Received: 7 March 2020 Revised: 4 May 2020 Accepted: 4 May 2020

DOI: 10.1111/cge.13772

REVIEW

Genetic predisposition in type 2 diabetes: A promising

approach toward a personalized management of diabetes

Mahmoud M. Sirdah Ph.D.1,2 | N. Scott Reading Ph.D.3,4

1
Division of Hematology, Department of
Internal Medicine, University of Utah School
of Medicine, Salt Lake City, Utah
2
Biology Department, Al Azhar University-
Gaza, Gaza, Palestine
3
Institute for Clinical and Experimental
Pathology, ARUP Laboratories, Salt Lake
City, Utah
4
Department of Pathology, University of Utah
School of Medicine, Salt Lake City, Utah
Correspondence
Dr. Mahmoud M. Sirdah, Biology Department,
Al Azhar University-Gaza, P O Box 1277, Gaza,
Palestine.
Email: sirdah@alazhar.edu.ps, m.sirdah@
utah.edu
Abstract
Diabetes mellitus, also known simply as diabetes, has been described as a chronic
and complex endocrine metabolic disorder that is a leading cause of death across the
globe. It is considered a key public health problem worldwide and one of four impor-
tant non-communicable diseases prioritized for intervention through world health
campaigns by various international foundations. Among its four categories, Type
2 diabetes (T2D) is the commonest form of diabetes accounting for over 90% of
worldwide cases. Unlike monogenic inherited disorders that are passed on in a simple
pattern, T2D is a multifactorial disease with a complex etiology, where a mixture of
genetic and environmental factors are strong candidates for the development of the
clinical condition and pathology. The genetic factors are believed to be key
predisposing determinants in individual susceptibility to T2D. Therefore, identifying
the predisposing genetic variants could be a crucial step in T2D management as it
may ameliorate the clinical condition and preclude complications. Through an under-
standing the unique genetic and environmental factors that influence the develop-
ment of this chronic disease individuals can benefit from personalized approaches to
treatment. We searched the literature published in three electronic databases:
PubMed, Scopus and ISI Web of Science for the current status of T2D and its associ-
ated genetic risk variants and discus promising approaches toward a personalized
management of this chronic, non-communicable disorder.

KEYWORDS

diabetes mellitus, genetic predisposition, genome-wide association studies, personalized

medicine, pharmacogenomics, T2DM

1 | I N T RO DU CT I O N in medicinal practice.5-8 The concept of personalized medicine has

Medicine is science-based conceptual framework and practices deal-
ing with the maintenance of health through prevention, diagnosis,
treatment, alleviation of symptoms, and cure of disease. Hence, medi-
cal practices are based on the current understanding of a disease or ill-
ness and gradually improve as new information and data fills in the
details.1-3 From the four humors of ancient Greece to today the prac-
tice of medicine has increasingly become more exact in defining dis-
4
ease and their treatments. Science has opened Pandora's genetic box
to discover another level of disease interaction to explore and address
been with humanity throughout generations and as time passes we
are increasing able to act upon our knowledge to affect the course of
disease at the individual level.4,9,10 The most advanced aspect of per-
sonalized medicine has been in the field of pharmacogenomics: to
address the right drug at the right dosage for the right response.11,12
Today advances in many aspects of medicine, biology, chemistry have
opened the doors to practical application of personalized medicine in
the treatment of different disorders.6,13,14 Advancements such as the
sequencing of the human genome, genome-wide association studies,
genetic architecture and molecular technologies brought forth a

Clinical Genetics. 2020;1–23. wileyonlinelibrary.com/journal/cge © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1
2 SIRDAH AND READING
genomic revolution to the medical field. This has the potential of
improving health treatments by understanding genetic etiologies of
diseases.
The incidence of Type 2 Diabetes (T2D) has risen rapidly in many
nations in the 21st century and due to its complex etiology, devastat-
ing pathology and humanistic and economic burdens it has drawn
attention of scientists from many diverse disciplines to better under-
stand the underlying mechanisms behind its severe complica-
tions.15-17 These studies (177 855 according to PubMed, accessed on
April 20, 2020) cover wide range of diabetes related topics including
but limited to: clinical trials, complications, diagnosis, prevention, risk
factors, and more recently the genetics issues. We believe it is impor-
tant to address the heritable aspects of T2D as a key public health
problem that severely impacting the national and global economies to
promote for a greater understanding of T2D pathophysiology and
advocate for novel managements supportive of a personalized medi-
cine approach. In this work we review the current status of genetic
risk factors associated with T2D and discuss promising approaches
toward personalized management of this widely distributed disorder.
We searched the literature published in three electronic databases:
PubMed, Scopus and ISI Web of Science for relevant journal articles
using “diabetes mellitus,” “Type 2 diabetes,” “personalized medicine,”
“personalized diabetes,” “precision diabetes,” “Type 2 diabetes
Genetic risk score,” “Type 2 diabetes genome-wide association studies
or GWAS,” “Type 2 diabetes Genetic architecture,” “Type 2 diabetes
candidate gene association studies,” “Type 2 diabetes linkage analy-
sis”, as the main keywords of the queries. The search was restricted to
English language publications despite the ethnicity of the population.
2 | D I A B E T E S M E LL I T U S
Diabetes mellitus, more commonly referred to as “diabetes,” has been
described as a complex, chronic, non-communicable, endocrine chal-
lenging, metabolic disorder characterized by persistent hyperglycemia
of such magnitude requiring continuous medical management. Other-
wise, over time it may cause serious pathologic damage and microvas-
cular complications especially in the nerves (neuropathy), kidney
(nephropathy), eye (retinopathy), as well as, macrovascular complica-
tions of blood vessels, leading to the development of cardiovascular,
cerebrovascular, and peripheral vascular diseases.18-20
2.1 | Epidemiology of diabetes
The prevalence of diabetes is dramatically increasing across the
15,21
globe. Although it has been described as a disease of wealthy and
developed nations, diabetes is now growing rapidly in poor and low-
income, developing nations as well.22 Owing to its morbidity, mortal-
ity, and economic burdens, diabetes is considered a key public health
problem worldwide and one of four important non-communicable dis-
eases for which public health campaigns have been initiated
(The World Diabetes Day, The World Health Day) and prioritized for
intervention by various health foundations: The International Diabetes
Federation (IDF), Centers for Disease Control and Prevention (CDC)
and the World Health Organization (WHO).23-26 The estimates pro-
vided by international specialized organizations like the IDF, WHO
and CDC for the prevalence of diabetes are frightening. The global
estimates for worldwide prevalence of diabetes among adults over
18 years has increased from 4.7% (108 million) in 1980 to 8.8% (425
million) in 2017 (95% CI 7.2%-11.3%), emphasizing a rapid rise in
middle- and low-income countries. Currently, diabetes is affecting
nearly half billions worldwide and its prevalence is anticipated to fur-
ther increase by 10.2% by 2030 and to a global prevalence of 10.9%
giving rise to more than 700 million people affected by diabetes in the
year 2045.23,27Figure 1 illustrates the IDF recent estimates of global
diabetes prevalence (9.3%, 95%CD: 7.4-12.1) in adults (20-79 years
old), and the prevalence within seven geographical regions of the
world. It is worth mentioning that North America-Caribbean region
and the Middle East and North Africa (MENA) region are ranked first
and second in the diabetic prevalence with 13.3% and 12.9%,
respectively.
According to the CDC 2017 report, 30.3 million (9.4% of the
U.S. population) people had diabetes, and 1 in 4 of them does not know
they have it. The CDC report also showed that the number of adults
diagnosed with diabetes has more than doubled in the last two decades.
Recently, the CDC considered diabetes as the seventh leading cause of
death.25,28 According to IDF recent estimate report, someone is dying
from diabetes or its deleterious complications every 7 seconds contribut-
ing to more than 4.2 million deaths per year, with large proportion of
those deaths occurring in individuals under the age of 60 years.23,27
2.2 | History and classification of diabetes
Diabetes occurs either due to insufficient insulin production or when
the body cannot efficiently utilize the produced insulin.29 The com-
mon clinical features and symptoms of diabetes rapid weight loss and
frequent urination, were described by ancient civilizations: Egyptians
on a 3600-year-old papyrus (1552 B.C.), as well as other civilizations
including the Greeks, Chinese, Arab and Indians.30-32 However, the
term diabetes (Greek word meaning to go through or siphon) has been
credited to Apollonius of Memphis around 250 to 230 B.C. to
describe a disease that drains patients of more liquid than they can
drink.33-35 In the 17th century, diabetes in Europe was known as the
“pissing evil,” and the term “mellitus” (meaning honeyed or sweet) was
coined by British anatomist and physician Thomas Willis due to the
sweetness of urine from diabetic patients.30,36,37
The classification and diagnosis of diabetes are multifaceted and
over the last decades many discussions, deliberation and amendments
were performed in order to agree on and establish the current widely
accepted classifications that included four main types of diabetes,
type 1 diabetes (T1D), T2D, gestational diabetes (GD) and specific
types of diabetes due to other causes,29 the first three classes are also
used by other international organizations including the IDF, CDC
and WHO.
SIRDAH AND READING
F I G U R E 1 Global and regional prevalence of diabetes in adults (20-79 years) according to IDF 2019 Atlas [Colour figure can be viewed at
wileyonlinelibrary.com]
2.2.1 | T1D
T1D is an organ-specific autoimmune disease usually leading to rela-
tive or absolute insulin deficiency. Loss of insulin production is primar-
ily due to the infiltration of Langerhans islets by autoreactive
lymphocytes and the consequent antibodies directed against and
destroying the insulin-producing β-cells of the islets. The result is usu-
ally an absolute dependence on exogenous insulin to regulate blood
glucose. T1D can develop at any age, yet it most frequently develops
before adulthood.29,38 T1D represents about 5% of the overall dia-
betic cases, with an increasing incidence worldwide that varies sub-
25
stantially by geographical regions. Although, the highest T1D rates
(incidence of 62.5/100000 per year in Finland) were reported in Scan-
dinavia and north-westEurope,39-42 it is becoming more common in
other ethnic groups such as (American Indians, Alaskan Natives, His-
43-46
panics), with Western Pacific ethnicities having the lowest rates.
In the United States, CDC estimated the incidence rate, from 2001 to
2015, of T1D in youth increased by 1.9% annually and now exceeds
20 per 100 000 population.25,47,48 In the Middle East and North Africa
(MENA) region, where Arabs constitute the ethnic majority, the IDF
recently estimated 149 400 children and adolescents (< 19 years old)
have T1D with an increase of 20 800 newly diagnosed cases annually.
Among MENA nations, the incidence of T1D varies from 1 per
100 000 population in Bahrain to about 420 per 100 000 population
in Algeria.49 Part of this variation is due to under-reporting among the
sub-Saharan nations where only 6.1% of the nations provided infor-
mation to the IDF. A substantial variation in the number of T1D cases
23
was reported among Arab countries. It worthwhile mentioning that
T1D incidence rate from African region (49 diverse sub-Saharan coun-
tries and territories) should be taken with caution as incidence rates
are available only from three countries (6.1%). The reasons behind the
global T1D incidence variations are still uncertain but a multifactorial,
complex interplay, including genetic and environmental factors, are
suspected..15,43,44,50,51
3
T1D is believed to have a genetic predisposition component. Sup-
port for this hypothesis has come from numerous GWAS linkage and
association studies, and candidate gene studies, which have identified
many T1D risk regions across the human genome. The earliest region
identified included the human leukocyte antigen (HLA) class II genes
and accounted for nearly half of T1D genetic risk. Other non-HLA
genes (eg, INS, CTLA4, PTPN22, and IL2RA) have also been identified
as contributing to the T1D genetic predisposition risk.52 Owing to
rapid analytical and technological development about 50 susceptibility
regions have identified as contributing to T1D with some loci com-
monly associated with immune-mediated disorders.53Onengut-
Gumuscu et al., (2016) identified in their comparative analysis study
with 15 immune-mediated disorders three novel loci that associated
with T1D. Their discussion stressed that there was a genetic similarity
between T1D and other autoimmune conditions such as juvenile idio-
pathic arthritis and ulcerative colitis. They also illustrated credible sets
for the T1D SNPs that mainly centralized to enhancer regions in thy-
mus, T and B cells, and CD34+ stem cells, opening the door for further
researches to identify causative genes and sequences.53
2.2.2 | T2D
T2D is the commonest form of diabetes and a risk factor for cardio-
vascular associated morbidity and mortality. Hyperglycemia in this
form of diabetes is due to ineffective use of insulin, insulin resistance,
or relative (rather than absolute) insulin deficiency that impairs glu-
cose transport and glucose homeostasis. Because autoimmune
destruction of pancreatic β-cells does not occur in T2D, most but not
all T2D patients do not need insulin treatment to survive.23,25,29,54-56
The specific causes of T2D are not known. The current hypothesis is
T2D is the result of multifactorial etiology where a mixture of genetic
and environmental factors are the underlying basis for the pathology
of the disease. A number of different genetic variants, but risk is small
4 SIRDAH AND READING
(small effect size with odds ratio of <1.5), have been identified as risk
factors for an individual's susceptibility for T2D development. How-
ever, these risk factors, alone or in combination may have the poten-
tial to substantially affect the clinical picture and cure of T2D
56-63
patients.
2.2.3 | Gestational diabetes
Any degree of glucose intolerance that first develops during preg-
nancy is called gestational diabetes (GD), where the blood glucose
level is above normal range, yet not of the diagnostic value for diabe-
tes.29,64 In pregnant women with GD, some hormones made by the
placenta obstructs the body from using insulin effectively (blocking
effect on insulin), so glucose builds up in the blood instead of being
utilized by the cells. This phenomenon usually occurs late in the sec-
ond trimester (20-24 weeks of pregnancy) and is called contra-insulin
effect.65,66 Gestational diabetes is reported in almost 7% of all preg-
nancies, however the prevalence is ranging from 1% to 14%
depending on the population and the diagnostic criteria.67-69 In the
United States between 7% and >20% of pregnant women are diag-
nosed with GD.70 Women with GD have a higher risk of complica-
tions in pregnancy and delivery, developing T2D within 5-15 years of
their diagnosis,67,71 and their children have an elevated risk of devel-
oping T2D.72-74 The American Diabetes Association (ADA) recom-
mends that women diagnosed with GD should receive lifestyle
interventions and have regular screenings for the development of
diabetes.29
2.2.4 | Specific types of diabetes due to other
causes
There are other less frequent types of diabetes with various known
etiologies that constitutes 1% to 5% of the overall hyperglycemic dia-
betic patients. These less common types are either genetically deter-
mined or result from some specific disease, infection, medication, or
chemical exposure.29,75-77 This class of diabetes include the subtypes
associated with monogenic defects (neonatal diabetes and maturity-
onset diabetes of the young [MODY]), pancreatitis, endocrinopathies,
drug-induced, and infection (congenital rubella, cytomegalovirus, ade-
novirus and mumps).29,78-80
3 | OVERVIEW OF T2D
Over the past few decades there have been significant advancements
in research toward a better understanding of T2D. According to
recent IDF estimates diabetes affects more than 463 million people
worldwide. The number of people living with this lifelong chronic dis-
ease continues to grow and is expected to reach 578 million in 2030
and 700 million in 2045. This epidemic is taking place on the back of
profound and pervasive detrimental alterations in lifestyle, principally
diet and physical activity. These figures do not reflect the state of pre-
diabetic patients whose blood glucose is elevated, but not high
enough to be classified as diabetes.23 Unfortunately, many people
with prediabetes have T2D within 10 years.81-83
The high prevalence of T2D, especially in low- and middle-income
countries, together with the high risk of developing both microvascu-
lar complications (including retinopathy, nephropathy and neuropathy)
and macrovascular complications (such as cardiovascular com-
orbidities) make T2D a seriously expanding global public health prob-
lem. A number of studies have shown T2D is formed by a complex or
multifactorial etiology where a mixture of genetic and environmental
(obesity, an unhealthy diet and physical inactivity) factors are strong
candidates for the impaired glucose homeostasis and subsequent
development of T2D clinical pathology. Therefore, T2D should be
considered, treated and managed as a chronic heterogeneous disorder
with multiple pathophysiological abnormalities, diverse susceptibility
to complications, and varied response to medical cure and strategic
interventions.84-86 Interventions may include key modifiable risk fac-
tors such as lifestyle, adiposity, physical inactivity, unhealthy diet
(quality of staple foods) as well as pharmacological issues.21,87-91
3.1 | Etiology and pathogenesis of T2D
T2D is a heterogeneous syndrome characterized by persistent hyper-
glycemia (increased hepatic glucose production and decreased periph-
eral glucose uptake in target tissues) due to insulin resistance and/or
relative impairment in insulin secretion as the main pathophysiological
features contributing to the development of symptoms, while disease
progression is attributed to gradual decrease of the functional pancre-
atic β cell mass and secretory capacity overtime.29,76,92,93
However, the causes of T2D are multifactorial and involve, to
varying extents, both genetic and environmental risk factors including,
but not limited to, those of carbohydrate and fat metabolism, obesity,
lack of exercise, stress, as well as aging.94-99 There are an increasing
number of scientific studies that support the possibility of genetic fac-
tors being involved as key determinants in individual susceptibility to
T2D, potentially some people inherit a predisposition for the disease
and become more likely to develop T2D than others.84-86 Therefore,
identifying T2D genetic risk variants is a crucial step in disease man-
agement as it may ameliorate the clinical condition and preclude the
complications.56,100-103 Until recently T2D was seen only in adults but
it is nowadays also reporting increasingly frequently in chil-
dren.15,104,105 Remarkably, during the last two decades the number of
T2D has tripled in the aged and overweight or obese populations
making it the fastest-increasing disease worldwide.15,106,107
The worldwide explosion of obesity in the past decade has
resulted in a markedly ever-increasing prevalence of T2D. Therefore,
understanding the pathogenesis of T2D is of great importance. This
effort is complicated by different risk factors that likely contribute to
the development of T2D and the varied clinical features emerging
from one or more synergistic combination of these risk fac-
tors.17,106,108 An increasing number of studies suggest the possibility
SIRDAH AND READING
of many genes, mostly in carbohydrate and fat metabolism, as
predisposing for T2D which with various environmental factors and
lifestyle changes are considered responsible for the onset and the rap-
idly increasing affected individuals with T2D. The genetic predisposi-
tion of T2D is not only affecting the development of the clinical
symptoms but also it has been linked to the disease serious pathologic
84,109-115
microvascular and macrovascular complications. Eventually,
the proper management and treatment of T2D necessitate the eluci-
dation of its molecular etiology by empirically defining the genes and
variants involved, as well as, effective interventions to combat the
obesity epidemic that is known to be a major risk factor for develop-
ing T2D.
3.2 | Genetics and architecture of T2D
We owe a debt of gratitude to the many researchers and patients
who have contributed to our current understanding of the genetic
variants associated with the development and prognosis of T2D.
These advances over the past 20 years have opened new vistas and
established the foundations toward elucidating the genetic architec-
ture risk and molecular basis underlying the pathophysiology of T2D.
Early linkage studies revealed a few genes (CAPN10, TCF7L2) and can-
didate gene studies built upon those findings to add a handful more
genes (PPARG, IRS1, IRS-2, KCNJ11, WFS-1, HNF1A, HNF1B, HNF4A)
that lead to T2D risk. However, none of these genes could provide a
substantial association to the observed heritability of T2D. Such
approach in researches was expanded through the linkage studies,
GWAS, and meta-analyses in diverse ethnic groups and multiple
populations.58,84,109,110,112-115 Currently large-scale genetic studies,
have identified more than 400 distinct genomic regions (genetic sig-
nals) influencing T2D, with few exclusions, most of them are common
and shared across different ethnicities and populations. Most of these
variants have modest predisposition effects on T2D and with a few
exceptions, most signals mapped to regulatory sequence, non-coding
sequences outside (intergenic) or within (intronic) the genes that are
probably to perturb gene expression rather than alter protein function
in disease-relevant tissues, like pancreatic islets. However, some have
been identified as human validated therapeutic targets through coding
variants that are causal for disease.60,116,117 These loci, usually
referred to by the name of the nearest genes, have substantially
improved the estimation of T2D genetic predisposition. However,
many other genes have been found to predispose to T2D in smaller-
84,109,112,115,118,119
scale studies in solitary specific populations.
In 1998 peroxisome proliferator-activatedreceptor-gamma
(PPARG) gene was the first candidate gene to be reproducibly associ-
120
ated with T2D. This nuclear receptor gene has been identified as a
key regulator of adipogenesis, glucose homeostasis, and lipid metabo-
lism. A relatively common substitution (Pro12Ala) in the PPARG gene
was found to be associated with lower body mass index and improved
insulin sensitivity among middle-aged and elderly individuals. 120-124
The variation at the hematopoietically expressed Homeobox (HHEX),
the Solute Carrier Family 30 Member 8 (SLC30A8), and the
5
transcription factor-7-like2 (TCF7L2) were the firstly identified as T2D
susceptibility loci through GWAS.125-128 The fundamental mecha-
nisms by which these genetic loci participate in T2D development or
even susceptibility is still lacking. So far, many susceptibility and pre-
disposition genetic loci have been described and found to be
influenced by other environmental factors such as obesity and life
style effects.84,103,129,130 However, there are an increasing molecular
evidence that emphasized on the role of some variants in coding
regions as causative genes that associated with T2D.112,131,132
The sibling-relative risk for T2D is 3 compared with 15 for
T1D.84,133 Genetic studies revealed the concordance of T2D in mono-
zygotic twins is about 70% to 90%, while it is only 20% to 30% in
dizygotic twins.58,59,84,134 The lifetime risk of developing T2D is 40%
for individuals who have one T2D parent and higher (70%) if both par-
ents are affected, however the risk of developing T2D is much higher
when the mother has the disease.130,135-137
As mentioned above, the polygenic, −multifactorial nature of T2D
is now well-established and the genetic architecture of T2D is
suggesting allelic heterogeneity with multiple genetic risk variants
identified to be associated mainly, but not limited, with β-cell function
(insulin production and release), insulin action (resistance/low sensitiv-
ity), and adiposity. Despite some debates about the consistency of the
T2D genetic architectures and the possible disease models, GWAS
studies have provided great understanding and insights into the
genetic architecture of T2D, including the number, frequency and
effect sizes of risk variants in different ethnicities and populations
worldwide. GWAS and genetic architecture studies should be contin-
ued for T2D, as well as for other polygenetic multifactorial diseases, in
diverse populations and including gene-environment interaction
which would likely contribute crucially to widening the terrain of
shared and unique population genetic effects for T2D.138,139 The
overarching goal of these studies should emphasize on the translation
and utilization of the gathered genetic information into daily clinical
practice as well as clarifying the molecular mechanism for early dis-
ease prediction, minimizing the complications and therapeutic
decision-making.139-143
3.2.1 | β-cell function and insulin secretion
A foremost metabolic characteristic for diabetes in general is insulin
deficiency resulting from relative to absolute pancreatic β-cell dys-
function.144,145 Accounting for less than 10% of the diabetic preva-
lence, the genetic basis of T1D with its autoimmune etiology has been
successfully determined that involved genetic variants associated
directly with β-cell functions as well as pancreatic development.146-149
On the other hand, in T2D and due to increased peripheral insulin
resistance, the β-pancreatic islets can no longer sustain higher com-
pensatory rates of insulin production get exhausted and dysfunc-
tional.93,150-152 In addition, increased β-cell apoptosis leading to
deficit in β-cell mass to a variable extent is also indicated in T2D
patients. This loss may be due a high secretory demand in overtly
hyperglycemic or obese individuals, high oxidative stress, misfolding in
 6

