Genetic Basis of DM

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Cellscience. Author manuscript; available in PMC 2006 August 3.
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Cellscience. 2006 April 30; 2(4): 100–131.
The Genetic Basis of Type 2 Diabetes
Swapan Kumar Das and Steven C Elbein

University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System,
Little Rock, Arkansas
Abstract
Type 2 Diabetes results from a complex physiologic process that includes the pancreatic beta cells,
peripheral glucose uptake in muscle, the secretion of multiple cytokines and hormone-like molecules
from adipocytes, hepatic glucose production, and likely the central nervous system. Consistent with
the complex web of physiologic defects, the emerging picture of the genetics will involve a large
number of risk susceptibility genes, each individually with relatively small effect (odds ratios below
1.2 in most cases). The challenge for the future will include cataloging and confirming the genetic
risk factors, and understanding how these risk factors interact with each other and with the known
environmental and lifestyle risk factors that increase the propensity to type 2 diabetes.
Type 2 Diabetes: A Prologue

Type 2 Diabetes Mellitus (T2DM) is a complex heterogeneous group of metabolic condition
characterized by elevated levels of serum glucose, caused mainly by impairment in both insulin
action and insulin secretion. T2DM exerts a huge toll in human suffering and economy. A
recent evaluation using a computerized generic formal disease model (DisMod II) revealed
that excess global mortality due to diabetes in the year 2000 was equivalent to 5.2% of all
deaths and diabetes is likely to be the fifth leading cause of death, similar in magnitude to
numbers reported for HIV/AIDS (1). The prevalence of diabetes for all age-groups worldwide
was estimated to be 2.8% in 2000 and is projected to be 4.4% in 2030 (most of which will be
T2DM). The total number of people with diabetes is projected to rise from 171 million in 2000
to 366 million in 2030, with India, China and USA being the top 3 countries estimated to have
the highest numbers of people with diabetes (2). T2DM accounts for 5–10% of the total health
care budget in many countries. In the United States, the American Diabetes Association
estimated the total cost of diabetes management in 2002 at $132 billion, which is about 1.3%
of US gross domestic product (3,4).
The recent global epidemic of T2DM almost certainly indicates the importance of
environmental triggers such as sedentary lifestyle and dietary changes over last several
decades. Nonetheless, T2DM is among many complex diseases for which a genetic
contribution is well accepted. Despite the diverse phenotypic nature of T2DM, twin and family
studies, and the wide spectrum of diabetes prevalence across populations provide convincing
evidence for an important role of
Identification of the genetic etiology of T2DM has proved challenging. Although many
laboratories have chosen a genetic approach to define its pathophysiology, the molecular
mechanisms for this strong genetic predisposition remain elusive. Based on epidemiological
data, the total sibling relative risk (λs) for T2DM has been estimated at 3–4, although the
number of loci that contribute to this risk is uncertain. Multiple genome scans and a plethora
of candidate gene association studies of T2DM in conglomerate lead to the inescapable
conclusion that early proposals of an oligogenic model of T2DM were overly optimistic. The
increasingly complex physiologic picture reflects this multifaceted genetic landscape. Early
views of T2DM as primarily a defect in insulin mediated muscle glucose uptake have been
tempered by a new appreciation of the key roles of the pancreatic β-cell, the adipocyte as a
Das and Elbein Page 2
secretory organ, a primary role of the liver, and possibly a key role of the central nervous
system. Identification of the genetic components of type 2 diabetes is one of the most important
areas of diabetes research because elucidation of the diabetes genes (alleles) will influence all
efforts toward a mechanistic understanding of the disease, its complications, and its treatment,
cure, and prevention. In this review we will discuss our current understanding of the genetic
basis of the pathophysiology of Type 2 diabetes.
T2DM Is a Genetic Disease: Classical Evidence

