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World J Diabetes. 2015 Jun 25; 6(6): 850–867. PMCID: PMC4478580

Published online 2015 Jun 25. doi: 10.4239/wjd.v6.i6.850 PMID: 26131326

Diabetes mellitus: The epidemic of the century

Akram T Kharroubi and Hisham M Darwish

Abstract

The epidemic nature of diabetes mellitus in different regions is reviewed. The Middle East and North
Africa region has the highest prevalence of diabetes in adults (10.9%) whereas, the Western Pacific region
has the highest number of adults diagnosed with diabetes and has countries with the highest prevalence of
diabetes (37.5%). Different classes of diabetes mellitus, type 1, type 2, gestational diabetes and other types
of diabetes mellitus are compared in terms of diagnostic criteria, etiology and genetics. The molecular ge‐
netics of diabetes received extensive attention in recent years by many prominent investigators and research
groups in the biomedical field. A large array of mutations and single nucleotide polymorphisms in genes
that play a role in the various steps and pathways involved in glucose metabolism and the development,
control and function of pancreatic cells at various levels are reviewed. The major advances in the molecu‐
lar understanding of diabetes in relation to the different types of diabetes in comparison to the previous un‐
derstanding in this field are briefly reviewed here. Despite the accumulation of extensive data at the molec‐
ular and cellular levels, the mechanism of diabetes development and complications are still not fully under‐
stood. Definitely, more extensive research is needed in this field that will eventually reflect on the ultimate
objective to improve diagnoses, therapy and minimize the chance of chronic complications development.

Keywords: Diabetes, Classification of diabetes, Type 1 diabetes, Type 2 diabetes, Gestational diabetes,
Diagnosis, Etiology, Genetics

Core tip: Diabetes mellitus is rising to an alarming epidemic level. Early diagnosis of diabetes and predia‐
betes is essential using recommended hemoglobin A1c criteria for different types except for gestational di‐
abetes. Screening for diabetes especially in underdeveloped countries is essential to reduce late diagnosis.
Diabetes development involves the interaction between genetic and non-genetic factors. Biomedical re‐
Back to Top
search continues to provide new insights in our understanding of the mechanism of diabetes development
that is reviewed here. Recent studies may provide tools for the use of several genes as targets for risk as‐
sessment, therapeutic strategies and prediction of complications.

DEFINITION OF DIABETES MELLITUS

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from
defects in insulin secretion, insulin action, or both. Metabolic abnormalities in carbohydrates, lipids, and
proteins result from the importance of insulin as an anabolic hormone. Low levels of insulin to achieve ad‐
equate response and/or insulin resistance of target tissues, mainly skeletal muscles, adipose tissue, and to a
lesser extent, liver, at the level of insulin receptors, signal transduction system, and/or effector enzymes or
genes are responsible for these metabolic abnormalities. The severity of symptoms is due to the type and
duration of diabetes. Some of the diabetes patients are asymptomatic especially those with type 2 diabetes
during the early years of the disease, others with marked hyperglycemia and especially in children with ab‐
solute insulin deficiency may suffer from polyuria, polydipsia, polyphagia, weight loss, and blurred vision.
Uncontrolled diabetes may lead to stupor, coma and if not treated death, due to ketoacidosis or rare from
nonketotic hyperosmolar syndrome[1-3].

CLASSIFICATION OF DIABETES MELLITUS

Although classification of diabetes is important and has implications for the treatment strategies, this is not
an easy task and many patients do not easily fit into a single class especially younger adults[1,4-6] and 10%
of those initially classified may require revision[7]. The classical classification of diabetes as proposed by
the American Diabetes Association (ADA) in 1997 as type 1, type 2, other types, and gestational diabetes
mellitus (GDM) is still the most accepted classification and adopted by ADA[1]. Wilkin[8] proposed the
accelerator hypothesis that argues “type 1 and type 2 diabetes are the same disorder of insulin resistance
set against different genetic backgrounds”[9]. The difference between the two types relies on the tempo, the
faster tempo reflecting the more susceptible genotype and earlier presentation in which obesity, and there‐
fore, insulin resistance, is the center of the hypothesis. Other predictors of type 1 diabetes include in‐
creased height growth velocity[10,11] and impaired glucose sensitivity of β cells[12]. The implications of
increased free radicals, oxidative stress, and many metabolic stressors in the development, pathogenesis
and complications of diabetes mellitus[13-18] are very strong and well documented despite the inconsis‐
tency of the clinical trials using antioxidants in the treatment regimens of diabetes[19-21]. The female hor‐
mone 17-β estradiol acting through the estrogen receptor-α (ER-α) is essential for the development and
preservation of pancreatic β cell function since it was clearly demonstrated that induced oxidative stress
leads to β-cell destruction in ER-α knockout mouse. The ER-α receptor activity protects pancreatic islets
against glucolipotoxicity and therefore prevents β-cell dysfunction[22].

