Journal of Pharmacognosy and Phytochemistry 2019; 8(6): 2362-2371

E-ISSN: 2278-4136
P-ISSN: 2349-8234
JPP 2019; 8(6): 2362-2371 Diabetes mellitus: A comprehensive review
Received: 09-09-2019
Accepted: 13-10-2019
Bidduth Kumar Sarkar, Rahima Akter, Joydeep Das, Ananya Das, Prema
Bidduth Kumar Sarkar Modak, Satyajit Halder, Arghya Prosun Sarkar and Sukalyan Kumar
Department of Pharmacy,
Jahangirnagar University, Kundu
Savar, Dhaka, Bangladesh
Abstract
Rahima Akter Diabetes mellitus (DM) is a group of metabolic diseases in which a person has high blood sugar. In this
Department of Pharmacy, disease either the body does not produce enough insulin, or cells do not respond to the insulin that is
Jahangirnagar University,
produced. High blood glucose levels are manifested during diabetes mellitus because of inadequate
Savar, Dhaka, Bangladesh
pancreatic insulin secretion or poor insulin-directed mobilization of cellular glucose. Etiologically,
Joydeep Das diabetes has been divided into three types namely: Type 1 DM or insulin-dependent diabetes mellitus
Department of Zoology, (IDDM) in which body fails to produce insulin, and presently requires the person to inject insulin. Type 2
Charuchandra College, DM or non-insulin-dependent diabetes mellitus (NIDDM), results from insulin resistance, a condition
University of Calcutta, Kolkata, where cells fail to use insulin properly, with or without an absolute insulin deficiency. The third main
West Bengal, India type is gestational diabetes which occurs when women without a previous history of diabetes develop a
high blood glucose level during her pregnancy. Currently available pharmacotherapy for the treatment of
Ananya Das diabetes mellitus includes insulin and oral hypoglycemic agents. Such drugs acts by either increasing the
Department of Pharmacy, secretion of insulin from pancreas or reducing plasma glucose concentrations by increasing glucose
Jahangirnagar University, uptake and decreasing gluconeogenesis. But the currently available drugs do not restore normal glucose
Savar, Dhaka, Bangladesh homeostasis effectively for a long time. Moreover they are not free from side effects like hypoglycemia,
kidney diseases, GIT problems, hepatotoxicity, heart risk problems, insulinoma. Besides these are to be
Prema Dodak
continued rest of life. Various herbal remedies are proved to be effective in the treatment of diabetes. The
Department of Pharmacy,
Jahangirnagar University, present review therefore is an attempt to focus on the physiological aspects of diabetes, its complications,
Savar, Dhaka, Bangladesh goals of management, and treatment of diabetes.

Satyajit Halder Keywords: Insulin, blood glucose levels, Insulinoma, hyperinsulinemia, hyperglycemia
Department of Pharmacy,
Jahangirnagar University, Introduction
Savar, Dhaka, Bangladesh Diabetes mellitus is a cluster of heterogeneous disorders showing episodes of hyperglycemia
Arghya Prosun Sarkar
and glucose intolerance. It develops due to lack of insulin, impaired insulin action, or both
Department of Pharmacy, (Sicree et al., 2006) [1]. These complications arise as a result of derangements in the regulatory
Islamic University, Kushtia, systems for storage and mobilization of metabolic fuels, which includes the catabolism and
Bangladesh anabolism of carbohydrates, lipids and proteins due to defective insulin secretion, insulin
action, or both (Shillitoe, 1988; Votey and Peters, 2004) [2, 3]. Classification of diabetes
Sukalyan Kumar Kundu mellitus is based on its diagnostics and clinical manifestations. Based on this, there are four
Department of Pharmacy, types or classes of diabetes mellitus like, type 1 diabetes, type 2 diabetes, gestational diabetes,
Jahangirnagar University,
and other specific types (Sicree et al., 2006) [1]. Type 1 diabetes accounts for only a minority
Savar, Dhaka, Bangladesh
of the total burden of diabetes in a population but its incidence is increasing in both rich and
poor countries. Moreover, a shift towards type 1 diabetes is occurring in children at earlier
ages (Sicree et al., 2006) [1]. 85 to 95% of all diabetes in rich and developing countries are of
type 2. It has an association with improper utilization of insulin by target cells and tissues. It is
currently a common and serious health concern worldwide. According to WHO (1994), this
problem has been aggravated by rapid cultural and social dynamics, ageing populations,
increasing urbanization, dietary changes, reduced physical activity and other unhealthy
lifestyle and behavioral patterns. Diabetes mellitus and impaired glucose tolerance, can now be
found in almost every population in the world and this trend is on the rise globally (WHO,
1994) [4].

Etymology of diabetes mellitus

The terms "Diabetes" and “Mellitus” have come from Greek where “Diabetes” denotes "a
passer through a siphon" and "Mellitus" refers to "sweet". The Greeks named it as the
excessive amounts of urine produced by diabetes patients attracted flies and bees. The ancient
Corresponding Author: Chinese diagnosed diabetes mellitus by observing whether ants are attracted to a person's urine
Bidduth Kumar Sarkar or not. In medieval ages, the European doctors tested for diabetes by testing the urine
Department of Pharmacy,
themselves (Patlak, 2002) [5].
Jahangirnagar University,
Savar, Dhaka, Bangladesh
~ 2362 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