Multiple lines of evidence support the view that genetic components plays an important role
in the pathogenesis of T2DM.
1. The spectrum of T2DM prevalence in different ethnic groups’ The prevalence of
T2DM varies widely among populations, from 1% in Chile Mapuche Indian, 2%
among Caucasians in Europe to as high as 41% in the Nauru (Pacific Island) and 50%
among Pima Indians in Arizona (5). Part of this observed ethnic variability can be
attributed to non-genetic environmental and cultural factors; however, the observation
that the disease prevalence varies substantially among ethnic groups that share a
similar environment supports the idea that genetic factors contribute to disease
predisposition.
2. Familial aggregation: Other than genes, families share environments, culture and
habits, yet familial aggregation of the disease is another source of evidence for a
genetic contribution to the disease. Evidence for a genetic role includes the nearly 4-
fold increased risk for T2DM in siblings of a diabetic proband compared with the
general population (λS of 3.5 to 4), the odds ratio (OR) of 3.4–3.5 with only a single
affected parent, and the increase in the OR to 6.1 if both parents are affected (6).
3. Twin studies: Multiple studies of twin concordance rates have been undertaken in
T2DM. Estimates for concordance rates have ranged from 0.29 to 1.00 in monozygotic
(MZ) twins, while in dizygotic (DZ) twins the range was 0.10–0.43 (7–10).
Concordance among both MZ and DZ twins increases with the duration of follow up
period (10). In spite of several caveats in twin studies, the high concordance in MZ
twins and the 50% fall in DZ twins provides compelling evidence for a genetic
component of T2DM.
4. Heritability of intermediate phenotypes: Insulin sensitivity and insulin secretion
deteriorate in parallel in most human T2DM. Both defects predicted subsequent
T2DM in several studies and both defects are shown to be present in nondiabetic but
genetically identical co-twins of a diabetic proband (11). Data from multiple
laboratories, including ours, support a genetic basis for measures of both insulin
sensitivity and insulin secretion (12–14).
Pathophysiology of T2DM: Current status

The early pathophysiology of T2DM remains uncertain and controversial. Three key defects
mark the onset of hyperglycemia in T2DM: increased hepatic glucose production, diminished
insulin secretion, and impaired insulin action (15,16). Unfortunately, at the time of
hyperglycemia, glucose and possibly lipid toxicity obscure the primary effects. Prospective
and cross-sectional analyses of euglycemic individuals at risk (relatives of T2DM individuals)
circumvent this dilemma, and suggest a key early and predictive role of reduced insulin
sensitivity in T2DM pathogenesis. Nonetheless, few individuals with genetic insulin resistance
develop diabetes, and 25% of nondiabetic individuals may have insulin sensitivity as low as
that seen in T2DM. The increase in hepatic glucose production was formerly viewed as a late
event, occurring only at the onset of hyperglycemia and glucose intolerance. However, knock
out murine models suggest a more primary role for hepatic insulin resistance.