TABLE 1 Genetic risk variants associated with T2D through β-Cell function and/or insulin secretion

Gene/nearest Genetic
gene Name of gene/nearest gene variant Context location RA OA RAF OR P value Population Study design Reference
NOTCH2 Notch receptor 2 rs10923931 Intron 1p13-p11 T G 0.11 1.13 4.1E−08 European GWAS meta-analysis 172
FAF1 Fas associated factor 1 rs17106184 Intron 1p32.3 G A 0.92 1.10 4.1E−09 Multi ethnic GWAS-meta-analysis 84,173,174
MACF1 Microtubule actin crosslinking factor 1 rs3768321 Intron 1p34.3 T G 0.19 1.13 2.4E−09 Multi ethnic GWAS-meta-analysis 175
PROX1 Prospero homeobox 1 rs340874 Intron 1q32.2-q32.3 C T 0.52 1.07 7.2E−10 European GWAS-meta-analysis 174,176
PROX1 Prospero homeobox 1 rs2075423 Intron 1q32.2-q32.3 G T 0.62 1.07 8.1E−09 European GWAS- meta-analysis 177
BCL11A B-cell lymphoma/leukemia 11A rs243021 Intergenic 2p16.1 A G 0.46 1.08 2.9E−15 European GWAS meta-analysis 178
THADA Thyroid adenoma associated rs7578597 Exon/missense 2p21 T C 0.90 1.15 1.1E−09 European GWAS meta-analysis 172
THADA Thyroid adenoma associated rs35720761 Exon/missense 2p21 C T 0.10 1.12 3.3E−10 Multi ethnic GWAS Meta-analysis 115
TMEM163 Transmembrane protein 163 rs6723108 Intergenic 2q21.3 T G 0.85 1.31 3.3E−09 Indian GWAS 179
COBLL1 Cordon-Bleu WH2 repeat protein like 1 rs7607980 Exon/missense 2q24.3 C T 0.12 1.15 8.3E−15 Multi ethnic GWAS meta-analysis 115
UBE2E2 Ubiquitin conjugating enzyme E2E2 rs7612463 Intron 3p24.3 C A 0.83 1.19 2.3E−09 Japanese GWAS 180
ADCY5 Adenylate cyclase 5 rs11708067 Intron 3q13.2-q21 A G 0.78 1.12 9.9E−21 European GWAS- meta-analysis 176
IGF2BP2 Insulin like growth factor 2 MRNA rs11927381 Intron 3q27.2 C T 0.33 1.14 3.0E−14 Multi ethnic GWAS- meta-analysis 175
binding protein 2
IGF2BP2 Insulin like growth factor 2 MRNA rs4402960 Intron 3q27.2 T G 0.30 1.17 8.9E−16 European GWAS 181,182
binding protein 2
ST6GAL1 ST6 beta-galactoside alpha-2,6-sialyltransferase rs16861329 Intron 3q27.3 G A 0.75 1.09 3.4E−08 South Asia GWAS 183
1
LPP LIM domain containing preferred translocation rs6808574 Intergenic 3q27.3-q28 C T 0.79 1.07 5.8E−09 Multi ethnic GWAS- meta-analysis 173,174
partner in lipoma
WFS1 Wolframin ER transmembrane glycoprotein rs6446482 Intron 4p16.1 G C 0.48 0.90 3.4E−07 UK populations Pooled analysis 184
WFS1 Wolframin ER transmembrane glycoprotein rs10010131 Intron 4p16.1 G A 0.59 1.12 0.001 Swedish and GWAS 185
Finnish
MAEA Macrophage erythroblast attacher rs6815464 Intron 4p16.3 C G 0.58 1.13 1.6E−20 East Asians GWAS meta-analysis 186
TMEM154 Transmembrane protein 154 rs6813195 Intergenic 4q31.3 C T 0.59 1.08 4.1E−14 Multi ethnic GWAS-meta-analysis 173,174
PAM Peptidylglycine alpha-amidating rs35658696 Exon/missense 5q21.1 G A 0.051 1.17 2.5E−17 European GWAS meta-analysis 187
monooxygenase. using
PPIP5K2 Diphosphoinositol pentakisphosphate kinase 2 rs36046591 Exon/missense 5q21.1 G A 0.05 1.19 3.3E−08 Multi ethnic GWAS meta-analysis 115
ZFAND3 Zinc finger AN1-type containing 3 rs9470794 Intron 6p21.2 C T 0.27 1.12 2.1E−10 East Asians GWAS meta-analysis 174,186
KCNK16 Potassium two pore domain channel subfamily rs1535500 Exon/missense 6p21.2 T G 0.42 1.08 2.3E−08 East Asians GWAS meta-analysis 174,186
K member 16
POU5F1/ POU class 5 homeobox 1./transcription factor rs3130501 Intron 6p21.33 G A 0.38 1.07 4.2E−09 Multi ethnic GWAS- meta-analysis 173,174
TCF19 19
CDKAL1 CDK5 regulatory subunit associated rs7766070 Intron 6p22.2 A C 0.27 1.12 1.9E−11 Multi ethnic GWAS- meta-analysis 175
protein 1 like 1
SIRDAH AND READING
TABLE 1 (Continued)

Gene/nearest Genetic
gene Name of gene/nearest gene variant Context location RA OA RAF OR P value Population Study design Reference
SSR1/ RREB1 Signal sequence receptor subunit 1/Ras rs9505118 Intron 6p24.3 A G 0.45 1.06 1.4E−09 Multi ethnic GWAS- meta-analysis 173,174
responsive element binding protein 1
SIRDAH AND READING

RREB1 Ras responsive element binding protein 1 rs9379084 Exon/missense 6p24.3 A G 0.11 1.13 4.0E−09 Multi ethnic GWAS meta-analysis 115
JAZF1 Juxtaposed with another zinc finger protein 1 rs849134 Intron 7p15.2-p15.1 A G 0.53 1.12 6.4E−13 Multi ethnic GWAS- meta-analysis 175
GCK Glucokinase (hexokinase 4) rs4607517 Intergenic 7p15.3-p15.1 A G 0.16 1.07 5.0E−08 European GWAS- meta-analysis 174,176
DGKB/ Diacylglycerol kinase, beta 90 kDa rs2191349 Intergenic 7p21.2 T G 0.52 1.06 1.0E−08 European GWAS- meta-analysis 174,176
TMEM195
GCC1/PAX4 GRIP and coiled-coil domain containing rs6467136 Intergenic 7q32.1 G A 0.79 1.11 5.0E−11 East Asians GWAS meta-analysis 174,186
1/paired box 4
PAX4 Paired box 4 rs2233580 Exon/missense 7q32.1 T C 0.1 1.79 9.3E−09 Multi ethnic GWAS meta-analysis 115
ANK1 Ankyrin-1 rs516946 Intron 8p11.21 C T 0.76 1.09 2.5E−10 European GWAS meta-analysis
TP53INP1 Tumor protein P53 inducible nuclear protein 1 rs896854 Exon/missense 8q22.1 T C 0.48 1.06 9.9E−10 European GWAS meta-analysis
SLC30A8 Solute carrier family 30 member 8 rs13266634 Exon/missense 8q24.11 C T 0.69 1.12 1.4E−11 Multi ethnic GWAS- meta-analysis 172,175
CDKN2A/ Cyclin dependent kinase inhibitor rs10811661 Intergenic 9p21 T C 0.82 1.14 2.3E−10 Multi ethnic GWAS- meta-analysis 175
CDKN2B 2A/cyclin dependent kinase inhibitor 2B
GLIS3 GLIS Family Zinc Finger 3 rs7041847 Intron 9p24.2 A G 0.41 1.10 2.0E−14 East Asians GWAS meta-analysis 186
CHCHD9/ Coiled-coil-helix-coiled-coil-helix domain rs13292136 Intergenic 9q21.31 C T 0.93 1.11 2.8E−08 European GWAS meta-analysis 178
TLE4 containing 2 pseudogene 9/TLE family
member 4, transcriptional corepressor
TLE1 TLE family member 1, transcriptional rs2796441 Intron 9q21.32 G A 0.57 1.07 5.4E−09 European GWAS meta-analysis 177
corepressor
GPSM1 G protein signaling modulator rs11787792 Intron 9q34.3 A G 0.87 1.15 1.7E−10 East Asia GWAS 188
GPSM1 G protein signaling modulator rs60980157 Exon/missense 9q34.3 T C 0.26 1.09 1.7E−09 Multi ethnic GWAS meta-analysis 115,174,177,
179-189
CDC123/ cell division cycle 123 homolog/calcium/ rs12779790 Intergenic 10p13 G A 0.18 1.11 1.2E−10 European GWAS meta-analysis 172
CAMK1D calmodulin dependent protein kinase type
1D
VPS26A VPS26, retromer complex component A rs1802295 30 UTR 10q22.1 A G 0.26 1.08 4.1E−08 South Asia GWAS 183
ZMIZ1 Zinc finger MIZ-type containing 1 rs12571751 Intron 10q22.3 A G 0.52 1.08 1.0E−10 European GWAS meta-analysis 177
HHEX/IDE Hematopoietically expressed homeobox/ rs1111875 Intergenic 10q23.33 C T 0.52 1.13 6.0E−10 European GWAS 181
insulin degrading enzyme
TCF7L2 transcriptional factor 7 like 2 rs7903146 Intron 10q25.2-q25.3 T C 0.18 1.37 1.0E−48 Finn GWAS 181
TCF7L2 transcriptional factor 7 like 2 rs7903146 Intron 10q25.2-q25.3 T C 0.30 1.65 1.5E−34 French GWAS 125
TCF7L2 transcriptional factor 7 like 2 rs34872471 Intron 10q25.2-q25.3 C T 0.28 1.31 6.4E−53 Multi ethnic GWAS- meta-analysis 175
ABCC8 ATP Binding Cassette Subfamily rs757110 Exon/missense 11p15.1 C A 0.40 1.07 1.7E−08 Multi ethnic GWAS meta-analysis 115
C Member 8
7

(Continues)
 8

TABLE 1 (Continued)