History of diabetes mellitus Middle East and North Africa Region, two out of five adults
Though treatments of diabetes were known since the Middle with diabetes remain undiagnosed. By 2040, in the South and
Ages, its pathogenesis elucidation occurred mainly in the 20th Central America Region, the number of people with diabetes
century. The role of the pancreas in diabetes was discovered will increase by 65%. In the Africa Region between 9.5
by Joseph Von Mering and Oskar Minkowski in 1889. In million and 29.3 million people live with diabetes according
1910, Sir Edward Albert Sharpey-Schafer suggested that to the report of 2015.
diabetics individuals lacked a single chemical which was
normally produced by the pancreas and later this chemical Economic burden of diabetes mellitus
was named as insulin (Himsworth, 1936) [6]. In 1921, Diabetes mellitus is a very expensive disease in terms of its
Frederick Grant Banting and Charles Herbert Best isolated long-term microvascular and macrovascular complications
insulin from bovine pancreases at the University of Toronto in and their treatment cost. These complications hampers both
Canada. Later Sir Harold Percival made the distinction life expectancy and quality of life (Ashcroft and Ashcroft,
between type I and type II diabetes (Himsworth, 1936) [6]. 1992; Collins, 2002; Votey and Peters, 2004) [8, 9, 3].
Other historical discoveries in this field are: identification of According to Kirigia et al. (2009) [10], diabetes mellitus poses
sulfonylureas in 1942, the radioimmunoassay for insulin a big economic burden with regards to health system costs,
discovered by Rosalyn Yallow and Solomon Berson, indirect costs arising from patient disability and premature
discovery of the metabolic syndrome by Reaven in 1988 and mortality, time spent by family members, and intangible costs
identification of thiazolidinediones in the 1990s in the of psychological pain to the family and loved ones. Barcelo et
treatment of diabetes (Patlak, 2002) [5]. al. (2003) [11] estimated total annual cost of diabetes in Latin
America and the Caribbean to be US$65.216 billion. With
Prevalence of diabetes mellitus type 1 diabetics in India, Shobhana et al. (2002) [12] estimated
Diabetes is one of the largest global health burdens of this that the cost of treatment could be as high as US$50 million.
century. Each year more and more people becoming prone to According to American Diabetes Association, the combined
this life-changing complication. About 415 million adults are direct and indirect costs of diabetes in 1997 were estimated at
estimated to currently have diabetes but many countries are US$98 billion in the United States of America. Total direct
still unaware of the social and economic impact of this costs of diabetes in Spain is over US$650 million in 1994
disease. This lack of understanding is the biggest barrier to according to Hart et al., (1997) [13]. In England and Wales, the
effective prevention strategies of diabetes (IDF, 2015) [7] estimated cost of type 1 diabetes is US$1.92 million
Most regions over the globe are facing a continuous increase according to Gray and Fenn (1995) [14]. As Kirigia et al.
in diabetics. The Western Pacific Region has 153 million (2009) [10] indicate, the effectiveness of prevention and control
adults with diabetes whereas the North America and of those illnesses rely largely on the performance of health
Caribbean Region has one out of eight adults with the disease. systems, functions of leadership and governance; health
Europe has approximately 140,000 number of children with workforce; medical products, vaccines and technologies;
type 1 diabetes. In the South-East Asia Region, 24.2% of all information; financing; and services delivery.
live births face high blood glucose during pregnancy. In the

Classification of diabetes mellitus

Table 1: Classification of diabetes mellitus (Deepthi et al., 2017) [15]

Type Characteristics feature
Type 1 (1a and 1b) Secretion of insulin was reduced due to damage of β-cells Own body tissues are damaged by self-antibodies.
Insulin scantiness occur due to Insulin secretion and insulin resistance. Imperfection of ß-cell functions genetically.
Type 2
Failure in insulin secretion genetically.
Pancreatic endocrinopathy. Indigenous infections like rubella and cytomegalovirus induced by drugs or chemicals.
Other specific types
Other genetic indisposition.
Temporary and appears during third trimester of pregnancy. After delivery, blood sugar levels generally return to
Gestational diabetes
normal.

Type 1 diabetes intestinal tract leading to the destruction of insulin producing

Auto immune response: It is expressed as a consequence of pancreatic β cells.
autoimmune disease (Reuveni et al. 2016; Zou et al., 2016;
Yanqiang et al., 2016; Allen et al., 2015; Zhang, 2013) [16, 17, Type 2 diabetes
18, 19]
where the beta cells of pancreas are slowly demolished Type 2 Diabetes ranges from Insulin Resistance with Relative
by the body's own immune system which reduces insulin Insulin Deficiency to Predominantly an Insulin Secretory
production. Defect with Insulin Resistance. This form of diabetes
Genetic factors: Investigators have designated at least 18 accounts for 90-95% of diabetes. It was previously referred to
genetic positions as IDDM1-IDDM18 (Insulin dependent as non-insulin dependent diabetes, type 2 diabetes, or adult-
diabetes mellitus), which are related to type 1 diabetes. The onset diabetes. It encompasses individuals with insulin
IDDM1 (Insulin dependent diabetes mellitus) region contains resistance and relative (rather than absolute) insulin
the HLA (Human leukocyte antigen) genes that encode deficiency. The specific etiologies are still unknown.
proteins called major histocompatibility complex. In this Autoimmune destruction of b-cells does not occur in this case.
location immune responses are affected by these genes. Most patients are found obese and this obesity itself causes
Environmental factors: Due to abrupt stress like an infection some degree of insulin resistance. Ketoacidosis often occurs
where the β-cells of pancreas falls below 5-10%. Coxsackie spontaneously in this diabetes. Type 2 diabetes frequently
viruses are a family of enteric viruses which attack the remains undiagnosed because of gradual onset of
~ 2363 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