The importance and timing of a β-cell defect have been hotly debated (17). Obese individuals,
those with a family history of diabetes, and individuals with impaired glucose tolerance (IGT)
are all characterized by absolute hyperinsulinemia until the development of overt
hyperglycemia. However, when β-cell function is viewed in the context of reduced insulin
sensitivity, considerable data support the early failure of insulin secretion in T2DM
pathogenesis (18,19). Animal models also support this concept. Despite much study, the signals
that cause normal β-cell compensation and hyperinsulinemia, the mechanisms of this
compensation, the point in the pathogenesis of T2DM where this compensatory mechanism
fails, and the etiology of this failure all remain subjects of speculation. Insulin sensitivity and
insulin secretion deteriorate in parallel in most human T2DM. The remarkable difficulty in
uncoupling these two defects may suggest a common mechanism.
Extensive investigation of humans and animal models has failed to clarify the key or early
events that lead to the inexorable rise in plasma glucose and eventual insulin deficiency. Current
models, which propose a role for multiple pathways affecting multiple organs, suggest a
complex genetic substructure. Most glucose after a meal is taken up by skeletal muscle, with
adipose playing a much smaller role. Traditionally, resistance to insulin mediated, non-
oxidative glucose metabolism was viewed as the early and primary defect leading to T2DM.
More recently, the progressive failure of the β-cell to compensate for insulin resistance has
received considerable attention (19), but the role of liver and adipose had been considered late
or relatively insignificant factors, respectively. Animal models have challenged even this
paradigm. Muscle-specific insulin receptor (INSR) inactivation did not lead to IGT despite
insulin resistance, whereas muscle specific inactivation of glucose transporter GLUT4 caused
both profound insulin resistance and T2DM (20). Unexpectedly, GLUT4 inactivation limited
to white adipose resulted in insulin resistance, glucose intolerance, and even T2DM with an
impairment in whole body glucose uptake markedly out of proportion to the expected
contribution of white adipose (20). This isolated defect in white adipose resulted in defective
insulin action in both muscle and liver. Paradoxically, inactivation of the adipocyte insulin
receptor gene resulted in improved insulin sensitivity and protection against obesity. These
studies suggest a central and previously under-appreciated role for adipocytes in the
pathogenesis of T2DM. However, insulin receptor inactivation in the liver also resulted in
hyperinsulinemia, hepatic insulin resistance, and peripheral insulin resistance (21–24). These
studies suggest considerable crosstalk among organ systems, as well as an important role for
insulin signaling pathways in the β-cell (25). Thus, T2DM is the final outcome of a multiorgan
disease which is characterized by early direct or indirect defects in muscle, adipocytes,
hepatocytes, β-cells, and possibly the central nervous system (CNS).
Cytokines, Adipokines and Inflammation

Insulin stimulated glucose uptake into muscle cells and adipocytes depends mostly on the
glucose transporter GLUT4, skeletal muscle being the principal site for this glucose uptake.
Downregulation of GLUT4 expression in adipose tissue is a common feature of insulin-
resistant states, including obesity, T2DM, and the metabolic syndrome (26). Given that skeletal
muscle is the major site for glucose disposal, the hyperglycemia associated with obesity and
T2DM cannot be explained by the decreased uptake of glucose into adipose tissue due to
downregulation of GLUT4 in adipocytes. Furthermore, adipocyte-selective knockout of
GLUT4 (adipose-Glut4 −/−) in mice resulted in systemic insulin resistance similar to that
induced by muscle-selective GLUT4 knockout mice (muscle-Glut4 −/−, 27,28). These studies
suggest that adipocyte GLUT4 deficiency results in circulating factors that are responsible for
cross-organ communication (“crosstalk”). Yang et. al (29) recently identified retinol binding
protein-4 (RBP4) as one candidate for that crosstalk in the adipose tissue of adipose-specific
Glut4 knockout mice. Furthermore, serum RBP4 protein levels were elevated in insulin-
resistant mice and obese and diabetic humans. Transgenic overexpression of the human

RBP4 gene or injection of recombinant RBP4 protein in normal mice caused insulin resistance,
whereas Rbp4 knockout mice had enhanced insulin sensitivity (29). Increased serum RBP4
protein levels induced hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase (PEPCK) and impaired insulin signaling in muscle.
Investigators have proposed other potential mediators of inter-organ crosstalk to explain T2DM
pathogenesis. Obesity predisposes to insulin resistance and T2DM. Adipocytes, both visceral
and peripheral, secrete a plethora of factors which may alter systemic insulin action and hepatic
glucose production, including adiponectin, resistin, leptin, cytokines IL-6 and TNFα, visfatin,
retinol binding protein 4 (RBP4), as well as free fatty acids (FFA) (30–32). In recent years, the
concept that obesity and elevated cytokine secretion results in an inflammatory state that is
itself the cause of insulin resistance has emerged (32–34). The inhibition of signaling
downstream of the insulin receptor may be a primary mechanism through which this
inflammatory state causes insulin resistance. Exposure of cells to TNF-α or elevated levels of
free fatty acids stimulates phosphorylation of serine residues of IRS-1. This phosphorylation
reduces tyrosine phosphorylation of IRS-1 in response to insulin, and thus signaling
downstream of IRS-1 (35–38). The inflammatory state is increased by the accumulation of
macrophages in adipose tissue with obesity (39;40). Thus, both adipose tissue and the
macrophages within adipose tissue serve in both endocrine and paracrine fashion to promote
inflammation and decrease insulin sensitivity (32,33).
Endoplasmic Reticulum Stress Response and Diabetes