Gene/nearest Genetic
gene Name of gene/nearest gene variant Context location RA OA RAF OR P value Population Study design Reference
KCNJ11 potassium channel, inwardly rectifying rs5215 Exon/missense 11p15.1 C T 0.27 1.14 5.0E−11 UK GWAS 190
subfamily J, member 11
KCNJ11 potassium channel, inwardly rectifying rs5219 Exon/missense 11p15.1 T C 0.46 1.14 6.7E−11 Finns GWAS 181
subfamily J, member 11
KCNQ1 Potassium channel voltage-gated channel, rs231362 Intron 11p15.5 G A 0.52 1.08 2.8E−13 European GWAS meta-analysis 178
KQT-like subfamily, member 1
ARAP1 ArfGAP with RhoGAP domain, ankyrin repeat rs1552224 50 UTR 11q13.4 A C 0.88 1.14 1.4E−22 European GWAS meta-analysis 178
and PH domain 1
MTNR1B Melatonin receptor 1B rs1387153 Intergenic 11q21-q22 T C 0.28 1.09 7.8E−15 European GWAS meta-analysis 178
TSPAN8/ Tetraspanin 8/leucine rich repeat containing G rs7961581 Intergenic 12q21.1 C T 0.27 1.09 1.1E−09 European GWAS meta-analysis 172
LGR5 protein-coupled receptor
CCDC63 Coiled-coil domain containing protein 63 rs11065756 Intron 12q24.11 G A 0.83 1.40 9.4E−09 Korean GWAS meta-analysis 191
SPRY2 Sprouty RTK signaling antagonist 2 rs1359790 Intergenic 13q31.1 G A 0.71 1.15 6.0E−09 Asian GWAS 192
RASGRP1 RAS guanyl releasing protein 1 rs7403531 Intron 15q14 T C 0.35 1.10 3.9E−09 Chinese Han GWAS 193
C2CD4A C2 calcium dependent domain containing rs7172432 Intergenic 15q22.2 A G 0.58 1.11 8.8E−14 Multi ethnic Meta-analysis 180
protein 4A
HMG20A High mobility group 20A rs7177055 Intron 15q24.3 A G 0.68 1.08 4.6E−09 European GWAS meta-analysis 177
HMG20A High mobility group 20A rs7178572 Intron 15q24.3 G A 0.52 1.09 7.1E−11 South Asia GWAS 183
ZFAND6 Zinc finger AN1-type containing 6 rs11634397 Intergenic 15q25.1 G A 0.60 1.06 2.4E−09 European GWAS meta-analysis 178
AP3S2 Adaptor related protein complex 3 subunit rs2028299 Non coding RNA 15q26.1 C A 0.31 1.10 1.9E−11 South Asia GWAS 183
sigma 2
PRC1 Protein regulator of cytokinesis 1 rs8042680 Intron 15q26.1 A C 0.22 1.07 2.4E−10 European GWAS meta-analysis 178
BCAR1 Breast cancer anti-estrogen resistance 1 rs7202877 Intergenic 16q23.1 T G 0.89 1.12 3.5E−08 European GWAS meta-analysis 177
SRR Serine racemase rs391300 Intron 17p13.3 G A 0.62 1.28 3.1E−09 Chinese Hans GWAS 194
HNF1B HNF1 Homeobox B rs4430796 Intron 17q12 G A 0.28 1.19 1.5E−11 Chinese Hans GWAS 193
TM6SF2 Gene transmembrane 6 superfamily member rs58542926 Exon/ missense 19p13.11 T C 0.08 1.14 3.2E−10 Multi ethnic GWAS meta-analysis 115
GIPR Gastric inhibitory polypeptide receptor rs1800437 Exon/missense 19q13.32 C G 0.21 1.09 4.6 × 10–9 European GWAS-meta-analysis 187
HNF4A Hepatocyte nuclear factor 4 alpha rs4812829 Intron 20q13.12 A G 0.29 1.09 2.6E−10 South Asia GWAS 183
MTMR3 Myotubularin related protein 3 rs41278853 Exon/missense 22q12.2 A G 0.08 1.14 5.6E−09 Multi ethnic GWAS meta-analysis 115
ASCC2 Activating signal cointegrator 1 complex rs11549795 Exon/missense 22q12.2 C T 0.08 1.13 1.0E−07 Multi ethnic GWAS meta-analysis 115
Subunit 2

Abbreviations: RA, risk allele; RAF, risk allele frequency; OA, other allele; OR, odds ratio.
SIRDAH AND READING
SIRDAH AND READING
the endoplasmic reticulum, or inflammatory signals of interleukin-1 β
produced within β-pancreatic islets cells. Unfortunately, β-cell dys-
function and the deficit β-cell mass progressively deteriorate insulin
secretion and aggravate the hyperglycemia, causing severe diabetic
complications over time.153-156
Involving different populations, GWAS data are providing an
ever-increasing number of T2D susceptibility variants. Interestingly,
and despite the fact that insulin resistance is the main etiological fac-
tor in T2D development,61,63,131,140,141,157-160 the majority variants
appear to influence insulin secretion and β-cell function rather than
insulin action. The TCF7L2 gene, a pleiotropic transcription factor
involved in glucose metabolism in many tissues, carried the strongest
association with T2D in multiple genetic studies (refs). Several SNP
(ie, rs12255372 and rs7903146) carried by TCF7L2 in several large
scale case–control studies, meta-analyses, and GWAS revealing the
remarkable consistency and relatively large effect size OR = 1.37-1.65,
among different ethnicities.161-171Table 1 provides a list of reproduc-
ibly identified genetic risk variants linked to T2D possibly thought
affecting β-cell dysfunction and reduced β-cell mass.
3.2.2 | Insulin action (insulin resistance/low insulin
sensitivity loci)
Insulin is a peptide hormone produced by the β-cells in the pancreatic
islets. It regulates the metabolism of carbohydrates by promoting the
uptake of glucose from the blood by liver, fat and skeletal muscle cells.
In T2D hyperglycemia is due to ineffective insulin response by the
body's cells (known as insulin resistance) resulting in disrupted glucose
homeostasis. Therefore, and despite sufficient insulin in the blood-
stream, the target cells remain locked and do not let blood glucose
195-198
into the cells. Unfortunately, individuals with insulin resistance
have built up a tolerance to insulin, making normal levels less effec-
tive. As a result, more insulin is produced and released in greater
quantities from the pancreas to persuade the target cells and tissues
to take up and store glucose. Over time, the β-cells of the pancreatic
islets get exhausted (dysfunction) and can no longer sustain these
higher rates of insulin production. Eventually, dysfunction of β-cells
result in higher blood glucose levels (prediabetes) and, ultimately,
T2D.93,150-152,199-201
The importance of insulin resistance in the T2D etiology is well-
established and acknowledged as the most powerful early predictor
93,202-206
and therapeutic target for T2D. There are several risk factors
that are assumed to play a role in developing insulin resistance includ-
ing genetic predisposition, ethnicity, overweight/obesity, and
aging.207-213 Some candidate genetic variants that make a person
more or less probably to develop insulin resistance leading to T2D
have been identified and confirmed in reproducible studies among dif-
ferent populations.214-218
In the pre-GWAS era the first genetic locus linked to T2D was
identified as a negative association with insulin resistance. Deeb et al,
1998 identified through a candidate gene approach that a Pro12Ala
polymorphism within the PPARG gene was associated with decreased
9
receptor activity, lower body mass index and improved insulin sensi-
tivity suggesting it may have as protecting effect for an individual
against T2D. The PPARG gene encodes a nuclear receptor protein that
regulates adipocyte differentiation, and possibly lipid metabolism and
expression of adipocyte-specific genes. The PPARG gene expressed in
adipocytes has an extra exon B and a common polymorphic substitu-
tion of a Proline for alanine at position 12 (Pro12Ala) of this protein,
which is cited in about 15% of the European population. This
Pro12Ala polymorphism was reproducibly shown to be linked with
increased transcriptional activity, increased insulin sensitivity and
hence protection against T2D. The strong association of the Pro12Ala
polymorphism of PPARG gene to T2D was supported by other studies
including GWAS, large scale, and meta-analysis.120-123,177,219-224
Table 2 summarizes other genetic variants that were reproducibly
identified by candidate gene association studies, linkage analysis and
GWAS to be associated to T2D probably through insulin action. In
addition to genetic risks, it is worthwhile mentioning that obesity and
decreased physical activity are also significant indicators of risk
toward developing an insulin-resistant condition. When these condi-
tions are added to the genetic predisposition for insulin resistance,
the development of T2D is accelerated.231-235
3.2.3 | Obesity and altered BMI
Obesity is a diabetogenic determinant that has an increasing world-
wide prevalence, especially in developing countries. While lifestyle
changes have driven obesity prevalence to epidemic proportions,
genetic predisposition is a substantial contributor that together with
environmental influences significantly increase the risk of obesity,
insulin resistance and ultimately T2D.17,108,236-239 The genetic vari-
ants contributing to alternation in BMI, and hence obesity, have been
the subjects for several GWAS and provide a better understanding of
the biological basis of obesity across different populations and ethnic-
ities.131,240-246 The considerable correlation between obesity from
one side and insulin resistance and β-cell dysfunction from the other
side is fundamental to answering the obesity-diabetes association
question and is expected to exacerbate the development of T2D and
its severe complications much earlier than in non-obese individuals.
Evidently, the excess fat in the glucose target cells makes these cells
less responsive to signals of insulin hormone, thus insulin resistance is
more probably to occur in overweight and obese
153,155,200,247-250
individuals.
Table 2 lists many of the genetic variants that have been discov-
ered through many genetic studies showing and association of BMI
and T2D in different populations. A significant variant with a high
T2D association is rs9939609 located in the intronic region of the Fat
mass and obesity-associated (FTO) gene, imposing an allelic 0.39 kg/
m2 increase in BMI.251,252 Other polymorphisms in the FTO locus
were shown to be strongly associated with extreme childhood obe-
sity.181,243,251,253-256 Obesity and T2D association are largely
described from epidemiological and pathophysiological perspectives.
Many genetic risk genes (FTO, MC4R, ADAMTS9, GRB14/COBLL1 and
10
QPCTL/GIPR) identified in obesity and T2D association studies carry
only a limited “indirect” or modest risk.86,112,138,160,243,253,255,257
4 | PERSONALIZED MEDICINE IN
DIABETES
Personalized medicine is a medical approach that stratify people or
patients into different groups based on their specific characteristics,
clinical presentations, and/or genetic makeup, thus directing diagnos-
tic and/or therapeutic strategies toward most effective treatment out-
comes. Although the term “personalized medicine,” interchangeably
precision medicine, individualized medicine or stratified medicine, has
become more practiced in the last few decades, the concept of tailor-
ing of treatment to patients dates back to at least 2500 years ago, to
the time of Hippocrates, the Greek physician and the father of mod-
ern medicine. Hippocrates was practitioner and advocate of personal-
ized medicine and provided written scripts about the individuality of
disease and the importance of giving different treatments to different
patients.258
Personalized medicine has been considered a quantum leap from
the 20th century paradigm of Western or conventional medicine
which was very useful for communicable diseases with a single etiol-
ogy to medicine for the 21st century which not only maintains the
progresses of the 20th century but also meritoriously handled
etiology-complex disorders.2 Among the most crucial advances that
favor the development of personalized medicine approach are GWAS
and massively parallel sequencing and other molecular technologies
which open the door for applying genetic-based risk assessment in
complex, non-monogenic disorders.143,259,260 Personalized medicine
approach not only provides superior care and improved welfare and
health than other approaches, it has the potential to save money and
alleviate economic burden of diseases on national health care sys-
tems.261-264 By practicing personalized medicine in the treatment of
diabetes, health professionals are individualizing health care and man-
agement plans based on a patient's susceptibility to disease and
response to treatment, thus maximizing benefits and minimizing
harms.6,265 In the case of diabetes, where the estimated total annual
global healthcare expenditures was more than United States 720 bil-
lion dollars,23,27 the potential savings to individuals and economies are
significant.
This DNA-centered view of personalized diabetes should not over-
shadow other factors, such as environmental, lifestyle and behavioral
factors, that besides the genetic factors may affect the development of
the symptoms.266,267 So far, personalized medicine has been success-
fully practiced in diabetes subtypes of simple etiology, monogenic dia-
betes, and become part of the clinical tools used at advanced diabetes
institutions. Nevertheless, in diabetes subtypes with complex or multi-
factorial etiology interesting and promising leads are emerging despite
some bridgeable challenges and gaps. With the ongoing technological
developments, smart utilization of big data, genomics and other
“-omics,” there is hope to make personalized medicine for complex eti-
ology diseases, for example, T2D, a reality in the near future.268
SIRDAH AND READING
4.1 | Personalized medicine in monogenic diabetes
Monogenic forms of diabetes characterized by pancreatic β-cell dys-
function, such as MODY and neonatal diabetes (ND), are eminent
examples of successful pharmacogenomics management that found a
place in clinical practice and where personalized diabetic care has
already become a reality.269,270 There are 13 distinct types of MODY
based on the dysfunctional gene causing the phenotype. The most
common type is MODY3 resulting from a mutation in HNF1A gene
that affects the transcription of multiple genes related to glucose
metabolism, insulin secretion, and insulin production.269 MODY
patients with HNF1A mutation have been found to be hypersensitive
to sulfonylureas as antidiabetic drugs due to decreased expression of
HNF1A regulated genes in the liver, leading to decreased uptake of
sulfonylureas. Therefore, very low doses of short acting sulfonylureas
has been recommended as initial treatment for MODY3 patients with
poor glycemic control on an appropriate diet.270,271
On the other hand, ND was found to have a number of gene eti-
ologies including, SNPs, chromosome duplication, and hyp-
omethylation. The clinical symptoms are most commonly caused by
activating mutations in KCNJ11 or ABCC8 genes thus affecting the
ATP-sensitive potassium channel in pancreatic β cells, resulting in
diminished insulin secretion and absolute dependence on exogenous
insulin.269,272 High doses of sulfonylureas have been found to fix
these alternations in the ATP-sensitive potassium channels, thus regu-
late the release of insulin. Nowadays, ND patients with KCNJ11 or
ABCC8 mutations are being successfully managed with oral sulfonyl-
ureas instead injectable insulin. Sulfonylureas not only substitute for
the more expensive, more invasive insulin injections, but it also mini-
mizes the greater risk for hypoglycemic episodes in ND patients. Per-
sonalized monogenic diabetes is now stretching beyond therapeutic
concerns to provide future information about additional clinical fea-
tures, complications, and probability of disease remission.273
4.2 | Personalized medicine in T2D
The etiology, clinical presentation, and complications of T2D are
greatly varied among patients complicating prevention and manage-
ment strategies. T2D remains effectively a diagnosis of exclusion. The
hallmark feature of patients categorized as T2D, after excluding the
other more defined causative forms of diabetes, is chronic hyperglyce-
mia.102 The roadmap in the T2D care protocol is based on remarkably
robust evidence and follows an algorithmic sequence that starts with
lifestyle (diet and exercise) adjustments plus the generally well toler-
ated biguanide antihyperglycemic agent (metformin HCL) as the first
recommended pharmacological treatment. Later, the protocols may
proceed to other drugs and/or insulin depending on the tolerability
and glycemic goals needed. Nevertheless, T2D patients have shown
variable responsiveness to drug treatment mainly due to genetic pre-
disposition and makeup, with a noteworthy number of patients having
exhibited some degree of drug resistance that lessen intervention
effectiveness.274-278 The benefits of lifestyle changes in diabetes
TABLE 2 Genetic risk variants associated with T2D through insulin action (resistance/low sensitivity) and/or adiposity

Gene/nearest
gene Name of Gene/nearest gene Genetic Variant Context location RA OA RAF OR P value Population Study design Reference
GCKR Glucokinase (hexokinase 4) regulator rs780094 Intron 2p23 C T 0.39 1.06 1.0E−09 European GWAS-meta-analysis 174,176
GCKR Glucokinase (hexokinase 4) regulator rs1260326 Exon/missense 2p23 C T 0.61 1.05 9.1E−10 European GWAS-meta-analysis 187
SIRDAH AND READING