TYPE 1 DIABETES MELLITUS

Autoimmune type 1 diabetes

This type of diabetes constitutes 5%-10% of subjects diagnosed with diabetes[23] and is due to destruction
of β cells of the pancreas[24,25]. Type 1 diabetes accounts for 80%-90% of diabetes in children and
adolescents[2,26]. According to International Diabetes Federation (IDF), the number of youth (0-14 years)
diagnosed with type 1 diabetes worldwide in 2013 was 497100 (Table ​1) and the number of newly diag‐
nosed cases per year was 78900[27]. These figures do not represent the total number of type 1 diabetes pa‐
tients because of the high prevalence of type 1 diabetes in adolescence and adults above 14 years of age.
One reported estimate of type 1 diabetes in the United States in 2010 was 3 million[28,29]. The number of
youth in the United States younger than 20 years with type 1 diabetes was estimated to be 166984 in the
year 2009[30]. The prevalence of type 1 diabetes in the world is not known but in the United States in
youth younger than 20 years was 1.93 per 1000 in 2009 (0.35-2.55 in different ethnic groups) with
2.6%-2.7% relative annual increase[26,31]. Type 1 diabetes is mainly due to an autoimmune destruction of
the pancreatic β cells through T-cell mediated inflammatory response (insulitis) as well as a humoral (B
cell) response[25]. The presence of autoantibodies against the pancreatic islet cells is the hallmark of type
1 diabetes, even though the role of these antibodies in the pathogenesis of the disease is not clear. These
autoantibodies include islet cell autoantibodies, and autoantibodies to insulin (IAA), glutamic acid decar‐
boxylase (GAD, GAD65), protein tyrosine phosphatase (IA2 and IA2β) and zinc transporter protein
(ZnT8A)[32]. These pancreatic autoantibodies are characteristics of type 1 diabetes and could be detected
in the serum of these patients months or years before the onset of the disease[33]. Autoimmune type 1 dia‐
betes has strong HLA associations, with linkage to DR and DQ genes. HLA-DR/DQ alleles can be either
predisposing or protective[1]. This autoimmune type 1 diabetes is characterized by the absence of insulin
secretion and is more dominant in children and adolescents.
 Table 1

Number of subjects with type 1 diabetes in children (0-14 years), with diabetes in adults (20-79 years) and with hyper‐
glycemia (type 2 or gestational diabetes) in pregnancy (20-49 years)

Region Type 1 diabetes in Diabetes in adults (20-79 yr) Hyperglycemia in

children (0-14 yr) pregnancy (20-49 yr)

2013 2013 2035 2013

Number Newly Number Comparative Number Comparative Cases in Comparative

in diagnosed in prevalence in prevalence live prevalence
thousands in millions millions births in
thousands millions

Africa 39.1 6.4 19.8 5.7% 41.5 6.0% 4.6 14.4%

Europe 129.4 20.0 56.3 6.8% 68.9 7.1% 1.7 12.6%

Middle 64.0 10.7 34.6 10.9% 67.9 11.3% 3.4 17.5%

East and
North
Africa

North 108.6 16.7 36.8 9.6% 50.4 9.9% 0.9 10.4%

America
and
Caribbean

South and 45.6 7.3 24.1 8.2% 38.5 8.2% 0.9 11.4%
Central
America

South East 77.9 12.5 72.1 8.7% 123.0 9.4% 6.3 25.0%
Asia

Western 32.5 5.3 138.2 8.1% 201.8 8.4% 3.7 11.9%

Pacific

World 497.1 78.9 381.8 8.3% 592.0 8.8% 21.4 14.8%

Data extracted from International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

In addition to the importance of genetic predisposition in type 1 diabetes, several environmental factors
have been implicated in the etiology of the disease[9,33]. Viral factors include congenital rubella[34,35],
viral infection with enterovirus, rotavirus, herpes virus, cytomegalovirus, endogenous retrovirus[36,37]
and Ljungan virus. Other factors include low vitamin D levels[38], prenatal exposure to pollutants, im‐
proved hygiene and living conditions decreased childhood infections in countries with high socioeconomic
status leading to increased autoimmune diseases (hygiene hypothesis), early infant nutrition such as using
cow’s milk formula instead of breast feeding[39] in addition to insulin resistance in early childhood due to
obesity or increased height growth velocity. The role of environmental factors remains controversial[40].
Recent evidence supported the causative effect of viral infections in diabetes[41-43].

Type 1 diabetes often develops suddenly and can produce symptoms such as polydipsia, polyuria, enuresis,
lack of energy, extreme tiredness, polyphagia, sudden weight loss, slow-healing wounds, recurrent infec‐
tions and blurred vision[27] with severe dehydration and diabetic ketoacidosis in children and adolescents.
The symptoms are more severe in children compared to adults. These autoimmune type 1 diabetes patients
are also prone to other autoimmune disorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s
disease, vitiligo, celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia[1]. The
complete dependence on insulin of type 1 diabetes patients may be interrupted by a honeymoon phase
which lasts weeks to months or in some cases 2-3 years. In some children, the requirement for insulin ther‐
apy may drop to a point where insulin therapy could be withdrawn temporarily without detectable
hyperglycemia[44].

Idiopathic type 1 diabetes

A rare form of type 1 diabetes of unknown origin (idiopathic), less severe than autoimmune type 1 diabetes
and is not due to autoimmunity has been reported. Most patients with this type are of African or Asian de‐
scent and suffer from varying degrees of insulin deficiency and episodic ketoacidosis[45].

Fulminant type 1 diabetes

This is a distinct form of type 1 diabetes, first described in the year 2000, and has some common features
with idiopathic type 1 diabetes being non-immune mediated[46,47]. It is characterized by ketoacidosis
soon after the onset of hyperglycemia, high glucose levels (≥ 288 mg/dL) with undetectable levels of
serum C-peptide, an indicator of endogenous insulin secretion[48]. It has been described mainly in East
Asian countries and accounted for approximately 20% of acute-onset type 1 diabetes patients in Japan
(5000-7000 cases) with an extremely rapid and almost complete beta-cell destruction resulting in nearly no
residual insulin secretion[48,49]. Both genetic and environmental factors, especially viral infection, have
been implicated in the disease. Anti-viral immune response may trigger the destruction of pancreatic beta
cells through the accelerated immune reaction with no detectable autoantibodies against pancreatic beta
cells[48,50]. Association of fulminant type 1 diabetes with pregnancy has also been reported[51].