Metabolic and inflammatory stresses of obesity may also disrupt cell metabolism, particularly
the processing of cellular proteins in the secretory cells of the liver, pancreas, and adipocyte.
The response to this increased demand is the endoplasmic reticulum stress response pathway,
which activates an extensive cascade which shuts down further translation, increases the
transcription of chaperone proteins, and if not successful, causes cellular apoptosis (41–43).
Among the activated proteins are IRE1 and XBP1. Özcan and colleagues (42) showed recently
that the endoplasmic reticulum stress pathway is active in adipose tissue and in the liver from
obese mice, leading to increased activation of c-jun N terminal kinase (JNK), which in turn
phosphorylates IRS-1 on serine residues, thus suppressing insulin action and downstream
signaling pathways. Similar data also support a role for endoplasmic reticulum stress pathways
in β-cell dysfunction and apoptosis (44).
Endoplasmic reticulum stress is a molecular link between obesity, decreased insulin sensitivity
and type 2 diabetes. Additionally, increased glucose metabolism can lead to a rise in
mitochondrial production of reactive oxygen species (ROS). Inflammatory pathways can be
initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such
as endoplasmic reticulum stress or excess ROS production by mitochondria. Signals from all
of these mediators converge on inflammatory signaling pathways, including the kinases JNK
and IKK. These pathways lead to the production of additional inflammatory mediators through
transcriptional regulation as well as to the direct inhibition of insulin signaling (45,46).
Mitochondria and Reactive Oxygen Species

Reactive Oxygen Species (ROS) are another factor suggested to have a role in insulin
resistance. ROS production is elevated in obesity, which in turn causes enhanced activation of
inflammatory pathways (47,48). Several lines of evidence support the association of oxidative
stress markers with diabetes (47–49). Houstis et al (50) recently connected these mechanisms
by showing that treatment of 3T3-L1 adipocyte with either TNFα (an inflammatory cytokine
that is elevated in obesity) or dexamethasone (an anti-inflammatory agent that causes insulin
resistance) increased the ROS level and resulted in decreased insulin action. Antioxidant
molecules or transgenes encoding ROS scavenging enzymes both ameliorated the insulin

resistance of TNFα or dexamethasone treated 3T3-L1 adipocytes to varying degrees.

Furthermore, antioxidant molecules improved insulin sensitivity and glucose homeostasis in
obese, insulin resistant ob/ob mice (50). Oxidative stress is also likely to be involved in
progression of pancreatic β-cell dysfunction in T2DM.
Reduced mitochondrial oxidative phosphorylation has recently been demonstrated in several

studies, using both microarrays to identify downregulated genes involved in oxidative
phosphorylation (OXPHOS genes). PGC1 appears to be at least partially responsible for this
defect (51,52). Supportive studies in humans have suggested a role for defective mitochondrial
fatty acid oxidation, mitochondrial dysfunction, and reduced numbers of skeletal muscle
mitochondria in T2DM pathogenesis, and have suggested that increased intramyocellular lipid
content was associated with defects in mitochondrial activity (53–56). Morino et al (56) found
38% less mitochondrial density in muscle of insulin resistant (IR) individuals compared to
controls, which was associated with a 50% increase in serine phosphorylation of IRS-1 and a
60% reduction in insulin stimulated Akt activation (a measure of insulin signaling). Decreased
mitochondrial fatty acid oxidation, caused by either mitochondrial dysfunction and/or reduced
mitochondrial numbers, produces increased levels of intracellular fatty acyl CoA and
diacylglycerol. These molecules activate a novel protein kinase C, which in turn activates a
serine kinase cascade, again leading to increased serine phosphorylation of IRS-1. As described
above, serine phosphorylation blocks IRS-1 tyrosine phosphorylation and inhibits downstream
signaling, including recruitment of GLUT4 to the plasma membrane and insulin-mediated
glucose uptake in skeletal muscle (53).
Oxidative Metabolism and the Pancreatic β-Cell

