precursor, glucose 6-phosphate.
Glycoside: A compound formed from a simple sugar and another compound by the
replacement of a hydroxyl group in the sugar molecule. Many drugs and
poisons derived from plants are glycosides.
Glycosuria: A condition characterized by an excess of sugar in the urine.
HbA1c: Glycated haemoglobin.
Homeostasis: Maintenance of the internal environment of an organism.
Hyperglycaemia: High increase in blood glucose levels.
Hyperlactatemia: Pathological state in which the resting blood lactate concentra-
tion is abnormally high.
Hypertrophy: The growth of muscle cells. This allows the size of the muscles to
enlarge.
Hypoglycaemia: Decrease in blood glucose levels.
Immunostimulants: Substances (drugs and nutrients) that stimulate the immune
system by inducing the activation or increasing the activity of any of its
components.
In vitro: Taking place in a test tube, culture dish, or elsewhere outside a living
organism.
In vivo: Taking place in a living organism.
Incretin: A metabolic hormone that stimulates a decrease in blood glucose levels.
Insulin: A hormone produced by pancreatic β-cells in the islets of Langerhans that
decreases glucose levels or allows a certain amount to pass through the
blood.
Insulin‑mimetic agents: Agents that have been shown to mimic the actions of
insulin.
Insulinoma: A small tumour in the pancreas that produces an excess amount of
insulin.
Intraperitoneal: The route of administration of drugs.
Ligand: Ions or molecules that bond to a central metal atom or ion to form a complex.
Lipolysis: The breakdown of fats and other lipids by hydrolysis to release fatty acids.
Macronutrients: Energy-providing chemical substances that come from food and
are consumed by organisms in large quantities. They can be subclassifed
into three groups: carbohydrates, lipids, and proteins.
Mangiferin: An xanthone extracted from different parts of the mango fruit, leaves,
stem, and bark.
Micronutrients: All the minerals and vitamins that the body needs.
Modus operandi: An expression referring to “way of working.”
Monotherapy: Use of a single drug to treat a particular disorder or disease.
Normoglycaemia: A normal blood glucose concentration.
Normoxic: Having normal oxygen concentrations.
Oleoresin: A natural or artifcial mixture of essential oils and a resin, e.g. balsam.
Permeation: Diffusion of molecules through a membrane or the interface of a sub-
stance in solution.
Polymorphism: The ability of an object to take on many forms.
Glossary 213
Postprandial: During or relating to the period after a meal.

Potency: The strength of an intoxicant or drug, as measured by the amount needed
to produce a certain response.
PPAR‑γ : A receptor that is of great importance in the regulation of adipogenesis;
in addition, it is essential in the prevention of adiposis and the treatment of
type-2 diabetes mellitus.
Purgative: A laxative.
Pyruvate: A carboxylic acid produced by the metabolism of glucose.
Streptozotocin:: An agent with specifc effects on pancreatic β-cells that is used to
induce type-1 diabetes or type-2 diabetes in animal models, such as rats
and mice.
Supplement: Something that is added to something to complete or improve it, e.g.
nutrients.
Terpenoid: Any of a large class of organic compounds including terpenes, diter-
penes, and sesquiterpenes. They have unsaturated molecules composed of
linked isoprene units, generally having the formula (C5H8)n.
Therapeutant: A therapeutic agent.
Tincture: A medicine made by dissolving a drug in alcohol.
Tolbutamide: An oral sulphonylurea hypoglycaemic drug.
Transition element: An element whose atom has a partially flled d subshell.
Type‑1 diabetes: Diabetes caused by the low or no production of insulin in the
pancreas.
Type‑2 diabetes: Diabetes caused by the low production of insulin in the pancreas.
Index
A Buah papaya, 66, 140
Bulb onion, 47, 144
Aam, 100, 140
Aanabahe-hindi, 66, 140
Acarbose, 15–18, 32 C
Ach, 108, 140 Caesarweed, 136, 144
Achi, 108, 140 Calabacero, 84, 144
Achiote, 60, 140 Calabash, 84, 144
African basil, 117, 145 Canadian ginseng, 120, 141
Ajmod, 54, 140 Canaglifozin
Alaf-e-Mar, 64, 140 farxiga, 25, 37
Alcaparro, 64, 140 Canton ginger, 137, 148
Aloe/Aloes, 50, 141 Cape periwinkle, 68, 143
Aloe vera, 50, 141 Caper bush, 64, 140
Alovis, 50, 141 Cappero, 64, 140
Alternative medicine, 153 Carailla, 105, 142
American ginseng, 120, 141 Caraquite, 97, 145
Annatto, 60, 140 Cariaquito, 97, 145
Apple Carille, 105, 142
custard, 52, 150 Caripeelay, 111, 144
hog, 108, 140 Carypoulay, 111, 144
Asian ginseng, 120, 141 Celeriac, 54, 140
Asiatic pennywort, 72, 148 Celery, 54, 140
Asthma plant, 93, 141 Cerasee, 105, 142
Asthma weed, 93, 141 Chandilay bush, 98, 148
Awltree, 108, 140 Cheese fruit, 108, 140
Chhui-mui, 104, 144
B Chiggery grapes, 135, 145
Chinese ginseng, 120, 141
Bacano, 70, 151 Chinese mustard, 61, 144
Balsam-pear, 105, 142 Chlorpropamide, 12
Bastard vervain, 129, 143 Christmas bush, 74, 150
Biguanides Christmas candlestick, 98, 148
metformin, 9–11, 26 Chromium, 159–161
Billygoat-weed, 45, 141 Cidra, 88, 147
Bindi, 43, 142 Cilantro, 82, 145
Bitter Gourd, 105, 142 Citronela, 91, 145
Bitter melon, 105, 142 Citronella grass, 91, 145
Bitter squash, 105, 142 Citron grass, 91, 145
Black jack, 58, 143 Clove basil, 117, 145
Black plum, 131, 143 Cobalt, 164–166
Black seed squash, 88, 147 Cobbler’s pegs, 58, 143
Blue porterweed, 129, 143 Common foss fower, 74, 150
Blue snake weed, 129, 143 Common ginger, 137, 148
Bo-aal, 108, 140 Common lantana, 97, 145
Bois cano, 70, 151 Common onion, 47, 144
Brazilian tea, 129, 143 Communist pacha, 74, 150
Bright eyes, 68, 143 Congo jute, 136, 144
Brown mustard, 61, 144 Congo pump, 70, 151
215
216 Index
Cooze mahot, 136, 144 Halia, 137, 148