TYPE 2 DIABETES MELLITUS

The global prevalence of diabetes in adults (20-79 years old) according to a report published in 2013 by
the IDF was 8.3% (382 million people), with 14 million more men than women (198 million men vs 184
million women), the majority between the ages 40 and 59 years and the number is expected to rise beyond
592 million by 2035 with a 10.1% global prevalence. With 175 million cases still undiagnosed, the number
of people currently suffering from diabetes exceeds half a billion. An additional 21 million women are di‐
agnosed with hyperglycemia during pregnancy. The Middle East and North Africa region has the highest
prevalence of diabetes (10.9%), however, Western Pacific region has the highest number of adults diag‐
nosed with diabetes (138.2 millions) and has also countries with the highest prevalence (Figure 1)[27].
​
Low- and middle-income countries encompass 80% of the cases, “where the epidemic is gathering pace at
alarming rates”[27]. Despite the fact that adult diabetes patients are mainly type 2 patients, it is not clear
whether the reported 382 million adults diagnosed with diabetes also include type 1 diabetes patients.

Figure 1

Comparative prevalence of diabetes in adults (20-79 years) in countries with high prevalence (≥ 10%). Data extracted from
International Diabetes Federation Diabetes Atlas, 6th ed, 2013.

More than 90%-95% of diabetes patients belong to this type and most of these patients are adults. The
number of youth (less than 20 years) with type 2 diabetes in the United States in the year 2009 was 0.46 in
1000 and accounted for approximately 20% of type 2 diabetes in youth[26]. The increased incidence of
type 2 diabetes in youth is mainly due to the change in the lifestyle of the children in terms of more seden‐
tary life and less healthy food. Obesity is the major reason behind insulin resistance which is mainly re‐
sponsible for type 2 diabetes[52-54]. The ADA recommends screening of overweight children and adoles‐
cence to detect type 2 diabetes[55,56]. The prevalence of obesity in children in on the rise[6] which is
probably the main reason for the increased incidence of type 2 diabetes in the young (30.3% overall in‐
crease in type 2 diabetes in children and adolescence between 2001 and 2009)[26].

Insulin resistance in type 2 diabetes patients increases the demand for insulin in insulin-target tissues. In
addition to insulin resistance, the increased demand for insulin could not be met by the pancreatic β cells
due to defects in the function of these cells[18]. On the contrary, insulin secretion decreases with the in‐
creased demand for insulin by time due to the gradual destruction of β cells[57] that could transform some
of type 2 diabetes patients from being independent to become dependent on insulin. Most type 2 diabetes
patients are not dependent on insulin where insulin secretion continues and insulin depletion rarely occurs.
Dependence on insulin is one of the major differences from type 1 diabetes. Other differences include the
absence of ketoacidosis in most patients of type 2 diabetes and autoimmune destruction of β cells does not
occur. Both type 1 and type 2 diabetes have genetic predisposition, however, it is stronger in type 2 but the
genes are more characterized in type 1 (the TCF7L2 gene is strongly associated with type 2 diabetes)[58].
Due to the mild symptoms of type 2 diabetes in the beginning, its diagnosis is usually delayed for years es‐
pecially in countries where regular checkup without symptoms is not part of the culture. This delay in di‐
agnosis could increase the incidence of long-term complications in type 2 diabetes patients since hyper‐
glycemia is not treated during this undiagnosed period.

In addition to diabetes, insulin resistance has many manifestations that include obesity, nephropathy, essen‐
tial hypertension, dyslipidemia (hypertriglyceridemia, low HDL, decreased LDL particle diameter, en‐
hanced postprandial lipemia and remnant lipoprotein accumulation), ovarian hyperandrogenism and pre‐
mature adrenarche, non-alcoholic fatty liver disease and systemic inflammation[6,54]. The presence of
type 2 diabetes in children and adolescence who are not obese[59-61], the occasional severe dehydration
and the presence of ketoacidosis in some pediatric patients with type 2 diabetes[55] had led to the misclas‐
sification of type 2 to type 1 diabetes.

Some patients with many features of type 2 diabetes have some type 1 characteristics including the pres‐
ence of islet cell autoantibodies or autoantibodies to GAD65 are classified as a distinct type of diabetes
called latent autoimmune diabetes in adults (LADA)[62]. People diagnosed with LADA do not require in‐
sulin treatment. In a recent study, Hawa et al[63] reported 7.1% of European patients with type 2 diabetes
with a mean age of 62 years, tested positive for GAD autoantibodies and the prevalence of LADA was
higher in patients diagnosed with diabetes at a younger age. This classification of LADA as a distinct type
of diabetes is still controversial[6,64-66].