RBMS1/ITGB6 RNA binding motif single stranded rs7593730 Intron 2q24.2 C T 0.82 1.11 4.0E−08 European GWAS 225
interacting protein 1/integrin subunit
beta 6
GRB14 Growth factor receptor bound protein 14 rs3923113 Intergenic 2q24.3 A C 0.74 1.09 1.0E−08 South Asian GWAS 183
IRS1 Insulin receptor substrate 1 rs7578326 Intron 2q36 A G 0.64 1.11 5.4E−20 European GWAS meta-analysis 178
CAPN10 Calcium-activated neutral proteinase 10 rs3792267 SNP-43 Intron 2q37.3 G A 0.88 1.38 0.03 African-Americans Meta-analysis 226
CAPN10 Calcium-activated neutral proteinase 10 rs3792267 SNP-43 Intron 2q37.3 G A 0.94 1.18 0.03 Asia Meta-analysis 227,228
CAPN10 Calcium-activated neutral proteinase 10 rs2975760 SNP-44 Intron 2q37.3 C T 0.16 1.1 0.0005 Multi ethnic Meta-analysis 229
ADAMTS9 ADAM metallopeptidase with rs4607103 Intron 3p14.1 C T 0.76 1.09 1.2E−08 European GWAS meta-analysis 172
thrombospondin type 1 motif, 9
PSMD6 Proteasome 26S subunit, non-ATPase 6 rs831571 Intergenic 3p14.1 C T 0.61 1.09 8.41E−11 East Asians GWAS meta-analysis 174,186
PPARG Peroxisome proliferator activated rs17036101 Intergenic 3p25.2 G A 0.93 1.15 2.0E−07 European GWAS meta-analysis 172
receptor gamma
PPARG Peroxisome proliferator activated rs1801282 Exon/missense 3p25.2 C G 0.88 1.16 6E−10 Multi ethnic GWAS-meta-analysis 173,174
receptor gamma
ANKRD55 Ankyrin repeat domain 55 rs459193 Intergenic 5q11.2 G A 0.70 1.08 6.0E−09 European GWAS meta-analysis 177
ANKRD55 Ankyrin repeat domain 55 rs9687833 Intron 5q11.2 A G 0.20 1.12 2.9E−09 Multi ethnic GWAS-meta-analysis 175
177
ARL15 ADP ribosylation factor like GTPase 15 rs702634 Intron 5q11.2 A G 0.76 1.06 6.9E−09 Multi ethnic GWAS-meta-analysis 84,173,174
ZBED3 Zinc finger BED-type containing 3 rs4457053 Intron 5q13.3 G A 0.26 1.08 2.8E−12 European GWAS meta-analysis 178
MIR129/LEP MicroRNA 129-1/Leptin rs791595 Intron 7q32.1 A G 0.08 1.17 2.6E−13 East Asian GWAS 188
KLF14 Krüppel-like factor 14 rs972283 Intergenic 7q32.2 G A 0.55 1.07 2.2E−10 European GWAS meta-analysis 178
PTPRD Protein tyrosine phosphatase receptor rs17584499 Intron 9p24.1-p23 T C 0.06 1.57 8.5E−10 Han Chinese GWAS 194
type D
GRK5 G protein-coupled receptor kinase 5 rs10886471 Intron 10q26.11 C T 0.78 1.12 7.0E−09 Han Chinese GWAS 193
HMGA2 High mobility group AT-hook 2 rs1531343 Intron 12q14.3 C G 0.10 1.1 3.6E−09 European GWAS meta-analysis 178
IGF1 Insulin like growth factor 1 rs35767 Near gene 5 12q23.2 G A 0.85 1.04 2.2E−09 European GWAS. meta-analysis 176
HNF1A HNF1 homeobox A rs7957197 Intron 12q24.31 T A 0.85 1.07 2.4E−08 European GWAS meta-analysis 178
FTO Fat mass and obesity-associated gene rs8050136 Intron 16q12.2 A C 0.38 1.17 1.3E−12 European GWAS 181,190
SLC16A11/A13 Solute carrier family 16 member 11/13 rs312457 Intron 17p13.1 G A 0.08 1.20 7.7E−13 East Asian GWAS 188
MC4R Melanocortin 4 receptor. rs12970134 Intergenic 18q21.32 A G 0.27 1.08 1.2E−08 European GWAS meta-analysis 177
BCL2 BCL2 apoptosis regulator rs12454712 Intron 18q21.33 T C 0.63 1.09 2.1E−08 multiethnic GWAS meta-analysis 230
CILP2 Cartilage intermediate layer protein 2 rs10401969 Intron 19p13.11 C T 0.08 1.13 7.0E−09 European GWAS meta-analysis 84,173,174
11

(Continues)
 12 SIRDAH AND READING

prevention and effectiveness of several antihyperglycemic drugs are

84,173,174
84,173,174
84,173,174
Reference
counterbalanced by the globally continuing increasing prevalence of
T2D.102 This may justifies the necessity for designing concomitant
prevention and an appropriate pharmacological treatment strategies
including personalized approaches to enhanced tolerability and
effectiveness.100,279-283
GWAS meta-analysis

GWAS meta-analysis

Based on the success in applying personalized approaches to

Study design

treating monogenic diabetes, T2D with its complex polygenic multi-

factorial etiology, could be only a few steps away from successful
GWAS

implementations. Stratification of T2D patients into multiple subtypes

is a major changeling issue for personalized care (Figure 2). Because
patients suffering from pancreatic islet β-cell dysfunction are unlikely
to respond to therapeutics that enhance insulin secretion identifying
East Asians
Population

South Asia
European

the mechanistic pathway of the T2D pathology is essential for more

tailored treatment choices.
0.56 1.10 1.3E−08
0.29 1.09 2.6E−10
0.79 1.27 3.0E−10
P value

4.2.1 | Pharmacogenomics in T2D

RA OA RAF OR

Pharmacogenomics applied to the T2D management is making

advancements in understanding the interaction between genetics and
molecular mechanisms of T2D drugs. Several studies have described
G
G
G

the impact of polymorphisms in important genes for sulfonylurea

metabolism and the sulfonylurea receptor, β-cell function, and insulin
A
A
A

action on the effectiveness of sulphonylureas as an antidiabetic drugs.

19q13.11
20q13.12
location

These include: ABCC8, KCNJ11, TCF7L2, CYP2C9, IRS1, CDKAL1,

Xq28

CDKN2A, CDKN2B, KCNQ1, NOS1AP and CAPN10 genes273 Similarly,

the influences of other T2D associated polymorphism on the effi-
ciency of other antidiabetic drugs such as biguanides and
Intergenic
Context

thiazolidinediones, as well as lipid-lowering drugs have been men-

Intron
Intron

tioned in several studies to include common variants in genes like

Abbreviations: RA, risk allele; RAF, risk allele frequency; OA, other allele; OR, odds ratio.

SLC22A1 and PPARG.284-290

Genetic Variant
rs3786897
rs4812829
rs5945326

4.2.2 | Polygenic risk score

In this era of advanced GWAS and other “omics” big data researchers
have identified about 400 distinct genetic signals influencing T2D risk
with a growing number of risk-alleles with lower frequency and small
effect size (modest effect on risk). However, when considered in com-
Hepatocyte nuclear factor 4 alpha

bination, the impact of these risk alleles could be significant and offer
dual-specificityphosphatase-9
Name of Gene/nearest gene

the capability to capture information on individual patterns of disease

predisposition.116,291 Expressed as a polygenic risk score these aggre-
gated genetic risks can identify individuals with a high future risk of
diabetes. The polygenic risk score is probabilistic rather than an
Peptidase D

evidence-based model and most suitably used as a predictor to quan-

(Continued)

tify a discrete increment in overall risk for disease. Although polygenic

risk score approach had been used for three T2D associated genetic
variants (KCNJ11, PPARG and TCF7L2) previously,292 the utilization of
Gene/nearest