Coraillie, 105, 142 Hardi, 89, 146
Coriander, 82, 145 Herbe á pic, 114, 148
Coriandre, 82, 145 Hibiscus, 94, 148
Cucumber, 86, 146 Hog apple, 108, 140
Curcuma, 89, 146 Holy basil, 117, 145
Curry leaf, 111, 144 Horseradish tree, 109, 147
Curry patta, 111, 144 Humble plant, 104, 144
Hyperglycaemia in pregnancy
D Gestational diabetes/ Diabetes in pregnancy, 3
Devil weed, 74, 150

I
Dhania, 82, 145
Diabetes mellitus, 1 Indian lilac, 56, 146
Diamicron Indian mulberry, 108, 140
gliclazide, 12–13, 28 Insulin transduction pathway, 4–5
Dogoyaro, 56, 146
Drumstick tree, 109, 147
J
E Jackass bitters, 114, 148
Jack in the box, 74, 150
East Indian basil, 117, 145 Jamaica vervain, 129, 143
Empaglifozin Jambolan, 131, 143
jardiance, 25, 38 Jamun, 131, 143
Janumet, 20
F Java plum, 131, 143
Jigger bush, 135, 145
Famine weed, 122, 150 Jiln ginseng, 120, 141
Farmers friend, 58, 143
Fever grass, 91, 145
Field pumpkin, 88, 147 K
Fig-leaf gourd, 88, 147 Kaddi patta, 111, 144
Kalbas, 84, 144
G Karela, 105, 142
Gale of the wind, 124, 147 Kebbar, 64, 140
Garden spurge, 93, 141 Key lime, 75, 149
Garlic, 48, 147 Klip dagga, 98, 148
Ginger, 137, 148 Korean ginseng, 120, 141
Ginseng, 120, 141 Krishna toolsie, 117, 145
Glimepiride, 12–14, 28 Kuze maho, 136, 144
Glipizide, 12–13, 27
Glyburide, 12–13, 27 L
Goatweed, 126, 149
Good Luck, 63, 148 Laajvanti, 104, 144
Goolab jamun, 131, 143 Lady fngers, 43, 142
Gotu kola, 72, 148 Lahasun, 48, 147
Grapefruit, 78, 148 Lajja, 104, 144
Graveyard plant, 68, 143 Lantana, 97, 145
Graviola, 52, 150 Leaf celery, 54, 140
Guanabana, 52, 150 Leaf mustard, 61, 144
Guigai, 120, 141 Lemon, 77, 149
Lemon grass, 91, 145
Licorice weed, 126, 149
H
Light-blue snakeweed, 129, 143
Hairy beggarticks, 58, 143 Lime, 75, 149
Haldi, 89, 146 Lion’s ear, 98, 148
Index 217
M Pop-a-gun, 70, 151