Insulin resistance and signaling

Defects in the insulin-dependent substrate proteins IRS-1 and IRS-2 mediated signaling pathway are impli‐
cated in the development of metabolic disorders, mainly diabetes. This pathway mediates the cellular re‐
sponse to insulin and involves a large array of insulin-stimulated protein kinases including the
serine/threonine kinase AKT and protein kinase C (PKC) that phosphorylate a large number of Ser/Thr
residues in the insulin receptor substrate (IRS) proteins involved in the metabolic response to insulin[67].
In addition, other non-insulin dependent kinases including the AMP-activated protein kinase, c-Jun N-ter‐
minal protein kinase and G protein-coupled receptor kinase 2 that are activated under various conditions
can phosphorylate the two insulin responsive substrates[67-71]. Disruption in the AKT and PKC kinases is
central to the development of diabetes[72] and is associated with all major features of the disease including
hyperinsulinemia, dyslipidemia and insulin resistance[73]. Replacing the wild type IRS-1 with a mutant
version of the protein having alanine instead of tyrosine in three locations using genetic knock-in approach
provided evidence to the central role of IRS-1 phosphorylation in the development of insulin
resistance[74]. Using a similar approach to generate IRS-1 mutant with a single mutation involving a spe‐
cific tyrosine residue, confirmed the role of IRS-1 phosphorylation in the development of insulin resistance
pathogenesis[75]. The large cumulative evidence indicates a complex array of factors including environ‐
mental factors[76] and a wide range of cellular disturbances in glucose and lipid metabolism in various
tissues[77] contribute to the development of insulin resistance. This condition generates complex cellular
metabolic changes in a variety of tissues, mainly liver and muscles, that include the inability of the liver to
transport and dispose glucose, control glucose production via gluconeogenesis, impaired storage of glu‐
cose as glycogen, de novo lipogenesis and hypertriglyceridemia[77]. Among the factors implicated in the
development of insulin resistance, obesity is the most predominant risk factor leading to insulin insensitiv‐
ity and diabetes which involves several mechanisms that participate in the pathogenesis of the disease[78].
Obesity-induced insulin resistance is directly linked to increased nutrient flux and energy accumulation in
tissues that directly affect cell responsiveness to insulin[77]. However, it seems that other insulin-indepen‐
dent mechanisms are involved in the overall metabolic disturbances of glucose homeostasis and diabetes
including activities in extra-hepatic tissues in addition to the central role of liver.

OTHER TYPES OF DIABETES MELLITUS

Monogenic diabetes

Characterization of the genetic etiology of diabetes enables more appropriate treatment, better prognosis,
and counseling[79]. Monogenic diabetes is due to a genetic defect in single genes in pancreatic β cells
which results in disruption of β cell function or a reduction in the number of β cells. Conventionally,
monogenic diabetes is classified according to the age of onset as neonatal diabetes before the age of six
months or Maturity Onset Diabetes of the Young (MODY) before the age of 25 years. However, certain fa‐
milial defects are manifested in neonatal diabetes, MODY or adult onset diabetes[2,9,80]. Others believe
that classification of diabetes as MODY and neonatal diabetes is obsolete and monogenic diabetes is cur‐
rently used relating specific genetic etiologies with their specific treatment implications[79]. Beta cell dif‐
ferentiation depends on the expression of the homeodomain transcription factor PDX1 where mutation in
the gene results in early onset diabetes (MODY) and its expression decreases before the onset of
diabetes[81]. The angiopoietin-like protein 8 (ANGPTL8) may represent a potential “betatrophin” that acts
to promote the proliferation of beta cells, however, studies using mice lacking the ANGPTL8 active gene
or overexpressed protein indicated that it did not seem to play a role in beta cells proliferation[82].

Mitochondrial diabetes is due to a point mutation in the mitochondrial DNA associated with deafness and
maternal transmission of the mutant DNA can result in maternally-inherited diabetes[1,83].

Mutations that result in mutant insulin or the inability to convert proinsulin to insulin result in glucose in‐
tolerance in some of these cases. Genetic defects in the insulin receptor or in the signal transduction path‐
way of insulin have been demonstrated to result in hyperinsulinemia and modest hyperglycemia to severe
diabetes[1].

Disease of the exocrine pancreas

Damage of the β cells of the pancreas due to diffused injury of the pancreas can cause diabetes. This dam‐
age could be due to pancreatic carcinoma, pancreatitis, infection, pancreatectomy, and trauma[1]. Atrophy
of the exocrine pancreas leads to progressive loss of the β cells[84]. Accumulation of fat in the pancreas or
pancreatic steatosis could lead to diabetes due to decreased insulin secretion but may require a long time
before the damage to β cells occurs[85]. In most cases, extensive damage of the pancreas is required before
diabetes occurs and the exocrine function of the pancreas is decreased in these patients[86]. Cirrhosis in
cystic fibrosis may contribute to insulin resistance and diabetes[2].

Hormones and drugs

Diabetes has been found in patients with endocrine diseases that secrete excess hormones like growth hor‐
mone, glucocorticoids, glucagon and epinephrine in certain endocrinopathies like acromegaly, Cushing’s
syndrome, glucagonoma, and pheochromocytoma, respectively[1]. Some of these hormones are used as
drugs such as glucocorticoids to suppress the immune system and in chemotherapy and growth hormone to
treat children with stunted growth.

Genetic syndromes

Diabetes has been detected in patients with various genetic syndromes such as Down syndrome, Klinefelter
syndrome, Turner syndrome and Wolfram syndrome[1].