Insulin secretion by the pancreatic β-cell is modulated by multiple stimuli. Oxidative
mitochondrial metabolism and adenosine triphosphate (ATP) generation is essential to glucose
stimulated insulin secretion. The increased ratio of ATP to adenosine diphosphate (ADP) in
the β-cell triggers a series of events: inhibition of the cell’s ATP/ADP-regulated potassium
channel (KATP, encoded by genes KCNJ11 and ABCC8), plasma membrane depolarization,
opening of a voltage-gated calcium channel, calcium influx, and transport and binding of
insulin granules to the cell surface (53). The ATP/ADP ratio is in turn altered by UCP2, an
integral mitochondrial membrane protein that permits protons to leak across the mitochondrial
inner membrane, thus uncoupling of glucose oxidative metabolism from ATP production
(57). By decreasing the amount of ATP generated from glucose, UCP2 expression negatively
regulates glucose-stimulated insulin secretion. Over-expression of UCP2 in β-cells in vitro
decreases glucose-stimulated insulin secretion (58), whereas targeted inactivation of the UCP2
gene in mice has the opposite effect (59). Importantly, heterozygosity for a null UCP2 allele
produces an effect that is intermediate between those observed in wild-type and homozygous
mice, indicating that even relatively small changes in UCP2 expression may have a substantial
impact on glucose-stimulated insulin secretion.
Glucose Homeostasis: The Central Nervous System

Levels of glucose in the blood are regulated by a complex interplay between the appearance
of glucose from both intestinal absorption and hepatic production and its disappearance through
insulin-dependent and insulin independent glucose uptake in a variety of tissues. After the
overnight fast, glucose is largely produced by glycogen breakdown and gluconeogenesis.
About 80% of this glucose released by liver is metabolized independent of insulin by brain and
other insulin–independent tissues (gut, red cells). The medial hypothalamus, a major integrator
of nutritional and hormonal signals, plays a pivotal role not only in the regulation of energy
balance but also in the modulation of liver glucose output. Diminished responses of first-order
neurons, such as those in the arcuate nucleus, may contribute to the pathogenesis of T2DM
(60–62). The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid

(LCFA) entry into mitochondria, where they undergo β-oxidation. Obici et al (63) observed
that the selective reduction of lipid oxidation in the hypothalamus by inhibiting or decreasing
the activity of CPT1, substantially diminished food intake and endogenous glucose production.
These results indicated that changes in the rate of lipid oxidation in selective hypothalamic
neurons signaled nutrient availability to the hypothalamus, which in turn modulated the
exogenous and endogenous inputs of nutrients into the circulation.
A recent study by Pocai et al (64) revealed an important role for circulating LCFA and insulin
levels, and a sensing role of hypothalamic (arcuate nucleus) KATP channels. Insulin infused into
the region of the arcuate nucleus potently reduced hepatic glucose production from the liver.
This effect was mediated by changing the level of activity of the hepatic branch of the vagus
nerve that provided the major neural input into the liver. KATP channel inhibitors infused into
the arcuate nucleus completely blocked the effects of CNS-infused insulin to reduce hepatic
glucose production. Consistent with these results, mice lacking the SUR1 (ABCC8) subunit
of the KATP channel were resistant to the inhibitory action of insulin on gluconeogenesis. Thus,
activation of hypothalamic KATP channels normally restrains hepatic gluconeogenesis.
Alterations within this central nervous system/hepatic circuit may contribute to diabetic
hyperglycaemia (64). Other peripheral signals to the hypothalamic centers include leptin and
insulin (61).
Glucose Homeostasis: Liver