this approach becomes more reliable in the GWAS, “omics,” and big
TABLE 2

data era.
HNF4A
DUSP9
PEPD
gene

As a part of the personalized medicine approach, different large

scale studies from various populations and ethnicities (European, and
SIRDAH AND READING
F I G U R E 2 Conventional and
personalized treatment approaches
[Colour figure can be viewed at
wileyonlinelibrary.com]
non-European) have emphasized the success of polygenic risk scores
to identify individuals or populations at high risk to develop
T2D.116,291,293,294 Polygenic risk scores have also been used in differ-
ential diagnosis in those with diabetes, providing a growing optimism
for offering significant clinical advantages and reducing morbidity and
mortality associated with diabetes.116 In their recent study, Ahlqvist
and coworkers illustrated the superiority of genetic risk score over
classical diabetes classifications in clustering, stratification and differ-
entiation of adult-onset diabetic cases into five distinct clusters that
include T1D and T2D novel subgroups, and its importance in enhanc-
ing and promoting precision medicine in diabetes. The researchers
also showed that clustering based on genetic risk score central to the
development of diabetes successfully identified patients at high risk
of diabetic complications at diagnosis and provided information about
the pathological mechanistic pathway, thereby guiding choice of
295
therapy.
As rare variants with small effect sizes are difficult to identify
296
using GWAS, the prediction value of polygenic risk scores derived
from GWAS could be complementary augmented by data from
whole-genome or whole-exome sequencing.297
4.2.3 | Sexual dimorphism in T2D
Adding to the complex etiology gender has been shown to play a role
in T2D. T2D has a higher occurrence in males than females, with dif-
fering manifestations in predisposition, glucose metabolism and pro-
gression of diabetic complications. Implementation of personalized
management for diabetes could not be successful without considering
the sexual dimorphic issues of this metabolic disorder. Although the
process of sexual dimorphism is not fully understood, gender specific-
ities in neonatal development, epigenetic modification, and the basic
disparities in sex hormones are possible inflecting factors. Recently,
the effect of T2D associated allele, Kruppel Like Factor 14 (KLF14) on
pre-adipocyte proliferation, lipogenesis disruption, and body fat distri-
298
bution were found to be female specific. In addition, human and
animal model experiments elucidated on the female-specific protec-
tion of endogenous Estrogen from T2D during their childbearing age.
13
Such sexual variations in T2D predisposition justifies the need for
sex-specific approaches in conventional and personalized diabetes
management.299
4.2.4 | Phenome-wide association studies
Very recently a new genotype-to-phenotype approach known as
phenome-wide association study (PheWAS) has been developed to
statistically estimate the association between single-nucleotide poly-
morphisms and many different phenotypes.300 This approach is not a
substitution of phenotype-to-genotype GWAS approach, but could
work complement GWAS as a reliable tools to advance personalized
Medicine300-302 This PheWAS approach has re-validatedprior-known
genetic variants and diabetes associations,303 and appears to have
application in understanding the complexities of many polygenic dis-
orders.300 Through this auxiliary PheWAS approach, further crucial
steps in personalized diabetes could be achieved.
5 | CHALLENGES AND LIMITATIONS
5.1 | Genome wide association studies
Despite the contribution of GWAS in developing genomics to its
understanding of genetic risk for a growing number of complex poly-
genic disorders including T2D, there are many challenges and limita-
tions associated with this technique and the generated data. These
include: small effect sizes of associations, difficulty in determining true
causal associations, conducting studies in highly admixed multi-ethnic
populations, heterogeneity of subjects in multicenter studies of very
large sample size, insufficient sample size, and a lack of well-defined
case and control groups (specifically for population stratifica-
tion).296,304,305 In addition, due to the steep infrastructural require-
ments this technique is not ubiquitously available in areas that are
dealing with T2D.143 We cannot ignore ethical concerns306 as well as
the financial, technological requirements, which are extremely costly
and hardly available for many research institutions worldwide.296,307
14
5.2 | Personalized medicine in T2D
Increasing application of personalized medicine based on individual
genetic and phenotypic profiles has provided promising medical
advantages for patient care and disease management. However, fur-
ther steps are necessary to integrate our current understanding of
complex disease architectures into a personalized medicine approach.
In the context of T2D diagnosis and treatment there are some chal-
lenges and limitations of the personalized medicine approach should
be taken into consideration. Many of which could impact the individ-
uals, healthcare systems, economy and society. These challenges and
limitations include: the heterogeneity of T2D, ethical concerns about
individual privacy and confidentiality, handling of genomic information
by insurance companies, quality and standardizations of phenotypic
data, stratification and genetic discrimination based on ethnicity, and
financial factors in areas with limited resources.101,273,308-310
Despites the remarkable success of personalized approach in the
management of monogenic forms of diabetes the great heterogeneity
of the multifactorial T2D remains a challenge in defining etiological
subgroups, refining the diagnostic and therapeutic pathways for opti-
mal management. There are a growing number of presumptive phar-
macogenomics associations, however, only robustly replicated
associations from larger prospective studies in ethnically diverse
populations across a range of age group should be exploited. In this
manner will we bridge the gap in clinical trial information regarding
T2D management in youth, adolescents, elderly, and pregnant
women.273 Notwithstanding of these challenges and limitations, the
technological developments in diagnosis and analytical tools are
expected to enhance our understanding of T2D heterogeneity and
broaden our capabilities to apply them to personalized medicine.
6 | C O N CL U S I O N
Personalized medicine shows promise in providing cost savings and
efficiencies in the treatment and management of T2D. Genetic variant
identification on the individual level and understanding their influence
in the predisposition and pathogenesis of T2D would be a critical
advance in disease management improving the clinical condition and
precluding complications. In our review we have identified the current
state of genetic risk variants associated with T2D and shown the
importance pharmacogenomics studies have in associating actionable
relationships between genetic and pharmacologic treatments. It is our
desire to forward the advance of personalized approaches toward
management of this growing diabetic epidemic.
We recommend that all involved stakeholders should start
national and international preparedness plans for establishing and
strengthening the infrastructure necessary for promoting T2D person-
alized medicine. The ongoing technological advances are the corner-
stones for developing the data to improve our understanding of the
etiology and architecture of T2D and translate those discoveries into
more effective prevention and therapeutic strategies. The economic
burden of implementing this approach should be considered very well
SIRDAH AND READING
specially in low and middle income countries. Ultimately, local and
global ethical legislations should be laid down to protect the rights
and privacy of the individuals' genetic records from being abused
worldwide.
AC KNOWLEDG EME NT S
Dr. Mahmoud Sirdah would like to thank Dr. Josef T. Prchal of the
Huntsman Cancer Institute, University of Utah, for hosting him as a
visiting scholar during his sabbatical leave. Also the authors would like
to thank Dr. Saleh N. Mwafy for his fine touches on the sketches.
CONFLIC T OF INT ER E ST
The authors declare no conflict of interest related to this work.
DATA AVAILABILITY STAT EMEN T
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
OR CID
Mahmoud M. Sirdah https://orcid.org/0000-0002-1146-5570
N. Scott Reading https://orcid.org/0000-0003-0806-5661
RE FE RE NCE S
1. Fokunang CN, Ndikum V, Tabi OY, et al. Traditional medicine: past,
present and future research and development prospects and integra-
tion in the National Health System of Cameroon. Afr J Tradit Comple-
ment Altern Med. 2011;8(3):284-295. https://doi.org/10.4314/
ajtcam.v8i3.65276.
2. Whitcomb DC. What is personalized medicine and what should it
replace? Nat Rev Gastroenterol Hepatol. 2012;9(7):418-424. https://
doi.org/10.1038/nrgastro.2012.100.
3. Croft P, Altman DG, Deeks JJ, et al. The science of clinical practice:
disease diagnosis or patient prognosis? Evidence about “what is
likely to happen” should shape clinical practice. BMC Med. 2015;13:
20. https://doi.org/10.1186/s12916-014-0265-4.
4. Steele FR. Personalized medicine: something old, something new.
Pers Med. 2009;6(1):1-5. https://doi.org/10.2217/17410541.6.1.1.
5. Korf BR. Genetics and medical practice: new approaches to “old” dis-
orders. Curr Opin Pediatr. 2002;14(6):688-690. https://doi.org/10.
1097/00008480-200212000-00007.
6. Vogenberg FR, Isaacson Barash C, Pursel M. Personalized medicine:
part 1: evolution and development into theranostics. P T. 2010;35
(10):560-576. http://www.ncbi.nlm.nih.gov/pubmed/21037908.
7. Offit K. Personalized medicine: new genomics, old lessons. Hum Genet.
2011;130(1):3-14. https://doi.org/10.1007/s00439-011-1028-3.
8. Milunsky A. The “new genetics” in clinical practice: a brief primer.
J Am Board Fam Med. 2017;30(3):377-379. https://doi.org/10.3122/
jabfm.2017.03.160316.
9. Tutton R. Personalizing medicine: futures present and past. Soc Sci
Med. 2012;75(10):1721-1728. https://doi.org/10.1016/j.socscimed.
2012.07.031.
10. Dirette DP. Personalized medicine: definitions, history, and implica-
tions for the OT profession. Open J Occup Ther. 2015;3(4):8. https://
doi.org/10.15453/2168-6408.1213.
11. de Leon J. Pharmacogenomics: the promise of personalized medicine
for CNS disorders. Neuropsychopharmacology. 2009;34(1):159-172.
https://doi.org/10.1038/npp.2008.147.
12. Mini E, Nobili S. Pharmacogenetics: implementing personalized med-
icine. Clin Cases Miner Bone Metab. 2009;6(1):17-24. http://www.
ncbi.nlm.nih.gov/pubmed/22461093.
SIRDAH AND READING
13. Redekop WK, Mladsi D. The faces of personalized medicine: a
framework for understanding its meaning and scope. Value Health.
2013;16(6 Suppl):S4-S9. https://doi.org/10.1016/j.jval.2013.
06.005.
14. Hayes DF, Markus HS, Leslie RD, Topol EJ. Personalized medicine:
risk prediction, targeted therapies and mobile health technology.
BMC Med. 2014;12:37. https://doi.org/10.1186/1741-7015-12-37.
15. Cataloguing WL. Global Report on Diabetes. Vol 978. Geneva, Swit-
zerland: World Health Organization; 2016. http://www.who.int/
about/licensing/.
16. Ginter E, Simko V. Type 2 diabetes mellitus, pandemic in 21st cen-
tury. Adv Exp Med Biol. 2012;771:42-50. https://doi.org/10.1007/
978-1-4614-5441-0_6.
17. Zimmet PZ. Diabetes and its drivers: the largest epidemic in human
history? Clin Diabetes Endocrinol. 2017;3:1. https://doi.org/10.1186/
s40842-016-0039-3.
18. Standards of medical care in diabetes- -2014. Diabetes Care. 2014;
37(Suppl 1):S14-S80. https://doi.org/10.2337/dc14-S014.
19. Beckman JA, Creager MA. Vascular complications of diabetes. Circ
Res. 2016;118(11):1771-1785. https://doi.org/10.1161/
CIRCRESAHA.115.306884.
20. Kosiborod M, Gomes MB, Nicolucci A, et al. Vascular complications
in patients with type 2 diabetes: prevalence and associated factors
in 38 countries (the DISCOVER study program). Cardiovasc Diabetol.
2018;17(1):150. https://doi.org/10.1186/s12933-018-0787-8.
21. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF diabetes
Atlas: global estimates for the prevalence of diabetes for 2015 and
2040. Diabetes Res Clin Pr. 2017;128:40-50. https://doi.org/10.
1016/j.diabres.2017.03.024.
22. Hu FB. Globalization of diabetes: the role of diet, lifestyle, and
genes. Diabetes Care. 2011;34(6):1249-1257. https://doi.org/10.
2337/dc11-0442.
23. IDF, Federation ID. IDF DIABETES ATLAS; Ninth Edition. 9th ed.
Brussels, Belgium: International Diabetes Federation; 2019.
24. (PAHO/WHO) PAHO-WRHO. Health Status Of The Population:
Noncommunicable Disease Prevention and Control. 2017.
25. National Diabetes Statistics Report, 2017. Estimates of Diabetes and
its Burden in the United States. Atlanta, GA, USA: National Center for
Chronic Disease Prevention and Health Promotion: Division of Dia-
betes Translation; 2017.
26. Organization WH, Organization WH. Global Status Report on Non-
communicable Diseases 2014. Geneva: World Health Organization;
2014.
27. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes
prevalence estimates for 2019 and projections for 2030 and 2045:
results from the international diabetes federation diabetes Atlas, 9
(th) edition. Diabetes Res Clin Pr. 2019;157:107843. https://doi.org/
10.1016/j.diabres.2019.107843.
28. Stokes A, Preston SH. The contribution of rising adiposity to the
increasing prevalence of diabetes in the United States. Prev Med.
2017;101:91-95. https://doi.org/10.1016/j.ypmed.2017.05.031.
29. 2. Classification and diagnosis of diabetes: standards of medical Care
in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S13-S28. https://
doi.org/10.2337/dc19-S002.
30. Karamanou M, Protogerou A, Tsoucalas G, Androutsos G, Poulakou-
Rebelakou E. Milestones in the history of diabetes mellitus: the main
contributors. World J Diabetes. 2016;7(1):1-7. https://doi.org/10.
4239/wjd.v7.i1.1.
31. Ahmed AM. History of diabetes mellitus. Saudi Med J. 2002;23(4):
373-378. http://www.ncbi.nlm.nih.gov/pubmed/11953758.
32. Loriaux DL. Diabetes and the Ebers papyrus 1552 B.C. Endocrinolo-
gist. 2006;16(2):1.
33. Das AK, Shah S. History of diabetes: from ants to analogs. J Assoc
Physicians India. 2011;59(Suppl 59):6-7. http://www.ncbi.nlm.nih.
gov/pubmed/21818991.
15
34. Lakhtakia R. The history of diabetes mellitus. Sultan Qaboos Univ
Med J. 2013;13(3):368-370. https://doi.org/10.12816/
0003257.
35. Goldman R, Zajac J, Shrestha A, Patel P, Poretsky L. The Main events
in the history of diabetes mellitus. In: Poretsky L, ed. Principles of
Diabetes Mellitus. 3rd ed. New York: Springer International Publish-
ing AG; 2017. https://doi.org/10.1007/978-3-319-18741-9.
36. Gregory R. Book review: the pissing evil, a comprehensive history of
diabetes. Br J Diabetes. 2018;18:1-2.
37. Bradwel S. The pissing evil: a comprehensive history of diabetes
mellitus. Soc Hist Med. 2019;32(3):3-654. https://doi.org/10.1093/
shm/hkz036.
38. Organization WH. Classification of Diabetes Mellitus. Geneva: World
Health Organization; 2019. https://apps.who.int/iris/rest/
bitstreams/1233344/retrieve.
39. Andersson T, Ahlbom A, Carlsson S. Diabetes prevalence in Sweden
at present and projections for year 2050. PLoS ONE. 2015;10(11):
e0143084. https://doi.org/10.1371/journal.pone.0143084.
40. Hussen HI, Yang D, Cnattingius S, Moradi T. Type I diabetes among
children and young adults: the role of country of birth, socioeco-
nomic position and sex. Pediatr Diabetes. 2013;14(2):138-148.
https://doi.org/10.1111/j.1399-5448.2012.00904.x.
41. Saraswathi S, Al-Khawaga S, Elkum N, Hussain K. A systematic
review of childhood diabetes research in the middle east region.
Front Endocrinol. 2019;10:805. https://doi.org/10.3389/fendo.2019.
00805.
42. Hakkarainen P, Sund R, Arffman M, et al. Working people with type
1 diabetes in the Finnish population. BMC Public Health. 2017;17(1):
805. https://doi.org/10.1186/s12889-017-4723-8.
43. Ji J, Hemminki K, Sundquist J, Sundquist K. Ethnic differences in
incidence of type 1 diabetes among second-generation immigrants
and adoptees from abroad. J Clin Endocrinol Metab. 2010;95(2):847-
850. https://doi.org/10.1210/jc.2009-1818.
44. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology
of type 1 diabetes. Endocrinol Metab Clin N Am. 2010;39(3):481-497.
https://doi.org/10.1016/j.ecl.2010.05.011.
45. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet.
2014;383(9911):69-82. https://doi.org/10.1016/S0140-6736(13)
60591-7.
46. Dzidzonu DK, Skrivarhaug T, Joner G, Moger TA. Ethnic differences
in the incidence of type 1 diabetes in Norway: a register-based study
using data from the period 2002-2009. Pediatr Diabetes. 2016;17(5):
337-341. https://doi.org/10.1111/pedi.12294.
47. Rogers MAM, Kim C, Banerjee T, Lee JM. Fluctuations in the inci-
dence of type 1 diabetes in the United States from 2001 to 2015: a
longitudinal study. BMC Med. 2017;15(1):199. https://doi.org/10.
1186/s12916-017-0958-6.
48. Mayer-Davis EJ, Lawrence JM, Dabelea D, et al. Incidence trends of
type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med.
2017;376(15):1419-1429. https://doi.org/10.1056/NEJMoa1610187.
49. Patterson CC, Karuranga S, Salpea P, et al. Worldwide estimates of
incidence, prevalence and mortality of type 1 diabetes in children
and adolescents: results from the international diabetes federation
diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:
107842. https://doi.org/10.1016/j.diabres.2019.107842.
50. Spanakis EK, Golden SH. Race/ethnic difference in diabetes and dia-
betic complications. Curr Diab Rep. 2013;13(6):814-823. https://doi.
org/10.1007/s11892-013-0421-9.
51. Diaz-Valencia PA, Bougneres P, Valleron AJ. Global epidemiology of
type 1 diabetes in young adults and adults: a systematic review.