PREDIABETES

Individuals with prediabetes do not meet the criteria of having diabetes but are at high risk to develop type
2 diabetes in the future. According to the ADA Expert Committee, individuals are defined to have predia‐
betes if they have either impaired fasting plasma glucose (IFG) levels between 100-125 mg/dL (5.6-6.9
mmol/L) or impaired glucose tolerance test (IGT) with 2-h plasma glucose levels in the oral glucose toler‐
ance test (OGTT) of 140-199 mg/dL (7.8-11.0 mmol/L). The World Health Organization (WHO) still
adopts the range for IFG from 110-125 mg/dL (6.1-6.9 mmol/L). Prediabetes has been shown to correlate
with increased cardiovascular mortality[87,88] and cancer[89]. The definition of prediabetes with the indi‐
cated cut off values is misleading since lower levels of glucose in the normal range are still correlated with
cardiovascular disease in a continuous glycemic risk perspective[90]. In accordance with the recommenda‐
tion of the ADA in 2009 to use hemoglobin A1c (HbA1c) to diagnose diabetes, ADA also recommended
the use of an HbA1c (5.7%-6.4%) to diagnose prediabetes[91]. The number of people with IGT according
to IDF was 316 million in 2013 (global prevalence 6.9% in adults) and is expected to rise to 471 million in
2030[27]. According to a report in 2014 by the Center for Disease Control and Prevention, 86 million
Americans (1 out of 3) have prediabetes[92]. Four of the top ten countries with the highest prevalence of
prediabetes are in the Middle East Arab States of the Gulf (Kuwait, Qatar, UAE and Bahrin with preva‐
lence of 17.9%, 17.1%, 16.6% and 16.3%, respectively)[27]. The number of people diagnosed with predia‐
betes is different according to the method and criteria used to diagnose prediabetes. The number of people
with prediabetes defined by IFG 100-125 mg/dL is 4-5 folds higher than those diagnosed using the WHO
criteria of 110-125 mg/dL[93]. Diabetes and prediabetes diagnosed using an HbA1c criteria give different
estimates compared to methods using FPG or OGTT. Higher percentages of prediabetes were diagnosed
using HbA1c compared to FPG[94-96]. Prediabetes is associated with metabolic syndrome and obesity
(especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL choles‐
terol, and hypertension[97]. Not all individuals with prediabetes develop diabetes in the future, exercise
with a reduction of weight 5%-10% reduces the risk of developing diabetes considerably (40%-70%)[98].
Individuals with an HbA1c of 6.0%-6.5% have twice the risk of developing diabetes (25%-50%) in five
years compared to those with an HbA1c of 5.5%-6.0%[99].

DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS

Diabetes mellitus is diagnosed using either the estimation of plasma glucose (FPG or OGTT) or HbA1c.
Estimation of the cut off values for glucose and HbA1c is based on the association of FPG or HbA1c with
retinopathy. Fasting plasma glucose of ≥ 126 mg/dL (7.0 mmol/L), plasma glucose after 2-h OGTT ≥ 200
mg/dL (11.1 mmol/L), HbA1c ≥ 6.5% (48 mmol/mol) or a random plasma glucose ≥ 200 mg/dL (11.1
mmol/L) along with symptoms of hyperglycemia is diagnostic of diabetes mellitus. In addition to monitor
the treatment of diabetes, HbA1c has been recommended to diagnose diabetes by the International Expert
Committee in 2009[100] and endorsed by ADA[101], the Endocrine Society, the WHO[102] and many sci‐
entists and related organizations all over the world. The advantages and disadvantages of the different tests
used to diagnose diabetes have been reviewed by Sacks et al[103]. The advantages of using HbA1c over
FPG to diagnose diabetes include greater convenience and preanalytical stability, lower CV (3.6%) com‐
pared to FPG (5.7%) and 2h OGTT (16.6%), stronger correlation with microvascular complications espe‐
cially retinopathy, and a marker for glycemic control and glycation of proteins which is the direct link be‐
tween diagnosis of diabetes and its complications[104-109]. It is recommended to repeat the HbA1c test in
asymptomatic patients within two weeks to reaffirm a single apparently diagnostic result[110].

A cut off value for HbA1c of ≥ 6.5% (48 mmol/mol) has been endorsed by many countries and different
ethnic groups, yet ethnicity seems to affect the cut off values to diagnose diabetes[111,112]. Cut-off values
of 5.5% (37 mmol/mol)[113] and 6.5% (48 mmol/mol)[114] have been reported in a Japanese study, 6.0%
(42 mmol/mol) in the National Health and Nutrition Examination Survey (NHANES III), 6.2% (44
mmol/mol) in a Pima Indian study, 6.3% (45 mmol/mol) in an Egyptian study as reported by
Davidson[105]; and three cut-off values for Chinese[112]. The Australians recommended the use of two
cut-off values: ≤ 5.5% to “rule-out” and ≥ 7.0% to “rule-in” diabetes[115]. Variations in the prevalence of
diabetes[94,116-119] and prediabetes[120] due to ethnicity have been documented. Most studies diagnosed
less subjects with diabetes using HbA1c compared to FPG or OGTT[121-123]. Yet, other studies reported
more subjects diagnosed with diabetes using HbA1c[96,124-126].

GESTATIONAL DIABETES

Hyperglycemia in pregnancy whether in the form of type 2 diabetes diagnosed before or during pregnancy
or in the form gestational diabetes has an increased risk of adverse maternal, fetal and neonatal outcome.
Mothers with gestational diabetes and babies born to such mothers have increased risk of developing dia‐
betes later in life. Hyperglycemia in pregnancy is responsible for the increased risk for macrosomia (birth
weight ≥ 4.5 kg), large for gestational age births, preeclampsia, preterm birth and cesarean delivery due to
large babies[127]. Risk factors for gestational diabetes include obesity, personal history of gestational dia‐
betes, family history of diabetes, maternal age, polycystic ovary syndrome, sedentary life, and exposure to
toxic factors[3].

Diagnosis of type 2 diabetes before or during pregnancy is based on criteria mentioned before. Fasting
plasma glucose ≥ 126 mg/dL (7.0 mmol/L) or 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) after a 75
g oral glucose load. However, gestational diabetes has been diagnosed at 24-28 wk of gestation in women
not previously diagnosed with diabetes using two approaches: the first approach is based on the “one-step”
International Association of the Diabetes and Pregnancy Study Groups (IADPSG) consensus[128] and re‐
cently adopted by WHO[129]. Gestational diabetes is diagnosed using this method by FPG ≥ 92 mg/dL
(5.1 mmol/L), 1-h plasma glucose after a 75 g glucose load ≥ 180 mg/dL (10.0 mmol/L) or 2-h plasma
glucose after a 75 g glucose load ≥ 153 mg/dL (8.5 mmol/L). This criteria is derived from the
Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study[127] even though the HAPO study
showed a continuous relationship between hyperglycemia and adverse short-term pregnancy outcome with
no threshold reported[130]. The second approach is used in the United States and is based on the “two-
step” NIH consensus[131]. In the first step 1-h plasma glucose after a 50 g glucose load under nonfasting
state ≥ 140 mg/dL (7.8 mmol/L) is followed by a second step under fasting conditions after a 100 g glu‐
cose load for those who screened abnormal in the first step. The diagnosis of gestational diabetes is made
when at least two of the four plasma glucose levels are met. The four plasma glucose levels according to
Carpenter/Coustan criteria are: FPG ≥ 95 mg/dL (5.3 mmol/L); 1-h ≥ 180 mg/dL (10.0 mmol/L); 2-h ≥
155 mg/dL (8.6 mmol/L); and 3-h ≥ 140 mg/dL (7.8 mmol/L)[1].