hyperglycemia and at earlier stages the patient shows none of abnormalities causing the inability to convert proinsulin to
the classic symptoms of diabetes. Risk for development of insulin have been identified is inherited in an autosomal
macrovascular and microvascular complications is greater dominant pattern. The resultant glucose intolerance is mild.
here. Whereas patients with this diabetes may have normal or Similarly, the production of mutant insulin molecules with
elevated insulin levels. Thus, insulin secretion is defective in resultant impaired receptor binding is associated with an
these patients and insufficient to compensate for insulin autosomal inheritance and only mildly impaired or even
resistance. Weight reduction and/or pharmacological normal glucose metabolism.
treatment of hyperglycemia may improve insulin resistance. Genes proposed to be associated with type 2 diabetes risk
The risk of onset of this form of diabetes increases with age, include:
obesity, and lack of physical activity. It occurs more  TCF7L2, affecting insulin secretion and glucose
frequently in women with prior Gestational Diabetes Mellitus production
and in individuals with hypertension or dyslipidemia, and its  the sulfonylurea urea receptor (ABCC8), which plays
frequency varies in different racial/ ethnic subgroups. A role in regulation of insulin
strong genetic predisposition is often observed here.  Calpain 10, associated with type 2 diabetes risk in
However, the complex genetics of this form of diabetes are Mexican Americans
not fully defined.  glucose transporter 2 (GLUT2), which helps glucose to
This kind of diabetes also has a powerful genetic move into the pancreas
predisposition. It is suggesting that twins have 100%  The glucagon receptor (GCGR), a glucagon hormone
approaching rate for diabetes. Nearly 85% of population with engaged in glucose regulation (Winter, 2014) [23].
type 2 diabetes (Tiki 2016; Yamada et al., 2016; Nealon et
al., 2016) [20, 21, 22] are obese that causes insulin resistance. To Biochemical background of diabetes mellitus
predict the risk of type 2 Body Mass Index (BMI) is used as a Glucose is the body’s primary energy source circulating in the
measure. blood as a mobilizable fuel source for living cells (Piero,
2006; Kibiti, 2006; Njagi, 2006) [24, 25, 26]. A pancreatic
Drug-or chemical-induced diabetes hormone, insulin is responsible for blood glucose level
Many drugs impairing insulin secretion may not cause regulation. Its receptor sites locate on peripheral side of the
diabetes by themselves, but they may precipitate diabetes in cell membranes. It affords entry of glucose into respiring cells
individuals with insulin resistance. Certain toxins such as and tissues via requisite channels. Insulin stimulates
Vacor (a rat poison) and intravenous pentamidine can catabolism on glucose into pyruvate through glycolysis. It
permanently destroy pancreatic b-cells. Many drugs and also upregulates glycogenesis from excessive cytosolic
hormones like nicotinic acid and glucocorticoids can impair glucose and lipogenesis from excessive cytosolic acetyl-CoA.
insulin action. These metabolic events are antagonistic to metabolic events
triggered by the hormone glucagon. At or below threshold
Infections related diabetes level, glucose stays in the blood instead of entering the cells
Diabetes occurs in patients infected with congenital rubella, (Belinda, 2004) [27] when the body attempts to arrest
coxsackievirus B, cytomegalovirus, adenovirus, and mumps. hyperglycemia, by drawing water out of the cells and into the
bloodstream. The excess sugar is excreted in the urine. As a
Uncommon forms of diabetes result, diabetics present with constant thirst, drinking large
In this category, there are two known conditions, and others amounts of water. So, polyuria develops as the cells try to get
are likely to occur. The stiff-man syndrome is an autoimmune rid of the extra glucose. This subsequently leads to glucosuria
disorder where patients usually have high titers of the GAD (Piero, 2006) [24]. As hyperglycemia prolongs, the body cells
autoantibodies, and one-third of them develop diabetes. Anti- are devoid of glucose due to the lack of insulin. Then the cells
insulin receptor antibodies can cause diabetes. They bind to start to seek alternative mobilizable energy sources. In this
the insulin receptor and block the binding of insulin to its regard, the cells turn to fatty acids stored in adipose tissue.
receptor of target tissues. Anti-insulin receptor antibodies are The fats are not fuel sources for the red blood cells, kidney
occasionally found in patients with systemic lupus cortex and the brain. The red blood cells lack mitochondria in
erythematosus and other autoimmune diseases. In case of which beta-oxidation pathway rests. The fatty acids cannot
extreme insulin resistance, patients with anti-insulin receptor pass the blood-brain barrier. To supply energy to such cells
antibodies exhibit acanthosis nigricans and this syndrome was and tissues, the acetyl-CoA arising from catabolism of fatty
termed type B insulin resistance. acids is diverted to ketogenesis to produce ketone bodies. This
in turn serve as alternative fuel sources for such cells and
Other genetic syndromes sometimes associated with tissues. These ketone bodies are also passed in the urine,
diabetes thereby leading to ketonuria, which characterizes diabetes
Many genetic syndromes like the chromosomal abnormalities mellitus. Buildup of ketone bodies in the blood produces
of Down syndrome, Klinefelter syndrome, and Turner ketosis. Ketone bodies are acidic in nature which lower blood
syndrome are accompanied by an increased incidence of pH, leading to acidosis. This resultant combination of ketosis
diabetes. Wolfram syndrome is an autosomal recessive and acidosis leads to a condition called ketoacidosis. If left
disorder presenting insulin-deficient diabetes and the absence untreated, ketoacidosis leads to coma and death (Belinda,
of b-cells at autopsy. Other manifestations include diabetes 2004) [27].
insipidus, hypogonadism, optic atrophy, and neural deafness.
Pathophysiological aspects
Genetic involvement of diabetes Type 2 DM is characterized by insulin insensitivity due to
The most common mutation occurs at position 3,243 in the insulin resistance which declines insulin production, and
tRNA leucine gene, leading to an A-to-G transition and this eventual pancreatic beta-cell failure. This leads to a decrease
point mutation is associated with Diabetes. Genetic in glucose transport into the liver, muscle cells and fat cells.
~ 2364 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

There is an increase in the breakdown of fat with attenuates long term potentiating and might lead to deficits in
hyperglycemia (Kahn 1994) [28]. Type 1 diabetic patients are learning and memory. Type 2 diabetes is accompanied both
usually young (children or adolescents) and not obese when by insulin resistance and by impaired insulin secretion, each
they first develop symptoms. There is an inherited of which are important in its pathogenesis. Such patients are
predisposition, with a 10-fold increased incidence in first- often obese and usually present in adult life, the incidence
degree relatives of an index case, and strong associations with rising progressively with age as B-cell function declines.
particular histocompatibility antigens (HLA types). Later this insulin resistance leads to both Aβ plaque formation
Experiment with identical twins have shown that genetically as well as tau hyperphosphorylation. During
predisposed individuals require to be exposed to an hyperinsulinemia, insulin and Aβ competes for insulin
environmental factor like viral infection. Viral infection may degrading enzyme, leading to Aβ accumulation and plaque
damage pancreatic B cells and expose antigens that initiate a formation. A decrease in insulin receptor signaling leads to
self-perpetuating autoimmune process. The patient becomes inhibition of Akt and dephosphorylation (activation) of GSK-
overtly diabetic only when more than 90% of the beta cells 3β and results in tau hyperphosphorylation (Rang and Dale,
have been destroyed. In this type, insulin deficiency 2007; Robertson, 1995) [29, 30]

Fig 1: Pathophysiology of Type I and Type II diabetes. Abbreviations: Aβ- Amyloid- β, GSK-3β-glycogen synthase kinase 3β, LTP- long term
potentiation, P- Phosphate (Chinmay et al., 2015) [31]

As the disease progresses, tissue or vascular damage ensues

severe diabetic complications such as retinopathy,
neuropathy, nephropathy, cardiovascular complications and
ulceration. Long standing type 1 DM patients are susceptible
to microvascular complications; and macrovascular disease
(coronary artery, heart and peripheral vascular diseases)
(Svensson et al., 2004; Saely et al., 2004) [32, 33]. Type 2 DM
caries a high risk of large vessel atherosclerosis which is
associated with hypertension, hyperlipidaemia and obesity.
Most patients with type 2 diabetes die from cardiovascular
complications and end stage renal disease (Bastaki et al.,
2005) [34].