BMC Public Health. 2015;15:255. https://doi.org/10.1186/s12889-
015-1591-y.
52. Rich SS. Genetics and its potential to improve type 1 diabetes care.
Curr Opin Endocrinol Diabetes Obes. 2017;24:279-284. https://doi.
org/10.1097/MED.0000000000000347.
16
53. Onengut-Gumuscu S, Chen WM, Burren O, et al. Fine mapping of
type 1 diabetes susceptibility loci and evidence for colocalization of
causal variants with lymphoid gene enhancers. Nat Genet. 2015;47:
381-386. https://doi.org/10.1038/ng.3245.
54. Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017;
389(10085):2239-2251. https://doi.org/10.1016/S0140-6736(17)
30058-2.
55. Martin-Timon I, Sevillano-Collantes C, Segura-Galindo A, Del
Canizo-Gomez FJ. Type 2 diabetes and cardiovascular disease: have
all risk factors the same strength? World J Diabetes. 2014;5(4):444-
470. https://doi.org/10.4239/wjd.v5.i4.444.
56. Malandrino N, Smith RJ. Personalized medicine in diabetes. Clin
Chem. 2011;57(2):231-240. https://doi.org/10.1373/clinchem.
2010.156901.
57. Nair AK, Baier LJ. Complex genetics of type 2 diabetes and effect
size: what have we learned from isolated populations? Rev Diabet
Stud. 2015;12(3–4):299-319. https://doi.org/10.1900/RDS.2015.
12.299.
58. Lyssenko V, Laakso M. Genetic screening for the risk of type 2 diabe-
tes: worthless or valuable? Diabetes Care. 2013;36(Suppl 2):S120-
S126. https://doi.org/10.2337/dcS13-2009.
59. Ali O. Genetics of type 2 diabetes. World J Diabetes. 2013;4(4):114-
123. https://doi.org/10.4239/wjd.v4.i4.114.
60. Mahajan A, Taliun D, Thurner M, et al. Fine-mapping type 2 diabetes
loci to single-variant resolution using high-density imputation and
islet-specific epigenome maps. Nat Genet. 2018;50(11):1505-1513.
https://doi.org/10.1038/s41588-018-0241-6.
61. Billings LK, Florez JC. The genetics of type 2 diabetes: what have we
learned from GWAS? Ann N Y Acad Sci. 2010;1212:59-77. https://
doi.org/10.1111/j.1749-6632.2010.05838.x.
62. Marouli E, Kanoni S, Mamakou V, et al. Evaluating the glucose rais-
ing effect of established loci via a genetic risk score. PLoS ONE.
2017;12(11):e0186669. https://doi.org/10.1371/journal.pone.
0186669.
63. Xue A, Wu Y, Zhu Z, et al. Genome-wide association analyses iden-
tify 143 risk variants and putative regulatory mechanisms for type
2 diabetes. Nat Commun. 2018;9(1):2941. https://doi.org/10.1038/
s41467-018-04951-w.
64. Coustan DR, Carpenter MW. The diagnosis of gestational diabetes.
Diabetes Care. 1998;21(Suppl 2):B5-B8. http://www.ncbi.nlm.nih.
gov/pubmed/9704220.
65. Ruiz-Palacios M, Ruiz-Alcaraz AJ, Sanchez-Campillo M, Larque E.
Role of insulin in placental transport of nutrients in gestational dia-
betes mellitus. Ann Nutr Metab. 2017;70(1):16-25. https://doi.org/
10.1159/000455904.
66. Dean L, McEntyre J. The Genetic Landscape of Diabetes. Bethesda
(MD): National Center for Biotechnology Information (US); 2004.
67. Herath H, Herath R, Wickremasinghe R. Gestational diabetes
mellitus and risk of type 2 diabetes 10 years after the index preg-
nancy in Sri Lankan women-a community based retrospective cohort
study. PLoS ONE. 2017;12(6):e0179647. https://doi.org/10.1371/
journal.pone.0179647.
68. Madhu SV. Diabetes in pregnancy—a critical window of opportunity.
Int J Diabetes Dev Ctries. 2018;38(1):3.
69. Federico C, Pridjian G. An overview of gestational diabetes. In:
Nair DB, ed. Nutritional and Therapeutic Interventions for Diabetes
and Metabolic Syndrome. Cambridge, MA: Elsevier B.V; 2018.
https://doi.org/10.1016/C2016-0-01904-6.
70. Sacks DB, Coustan DR, Cundy T, Donovan L, Hod M. Gestational
diabetes mellitus: why the controversy? Clin Chem. 2018;64(3):431-
438. https://doi.org/10.1373/clinchem.2016.266577.
71. Baptiste-Roberts K, Barone BB, Gary TL, et al. Risk factors for type
2 diabetes among women with gestational diabetes: a systematic
review. Am J Med. 2009;122(3):207-214 e4. https://doi.org/10.
1016/j.amjmed.2008.09.034.
SIRDAH AND READING
72. Buchanan TA, Xiang AH, Page KA. Gestational diabetes mellitus:
risks and management during and after pregnancy. Nat Rev
Endocrinol. 2012;8(11):639-649. https://doi.org/10.1038/nrendo.
2012.96.
73. Jarvela IY, Juutinen J, Koskela P, et al. Gestational diabetes iden-
tifies women at risk for permanent type 1 and type 2 diabetes in
fertile age: predictive role of autoantibodies. Diabetes Care. 2006;
29(3):607-612. https://doi.org/10.2337/diacare.29.03.06.dc05-
1118.
74. Al-Hakeem MM. Pregnancy outcome of gestational diabetic mothers:
experience in a tertiary center. J Fam Community Med. 2006;13(2):55-
59. http://www.ncbi.nlm.nih.gov/pubmed/23012105.
75. Forlenza GP, Moran A, Nathan B. Other specific types of diabe-
tes. In: Cowie CC, Menke A, Cissell MA, et al., eds. Diabetes in
America. 3rd ed.National Institutes of Health: Bethesda, MD;
2018.
76. Mayer-Davis EJ, Kahkoska AR, Jefferies C, et al. ISPAD clinical prac-
tice consensus guidelines 2018: definition, epidemiology, and classi-
fication of diabetes in children and adolescents. Pediatr Diabetes.
2018;19(Suppl 2):7-19. https://doi.org/10.1111/pedi.12773.
77. Bullard KM, Cowie CC, Lessem SE, et al. Prevalence of diagnosed
diabetes in adults by diabetes type - United States, 2016. MMWR
Morb Mortal Wkly Rep. 2018;67(12):359-361. https://doi.org/10.
15585/mmwr.mm6712a2.
78. Feingold KR. Atypical forms of diabetes. In: Feingold KR, Anawalt B,
Boyce A, et al., eds. Endotext. South Dartmouth, MA: MDText.com,
Inc.; 2000. http://www.ncbi.nlm.nih.gov/pubmed/25905351.
79. Resmini E, Minuto F, Colao A, Ferone D. Secondary diabetes associ-
ated with principal endocrinopathies: the impact of new treatment
modalities. Acta Diabetol. 2009;46(2):85-95. https://doi.org/10.
1007/s00592-009-0112-9.
80. Filippi CM, von Herrath MG. Viral trigger for type 1 diabetes: pros
and cons. Diabetes. 2008;57(11):2863-2871. https://doi.org/10.
2337/db07-1023.
81. Tabak AG, Herder C, Rathmann W, Brunner EJ, Kivimaki M. Predia-
betes: a high-risk state for diabetes development. Lancet. 2012;379
(9833):2279-2290. https://doi.org/10.1016/S0140-6736(12)
60283-9.
82. DeJesus RS, Breitkopf CR, Rutten LJ, Jacobson DJ, Wilson PM,
Sauver JS. Incidence rate of prediabetes progression to diabetes:
modeling an optimum target group for intervention. Popul Health
Manag. 2017;20(3):216-223. https://doi.org/10.1089/pop.2016.
0067.
83. Yudkin JS. “Prediabetes”: are there problems with this label? Yes,
the label creates further problems! Diabetes Care. 2016;39(8):1468-
1471. https://doi.org/10.2337/dc15-2113.
84. Prasad RB, Groop L. Genetics of type 2 diabetes-pitfalls and possibil-
ities. Genes (Basel). 2015;6(1):87-123. https://doi.org/10.3390/
genes6010087.
85. van Tilburg J, van Haeften TW, Pearson P, Wijmenga C. Defining
the genetic contribution of type 2 diabetes mellitus. J Med Genet.
2001;38(9):569-578. https://doi.org/10.1136/jmg.38.9.569.
86. Ingelsson E, McCarthy MI. Human genetics of obesity and type 2 dia-
betes mellitus: past, present, and future. Circ Genom Precis Med.
2018;11(6):e002090. https://doi.org/10.1161/CIRCGEN.118.
002090.
87. Manne-Goehler J, Siedner MJ, Montana L, et al. Hypertension and
diabetes control along the HIV care cascade in rural South Africa.
J Int AIDS Soc. 2019;22(3):e25213. https://doi.org/10.1002/jia2.
25213.
88. Dunachie S, Chamnan P. The double burden of diabetes and global
infection in low and middle-income countries. Trans R Soc Trop Med
Hyg. 2019;113(2):56-64. https://doi.org/10.1093/trstmh/try124.
89. Dagenais GR, Gerstein HC, Zhang X, et al. Variations in diabetes
prevalence in low-, middle-, and high-income countries: results from
SIRDAH AND READING
the prospective urban and rural epidemiological study. Diabetes Care.
2016;39(5):780-787. https://doi.org/10.2337/dc15-2338.
90. Narayan KM, Rhodes EC. Addressing noncommunicable diseases in
primary care: the case of type 2 diabetes. J R Coll Physicians Edinb.
2016;46(4):272-277. https://doi.org/10.4997/JRCPE.2016.414.
91. Shirinzadeh M, Afshin-Pour B, Angeles R, Gaber J, Agarwal G. The
effect of community-based programs on diabetes prevention in low-
and middle-income countries: a systematic review and meta-analy-
sis. Glob Health. 2019;15(1):10. https://doi.org/10.1186/s12992-
019-0451-4.
92. Lin Y, Sun Z. Current views on type 2 diabetes. J Endocrinol. 2010;
204(1):1-11. https://doi.org/10.1677/JOE-09-0260.
93. Cantley J, Ashcroft FM. Q&A: insulin secretion and type 2 diabetes:
why do beta-cells fail? BMC Biol. 2015;13:33. https://doi.org/10.
1186/s12915-015-0140-6.
94. Colberg SR, Sigal RJ, Fernhall B, et al. Exercise and type 2 diabetes:
the American College of Sports Medicine and the American Diabe-
tes Association: joint position statement executive summary. Dia-
betes Care. 2010;33(12):2692-2696. https://doi.org/10.2337/
dc10-1548.
95. Kaku K, Daida H, Kashiwagi A, et al. Long-term effects of
pioglitazone in Japanese patients with type 2 diabetes without a
recent history of macrovascular morbidity. Curr Med Res Opin. 2009;
25(12):2925-2932. https://doi.org/10.1185/03007990903328124.
96. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type
2 diabetes and recent advances in the treatment and prevention. Int
J Med Sci. 2014;11(11):1185-1200. https://doi.org/10.7150/ijms.
10001.
97. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical
activity/exercise and type 2 diabetes. Diabetes Care. 2004;27(10):
2518-2539. https://doi.org/10.2337/diacare.27.10.2518.
98. Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose
metabolism, hyperglycemia, and cardiovascular risk. Circ Res. 2018;
123(7):886-904. https://doi.org/10.1161/CIRCRESAHA.118.
312806.
99. Boles A, Kandimalla R, Reddy PH. Dynamics of diabetes and obesity:
epidemiological perspective. Biochim Biophys Acta Mol basis Dis.
2017;1863(5):1026-1036. https://doi.org/10.1016/j.bbadis.2017.
01.016.
100. Liao WL, Tsai FJ. Personalized medicine in type 2 diabetes. Biomedi-
cine. 2014;4:8. https://doi.org/10.7603/s40681-014-0008-z.
101. Grant RW, Wexler DJ. Personalized medicine in type 2 diabetes:
what does the future hold? Diabetes Manag. 2012;2(3):199-204.
https://doi.org/10.2217/dmt.12.15.
102. Fitipaldi H, McCarthy MI, Florez JC, Franks PW. A global overview
of precision medicine in type 2 diabetes. Diabetes. 2018;67(10):
1911-1922. https://doi.org/10.2337/dbi17-0045.
103. Udler MS, Kim J, von Grotthuss M, et al. Type 2 diabetes genetic loci
informed by multi-trait associations point to disease mechanisms
and subtypes: a soft clustering analysis. PLoS Med. 2018;15(9):
e1002654. https://doi.org/10.1371/journal.pmed.1002654.
104. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M.
Type 2 diabetes in the young: the evolving epidemic: the interna-
tional diabetes federation consensus workshop. Diabetes Care.
2004;27(7):1798-1811. https://doi.org/10.2337/diacare.27.7.1798.
105. Reinehr T. Lifestyle intervention in childhood obesity: changes and
challenges. Nat Rev Endocrinol. 2013;9(10):607-614. https://doi.org/
10.1038/nrendo.2013.149.
106. Bhupathiraju SN, Hu FB. One (small) step towards precision nutri-
tion by use of metabolomics. Lancet Diabetes Endocrinol. 2017;5(3):
154-155. https://doi.org/10.1016/S2213-8587(17)30007-4.
107. Arslanian S, Bacha F, Grey M, Marcus MD, White NH, Zeitler P.
Evaluation and management of youth-onset type 2 diabetes: a posi-
tion statement by the American Diabetes Association. Diabetes Care.
2018;41(12):2648-2668. https://doi.org/10.2337/dci18-0052.
17
108. Thibault V, Belanger M, LeBlanc E, et al. Factors that could
explain the increasing prevalence of type 2 diabetes among adults
in a Canadian province: a critical review and analysis. Diabetol
Metab Syndr. 2016;8:71. https://doi.org/10.1186/s13098-016-
0186-9.
109. Mohlke KL, Boehnke M. Recent advances in understanding the
genetic architecture of type 2 diabetes. Hum Mol Genet. 2015;24
(R1):R85-R92. https://doi.org/10.1093/hmg/ddv264.
110. Grant RW, Moore AF, Florez JC. Genetic architecture of type 2 dia-
betes: recent progress and clinical implications. Diabetes Care. 2009;
32(6):1107-1114. https://doi.org/10.2337/dc08-2171.
111. Jonsson A, Ladenvall C, Ahluwalia TS, et al. Effects of common
genetic variants associated with type 2 diabetes and glycemic
traits on alpha- and beta-cell function and insulin action in
humans. Diabetes. 2013;62(8):2978-2983. https://doi.org/10.
2337/db12-1627.
112. Sun X, Yu W, Hu C. Genetics of type 2 diabetes: insights into the
pathogenesis and its clinical application. Biomed Res Int. 2014;2014:
926713-926715. https://doi.org/10.1155/2014/926713.
113. Gan W, Bragg F, Walters RG, et al. Genetic predisposition to type
2 diabetes and risk of subclinical atherosclerosis and cardiovascular
diseases among 160,000 Chinese adults. Diabetes. 2019;68(11):
2155-2164. https://doi.org/10.2337/db19-0224.
114. Hara K, Shojima N, Hosoe J, Kadowaki T. Genetic architecture of
type 2 diabetes. Biochem Biophys Res Commun. 2014;452(2):213-
220. https://doi.org/10.1016/j.bbrc.2014.08.012.
115. Fuchsberger C, Flannick J, Teslovich TM, et al. The genetic architec-
ture of type 2 diabetes. Nature. 2016;536(7614):41-47. https://doi.
org/10.1038/nature18642.
116. Udler MS, McCarthy MI, Florez JC, Mahajan A. Genetic risk scores
for diabetes diagnosis and precision medicine. Endocr Rev. 2019;40:
1500-1520. https://doi.org/10.1210/er.2019-00088.
117. Wesolowska-Andersen A, Yu GZ, Nylander V, et al. Deep learning
models predict regulatory variants in pancreatic islets and refine
type 2 diabetes association signals. elife. 2020;9:1-21. https://doi.
org/10.7554/eLife.51503.
118. Gamboa-Melendez MA, Huerta-Chagoya A, Moreno-Macias H, et al.
Contribution of common genetic variation to the risk of type 2 dia-
betes in the Mexican mestizo population. Diabetes. 2012;61(12):
3314-3321. https://doi.org/10.2337/db11-0550.
119. Talmud PJ, Cooper JA, Morris RW, et al. Sixty-five common genetic
variants and prediction of type 2 diabetes. Diabetes. 2015;64(5):
1830-1840. https://doi.org/10.2337/db14-1504.
120. Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in
PPARgamma2 associated with decreased receptor activity, lower
body mass index and improved insulin sensitivity. Nat Genet. 1998;
20(3):284-287. https://doi.org/10.1038/3099.
121. Mansoori A, Sotoudeh G, Djalali M, et al. Effect of DHA-rich fish oil
on PPARgamma target genes related to lipid metabolism in type
2 diabetes: a randomized, double-blind, placebo-controlled clinical
trial. J Clin Lipidol. 2015;9(6):770-777. https://doi.org/10.1016/j.
jacl.2015.08.007.
122. Dong C, Zhou H, Shen C, et al. Role of peroxisome proliferator-
activated receptors gene polymorphisms in type 2 diabetes and met-
abolic syndrome. World J Diabetes. 2015;6(4):654-661. https://doi.
org/10.4239/wjd.v6.i4.654.
123. Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS. The peroxi-
some proliferator-activatedreceptor-gamma2 gene polymorphism
(Pro12Ala) beneficially influences insulin resistance and its tracking
from childhood to adulthood: the Bogalusa heart study. Diabetes.
2003;52(5):1265-1269. https://doi.org/10.2337/diabetes.52.5.
1265.
124. Ochoa M, Razquin C, Miguel M-G, Marti A. Role of PPAR-γ2
polymorphisms inbodyweight regulation. Futur Lipidol. 2008;3
(1):11.
18
125. Sladek R, Rocheleau G, Rung J, et al. A genome-wide association
study identifies novel risk loci for type 2 diabetes. Nature. 2007;445
(7130):881-885. https://doi.org/10.1038/nature05616.
126. Pascoe L, Tura A, Patel SK, et al. Common variants of the novel type
2 diabetes genes CDKAL1 and HHEX/IDE are associated with
decreased pancreatic beta-cell function. Diabetes. 2007;56(12):
3101-3104. https://doi.org/10.2337/db07-0634.
127. Horikoshi M, Hara K, Ito C, Nagai R, Froguel P, Kadowaki T. A
genetic variation of the transcription factor 7-like 2 gene is associ-
ated with risk of type 2 diabetes in the Japanese population.
Diabetologia. 2007;50(4):747-751. https://doi.org/10.1007/
s00125-006-0588-6.
128. Grarup N, Rose CS, Andersson EA, et al. Studies of association of
variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type
2 diabetes and impaired insulin release in 10,705 Danish subjects:
validation and extension of genome-wide association studies. Diabe-
tes. 2007;56(12):3105-3111. https://doi.org/10.2337/db07-0856.
129. Cornelis MC, Zaitlen N, Hu FB, Kraft P, Price AL. Genetic and environ-
mental components of family history in type 2 diabetes. Hum Genet.
2015;134(2):259-267. https://doi.org/10.1007/s00439-014-1519-0.
130. Lyssenko V, Groop L, Prasad RB. Genetics of type 2 diabetes: it mat-
ters from which parent we inherit the risk. Rev Diabet Stud. 2015;12
(3–4):233-242. https://doi.org/10.1900/RDS.2015.12.233.
131. Basile KJ, Johnson ME, Xia Q, Grant SF. Genetic susceptibility to
type 2 diabetes and obesity: follow-up of findings from genome-
wide association studies. Int J Endocrinol. 2014;2014:769671-
769613. https://doi.org/10.1155/2014/769671.
132. Grant SFA. The TCF7L2 Locus: A Genetic Window Into the Patho-
genesis of Type 1 and Type 2 Diabetes. Diabetes Care. 2019;42(9):
1624-1629. https://doi.org/10.2337/dci19-0001.
133. Skyler JS, Bakris GL, Bonifacio E, et al. Differentiation of diabetes by
pathophysiology, natural history, and prognosis. Diabetes. 2017;66
(2):241-255. https://doi.org/10.2337/db16-0806.
134. Medici F, Hawa M, Ianari A, Pyke DA, Leslie RD. Concordance rate
for type II diabetes mellitus in monozygotic twins: actuarial analysis.
Diabetologia. 1999;42(2):146-150. https://doi.org/10.1007/
s001250051132.
135. Ahlqvist E, Ahluwalia TS, Groop L. Genetics of type 2 diabetes. Clin
Chem. 2011;57(2):241-254. https://doi.org/10.1373/clinchem.
2010.157016.
136. Groop L, Forsblom C, Lehtovirta M, et al. Metabolic consequences
of a family history of NIDDM (the Botnia study): evidence for sex-
specific parental effects. Diabetes. 1996;45(11):1585-1593. https://
doi.org/10.2337/diab.45.11.1585.
137. Goran MI, Bergman RN, Avila Q, et al. Impaired glucose tolerance
and reduced beta-cell function in overweight Latino children with a