The use IADPSC criteria in comparison with the Carpenter/Coustan criteria was associated with a 3.5-fold
increase in GDM prevalence as well as significant improvements in pregnancy outcomes, and was cost-
effective[132]. In another retrospective cohort study of women diagnosed with gestational diabetes,
Ethridge et al[133] have shown that newborns of women diagnosed with gestational diabetes by IADPSG
approach have greater measures of fetal overgrowth compared with Carpenter-Coustan “two-step” ap‐
proach neonates. A strategy of using fasting plasma glucose as a screening test and to determine the need
for OGTT is valid[134,135]. According to Sacks[136], correlation of glucose concentrations and the risk
of subsequent complications will eventually lead to universal guidelines.

The use of ADA/WHO cut off value of HbA1c ≥ 6.5% (48 mmol/mol) to diagnose gestational diabetes is
not recommended by the “one step” IADPSC criteria or the “two-step” NIH criteria. Further investigation
is required in light of recent reports on HbA1c in combination with OGTT and its usefulness to predict ad‐
verse effect of gestational diabetes or obviate the use OGTT in all women with gestational diabetes[137-
141].

DIABETES AND GENETICS

Diabetes is a complex disease that involves a wide range of genetic and environmental factors. Over the
past several years, many studies have focused on the elucidation of the wide spectrum of genes that played
a role in the molecular mechanism of diabetes development[142-144]. However, despite the vast flow of
genetic information including the identification of many gene mutations and a large array of single nucleo‐
tide polymorphisms (SNPs) in many genes involved in the metabolic pathways that affect blood glucose
levels, the exact genetic mechanism of diabetes remains elusive[145,146]. Evidently, a major complication
is the fact that a single gene mutation or polymorphism will not impose the same effect among different in‐
dividuals within a population or different populations. This variation is directly or indirectly affected by the
overall genetic background at the individual, family or population levels that are potentially further compli‐
cated by interaction with highly variable environmental modifier factors[147,148].