Pathological pathways involved in diabetes

There are four key metabolic pathways playing major role in
hyperglycaemia-induced cell damage and diabetes associated
complications such as
(a) increased polyol pathway flux;
(b) increased advanced glycation end product (AGE)
formation;
(c) activation of protein kinase C and Fig 2: Hyperglycaemia-induced reactive oxygen species (ROS)
(d) increased hexosamine pathway flux (Robertson, 1995) [30] generation and diabetic-associated pathological complications. ↑:
In diabetes, cell damages are manifested through damage to Stimulate↓: Inhibit (Swagat et al., 2016) [35]
proteins, lipids and carbohydrates, while the diabetic-
associated complications include diabetic nephropathy, Role of insulin in diabetes mellitus
retinopathy, neuropathy, etc. Insulin is a polypeptide hormone synthesized in humans and

~ 2365 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

other mammals within the beta cells of the islets of release. Insulin is the major hormone that enables muscle and
Langerhans in the pancreas. The islets of Langerhans form the fat cells to uptake glucose from the bloodstream. Insulin
endocrine part of pancreas, accounting for 2% of the total causes most body tissues to remove glucose from the blood
mass of the pancreas, with beta cells constituting 60-80% of for use as fuel, for conversion to other needed molecules, or
all the cells of islets of Langerhans (Anon, 2004) [36]. Insulin for storage in body. Besides, insulin acts as the major
keeps a number of effects in many tissues, with liver, muscle, regulatory signal for glycogenesis in the hepatocytes and
and adipose tissue as its important target organs. The basic myocytes (WHO, 1999) [41]. Higher insulin levels cause
physiological function of insulin is promoting the synthesis of upregulation of various anabolic processes including cell
carbohydrates, proteins, lipids, and nucleic acids. The effects growth, cellular protein synthesis, and fat storage. Insulin is
of insulin on carbohydrate metabolism are like stimulation of more of an anabolic hormone rather than catabolic. Scantiness
glucose transport across muscle and adipocyte cell of insulin or poor cellular response to insulin and defective
membranes, regulation of hepatic glycogen synthesis, and insulin leads to improper handling of glucose by body cells.
inhibition of glycogenolysis and gluconeogenesis (Piero, This also leads to improper glucose storage in the liver and
2006) [24]. The end result of these actions is a reduction in muscles which eventually leads to persistently high levels of
blood glucose concentration. In case of protein metabolism, blood glucose, poor protein synthesis, and different metabolic
insulin promotes transfer of amino acids across membranes, derangements (WHO, 1999) [41]. The chronic hyperglycemia
stimulates protein synthesis, and also inhibits proteolysis. arising from diabetes mellitus accompanies long-term
Incorporation of fatty acids from circulating triglyceride into damage, dysfunction, and failure of various organs, especially
adipose triglyceride and lipid synthesis are stimulated by the eyes, kidneys, nerves, heart, and blood vessels.
insulin; lipolysis is inhibited. Insulin also plays role in nucleic Autoimmune destruction of the pancreatic beta cells leads to
acid synthesis by stimulating the formation of ATP, DNA, insulin deficiency and bio-signalling derangements. These are
and RNA (Cahill, 1971) [37]. Insulin initiates its physiological consequent to insulin resistance or insensitivity. Defective
effects by binding to a high affinity specific receptor located insulin secretion and defective insulin action frequently
on the plasma membrane. The insulin receptor is saturable, coexist in the same patient. In type 2 diabetes mellitus,
and both the binding capacity and at a plasma insulin postabsorptive hepatic glucose production is increased and it
concentration of 20 to 30 μU/ml the binding capacity and is correlated with fasting plasma glucose concentration. In
biological activity are maximal. Insulin is not altered during type 2 diabetes mellitus, gluconeogenesis drastically increases
the binding process, and reaction of the disulfide bonds is not rather than glycogenolysis (Consoli, 1992) [42]. This enhanced
involved. Upon binding to the receptor, insulin transmits its release of gluconeogenic precursors causes increased total
signal to the interior of the cell using a second messenger to glucose output. But this unnecessary gluconeogenesis can be
influence enzymatic processes. By this way, insulin probably improved by inhibition of glycogenolysis and/or
carries out its actions without entering the cell (Kibiti, 2006) gluconeogenesis from endogenous precursors. Stimulation of
[25]
. Two membrane-bound enzyme systems are involved in intrahepatic disposal of neoformed glucose contributes to
the insulin signal: the adenyl cyclase- cAMP and the autoregulation. According to Tappy (1995) [43], intrahepatic
Magnesium - activated Sodium- Potassium- ATPase systems. disposal of glucose-6-phosphate plays a major role in the
Insulin inhibits cAMP formation only in situations where it control of endogenous glucose production. Studies by Kahn
has been previously stimulated by catecholamines, glucagons, and Porte (1988) [28], established that the degree of impaired
or other hormones. Insulin also stimulates intracellular beta-cell responsiveness to glucose is closely related to the
Potassium transport (Steiner, 1977) [38]. In turn, potassium is degree of fasting hyperglycemia but in a curvilinear fashion.
an important factor in membrane potential and enzymatic Decreased insulin secretion and defective cellular insulin
regulation. Magnesium is involved in the activation of many action also compromises efficient glucose uptake by
intracellular enzymes. Intracellular Magnesium accumulation peripheral tissues. This derangement gets more predominant
is also promoted by insulin. It has been proposed that the as the islet dysfunction declines. Halter et al. (1985) [44] argue
insulin membrane receptor is located in the vicinity of the that even if fasting insulin levels are comparable between type
Magnesium-dependent Sodium-Potassium-ATPase system 2 diabetics and normal subjects, insulin secretion is markedly
and that activation of the receptor modifies the activity of this impaired in type 2 diabetics in relation to the degree of
system. This accumulation of intracellular magnesium causes hyperglycemia present. Furthermore, in a noninsulin-
activation of critical intracellular enzymes. After an overnight dependent diabetes mellitus the extent of fasting
fast, the 8.00 am normal plasma insulin concentration ranges hyperglycemia patient is closely related to the degree of
from 5 to 15 µU/ml. Postprandial values, 100g glucose can be impaired pancreatic beta-cell responsiveness to glucose.
5 to 10 times higher than the baseline. Insulin output under
basal condition approximates 0.5 to 1.0 U/h and increases Complications of diabetes mellitus
about 5 times after food ingestion (Steiner, 1977) [38]. The complications are far less common and less severe if the
Mediating tissue glucose uptake by insulin is an important blood sugar levels have been well-controlled. According to
step in glucose homeostasis and to clear the postprandial Edwin and his colleague’s, acute complications include
glucose load (Reaven, 1983) [39]. The insulin production is diabetic ketoacidosis, non-ketotic hyperosmolar coma, and
directly proportional to the amount of sugar (carbohydrate) diabetic coma. In case of chronic complication, chronic
consumed. In case of more sugar consumption, the body will elevation of fasting blood glucose level leads to damage of
have to produce more insulin. But the tiny pancreatic beta blood vessels (Edwin et al., 2008) [45]. This chronically
cells cannot produce this required level of insulin. Because of elevated blood glucose levels lead to increased mitochondrial
a limited capacity to produce insulin, the forced over- reactive oxygen species (ROS) production. This in turn
production of insulin will eventually exhaust that capacity and activates a number of metabolic pathways whose end products
the cells will cease to operate (Robert, 2002) [40]. However, leads to the development of long-term complication of
blood glucose levels always do not act as the regulatory factor diabetes (Weiss and Sumpio, 2006) [46]. These metabolic
for insulin production and insulin is stored in cells before its pathways are activated by hyperglycemia-induced ROS that
~ 2366 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

includes the polyol pathway, formation of AGE, hexosamine retinopathy, neuropathy and nephropathy. Macro-vascular
pathway and the protein kinase C (PKC) pathway as shown complications can also lead to cardiovascular disease and
the figure 2 (Forbes and Cooper, 2013) [47]. In diabetes, the atherosclerosis disorders namely: (1) Coronary artery disease,
subsequent problems are grouped under "micro-vascular (2) Stroke (mainly ischemic type), (3) Peripheral vascular
complication” due to damage to small blood vessels and disease, which contributes to intermittent claudication
"macro-vascular complication" due to damage of the arteries (exertion-related foot pain) as well as diabetic foot (Edwin et
(ADA, 2011) [48]. Micro-vascular complications can lead to al., 2008) [49].