Prickly custard apple, 52, 150
Madagascar periwinkle, 68, 143 Pudina, 102, 151
Malabar gourd, 88, 147 Pumpkin, 88, 147
Malabar plum, 131, 143
Manako, 100, 140
Mango, 100, 140 R
Man to Man, 123, 149 Rai, 61, 144
Margosa tree, 56, 146 Rat-ear, 123, 149
Metallo-drugs, 153–155 Red ginseng, 120, 141
Metallopharmaceuticals, 153 Red sage shrub, 97, 145
Mexican lime, 75, 149 Remoglifozin etabonate, 24
Mexican thornless key lime, 75, 149 Repaglinide, 15, 30
Miglitol, 15–18, 32 Resurrection plant, 63, 148
Miracle fruit, 84, 144 Rompe saragüey, 74, 150
Molybdenum, 169–170 Root celery, 54, 140
Moringa, 109, 147 Rose mallow, 94, 148
Mother’s best friend, 109, 147 Rose periwinkle, 68, 143
Mustard greens, 61, 144 Rosiglitazone
avandia, 20, 34
N Roucou, 60, 140
Rum tree, 84, 144
Nateglinide, 15, 31–32
Needle bush, 58, 143
Neem, 56, 146 S
Nimtree, 56, 146
Sabila, 50, 141
Ninjin, 120, 141
Saffower, 89, 146
Noni, 108, 140
Saijan, 109, 147
Nono, 108, 140
Saint John’s bush, 96, 149
Nonu, 108, 140
Santa-Maria, 122, 150
Santa Maria feverfew, 122, 150
O Scoparia-weed, 126, 149
Ochro, 43, 142 Seed-under-leaf, 124, 147
Okra, 43, 142 Senna, 128, 150
Okro, 43, 142 Senne, 128, 150
Old maid, 68, 143 Sensitive plant, 104, 144
Ookoo plant, 60, 140 Serglifozin etabonate, 23–24
Orange, 81, 149 Shameful plant, 104, 144
Oriental ginseng, 120, 141 Shining bush plant, 123, 149
Ozark melon, 88, 147 Shoe black plant, 94, 148
Shoe fower plant, 94, 148
P Siam weed, 74, 150
Silverbush, 123, 149
Panax schinseng, 120, 141 Snakeweed, 93, 141
Papaw, 65, 140 Snakewood, 70, 151
Papaya, 65, 140 Soro Soro, 93, 141
Paradise citrus, 78, 148 Soursop, 52, 150
Pawpaw, 66, 140 Spade leaf, 72, 148
Pepper elder, 123, 149 Spanish needle, 58, 143
Peppermint, 102, 151 Spearmint, 102, 151
Phlorizin, 22 Stem ginger, 137, 148
Pink chineseburr, 136, 144 Sticky beaks, 58, 143
Pink periwinkle, 68, 143 Stonebreaker, 124, 147
Pioglitazone Sweet-broom, 126, 149
actos, 20, 34 Sweet orange, 81, 149
218 Index
T Vildagliptin, 18, 33
Voglibose, 15–16, 18
Tamarind, 134, 150
Tambran, 134, 150
Teemarie, 104, 144 W
Texas gourd, 88, 147 Water mint, 102, 151
Ti-Marie, 104, 144 West Indian ben, 109, 147
Tolazamide, 12, 14, 29 West Indian lantana, 97, 145
Tolbutamide, 12–14, 29 West Indian saffron, 89, 146
Totumo, 84, 144 Whitehead broom, 122, 150
Touch-me-not plant, 104, 144 Whitetop weed, 122, 150
Traditional Arabic and Islamic medicine, 40, 42 Wild basil, 117, 145
Traditional Chinese medicine, 40, 41 Wild celery, 54, 140
Traditional Indian medicine, 40 Wild mint, 102, 151
Tree-of-laziness, 70, 151 Wild pawpaw, 70, 151
Troglitazone Wild watermelon, 64, 140
rezulin, 20–21, 35 Wonder of the world, 63, 148
Tropical whiteweed, 45, 141
Trumpet tree, 70, 151
Tulasi, 117, 145 Y
Tulipan, 94, 148 Yellow ginger, 89, 146
Tulsi, 117, 145
Tungsten, 166–169
Turmeric, 89, 146 Z
Type-1 diabetes mellitus, 1 Zeb-a-fam, 45, 141
Zeb-a-pique, 114, 148
V Zinc, 161–164
Vanadium, 155–158
Verbena yellow sage, 97, 145