Molecular genetics and type 2 diabetes

One of the major focuses of biomedical research is to delineate the collective and broad genetic variants in
the human genome that are involved in the development of diabetes. This major effort will potentially pro‐
vide the necessary information to understand the molecular genetics of the different forms of diabetes in‐
cluding type 1, type 2 and monogenic neonatal diabetes among individuals of all populations and ethnic
groups. Despite the fact that linkage and association studies allowed the identification and characterization
of many candidate genes that are associated with type 2 diabetes[144,149,150], however, not all of these
genes showed consistent and reproducible association with the disease[151]. Genome wide association
studies (GWAS) in various populations identified 70 loci associated with type 2 diabetes and revealed posi‐
tive linkage of many mutations and SNPs that influence the expression and physiological impact of the re‐
lated proteins and risk to develop type 2 diabetes. One study involved several thousand type 2 diabetes pa‐
tients and control subjects from the United Kingdom allowed the identification of several diabetes putative
loci positioned in and around the CDKAL1, CDKN2A/B, HHEX/IDE and SLC30A8 genes in addition to
the contribution of a large number of other genetic variants that are involved in the development of the
disease[152]. Two similar studies from the Finns and Swedish populations and the United States resulted
in the identification of similar single nucleotide variants[153] that are linked to the risk of acquiring type 2
diabetes[154,155]. The study in the United States population included in addition to type 2 diabetes, the
association of the identified SNPs with the level of triglycerides in the tested subjects[155]. These SNPs
are located near several candidate genes including IGFBP2 and CDKAL1 and other genes in addition to
several other variants that are located near or in genes firmly associated with the risk of acquiring type 2
diabetes. Other GWAS analysis studies were performed in the Chinese, Malays, and Asian-Indian popula‐
tions which are distinct from the European and United States populations in addition to meta-analysis of
data from other populations in the region revealed relevant findings among patients with European
ancestry[156]. The results of the combined analysis showed significant association of SNPs in the
CDKAL1, CDKN2A/B, HHEX, KCNQ1 and SLC30A8 genes after adjustment with gender and body mass
index. More recently, meta-analysis of GWAS data involving African American type 2 diabetes patients
identified similar loci to the previous studies with the addition of two novel loci, HLA-B and INS-
IGF[157]. These results provide strong evidence of common genetic determinants including common spe‐
cific genes that are linked to diabetes. A small list of specific genetic markers seem strongly associated
with the risk of developing type 2 diabetes including the TCF7L2[158] and CAPN10[159,160] genes
which also play a significant role in the risk and pathogenesis of the disease[158,159]. The association of
TCF7L2 gene variants with type 2 diabetes and its mechanism of action received special attention by sev‐
eral investigators[161,162]. Over expression of the protein was shown to decrease the sensitivity of beta
islet cells to secrete insulin[163,164] and was more precisely involved in the regulation of secretary gran‐
ule fusion that constitute a late event in insulin secretion pathway[165]. The role of TCF7L2 in insulin se‐
cretion was partially clarified[166] that involves modifying the effect of incretins on insulin secretion by
lowering the sensitivity of beta cells to incretins. Several other genes have been found to be significantly
associated with the risk of developing type 2 diabetes including a specific SNP in a hematopoietically-ex‐
pressed homeobox (HHEX) gene[167]. The islet zinc transporter protein (SLC30A8)[168] showed positive
correlation with the risk of developing type 2 diabetes where variant mutations in this gene seem protec‐
tive against the disease which provides a potential tool for therapy[169]. More recently, a low frequency
variant of the HNF1A identified by whole exome sequencing was associated with the risk of developing
type 2 diabetes among the Latino population and potentially may serve as a screening tool[170]. Genetic
variants and specific combined polymorphisms in the interleukin and related genes including interlukin-6
(IL-6), tumor necrosis factor-α and IL-10 genes were found to be associated with greater risk of develop‐
ing type 2 diabetes[171], in addition to genetic variants in the genes for IL12B, IL23R and IL23A
genes[172]. In a study involving the hormone sensitive lipase responsible for lipolysis in adipose tissues, a
deletion null mutation, which resulted in the absence of the protein from adipocytes, was reported to be as‐
sociated with diabetes[173]. Nine specific rare variants in the peroxisome proliferator-activated receptor
gamma (PPARG) gene that resulted in loss of the function of the protein in adipocytes differentiation, were
significantly associated with the risk of developing type 2 diabetes[174]. In addition, certain SNPs in the
alpha 2A adrenergic receptor (ADRA2A) gene, involved in the sympathetic nervous system control of in‐
sulin secretion and lipolysis, were found to be associated with obesity and type 2 diabetes[175]. Link
analysis between the melatonin MT2 receptor (MTNR1B) gene, a G-protein coupled receptor, identified 14
mutant variants from 40 known variants revealed by exome sequencing, to be positively linked with type 2
diabetes[176]. The authors suggested that mutations in the MT2 gene could provide a tool with other re‐
lated genes in modifying therapy for type 2 diabetes patients based on their specific genetic background to
formulate personalized therapies which potentially may ensures the optimum response. Interestingly, muta‐
tions in the clock[177,178] and Bmal1[179] transcription factor genes which are involved in beta cells bio‐
logical clock affecting growth, survival and synaptic vesicle assembly in these cells, resulted in reduced in‐
sulin secretion and diabetes. Evidently, prominent metabolic functions involve the production of specific
reactive metabolites, leading to oxidative stress, which affect lipids, proteins and other biological com‐
pounds leading to serious damage in various tissues and organs. Mutations and SNPs in the antioxidant
genes, including superoxide dismutase, catalase and glutathione peroxidase, that decrease their activity are
implicated in the risk and pathogenesis of type 2 diabetes[180]. The metabolic syndrome was shown to be
associated with the development of type 2 diabetes in a population that is described as highly endogenous
especially in individuals over 45 years of age[181]. Since consanguinity marriages is high in this popula‐
tion, screening for this syndrome among families could provide an informative marker on the risk of devel‐
oping type 2 diabetes[181].

Molecular genetics of type 1 diabetes

Even though type 1 diabetes is basically described as an autoimmune disease that results in the destruction
of pancreatic beta cells, however, single gene mutations and SNPs have been found to be associated with
the susceptibility to this type of diabetes. Initially, two gene mutations were linked to the development of
type 1 diabetes including the autoimmune regulator (AIRE) gene which affect the immune tolerance to self
antigens leading to autoimmunity[182] and the FOXP3 gene which results in defective regulatory T
cells[183]. In addition, a mutation in the histone deacetylase SIRTI gene predominantly expressed in beta
cells involved in the regulation of insulin secretion[184] and played a role in modulating the sensitivity of
peripheral tissues to insulin[185] was detected in type 1 diabetes patients[186]. Recently, additional muta‐
tions and SNPs in the CTLA-4 +49A/G and HLA-DQB1 and INS gene VNTR alleles were found to be as‐
sociated with type 1 diabetes, which have the advantage of differentiating between Latent autoimmune type
1 diabetes and type 2 diabetes[187]. The HLA-DQB1, in combination with HLA-DR alleles and a poly‐
morphism in PTPN22 gene seem to be associated with the age onset of late type 1 diabetes[188,189]. Two
specific polymorphisms in the promoter region of a transmembrane protein (DC-SIGN) gene expressed in
macrophages and played an important role of T- cell activation and inflammation were found to be protec‐
tive against type 1 diabetes[190]. An innovative non-parametric SNP enrichment tool using summary
GWAS DATA allowed the identification of association between several transcription factors and type 1 di‐
abetes and are located in a type 1 diabetes susceptibility region[191]. Nine SNP variants in several genes
associated with type 1 diabetes, not including the major histocompatibility gene region, were identified us‐
ing extensive GWAS analysis[192]. Furthermore, several novel SNPs in a region in chromosome 16 lo‐
cated in the CLEC16A gene were shown to be associated with type 1 diabetes and seem to function
through the reduced expression of DEX1 in B lymphoblastoid cells[193]. Since more than 40 regions in
the human genome were identified to be associated with the susceptibility to type 1 diabetes[194-196], a
weighted risk model was developed utilizing selected genes SNPs could be used for testing infants for
these genetic markers that could provide insights in the susceptibility to type 1 diabetes development or
safe prevention of the disease among young children[197].