Fig 3: Metabolic pathways activated by chronically elevated blood glucose levels and long-term complications of diabetes mellitus, DAG-
Diacylglycerol, PKC- protein Kinase C, Glc - Glucosamine, UDP- Uridine diphosphate, Nac- N- Acetylglucosamine (Weiss and Sumpio, 2006)
[46]

Diagnosis of diabetes mellitus 126 mg/dL (7 mmol/L) or higher on two separate tests
According to the American Diabetes Association (ADA), the diabetes is confirmed.
fasting glucose concentration should be used in routine
screening for diabetes; but postprandial blood sugar, random Oral glucose tolerance test: Blood sugar level is measured
blood sugar and glucose tolerance tests are also used for blood after fasting overnight. Then blood sugar levels are tested
sugar determination. For the diagnosis of diabetes, at least one periodically for the next two hours after consuming a sugary
criterion must apply: Symptoms of diabetes (polyurea, liquid. If blood sugar level is less than 140 mg/dL (7.8
polydipsia, unexplained weight loss, etc.) as well as casual mmol/L), it is normal. A reading of more than 200 mg/dL
plasma glucose concentration = 11.1 mmol/L (200 mg/dL). (11.1 mmol/L) after two hours is indicative of diabetes. A
The normal range of fasting plasma glucose is 70-110 mg/dl result between 140 and 199 mg/dL (7.8 mmol/L and 11.0
with no caloric intake for at least 8 h. The World Health mmol/L) indicates prediabetes.
Organization (WHO) proposed classification that includes If type 1 diabetes is suspicious, urine will be tested to find the
both clinical stages (normoglycaemia, impaired glucose presence of a byproduct produced when muscle and fat tissue
tolerance/impaired fasting glucose (IGT/IFG), diabetes) and are used for energy when the body doesn't have enough
etiological types of diabetes mellitus, identical to the ADA insulin to use the available glucose (ketones) (Mayo Clinic,
except that WHO group includes classification formerly 2014) [49].
known as gestational impaired glucose tolerance (GIGT) and
GDM: fasting glucose = 7.0 mmol/L (126 mg/dL) and/or 2-h Management of diabetes mellitus
glucose = 7.8 mmol/L (140 mg/dL) after a 75-g OGTT. Goals of management
Primary prevention is the main aim at preventing diabetes
Diagnostics tests for diabetes and prediabetes from occurring in susceptible individuals or in general
Popularly used diagnostic criteria for diabetes is below population. Regular physical activity is an important
component of the prevention and management of type 2
Random blood sugar test: Randomly taken blood sugar level diabetes mellitus. According to Ross et al., (2000) [50],
of 200 milligrams per deciliter (mg/dL)-11.1 millimoles per increased physical activity, independently of other risk
liter (mmol/L)-or higher suggests diabetes. factors, has a protective effect against the development of
type 2 diabetes. Dietary and lifestyle modifications are the
Fasting blood sugar test: An overnight fasting blood sugar main goals of treatment and management for type 2 diabetes.
level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting The majority of people with type 2 diabetes is overweight and
blood sugar level between 100 and 125 mg/dL (5.6 to 6.9 usually has other metabolic disorders of the insulin resistance
mmol/L) is determined as an indicator of prediabetes. If it's syndrome, so the major aims of dietary and lifestyle changes
~ 2367 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