positive family history for type 2 diabetes. J Clin Endocrinol Metab.
2004;89(1):207-212. https://doi.org/10.1210/jc.2003-031402.
138. Abdullah N, Attia J, Oldmeadow C, Scott RJ, Holliday EG. The archi-
tecture of risk for type 2 diabetes: understanding Asia in the context
of global findings. Int J Endocrinol. 2014;2014:593982-593921.
https://doi.org/10.1155/2014/593982.
139. Sanghera DK, Blackett PR. Type 2 diabetes genetics: beyond GWAS.
J Diabetes Metab. 2012;3(198):1-12. https://doi.org/10.4172/2155-
6156.1000198.
140. McCarthy MI, Zeggini E. Genome-wide association studies in type
2 diabetes. Curr Diab Rep. 2009;9(2):164-171. https://doi.org/10.
1007/s11892-009-0027-4.
141. Cirillo E, Kutmon M, Gonzalez Hernandez M, et al. From SNPs to
pathways: biological interpretation of type 2 diabetes (T2DM)
genome wide association study (GWAS) results. PLoS ONE. 2018;13
(4):e0193515. https://doi.org/10.1371/journal.pone.0193515.
142. Visscher PM, Wray NR, Zhang Q, et al. 10 years of GWAS discovery:
biology, function, and translation. Am J Hum Genet. 2017;101(1):5-
22. https://doi.org/10.1016/j.ajhg.2017.06.005.
SIRDAH AND READING
143. Bush WS, Moore JH. Chapter 11: genome-wide association studies.
PLoS Comput Biol. 2012;8(12):e1002822. https://doi.org/10.1371/
journal.pcbi.1002822.
144. Remedi MS, Emfinger C. Pancreatic beta-cell identity in diabetes.
Diabetes Obes Metab. 2016;18(Suppl 1):110-116. https://doi.org/
10.1111/dom.12727.
145. Park YJ, Woo M. Pancreatic beta cells: gatekeepers of type 2 diabe-
tes. J Cell Biol. 2019;218(4):1094-1095. https://doi.org/10.1083/
jcb.201810097.
146. Vana DR, Adapa D, VSS P, Choudhury A, Choudhury A, Ahuja G.
Diabetes mellitus types: key genetic determinants and risk assess-
ment. Genet Mol Res. 2019;18(2):27.
147. Saberzadeh-Ardestani B, Karamzadeh R, Basiri M, et al. Type 1 dia-
betes mellitus: cellular and molecular pathophysiology at a glance.
Cell J. 2018;20(3):294-301. https://doi.org/10.22074/cellj.2018.
5513.
148. Nyaga DM, Vickers MH, Jefferies C, Perry JK, O'Sullivan JM. The
genetic architecture of type 1 diabetes mellitus. Mol Cell Endocrinol.
2018;477:70-80. https://doi.org/10.1016/j.mce.2018.06.002.
149. Storling J, Pociot F. Type 1 diabetes candidate genes linked to pan-
creatic islet cell inflammation and beta-cell apoptosis. Genes (Basel).
2017;8(2):1-12. https://doi.org/10.3390/genes8020072.
150. Cerf ME. Beta cell dysfunction and insulin resistance. Front
Endocrinol. 2013;4:37. https://doi.org/10.3389/fendo.2013.00037.
151. Chen C, Cohrs CM, Stertmann J, Bozsak R, Speier S. Human beta
cell mass and function in diabetes: recent advances in knowledge
and technologies to understand disease pathogenesis. Mol Metab.
2017;6(9):943-957. https://doi.org/10.1016/j.molmet.2017.06.019.
152. Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes.
J Clin Invest. 2006;116(7):1802-1812. https://doi.org/10.1172/
JCI29103.
153. Meier JJ, Bonadonna RC. Role of reduced beta-cell mass versus
impaired beta-cell function in the pathogenesis of type 2 diabetes.
Diabetes Care. 2013;36(Suppl 2):S113-S119. https://doi.org/10.
2337/dcS13-2008.
154. Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and
pancreatic beta-cell death. Trends Endocrinol Metab. 2011;22(7):
266-274. https://doi.org/10.1016/j.tem.2011.02.008.
155. Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL. Mecha-
nisms of pancreatic beta-cell death in type 1 and type 2 diabetes:
many differences, few similarities. Diabetes. 2005;54(Suppl 2):S97-
S107. https://doi.org/10.2337/diabetes.54.suppl_2.s97.
156. Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum
stress in diabetes mellitus. Endocr Rev. 2008;29(1):42-61. https://
doi.org/10.1210/er.2007-0015.
157. Frau F, Crowther D, Ruetten H, Allebrandt KV. Type-2diabetes-
associated variants with cross-trait relevance: post-GWAs strategies
for biological function interpretation. Mol Genet Metab. 2017;121(1):
43-50. https://doi.org/10.1016/j.ymgme.2017.03.004.
158. Adeyemo AA, Tekola-Ayele F, Doumatey AP, et al. Evaluation of
genome wide association study associated type 2 diabetes suscepti-
bility loci in sub Saharan Africans. Front Genet. 2015;6:335. https://
doi.org/10.3389/fgene.2015.00335.
159. Scott RA, Scott LJ, Magi R, et al. An expanded genome-wide associa-
tion study of type 2 diabetes in Europeans. Diabetes. 2017;66(11):
2888-2902. https://doi.org/10.2337/db16-1253.
160. Karaderi T, Drong AW, Lindgren CM. Insights into the genetic sus-
ceptibility to type 2 diabetes from genome-wide association studies
of obesity-related traits. Curr Diab Rep. 2015;15(10):83. https://doi.
org/10.1007/s11892-015-0648-8.
161. Turki A, Al-Zaben GS, Mtiraoui N, Marmmuoch H, Mahjoub T,
Almawi WY. Transcription factor-7-like 2 gene variants are
strongly associated with type 2 diabetes in Tunisian Arab subjects.
Gene. 2013;513:244-248. https://doi.org/10.1016/j.gene.2012.
10.086.
SIRDAH AND READING
162. Chandak GR, Janipalli CS, Bhaskar S, et al. Common variants in the
TCF7L2 gene are strongly associated with type 2 diabetes mellitus
in the Indian population. Diabetologia. 2007;50:63-67. https://doi.
org/10.1007/s00125-006-0502-2.
163. Huang Z, Liao Y, Huang R, Chen J, Sun H. Possible role of TCF7L2 in
the pathogenesis of type 2 diabetes mellitus. Biotechnol Biotechnol
Equip. 2018;32(4):5.
164. Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replication study
for the association of TCF7L2 with susceptibility to type 2 diabetes
in a Japanese population. Diabetologia. 2007;50:980-984. https://
doi.org/10.1007/s00125-007-0618-z.
165. Rees SD, Bellary S, Britten AC, et al. Common variants of the
TCF7L2 gene are associated with increased risk of type 2 diabetes
mellitus in a UK-resident south Asian population. BMC Med Genet.
2008;9(8):1-6. https://doi.org/10.1186/1471-2350-9-8.
166. Al Ali M, El hajj Chehadeh S, Osman W, et al. Investigating the asso-
ciation of rs7903146 of TCF7L2 gene, rs5219 of KCNJ11 gene,
rs10946398 of CDKAL1 gene, and rs9939609 of FTO gene with
type 2 diabetes mellitus in Emirati population. Meta Gene. 2019;21:
100600. https://doi.org/10.1016/j.mgene.2019.100600.
167. Al-Safar H, Hassoun A, Almazrouei S, Kamal W, Afandi B, Rais N.
Association of the genetic polymorphisms in transcription factor
7-like 2 and peroxisome proliferator-activatedreceptors- γ 2 with
type 2 diabetes mellitus and its interaction with obesity status in
Emirati population. J Diabetes Res. 2015;2015:1-8. https://doi.org/
10.1155/2015/129695.
168. Gloyn AL, Braun M, Rorsman P. Type 2 diabetes susceptibility gene
TCF7L2 and its role in beta-cell function. Diabetes. 2009;58(4):800-
802. https://doi.org/10.2337/db09-0099.
169. Scott LJ, Bonnycastle LL, Willer CJ, et al. Association of transcription
factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish
sample. Diabetes. 2006;55(9):2649-2653. https://doi.org/10.2337/
db06-0341.
170. Tong Y, Lin Y, Zhang Y, Yang J, Liu H, Zhang B. Association between
TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes
mellitus: a large human genome epidemiology (HuGE) review and
meta-analysis. BMC Med Genet. 2009;10:15. https://doi.org/10.
1186/1471-2350-10-15.
171. Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcrip-
tion factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.
Nat Genet. 2006;38(3):320-323. https://doi.org/10.1038/ng1732.
172. Zeggini E, Scott LJ, Saxena R, et al. Meta-analysis of genome-wide
association data and large-scale replication identifies additional sus-
ceptibility loci for type 2 diabetes. Nat Genet. 2008;40:638-645.
https://doi.org/10.1038/ng.120.
173. Mahajan A, Go MJ, Zhang W, et al. Genome-widetrans-ancestry-
meta-analysis provides insight into the genetic architecture of type
2 diabetes susceptibility. Nat Genet. 2014;46(3):234-244. https://
doi.org/10.1038/ng.2897.
174. Kwak SH, Park KS. Recent progress in genetic and epigenetic
research on type 2 diabetes. Exp Mol Med. 2016;48:e220. https://
doi.org/10.1038/emm.2016.7.
175. Cook JP, Morris AP. Multi-ethnicgenome-wide association study
identifies novel locus for type 2 diabetes susceptibility. Eur J Hum
Genet. 2016;24:1175-1180. https://doi.org/10.1038/ejhg.2016.17.
176. Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated
in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Nat Genet. 2010;42:105-116. https://doi.org/10.1038/ng.520.
177. Morris AP, Voight BF, Teslovich TM, et al. Large-scale association
analysis provides insights into the genetic architecture and patho-
physiology of type 2 diabetes. Nat Genet. 2012;44(9):981-990.
https://doi.org/10.1038/ng.2383.
178. Voight BF, Scott LJ, Steinthorsdottir V, et al. Twelve type 2 diabetes
susceptibility loci identified through large-scale association analysis.
Nat Genet. 2010;42(7):579-589. https://doi.org/10.1038/ng.609.
19
179. Tabassum R, Chauhan G, Dwivedi OP, et al. Genome-wide associa-
tion study for type 2 diabetes in Indians identifies a new susceptibil-
ity locus at 2q21. Diabetes. 2013;62(3):977-986. https://doi.org/10.
2337/db12-0406.
180. Yamauchi T, Hara K, Maeda S, et al. A genome-wide association
study in the Japanese population identifies susceptibility loci for
type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet.
2010;42(10):864-868. https://doi.org/10.1038/ng.660.
181. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide associa-
tion study of type 2 diabetes in Finns detects multiple susceptibility
variants. Science (80). 2007;316(5829):1341-1345. https://doi.org/
10.1126/science.1142382.
182. Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association
analysis identifies loci for type 2 diabetes and triglyceride levels. Sci-
ence (80). 2007;316:1331-1336. https://doi.org/10.1126/science.
1142358.
183. Kooner JS, Saleheen D, Sim X, et al. Genome-wide association study
in individuals of south Asian ancestry identifies six new type 2 diabe-
tes susceptibility loci. Nat Genet. 2011;43:984-989. https://doi.org/
10.1038/ng.921.
184. Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in
WFS1 confer risk of type 2 diabetes. Nat Genet. 2007;39(8):951-
953. https://doi.org/10.1038/ng2067.
185. Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA
variants, and the development of type 2 diabetes. N Engl J Med.
2008;359:2220-2232. https://doi.org/10.1056/NEJMoa0801869.
186. Cho YS, Chen CH, Hu C, et al. Meta-analysis of genome-wide associa-
tion studies identifies eight new loci for type 2 diabetes in east Asians.
Nat Genet. 2011;44(1):67-72. https://doi.org/10.1038/ng.1019.
187. Mahajan A, Wessel J, Willems SM, et al. Refining the accuracy of
validated target identification through coding variant fine-mapping
in type 2 diabetes article. Nat Genet. 2018;50:559-571. https://doi.
org/10.1038/s41588-018-0084-1.
188. Hara K, Fujita H, Johnson TA, et al. Genome-wide association study
identifies three novel loci for type 2 diabetes. Hum Mol Genet. 2014;
23:239-246. https://doi.org/10.1093/hmg/ddt399.
189. Huyghe JR, Jackson AU, Fogarty MP, et al. Exome array analysis
identifies new loci and low-frequency variants influencing insulin
processing and secretion. Nat Genet. 2013;45(2):197-201. https://
doi.org/10.1038/ng.2507.
190. Zeggini E, Weedon MN, Lindgren CM, et al. Multiple type 2 diabetes
susceptibility genes following genome- wide association scan in UK
samples. Science. 2007;316(5829):1336-1341. https://doi.org/10.
1126/science.1142364.
191. Go MJ, Hwang JY, Park TJ, et al. Genome-wide association study
identifies two novel loci with sex-specific effects for type 2 diabe-
tes mellitus and glycemic traits in a Korean population. Diabetes
Metab J. 2014;38:375-387. https://doi.org/10.4093/dmj.2014.38.
5.375.
192. Shu XO, Long J, Cai Q, et al. Identification of new genetic risk vari-
ants for type 2 diabetes. PLoS Genet. 2010;6(9):e1001127. https://
doi.org/10.1371/journal.pgen.1001127.
193. Li H, Gan W, Lu L, et al. A genome-wide association study identifies
GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabe-
tes. 2013;62(1):291-298. https://doi.org/10.2337/db12-0454.
194. Tsai FJ, Yang CF, Chen CC, et al. A genome-wide association study
identifies susceptibility variants for type 2 diabetes in Han Chinese.
PLoS Genet. 2010;6(2):e1000847. https://doi.org/10.1371/journal.
pgen.1000847.
195. Johnson AM, Olefsky JM. The origins and drivers of insulin resis-
tance. Cell. 2013;152(4):673-684. https://doi.org/10.1016/j.cell.
2013.01.041.
196. Kahn BB. Type 2 diabetes: when insulin secretion fails to compen-
sate for insulin resistance. Cell. 1998;92(5):593-596. https://doi.org/
10.1016/s0092-8674(00)81125-3.
20
197. Ormazabal P, Scazzocchio B, Vari R, et al. Effect of protocatechuic
acid on insulin responsiveness and inflammation in visceral adipose
tissue from obese individuals: possible role for PTP1B. Int J Obes.
2018;42(12):2012-2021. https://doi.org/10.1038/s41366-018-
0075-4.
198. Czech MP. Insulin action and resistance in obesity and type 2 diabe-
tes. Nat Med. 2017;23(7):804-814. https://doi.org/10.1038/nm.
4350.
199. Weir GC. Can we make surrogate beta-cells better than the original?
Semin Cell Dev Biol. 2004;15(3):347-357. https://doi.org/10.1016/j.
semcdb.2004.02.004.
200. Kahn SE. Clinical review 135: the importance of beta-cell failure in
the development and progression of type 2 diabetes. J Clin
Endocrinol Metab. 2001;86(9):4047-4058. https://doi.org/10.1210/
jcem.86.9.7713.
201. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resis-
tance and hyperinsulinemia: is hyperinsulinemia the cart or the
horse? Diabetes Care. 2008;31(Suppl 2):S262-S268. https://doi.org/
10.2337/dc08-s264.
202. Taylor R. Insulin resistance and type 2 diabetes. Diabetes. 2012;61
(4):778-779. https://doi.org/10.2337/db12-0073.
203. Patil PD, Mahajan UB, Patil KR, et al. Past and current perspective
on new therapeutic targets for type-II diabetes. Drug Des Devel
Ther. 2017;11:1567-1583. https://doi.org/10.2147/DDDT.
S133453.
204. DeFronzo RA, Triplitt CL, Abdul-Ghani M, Cersosimo E. Novel
agents for the treatment of type 2 diabetes. Diabetes Spectr. 2014;
27(2):100-112. https://doi.org/10.2337/diaspect.27.2.100.
205. Henry RR. Insulin resistance: from predisposing factor to therapeutic
target in type 2 diabetes. Clin Ther. 2003;25(Suppl B):B47-B63.
https://doi.org/10.1016/s0149-2918(03)80242-4.
206. Cheng Z, Schmelz EM, Liu D, Hulver MW. Targeting mitochondrial
alterations to prevent type 2 diabetes- -evidence from studies of
dietary redox-active compounds. Mol Nutr Food Res. 2014;58(8):
1739-1749. https://doi.org/10.1002/mnfr.201300747.
207. Eckel RH. Obesity. Circulation. 2005;111(15):e257-e259. https://
doi.org/10.1161/01.CIR.0000163653.38992.E5.
208. DeFronzo RA. Dysfunctional fat cells, lipotoxicity and type 2 diabe-
tes. Int J Clin Pr Suppl. 2004;143:9-21. https://doi.org/10.1111/j.
1368-504x.2004.00389.x.
209. Tagi VM, Giannini C, Chiarelli F. Insulin resistance in children. Front
Endocrinol. 2019;10:342. https://doi.org/10.3389/fendo.2019.00342.
210. Martinez LC, Sherling D, Holley A. The screening and prevention of
diabetes mellitus. Prim Care. 2019;46(1):41-52. https://doi.org/10.
1016/j.pop.2018.10.006.
211. Lentferink YE, Elst MAJ, Knibbe CAJ, van der Vorst MMJ. Predictors
of insulin resistance in children versus adolescents with obesity.
J Obes. 2017;2017:3793868. https://doi.org/10.1155/2017/
3793868.
212. Ling JC, Mohamed MN, Jalaludin MY, Rampal S, Zaharan NL,
Mohamed Z. Determinants of high fasting insulin and insulin resis-
tance among overweight/obese adolescents. Sci Rep. 2016;6:36270.
https://doi.org/10.1038/srep36270.
213. Okura T, Nakamura R, Fujioka Y, et al. Body mass index ≥23 is a risk
factor for insulin resistance and diabetes in Japanese people: a brief
report. PLoS ONE. 2018;13:e0201052. https://doi.org/10.1371/
journal.pone.0201052.
214. Scott RA, Fall T, Pasko D, et al. Common genetic variants highlight
the role of insulin resistance and body fat distribution in type 2 dia-
betes, independent of obesity. Diabetes. 2014;63(12):4378-4387.
https://doi.org/10.2337/db14-0319.
215. Klimentidis YC, Zhou J, Wineinger NE. Identification of allelic het-
erogeneity at type-2 diabetes loci and impact on prediction. PLoS
ONE. 2014;9(11):e113072. https://doi.org/10.1371/journal.pone.
0113072.
SIRDAH AND READING
216. Do R, Bailey SD, Desbiens K, et al. Genetic variants of FTO influence
adiposity, insulin sensitivity, leptin levels, and resting metabolic rate
in the Quebec family study. Diabetes. 2008;57(4):1147-1150.
https://doi.org/10.2337/db07-1267.
217. Kotnik P, Knapic E, Kokosar J, et al. Identification of novel alleles
associated with insulin resistance in childhood obesity using pooled-
DNAgenome-wide association study approach. Int J Obes. 2018;42
(4):686-695. https://doi.org/10.1038/ijo.2017.293.
218. Brown AE, Walker M. Genetics of insulin resistance and the meta-
bolic syndrome. Curr Cardiol Rep. 2016;18(8):75. https://doi.org/10.
1007/s11886-016-0755-4.
219. Ma J, Li Y, Zhou F, Xu X, Guo G, Qu Y. Meta-analysis of association
between the Pro12Ala polymorphism of the peroxisome
proliferator-activatedreceptor-gamma2 gene and diabetic retinopa-
thy in Caucasians and Asians. Mol Vis. 2012;18:2352-2360. http://
www.ncbi.nlm.nih.gov/pubmed/22993484.
220. Galbete C, Toledo E, Martinez-Gonzalez MA, Martinez JA, Guillen-
Grima F, Marti A. Pro12Ala variant of the PPARG2 gene increases
body mass index: an updated meta-analysis encompassing 49,092
subjects. Obesity (Silver Spring). 2013;21(7):1486-1495. https://doi.
org/10.1002/oby.20150.
221. Ghoussaini M, Meyre D, Lobbens S, et al. Implication of the
Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabe-
tes and obesity in the French population. BMC Med Genet. 2005;6:
11. https://doi.org/10.1186/1471-2350-6-11.
222. Tonjes A, Scholz M, Loeffler M, Stumvoll M. Association of Pro12Ala
polymorphism in peroxisome proliferator-activated receptor gamma
with pre-diabetic phenotypes: meta-analysis of 57 studies on