Molecular genetics of monogenic diabetes

A large array of genes were identified to be involved in the development of monogenic diabetes[80] which
represent about 2%-5% of diabetes patients. Monogenic diabetes results primarily from gene defects that
lead to a decrease in beta cell number or function. Monogenic diabetes genes were identified using linkage
studies or code for proteins that directly affected glucose homeostasis. The majority of genes responsible
for monogenetic diabetes code for either transcription factors that participate in the control of nuclear gene
expression or proteins that are located on the cell membrane, cytoplasm and endoplasmic reticulum, pro‐
teins involved in insulin synthesis and secretion, exocrine pancreatic proteins and autoimmune diabetes
proteins[80]. The collective function of these proteins is their participation in glucose metabolism at differ‐
ent levels. Evidently, the hierarchy of a specific gene in the overall glucose metabolism pathway deter‐
mines the onset of diabetes in the patient and whether it is neonataly expressed or have late onset expres‐
sion (adulthood). Consequently, molecular defects in the structure and function of these genes lead to the
disturbance of plasma glucose level, the primary pathological sign of diabetes. The molecular mechanism
of permanent neonatal diabetes mellitus (PNDP) in addition to MODY explains the observed phenotype of
monogenetic diabetes that involves loss of function of the expressed mutant protein. The first gene impli‐
cated in monogenic diabetes was the glucokinase (GCK) gene[198] which functions as a pancreatic sensor
for blood glucose where more than 70 mutations in the gene were identified that affected its activity[199].
A recent study on GCK gene mutations causing neonatal and childhood diabetes showed that the majority
of mutations resulted in the loss of the enzyme function primarily due to protein instability[148,150]. Two
hepatocytes nuclear factor genes that code for the HNF4A and HNF1A transcription factors were closely
associated with MODY1 and MODY2[148,149]. Definitely, a whole list of other genes involved in mono‐
genic diabetes are either overlooked or included in the genetic determinants of type 1 and type 2 diabetes
which will be identified and clarified through more careful future studies.

MOLECULAR GENETICS OF DIABETES COMPLICATIONS

In addition to the genetic determinants of diabetes, several gene mutations and polymorphisms have been
associated with the clinical complications of diabetes. The cumulative data on diabetes patients with a va‐
riety of micro- and macrovascular complications support the presence of strong genetic factors involved in
the development of various complications[200]. A list of genes have been reported that are associated with
diabetes complications including ACE and AKR1B1 in nephropathy, VEGF and AKRB1 in retinopathy and
ADIPOQ and GLUL in cardiovascular diseases[200]. A study on Chinese patients revealed a single SNP in
the promoter region of the smooth muscle actin (ACTA2) gene correlates with the degree of coronary
artery stenosis in type 2 diabetes patients[201]. Furthermore, the alpha kinase 1 gene (ALPK1) identified
as a susceptibility gene for chronic kidney disease by GWAS[202], was demonstrated in type 2 diabetes
patients[203]. Three additional genes have been strongly correlated with this risk of diabetic retinopathy
(DR) including the vascular endothelial growth receptor, aldose reductase and the receptor for advanced
glycation products genes[204] where specific polymorphisms in these genes seem to increase the risk of
DR development in diabetes patients[204]. A significant differential proteome (involving 56 out of 252
proteins) is evident that characterizes vitreous samples obtained from diabetes patients with the complica‐
tion in comparison to diabetes patients without the complication and control individuals[205].
Interestingly, a large portion of these proteins (30 proteins) belong to the kallikrein-kinin, coagulation and
complement systems including complement C3, complement factor 1, prothrombin, alpha-1-antitrypsin
and antithrombin III that are elevated in diabetic patients with retinopathy[205]. In addition, 2 single nu‐
cleotides polymorphisms in the human related B7-I gene seem to mediate podocyte injury in diabetic
nephropathy[206]. Furthermore, increased concentration of the ligand of B7-1 correlates with the progres‐
sion of end-stage renal disease (ESRD) in diabetes patients[206]. These results indicate that B7-I inhibition
may serve as a potential target for diabetes nephropathy prevention and/or treatment. Recently, it was
shown that direct correlation is evident between circulating levels of tumor necrosis factors 1 and 2 and in‐
creased risk of ESRD in American Indian patients[207]. The link between diabetes and proper bone devel‐
opment and health is evident. Studies using animal models with major significant reduction in insulin re‐
ceptor (IR) in osteoprogenitor cells resulted in thin and rod-like weak bones with high risk of
fractures[208]. Similar findings were observed in animal models with bone-specific IR knockdown animals
which points to the central role of IR in the proper development of bones[208]. Type 2 diabetes is also as‐
sociated with mitochondrial dysfunction in adipose tissues. Using knockout animal models of specific mi‐
tochondrial genes led to significant reduction in key electron transport complexes expression and eventu‐
ally adipocytes death[209]. These animals exhibited Insulin resistance in addition to other complications
that can potentially lead to cardiovascular disease[209].

CONCLUSION

Diabetes mellitus is the epidemic of the century and without effective diagnostic methods at an early stage,
diabetes will continue to rise. This review focuses on the types of diabetes and the effective diagnostic
methods and criteria to be used for diagnosis of diabetes and prediabetes. Evidently, diabetes is a complex
disease with a large pool of genes that are involved in its development. The precise identification of the ge‐
netic bases of diabetes potentially provides an essential tool to improve diagnoses, therapy (more towards
individualized patient targeted therapy) and better effective genetic counseling. Furthermore, our advanced
knowledge of the association between medical genetics and the chronic complications of diabetes, will pro‐
vide an additional advantage to delay or eradicate these complications that impose an immense pressure on
patient’s quality of life and the significantly rising cost of health-care services.

Footnotes

Conflict-of-interest: The authors declare that there is no conflict of interest associated with this manuscript.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by
external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC
4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their
derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: November 23, 2014

First decision: February 7, 2015

Article in press: April 14, 2015

P- Reviewer: Hegardt FG, Surani S, Traub M S- Editor: Gong XM L- Editor: A E- Editor: Wang CH

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