are to reduce weight, improve glycemic control and reduce in elderly patients with DM and use of short-acting glipizide
the risk of coronary heart disease (CHD), which accounts for should be preferred (Chiniwala and Jabbour, 2011) [55].
70% to 80% of deaths among those with diabetes (Bethesda, iii). Meglitinides: Repaglinide and nateglinide are non-
1995) [51]. Insulin replacement therapy is the only option for sulfonylurea secretagogues which act on the ATP-dependent
patients with type 1 DM while diet and lifestyle modifications K-channel in the pancreatic beta cells thereby stimulating the
are considered the cornerstone for the treatment and release of insulin from the beta cells, similar to sulfonylurea,
management of type 2 DM. Insulin is also important in type 2 though the binding site is different (Fuhlendorff et al., 1998)
[59]
DM when blood glucose levels cannot be controlled by diet, . Meglitinides exhibit a rapid onset and a short duration of
weight loss, exercise and oral medications. Oral action (4-6 hrs) and thus lower risk of hypoglycemia. These
hypoglycemic agents are also useful in the treatment of type 2 agents are given before meals for postprandial blood glucose
DM. Available oral hypoglycemics include sulphonylureas, control. Preprandial administration allows flexibility in case a
biguanides, alpha glucosidase inhibitors and meal is missed without increased risk of hypoglycemia
thiazolidenediones. Their main goal is to restore normal (Blicklé, 2006) [60]. Repaglinide is mainly metabolized in the
metabolic disorder such as insulin resistance and inadequate liver with very minimal amounts excreted via the kidneys and
insulin secretion from pancreas. Diet and lifestyle strategies thus dose adjustment is not necessary in patients with renal
are to reduce weight, improve glycemic control and reduce insufficiency except those with end-stage renal disease
the risk of cardiovascular complications, which account for (Fuhlendorff et al., 1998) [59].
70% to 80% of deaths among those with diabetes (Kumar et iv). Thiazolidinediones: Thiazolidinedione is an insulin
al., 2002) [52]. sensitizer, selective ligands transcription factor peroxisomes
proliferator-activated gamma. They are the first drugs to
Life style management address the basic problem of insulin resistance in type 2 DM
It is apparently the cornerstone of management of diabetes patients (Yki-jarvinen, 2004) [61] whose class now includes
mellitus. Lifestyle modification programs have exhibited mainly pioglitazone after the restricted use of rosiglitazone
significant improvement of risk factors for diabetes; although, recommended by Food and Drug Administration (FDA)
the effect on diabetes incidence has not been reported recently due to increased cardiovascular events reported with
(Rebecca et al., 2009) [53]. The dietary management of rosiglitazone. Pioglitazone use is not associated with
diabetes mellitus complementary to lifestyle management. In hypoglycemia and can be used in cases of renal impairment
type 2 diabetes, the dietary objective is for improved glycemic and thus well tolerated in older adults. On the other hand, due
and lipid levels and weight loss as appropriate (Piero et al., to concerns regarding peripheral edema, fluid retention and
2006) [24]. Suggesting that majority of type 2 DM can be fracture risk in women, its use can be limited in older adults
prevented by lifestyle modification. Patients with type 2 DM with DM. Pioglitazone should be avoided in elderly patients
should receive a medical nutrition evaluation and their with congestive heart failure and is contraindicated in patients
lifestyle recommendations should be tailored according to with class III-IV heart failure (Coniff et al., 1995) [62].
physical and functional ability. v). Alpha-Glucosidase Inhibitors: Acarbose, Voglibose and
Miglitol have not widely been used to treat type 2 DM
Pharmacological agents individuals but are likely to be safe and effective. These
i). Biguanides: Metformin is the most commonly used agents are most effective for postprandial hyperglycemia and
Biguanide in overweight and obese patients which suppresses should be avoided in patients with significant renal
hepatic glucose production, increases insulin sensitivity, impairment. Their use is usually limited due to high rates of
enhances glucose uptake by phosphorylating GLUT-enhancer side-effects such as diarrhoea and flatulence (Chiniwala et al.,
factor, increases fatty acid oxidation, and decreases the 2011) [55]. Voglibose, the newest of this class, has been shown
absorption of glucose from the gastrointestinal tract (Collier et significantly improved glucose tolerance, in terms of delayed
al., 2006) [54] Research published in 2008 shows further disease progression and in the number of patients who
mechanism of action of metformin as activation of AMP- achieved normoglycemia (Kawamori et al., 2009) [63].
activated protein kinase, an enzyme that plays a role in the vi). Incretin-Based Therapies: Glucagon-like peptide 1 (GLP-
expression of hepatic gluconeogenic genes. Due to the 1) analogues are the foundation of incretin-based therapies
concern of development of lactic acidosis, metformin should which are to target this previously unrecognized feature of
be used with caution in elderly diabetic individuals with renal DM pathophysiology resulting in sustained improvements in
impairment. It has a low incidence of hypoglycemia glycemic control and improved body weight control
compared to sulfonylureas (Collier et al., 2006) [54]. (Stonehouse et al., 2011) [64]. They are available for use as
ii). Sulfonylureas: These are generally well tolerated but monotherapy, as an adjunct to diet and exercise or in
because they stimulate endogenous insulin secretion, they combination with oral hypoglycemic agents in adults with
carry a risk of hypoglycemia (Chiniwala and Jabbour, 2011) type 2 DM. Examples are Exenatide, an incretin mimetic, and
[55]
. Elderly patients, with DM who are treated with Liraglutide (Chiniwala et al., 2011) [55]. There is no risk of
sulfonylureas have a 36% increased risk of hypoglycemia hypoglycemia with the use of GLP1 therapies (unless
compared to younger patients (Staa et al., 1997) [56]. combined with insulin secretagogues). According to emerging
Glyburide is associated with higher rates of hypoglycemia evidence, incretin-based therapies may show a positive impact
compared to glipizide (Shorr et al., 1996) [57]. Some age- on inflammation, cardiovascular and hepatic health, sleep, and
related risk factors of hyperglycemia are impaired renal the central nervous system (Stonehouse et al., 2011) [64].
function, simultaneous use of insulin or insulin sensitizers, vii). Dipeptidyl-Peptidase IV Inhibitors: These agents inhibit
age greater than 60 years, recent hospital discharge, alcohol dipeptidyl peptidase-4 (DPP-4), a ubiquitous enzyme that
abuse, caloric restriction, multiple medications or medications rapidly inactivates both GLP-1 and GIP, increase active levels
that potentiate sulfonylurea actions (Scheen, 2005) [58]. Use of of these hormones and, in doing so, improves islet function
long acting sulfonylurea such as glyburide should be avoided and glycemic control in type 2 DM (Pratley et al., 2007) [65].
This new class of anti-diabetogenic drugs provides
~ 2368 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

comparable efficacy to current treatments. This drugs are well The long acting forms are cause lesser extent of
tolerated, carry a low risk of hypoglycemia and are weight hypoglycemia compared to the short acting forms.
neutral. However, they are relatively expensive (Pratley and ix). Insulin analogues: Insulin therapy was limited in its
Salsali, 2007) [65]. The long-term durability of effect on ability to mimic normal physiologic insulin secretion.
glycemic control and beta-cell morphology and function Traditional intermediate- and long acting insulins (NPH
remain to be established (Pratley et al., 2007) [65]. insulin, lente insulin, and ultralente insulin) are limited by
viii). Insulin: Insulin is used alone or in combination with oral inconsistent absorption and peaks of action that may result in
hypoglycemic agents. Basal insulin provides beneficial hypoglycemia (Burge and Schade, 1997; Cameron and
augmentation therapy if some beta cell function remains. Bennett, 2009) [67, 68]. The pharmacokinetic profiles of the new
Replacement of basal-bolus insulin is required is case of beta insulin analogues are distinct from those of the regular
cell exhaustion. Rescue therapy using replacement is insulins, and their onset and durations of action range from
necessary in cases of glucose toxicity which should mimic the rapid to prolonged. Currently, two rapid-acting insulin
normal release of insulin by the beta cells of the pancreas analogues, insulin lispro and insulin aspart, and one long-
(Mayfield et al., 2004) [66] Insulin comes in injectable forms - acting insulin analogue, insulin glargine, are available (Burge
rapid acting, short acting, intermediate acting and long acting. and Schade, 1997; Cameron and Bennett, 2009) [67, 68]

Fig 4: Major target organs and actions of orally administered antihyperglycemic agents in type 2 diabetes mellitus. Abbreviations: TZD =
thiazolidinedione; FFA = free fatty acid; AGI = alpha glucosidase inhibitor (Cheng and Funtus, 2005) [69]