nondiabetic individuals. Diabetes Care. 2006;29(11):2489-2497.
https://doi.org/10.2337/dc06-0513.
223. Kruzliak P, Haley AP, Starcevic JN, Gaspar L, Petrovic D. Polymor-
phisms of the peroxisome proliferator-activatedreceptor-gamma
(rs1801282) and its coactivator-1 (rs8192673) are associated with
obesity indexes in subjects with type 2 diabetes mellitus. Cardiovasc
Diabetol. 2015;14:42. https://doi.org/10.1186/s12933-015-
0197-0.
224. Chan KH, Niu T, Ma Y, et al. Common genetic variants in peroxi-
some proliferator-activatedreceptor-gamma(PPARG) and type 2 dia-
betes risk among Women's health initiative postmenopausal
women. J Clin Endocrinol Metab. 2013;98(3):E600-E604. https://doi.
org/10.1210/jc.2012-3644.
225. Qi L, Cornelis MC, Kraft P, et al. Genetic variants at 2q24 are associ-
ated with susceptibility to type 2 diabetes. Hum Mol Genet. 2010;19
(13):2706-2715. https://doi.org/10.1093/hmg/ddq156.
226. Garant MJ, Linda Kao WH, Brancati F, et al. SNP43 of CAPN10 and
the risk of type 2 diabetes in African-Americans: the atherosclerosis
risk in communities study. Diabetes. 2002;51:231-237. https://doi.
org/10.2337/diabetes.51.1.231.
227. Li Y, Ge Gong HG, Yang Z, et al. CAPN10 SNP43 G>a gene poly-
morphism and type 2 diabetes mellitus in the Asian population: a
meta-analysis of 9353 participants. Endocr J. 2015;62(2):183-194.
228. Song Y, You NC, Hsu YH, et al. Common genetic variation in
calpain-10 gene (CAPN10) and diabetes risk in a multi-ethnic cohort
of American postmenopausal women. Hum Mol Genet. 2007;16:
2960-2971. https://doi.org/10.1093/hmg/ddm256.
229. Weedon MN, Schwarz PEH, Horikawa Y, et al. Meta-analysis and a
large association study confirm a role for calpain-10 variation in type
2 diabetes susceptibility. Am J Hum Genet. 2003;73:1208-1212.
https://doi.org/10.1086/379285.
230. Saxena R, Elbers CC, Guo Y, et al. Large-scalegene-centricmeta-analysis
across 39 studies identifies type 2 diabetes loci. Am J Hum Genet. 2012;
90(3):410-425. https://doi.org/10.1016/j.ajhg.2011.12.022.
231. Kim SH, Reaven G. Obesity and insulin resistance: an ongoing saga.
Diabetes. 2010;59(9):2105-2106. https://doi.org/10.2337/db10-
0766.
SIRDAH AND READING
232. Noakes TD. So what comes first: the obesity or the insulin resis-
tance? And which is more important? Clin Chem. 2018;64(1):7-9.
https://doi.org/10.1373/clinchem.2017.282962.
233. Ye J. Mechanisms of insulin resistance in obesity. Front Med. 2013;7
(1):14-24. https://doi.org/10.1007/s11684-013-0262-6.
234. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;
106(4):473-481. https://doi.org/10.1172/JCI10842.
235. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to
insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840-
846. https://doi.org/10.1038/nature05482.
236. Bhurosy T, Jeewon R. Overweight and obesity epidemic in develop-
ing countries: a problem with diet, physical activity, or socioeco-
nomic status? ScientificWorldJournal. 2014;2014:964236-964237.
https://doi.org/10.1155/2014/964236.
237. Hu FB, Malik VS. Sugar-sweetened beverages and risk of obe-
sity and type 2 diabetes: epidemiologic evidence. Physiol Behav.
2010;100(1):47-54. https://doi.org/10.1016/j.physbeh.2010.
01.036.
238. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the devel-
oping world- -a growing challenge. N Engl J Med. 2007;356(3):213-
215. https://doi.org/10.1056/NEJMp068177.
239. Worldwide trends in diabetes since 1980: a pooled analysis of
751 population-based studies with 4.4 million participants. Lancet.
2016;387(10027):1513-1530. https://doi.org/10.1016/S0140-
6736(16)00618-8.
240. Magi R, Manning S, Yousseif A, et al. Contribution of 32 GWAS-
identified common variants to severe obesity in European adults
referred for bariatric surgery. PLoS ONE. 2013;8(8):e70735. https://
doi.org/10.1371/journal.pone.0070735.
241. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass
index yield new insights for obesity biology. Nature. 2015;518
(7538):197-206. https://doi.org/10.1038/nature14177.
242. Xi B, He D, Hu Y, Zhou D. Prevalence of metabolic syndrome and its
influencing factors among the Chinese adults: the China health and
nutrition survey in 2009. Prev Med. 2013;57(6):867-871. https://
doi.org/10.1016/j.ypmed.2013.09.023.
243. Grarup N, Sandholt CH, Hansen T, Pedersen O. Genetic susceptibil-
ity to type 2 diabetes and obesity: from genome-wide association
studies to rare variants and beyond. Diabetologia. 2014;57(8):1528-
1541. https://doi.org/10.1007/s00125-014-3270-4.
244. Wang K, Li WD, Zhang CK, et al. A genome-wide association study
on obesity and obesity-related traits. PLoS ONE. 2011;6(4):e18939.
https://doi.org/10.1371/journal.pone.0018939.
245. Sandholt CH, Hansen T, Pedersen O. Beyond the fourth wave of
genome-wide obesity association studies. Nutr Diabetes. 2012;2:
e37. https://doi.org/10.1038/nutd.2012.9.
246. Kong X, Xing X, Hong J, Zhang X, Yang W. Genetic variants associ-
ated with lean and obese type 2 diabetes in a Han Chinese popula-
tion: a case-control study. Medicine. 2016;95(23):e3841. https://doi.
org/10.1097/MD.0000000000003841.
247. Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes
mellitus and obesity. Diabetes Metab Syndr Obes. 2014;7:587-591.
https://doi.org/10.2147/DMSO.S67400.
248. Lorenzo C, Wagenknecht LE, D'Agostino RB Jr, Rewers MJ,
Karter AJ, Haffner SM. Insulin resistance, beta-cell dysfunction, and
conversion to type 2 diabetes in a multiethnic population: the insulin
resistance atherosclerosis study. Diabetes Care. 2010;33(1):67-72.
https://doi.org/10.2337/dc09-1115.
249. Kahn SE. The relative contributions of insulin resistance and beta-
cell dysfunction to the pathophysiology of type 2 diabetes.
Diabetologia. 2003;46(1):3-19. https://doi.org/10.1007/s00125-
002-1009-0.
250. Montanya E. Insulin resistance compensation: not just a matter of
β-cells? Diabetes. 2014;63:832-834. https://doi.org/10.2337/db13-
1843.
21
251. Loos RJ, Yeo GS. The bigger picture of FTO: the first GWAS-
identified obesity gene. Nat Rev Endocrinol. 2014;10(1):51-61.
https://doi.org/10.1038/nrendo.2013.227.
252. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of
249,796 individuals reveal 18 new loci associated with body mass
index. Nat Genet. 2010;42(11):937-948. https://doi.org/10.1038/
ng.686.
253. Frayling TM. Genome-wide association studies provide new insights
into type 2 diabetes aetiology. Nat Rev Genet. 2007;8(9):657-662.
https://doi.org/10.1038/nrg2178.
254. Scuteri A, Sanna S, Chen WM, et al. Genome-wide association scan
shows genetic variants in the FTO gene are associated with obesity-
related traits. PLoS Genet. 2007;3(7):e115. https://doi.org/10.1371/
journal.pgen.0030115.
255. Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to
childhood obesity and severe adult obesity. Nat Genet. 2007;39(6):
724-726. https://doi.org/10.1038/ng2048.
256. Fawcett KA, Barroso I. The genetics of obesity: FTO leads the way.
Trends Genet. 2010;26(6):266-274. https://doi.org/10.1016/j.tig.
2010.02.006.
257. Schwenk RW, Vogel H, Schurmann A. Genetic and epigenetic con-
trol of metabolic health. Mol Metab. 2013;2(4):337-347. https://doi.
org/10.1016/j.molmet.2013.09.002.
258. Sykiotis GP, Kalliolias GD, Papavassiliou AG. Pharmacogenetic prin-
ciples in the Hippocratic writings. J Clin Pharmacol. 2005;45:1218-
1220. https://doi.org/10.1177/0091270005281091.
259. DLV FM, Bustamante CD, Leal SM. Genome-wide association map-
ping and rare alleles: from population genomics to personalized
medicine - session introduction. Pac Symp Biocomput. 2011;74-75.
https://doi.org/10.1142/9789814335058_0008.
260. Suwinski P, Ong C, Ling MHT, Poh YM, Khan AM, Ong HS. Advanc-
ing personalized medicine through the application of whole exome
sequencing and big data analytics. Front Genet. 2019;10:49. https://
doi.org/10.3389/fgene.2019.00049.
261. Rossbach SJ, Rossbach M. An economic perspective on personalized
medicine. HUGO J. 2013;7:6. https://doi.org/10.1186/1877-6566-
7-1.
262. Mathur S, Sutton J. Personalized medicine could transform
healthcare. Biomed Rep. 2017;7(1):3-5. https://doi.org/10.3892/br.
2017.922.
263. Kasztura M, Richard A, Bempong NE, Loncar D, Flahault A. Cost-
effectiveness of precision medicine: a scoping review. Int J Public
Health. 2019;64(9):1261-1271. https://doi.org/10.1007/s00038-
019-01298-x.
264. Ginsburg GS, Phillips KA. Precision medicine: from science to value.
Health Aff. 2018;37(5):694-701. https://doi.org/10.1377/hlthaff.
2017.1624.
265. Louca S. Personalized medicine- -a tailored health care system: chal-
lenges and opportunities. Croat Med J. 2012;53(3):211-213. https://
doi.org/10.3325/cmj.2012.53.211.
266. Olden K, Freudenberg N, Dowd J, Shields AE. Discovering how envi-
ronmental exposures alter genes could lead to new treatments for
chronic illnesses. Health Aff. 2011;30(5):833-841. https://doi.org/
10.1377/hlthaff.2011.0078.
267. Rappaport SM. Genetic factors are not the major causes of chronic
diseases. PLoS ONE. 2016;11(4):e0154387. https://doi.org/10.
1371/journal.pone.0154387.
268. Mohan V, Radha V. Precision diabetes is slowly becoming a reality.
Med Princ Pract. 2019;28:1-9. https://doi.org/10.1159/000497241.
269. Kavvoura FK. Monogenic diabetes. Owen KR. Med (United King-
dom): Monogenic diabetes; 2019. https://doi.org/10.1016/j.
mpmed.2018.10.007.
270. Kleinberger JW, Pollin TI, Medicine G. Personalized medicine in dia-
betes mellitus: current opportunities and future prospects. Ann N Y
Acad Sci. 2015;1346(1):45-56. https://doi.org/10.1111/nyas.12757.
22
271. Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT. Sen-
sitivity to sulphonylureas in patients with hepatocyte nuclear factor-
1α gene mutations: evidence for pharmacogenetics in diabetes.
Diabet Med. 2000;17:543-545. https://doi.org/10.1046/j.1464-
5491.2000.00305.x.
272. Hattersley AT, Patel KA. Precision diabetes: learning from mono-
genic diabetes. Diabetologia. 2017;60:769-777. https://doi.org/10.
1007/s00125-017-4226-2.
273. Gloyn AL, Drucker DJ. Precision medicine in the management of
type 2 diabetes. Lancet Diabetes Endocrinol. 2018;6:891-900.
https://doi.org/10.1016/S2213-8587(18)30052-4.
274. Marin-Penalver JJ, Martin-Timon I, Sevillano-Collantes C, Del
Canizo-Gomez FJ. Update on the treatment of type 2 diabetes
mellitus. World J Diabetes. 2016;7(17):354-395. https://doi.org/10.
4239/wjd.v7.i17.354.
275. Nathan DM. Progress in diabetes research- -what's next. JAMA.
2009;301(15):1599-1601. https://doi.org/10.1001/jama.2009.509.
276. Chitre MM, Burke S. Treatment algorithms and the pharmacological
management of type 2 diabetes. Diabetes Spectr. 2006;19(4):7-255.
https://doi.org/10.2337/diaspect.19.4.249.
277. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement
by the American Association of Clinical Endocrinologists and Ameri-
can College of endocrinology on the comprehensive type 2 diabetes
management algorithm - 2019 executive summary. Endocr Pr. 2019;
25(1):69-100. https://doi.org/10.4158/CS-2018-0535.
278. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the
incidence of type 2 diabetes with lifestyle intervention or metfor-
min. N Engl J Med. 2002;346(6):393-403. https://doi.org/10.1056/
NEJMoa012512.
279. Gallo M, Mannucci E, De Cosmo S, et al. Algorithms for personalized
therapy of type 2 diabetes: results of a web-based international sur-
vey. BMJ Open Diabetes Res Care. 2015;3(1):e000109. https://doi.
org/10.1136/bmjdrc-2015-000109.
280. Hu C, Jia W. Diabetes in China: epidemiology and genetic risk fac-
tors and their clinical utility in personalized medication. Diabetes.
2018;67(1):3-11. https://doi.org/10.2337/dbi17-0013.
281. Peter PR, Lupsa BC. Personalized Management of Type 2 diabetes.
Curr Diab Rep. 2019;19(11):115. https://doi.org/10.1007/s11892-
019-1244-0.
282. Subramanian S, Hirsch IB. Personalized diabetes management: mov-
ing from algorithmic to individualized therapy. Diabetes Spectr.
2014;27(2):87-91. https://doi.org/10.2337/diaspect.27.2.87.
283. Raz I. Guideline approach to therapy in patients with newly diag-
nosed type 2 diabetes. Diabetes Care. 2013;36(Suppl 2):S139-S144.
https://doi.org/10.2337/dcS13-2035.
284. Pollastro C, Ziviello C, Costa V, Ciccodicola A. Pharmacogenomics of
drug response in type 2 diabetes: toward the definition of tailored
therapies? PPAR Res. 2015;2015:415149-415110. https://doi.org/
10.1155/2015/415149.
285. Costa V, Federico A, Pollastro C, et al. Computational analysis of sin-
gle nucleotide polymorphisms associated with altered drug respon-
siveness in type 2 diabetes. Int J Mol Sci. 2016;17(7):1-14. https://
doi.org/10.3390/ijms17071008.
286. Maruthur NM, Gribble MO, Bennett WL, et al. The
pharmacogenetics of type 2 diabetes: a systematic review. Diabetes
Care. 2014;37(3):876-886. https://doi.org/10.2337/dc13-1276.
287. Becker ML, Pearson ER, Tkac I. Pharmacogenetics of oral anti-
diabetic drugs. Int J Endocrinol. 2013;2013:686315-686310. https://
doi.org/10.1155/2013/686315.
288. Pearson ER. Diabetes: is there a future for pharmacogenomics
guided treatment? Clin Pharmacol Ther. 2019;106(2):329-337.
https://doi.org/10.1002/cpt.1484.
289. Singh S, Usman K, Banerjee M. Pharmacogenetic studies update in
type 2 diabetes mellitus. World J Diabetes. 2016;7(15):302-315.
https://doi.org/10.4239/wjd.v7.i15.302.
SIRDAH AND READING
290. Ordelheide AM, Hrabe de Angelis M, Haring HU, Staiger H.
Pharmacogenetics of oral antidiabetic therapy. Pharmacogenomics.
2018;19(6):577-587. https://doi.org/10.2217/pgs-2017-0195.
291. Läll K, Mägi R, Morris A, Metspalu A, Fischer K. Personalized risk pre-
diction for type 2 diabetes: the potential of genetic risk scores. Genet
Med. 2017;19:322-329. https://doi.org/10.1038/gim.2016.103.
292. Weedon MN, McCarthy MI, Hitman G, et al. Combining information
from common type 2 diabetes risk polymorphisms improves disease
prediction. PLoS Med. 2006;3:e374. https://doi.org/10.1371/
journal.pmed.0030374.
293. Layton J, Li X, Shen C, et al. Type 2 diabetes genetic risk scores are
associated with increased type 2 diabetes risk among African Ameri-
cans by cardiometabolic status. Clin Med Insights Endocrinol Diabetes.
2018;11:117955141774894. https://doi.org/10.1177/
1179551417748942.
294. Multhaup ML, Kita R, Eriksson N, et al. 304-OR: polygenic risk score
predicts type 2 diabetes susceptibility in a diverse consumer genetic
database. Diabetes. 2019;68:304-3OR. https://doi.org/10.2337/
db19-304-or.
295. Ahlqvist E, Storm P, Käräjämäki A, et al. Novel subgroups of adult-
onset diabetes and their association with outcomes: a data-driven
cluster analysis of six variables. Lancet Diabetes Endocrinol. 2018;6:
361-369. https://doi.org/10.1016/S2213-8587(18)30051-2.
296. Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits
and limitations of genome-wide association studies. Nat Rev
Genet. 2019;20:467-484. https://doi.org/10.1038/s41576-019-
0127-1.
297. Flannick J, Mercader JM, Fuchsberger C, et al. Exome sequencing of
20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019;
570:71-76. https://doi.org/10.1038/s41586-019-1231-2.
298. Small KS, Todorčevic M, Civelek M, et al. Regulatory variants at
KLF14 influence type 2 diabetes risk via a female-specific effect on
adipocyte size and body composition. Nat Genet. 2018;50:572-580.
https://doi.org/10.1038/s41588-018-0088-x.
299. Tramunt B, Smati S, Grandgeorge N, et al. Sex differences in meta-
bolic regulation and diabetes susceptibility. Diabetologia. 2020;63:
453-461. https://doi.org/10.1007/s00125-019-05040-3.
300. Verma A, Bang L, Miller JE, et al. Human-disease phenotype map
derived from PheWAS across 38,682 individuals. Am J Hum Genet.
2019;104:55-64. https://doi.org/10.1016/j.ajhg.2018.11.006.
301. Hebbring SJ. The challenges, advantages and future of phenome-
wide association studies. Immunology. 2014;141:157-165. https://
doi.org/10.1111/imm.12195.
302. Robinson JR, Denny JC, Roden DM, Van Driest SL. Genome-wide
and phenome-wide approaches to understand variable drug actions
in electronic health records. Clin Transl Sci. 2018;11:112-122.
https://doi.org/10.1111/cts.12522.
303. Safarova MS, Satterfield BA, Fan X, et al. A phenome-wide associa-
tion study to discover pleiotropic effects of PCSK9, APOB, and
LDLR. NPJ Genom Med. 2019;4:3. https://doi.org/10.1038/s41525-
019-0078-7.
304. Li YR, Keating BJ. Trans-ethnicgenome-wide association studies:
advantages and challenges of mapping in diverse populations.
Genome Med. 2014;6:91. https://doi.org/10.1186/s13073-014-
0091-5.
305. Medina-Gomez C, Felix JF, Estrada K, et al. Challenges in conducting
genome-wide association studies in highly admixed multi-ethnic
populations: the generation R study. Eur J Epidemiol. 2015;30:317-
330. https://doi.org/10.1007/s10654-015-9998-4.
306. McGuire AL, Basford M, Dressler LG, et al. Ethical and practical chal-
lenges of sharing data from genome-wide association studies: the
eMERGE consortium experience. Genome Res. 2011;21:1001-1007.
https://doi.org/10.1101/gr.120329.111.
307. Du Y, Xie J, Chang W, Han Y, Cao G. Genome-wide association
studies: inherent limitations and future challenges. Front Med
SIRDAH AND READING 23

China. 2012;6:444-450. https://doi.org/10.1007/s11684-012- heterogeneity. J Diabetes Res. 2018;2018:1-12. https://doi.org/10.

0225-3. 1155/2018/3061620.
308. Brothers KB, Rothstein MA. Ethical, legal and social implications of
incorporating personalized medicine into healthcare. Pers Med.
2015;12:43-51. https://doi.org/10.2217/pme.14.65.
309. Geneviève LD, Martani A, Shaw D, Elger BS, Wangmo T. Struc- How to cite this article: Sirdah MM, Reading NS. Genetic
tural racism in precision medicine: leaving no one behind. BMC predisposition in type 2 diabetes: A promising approach
Med Ethics. 2020;21:17. https://doi.org/10.1186/s12910-020-
toward a personalized management of diabetes. Clinical
0457-8.
310. Bowman P, Flanagan SE, Hattersley AT. Future roadmaps for preci-
Genetics. 2020;1–23. https://doi.org/10.1111/cge.13772
sion medicine applied to diabetes: rising to the challenge of