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Alternative Medicines for Diabetes Management: Advances in Pharmacognosy

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Chapter 1 Etiology ................................................................................................1

Chapter 2 Allopathic Medicines ...........................................................................7

Chapter 3 Ayurvedic Medicines: (Ethnopharmacological Treatments) ............. 39

3.6 Aloe barbadensis Mill. (ABM) ................................................ 50

3.47 Phyllanthus amarus Linn. (PA)............................................. 124

Chapter 4 Metallopharmaceuticals ................................................................... 153

Conclusion ............................................................................................................ 171

Nalini Kathleen Singh is currently employed at UTT as

1.1 DIABETES MELLITUS (DM)

1.1.1 TYPE-1 DIABETES

FIGURE 1.1 International Diabetes Federation Diabetes Atlas (2021).

The incidence of T1DM is increasing worldwide, but there is considerable variation

1.1.2 TYPE-2 DIABETES

1.1.3 HYPERGLYCAEMIA IN PREGNANCY

1.1.4 OTHER TYPES OF DIABETES

1.2 INSULIN TRANSDUCTION PATHWAY

FIGURE 1.2 Diagrammatic representation of the human insulin receptor glycoprotein

FIGURE 1.3 Schematic diagram of the insulin transduction pathway.

1.3 OUR GOAL

seen to be the therapeutant of choice, while insulinotropic sulfonylureas such as

FIGURE 2.1 Structure of metformin.

In 2017, Abbas et al. formulated a new family of biguanide hydrochloride salts

FIGURE 2.4 Structural formula of sulfonylureas.

FIGURE 2.6 Structural formulae of second-generation sulfonylureas: (a) glibenclamide;

FIGURE 2.7 Structural formulae of frst-generation sulfonylureas: (a) tolbutamide,

2.5 ALPHA-GLUCOSIDASE INHIBITORS

carbohydrase that is responsible for breaking down complex carbohydrates to glu-

Miglitol is the frst pseudo-monosaccharide that comes from a 1-deoxynojirimy-

2.6 DPP-4 INHIBITORS

FIGURE 2.11 Structural formulae of dipeptidyl-peptidase IV (DPP-4) inhibitors:

FIGURE 2.13 Structural formulae of thiazolidinediones: (a) rosiglitazone (Avandia),

FIGURE 2.14 Schematic diagram of the effect of thiazolidinediones in adipose tissue.

2.8 SGLT-2 INHIBITORS

FIGURE 2.15 Structural formula of phlorizin.

It is known that renal tubular reabsorption undergoes adaptations in uncontrolled

FIGURE 2.17 Structural formulae of O-glucosides: (a) serglifozin etabonate and

Symptomatic side effects that include mostly urinary or genital irritation or

TABLE 2.1 (CONTINUED)

Tolbutamide (Orinase) (L. Stimulates the pancreas to produce 500 Hypoglycaemia –

TABLE 2.1 (CONTINUED)

TABLE 2.1 (CONTINUED)

Alpha‑glucosidase inhibitor: (n = 962)

DPP‑4 inhibitor: (n = 443) @ 100 mg

DPP‑4 inhibitor: (n = 1855)

TABLE 2.1 (CONTINUED)

Troglitazone (Rezulin) Promotes insulin sensitivity in the 200 Infection 18

was also consistent with an idiosyncratic drug reaction.

TABLE 2.1 (CONTINUED)

TABLE 2.1 (CONTINUED)

Esteemed researchers in the feld of ethnomedicine such as Associate Professor,

3.1.2.1 Traditional Indian Medicine

3.1.2.2 Traditional Chinese Medicine

3.1.2.3 Traditional Arabic and Islamic Medicine

3.2 ABELMOSCHUS ESCULENTUS LINN. (AE)

FIGURE 3.1 Illustration of Abelmoschus esculentus.

mucilage yield, glucose entrapping capability, and α-glucosidase inhibitory potential

3.3 AGERATUM CONYZOIDES LINN. (AgC)

FIGURE 3.3 Illustration of Ageratum conyzoides.

FIGURE 3.4 General structural formula of favonoids (polyphenolic compounds).

at doses of 16 mg/kg.bw of F1a, 16 mg/kg.bw of F1b, and 88 mg/kg.bw of F1c.

3.4 ALLIUM CEPA LINN. (AC)

FIGURE 3.5 Illustration of Allium cepa.

3.5 ALLIUM SATIVUM LINN. (AS)

FIGURE 3.7 Illustration of Allium sativum.