Conclusion Funding/ Support

Diabetes mellitus, a combination of several different There was no funding for this study and authors are thankful
metabolic disorders, if left untreated, causes abnormally high to Jahangirnagar University, Savar, Dhaka, Bangladesh for
concentration glucose in the blood. Diabetes mellitus type 1 different supports.
develops when the pancreas no longer produces significant
amounts of the hormone insulin due to the autoimmune References
destruction of the insulin-producing beta cells of the pancreas. 1. Sicree R Shaw J, Zimmet P. The Global Burden.
On the other hand, Diabetes mellitus type 2 is thought to Diabetes and Impaired Glucose Tolerance. Prevalence
result from autoimmune attacks on the pancreas and/or insulin and Projections. In: Gan, D. ed. Diabetes Atlas, 3rd edn.
resistance. The pancreas of a type 2 diabetic individual may Brussels: International Diabetes Federation, 2006, 16-
be producing normal or even abnormally excessive amounts 103.
of insulin. The main goal of diabetes management mainly 2. Shillitoe RW. Psychology and diabetes: Psychosocial
focuses to restore carbohydrate metabolism to a normal state. factors in management and control, 1988.
To achieve this goal, individuals with an absolute deficiency 3. Votey SR, Peters AL. Diabetes mellitus type 2. A review.
of insulin require insulin replacement therapy in the form of http://www.emedicine.com/emerg/topic133.htm
injectables or tablets. In contrast, dietary modifications and Accessed, 2006.
exercise can correct insulin resistance. Other goals of diabetes 4. World Health Organization. Prevention of diabetes
management are to prevent or treat the many complications mellitus, Technical Report Series no. 844. Geneva:
arising from diabetes and to make its treatment safe. By World Health Organization, 1994.
maintaining a controlled the blood sugar, diabetes cannot 5. Patlak M. New weapons to combat an ancient disease:
prevent a patient from enjoying a joyful life. Treating diabetes. Federation of American Society for
Experimental Biology. 2002;16(14):1853-1857.
Conflict of interests 6. Himsworth HP. Diabetes mellitus: its differentiation into
The authors have no conflicts of interests. insulin-sensitive and insulin-insensitive types. Lancet.
1936; 227(5864):127-130.

~ 2369 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

7. In Gan, D ed. Diabetes Atlas, 3rd edn. Brussels: 25. Kibiti CM. Hypoglycaemic potential of some Kenyan
International Diabetes Federation. 2006, 16-103. plants used in traditional medicine in Rift valley, Nairobi
8. Ashcroft FM, Ashcroft SJH. Insulin, Molecular Biology and Eastern provinces, Msc thesis, Kenyatta University,
to Pathology. Oxford University Press, 1992, 266-284. 2006.
9. Collins FM. Current treatment approaches to type 2 26. Njagi JM. Hypoglycemic effects of some Kenyan plants
diabetes mellitus successes and shortcomings. American used traditionally in the management of diabetes mellitus
Journal of Managed Care. 2002; 8(16):460-471. in Gachoka division, Mbeere district, Msc thesis,
10. Kirigia JM, Sambo HB, Sambo LG, Barry SP. Economic Kenyatta University, Kenya, 2006.
burden of diabetes mellitus in the WHO African region. 27. Belinda R. Gale Encyclopaedia of Alternative Medicine,
BMC International Health and Human Rights, 2009, 9:6. 2004; 2603-2605.
11. Barcelo A, Aedo C, Rajpathak S, Robles S. The cost of 28. Kahn SE, Porte DJr. Islet dysfunction in noninsulin-
diabetes in Latin America and the Caribbean. Bulletin of dependent diabetes mellitus. AM J Med. 1988; 85(5A):4-
the World Health Organization. 2003; 81(1):19-27. 8
12. Shobhana R, Rao PR, Lavanya A, Williams R, Padman 29. Rang HP, Dale MM, Ritter JM, Flower RJ. The
C, Vijay V et al. Cost incurred by families having Type 1 endocrine pancreas and the control of blood glucose in
diabetes in a developing country – a study from Southern Rang and Dales Pharmacology, 6th ed, Edinburgh:
India. Diabetes Research and Clinical Practice, 2002; Church Livingstone, 2007; 397-409.
55(1):45-48. 30. Robertson RP. Antagonist: diabetes and insulin
13. Hart WM, Espinosa C, Rovira J. Cost of unknown resistance–philosophy, science, and the multiplier
diabetes mellitus in Spain. Med Clin (Barcelona). 1997; hypothesis. J Lab Clin Med. 1995; 125(5):560-564.
109:289-293. 31. Chinmay DD, Jain A. Diabetes Mellitus: A Review Int. J.
14. Gray A, McGuire A, Fenn P. The cost of insulin Pure App. Biosci. 2015; 3(3):224-230.
dependent diabetes mellitus (IDDM) in England and 32. Svensson M, Eriksson JW, Dahlquist G. Early glycemic
Wales. Diabetic Med. 1995; 12(12):1068-1076. control, age at onset, and development of microvascular
15. Deepthi B, Sowjanya K, Lidiya B, et al. A Modern complications in childhood-onset type 1 diabetes: a
Review of Diabetes Mellitus: An Annihilatory Metabolic population-based study in northern Sweden. Diabetes
Disorder. J In Silico In Vitro Pharmacol. 2017; 3:1. Care. 2004; 27:955-962.
16. Reuveni D, Gertel-Lapter S, Aricha R, Mittleman M, 33. Saely CH, Aczel S, Marte T. Cardiovascular
Fuchs S, et al. Erythropoietin Ameliorates Experimental complications in type 2 diabetes mellitus depend on the
Autoimmune Myasthenia Gravis. J Clin Exp coronary angiographic state rather than on the diabetes
Neuroimmunol, 2016, 1:108. state. Diabetologia. 2004; 47:145-146.
17. Zou L, Karim RM, Wang YF. The Research Progress of 34. Bastaki S. Review Diabetes mellitus and its treatment, Int
Long Noncoding RNAs in Autoimmune Diseases. J J Diabetes & Metabolism. 2005; 13:111-134.
Neurol Neurophysiol, 2016; 7:359 35. Swagat KD, Dibyajyoti S, Jayanta KP, Luna S, Thatoi H.
18. Allen HB, Shaver CM, Etzler CA, Joshi SG. Antidiabetic potential of mangrove plants: a review.
Autoimmune Diseases of the Innate and Adaptive Frontiers in Life Science. 2016; 9(1):75-88.
Immune System including Atopic Dermatitis, Psoriasis, 36. Anonymous Diagnosis and Classification of Diabetes
Chronic Arthritis, Lyme Disease and Alzheimer’s Mellitus – Position Statement, 2004.
Disease. Immunochem Immunopathol, 2015; 1:112. 37. Cahill GF Jr, Boston MD. Physiology of insulin in man.
19. Zhang Y. Emerging Vitamin D Receptor-Centered Diabetes. 1971; 20(12):785-799.
Patterns of Genetic Overlap across Some Autoimmune 38. Steiner DF. Insulin today, Diabetes. 1977; 26:322-340
Diseases and Associated Cancers. J Genet Syndr Gene 39. Reaven PD, Moritz TE, Schwenke DC, Anderson RJ,
Ther, 2013; 4:123. Criqui M, Detrano R et al. Intensive glucose lowering
20. Tiki T. Prevalence and Associated Factors of Depression therapy reduces cardiovascular disease events in VADT
among Type 2 Diabetes Mellitus Patients on Follow up at participants with lower calcified coronary atherosclerosis.
Ambo General Hospital, Oromia Regional State, Diabetes. 2009; 58:2642-2648.
Ethiopia, Institutional Based Cross-Sectional Study. J 40. Robert H. Diabetes Mellitus. Slim Forever International.
Depress Anxiety, 2016; 6:259. Diabetes Care. 2002; 1:27-31.
21. Yamada H, Suzuki D, Kakei M, Kusaka I, Ishikawa S. 41. World Health Organization. Department of
Close Association of Hypoadiponectinemia and Increased Noncommunicable Disease Surveillance. Definition,
Insulin Resistance in Non-Obese Japanese Type 2 diagnosis and classification of diabetes mellitus and its
Diabetes with Visceral Adiposity. J Metabolic Synd, complications; Geneva, 1999.
2016; 5:215. 42. Consoli A. Role of liver in pathophysiology of NIDDM.
22. Nealon RS, Sukala WR, Coutts RA, Zhou S. The Effect Diabetes Care,1992; 15(3):430-41.
of 28 Days of Beta-alanine Supplementation on Exercise 43. Tappy L. Regulation of hepatic glucose production in
Capacity and Insulin Sensitivity in Individuals with Type healthy subjects and patients with noninsulin-dependent
2 Diabetes Mellitus: A Randomised, Double-blind and diabetes mellitus. Diabetes metabolism 1995; 21(4):233-
Placebo-controlled Pilot Trial. Sports Nutr Ther, 2016; 40.
2:111. 44. Halter JB, Ward WK, Porte D Jr, Best JD, Pfeifer MA.
23. Winter S. The Role of Heredity in Type 2 Diabetes, 2014. Glucose regulation in non-insulindependent diabetes
http//www.healthline.com/health/type-2diabetes/genetics mellitus. Interaction between pancreatic islets and the
24. Piero MN. Hypoglycemic effects of some Kenyan plants liver. Am J Hart WM, Espinosa C and Rovira J Cost of
traditionally used in management of diabetes mellitus in unknown diabetes mellitus in Spain. Med Clin
eastern province, Msc thesis, Kenyatta University, 2006. (Barcelona). 1997; 109:289-293.

~ 2370 ~
Journal of Pharmacognosy and Phytochemistry http://www.phytojournal.com

45. Edwin J, Siddaheswar B, Dharam C. Diabetes and Herbal 64. Stonehouse AH, Darsow T, Maggs DG. Incretin-based
Medicines I.J.P.T. 2008; 7(1) 97-106. therapies. J Diabetes, 2011.
46. Weiss J, Sumpio B. Review of prevalence and outcome 65. Pratley RE, Salsali A. Inhibition of DPP-4: a new
of vascular disease in patients with diabetes mellitus. Eur therapeutic approach for the treatment of type 2 diabetes.
J Vasc Endovasc Surg. 2006; 31(2):143-150. Curr Med Res Opin. 2007; 23(4):919- 931.
47. Forbes J, Cooper M. Mechanisms of Diabetic 66. Mayfield JA, White RD. Insulin therapy for type 2
Complications Physiological Reviews Published. 2013; diabetes: rescue, augmentation, and replacement of beta-
93:137-188. cell function. Am Fam Physician 2004; 70(3):489-500.
48. ADA. Review on Diagnosis and Classification of 67. Burge MR, Schade DS. Insulins. Endocrinol Metab Clin
Diabetes Mellitus. Diabetes care. 2011; 34:62-69. North Am. 1997; 26(3):575-598.
49. Mayo Clinic. Test and Diagnosis of diabetes. 68. Cameron CG, Bennett HA. Cost-effectiveness of insulin
http://www.mayoclinic.org/diseases analogues for diabetes mellitus. CMAJ. 2009;
conditions/diabetes/basics/tests-diagnosis, 2014. 180(4):400-407.
50. Ross R, Dagnone D, Jones PJ. Reduction in obesity and 69. Cheng A, Fantus IG. Oral antihyperglycemic therapy for
related co-morbid conditions after diet induced weight type 2 diabetes mellitus. Canadian Medical Association
loss or exercise-induced weight loss in men. A Journal. 2005; 172:213-226.
randomized, controlled trial. Ann Int Med. 2000; 133:92-
103.
51. National Institutes of Health. Diabetes in America, 2nd
edition, Bethesda. MD: National Institutes of Health,
1995, 95-1468.
52. Kumar A, Goel MK, Jain RB, Khanna P, Chaudhary V.
India towards diabetes control: Key issues. Australas
Med J. 2013; 6(10):524-31.
53. Rebecca K, Ramaswamy R, Ganapathi B, Anura VK.
Effect of Supplementation of Coccinia Cordifolia extract
on Newly Detected Diabetic Patients. Diabetes Care.
2008; 31(2):216-220.
54. Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck
DJ. Metformin counters the insulin induced suppression
of fatty acid oxidation and stimulation of triacyglycerol
storage in rodents skeletal muscle.
55. Chiniwala N, Jabbour S. Management of diabetes
mellitus in the elderly. Curr Opin Endocrinol Diabetes
Obes. 2011; 18(2):148-152.
56. van Staa T, Abenhaim L, Monette J. Rates of
hypoglycemia in users of sulfonylureas. J Clin
Epidemiol. 1997; 50(6):735-741.
57. Shorr RI, Ray WA, Daugherty JR, Griffin MR.
Individual sulfonylureas and serious hypoglycemia in
older people. J Am Geriatr Soc. 1996; 44(7):751-755.
58. Scheen AJ. Drug interactions of clinical importance with
antihyperglycaemic agents: an update. Drug Saf. 2005;
28(7):601-631.
59. Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B,
MacKay P, et al. Stimulation of insulin release by
repaglinide and glibenclamide involves both common
and distinct processes. Diabetes. 1998; 47(3):345-351.
60. Blicklé JF. Meglitinide analogues: a review of clinical
data focused on recent trials. Diabetes Metab. 2006;
32(2):113-120.
61. Yki-jarvinen H. Thiazolidinediones. N Engl J Med. 2004;
351(11):1106-1118.
62. Coniff RF, Shapiro JA, Seaton TB, Bray GA.
Multicenter, placebo-controlled trial comparing acarbose
(BAY g 5421) with placebo, tolbutamide, and
tolbutamide-plus-acarbose in non-insulin-dependent
diabetes mellitus. Am J Med. 1995; 98(5):443-451.
63. Kawamori R, Tajima N, Iwamoto Y, Kashiwagi A,
Shimamoto K, Kaku K et al. Voglibose Ph-3 Study
Group. Voglibose for prevention of type 2 diabetes
mellitus: a randomized, double-blind trial in Japanese
individuals with impaired glucose tolerance. Lancet.
2009; 373(9675):1607-1614.

~ 2371 ~