Glycogenolysis and gluconeogenesis are the two known source of hepatic glucose production
(HGP). HGP is controlled by the integrated metabolite fluxes to and from the liver, hormonal
cues, and as reviewed above, neurotransmitter release. Fasting promotes glucose production
through cAMP-dependent mechanisms, whereas feeding inhibits glucose production through
insulin. In the absorptive state, insulin silences hepatic PGC-1α transcription, and suppresses
gluconoegenic enzymes PEPCK and G6Pase through the insulin signaling pathway (IRS2-Akt-
mediated phosphorylation, 65). Glucagon opposes these actions by stimulating the
transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (cAMP
response element–binding protein), thus increasing HGP. Recent findings (66–69) have begun
to elucidate the role of additional hormone-regulated transcription factors that control
gluconeogenesis. LKB1, a tumor-suppressor gene which encodes a protein-threonine kinase,
phosphorylates and activates AMPK (adenosine monophosphate activated protein kinase) and
SIK2 (Salt-inducible kinase) in liver (67). The deletion of LKB1 in the liver of adult mice
resulted in a nearly complete loss of AMPK activity and hyperglycemia with increased
gluconeogenic and lipogenic gene expression. LKB1 acts through TORC2 (transducer of
regulated CREB activity 2), a transcriptional coactivator of CREB which in turn acts on
PGC-1α to increase gluconeogenesis. Downregulation of TORC2 reduced PGC-1α expression
and normalized blood glucose levels in mice with liver specific LKB1 inactivation, indicating
that TORC2 is a critical target of LKB1/AMPK signaling (67).
The β-Cell and Type 2 Diabetes

Impairment of insulin secretion from pancreatic β-cell is also a major component of T2DM
pathogenesis. Analysis of mutations involved in six different maturity onset diabetes of the
young (MODY) genes have revealed the important role of transcription factors in the insulin
secretion. In a recent gene expression analysis of pancreatic islets isolated from T2DM and
NGT individuals, Gunton et al (70) found a 90% decrease of the transcription factor,
arylhydrocarbon nuclear receptor translocator (ARNT) in T2DM islets compared with
nondiabetic individuals. Mice lacking ARNT in β-cells exhibited abnormal glucose tolerance,
impaired insulin secretion and changes in islet gene expression similar to human T2DM (70).
ARNT and its partner proteins are members of the basic helix-loop-helix Per/AhR/ARNT/Sim
(bHLH-PAS) family of transcription factors. ARNT interacting partners include HIF1α,

HIF2α and AhR, which together regulate the transcription of genes required for optimal
glucose-responsive insulin secretion by β-cells. ARNT-HIF dimers may directly regulate the
expression of several glycolytic enzymes. Oxygen and NO may also regulate insulin secretion
through this ARNT-related pathway. ARNT is an obligate partner of several transcription

factors involved in the response to toxins and hypoxic stress, and may integrate the genetic and
environmental insults leading to T2DM pathogenesis (71).
Many mechanisms contributing to T2DM may trigger β-cell apoptosis and reduced β-cell mass
or ability to compensate for insulin resistance (72). Mechanisms include endoplasmic reticulum
stress (44), chronic hyperglycemia (glucotoxicity, 73,74), chronic hyperlipidemia
(lipotoxicity) (75;76), oxidative stress (77), and inflammatory cytokines (78). Decreased IRS-2
expression, an essential β-cell growth factor, may lead to spontaneous β-cell apoptosis (79).
Because several mechanisms relevant to pathogenesis of T2DM may increase IRS-2 serine/
threonine phosphorylation (80,81) with resultant IRS-2 ubiqutination and proteosomal
degradation, defects in insulin signaling and insulin secretion may be coupled.
Multiple pathways may lead to the T2DM phenotype. This review of the pathophysiology has
covered only a fraction of the genes and pathways that may be implicated in T2DM
pathogenesis, and that may harbor genetic variants. Based on the intertwined and complex
physiologic pathway, a complicated genetic picture can be well anticipated. Indeed, such a
picture is now emerging and is reviewed below.
The Quest for T2DM Susceptibility Loci: A Linkage Approach

As we reviewed above, decades of careful research have failed to clarify a unified model of
the pathogenesis of T2DM. hence, using pathophysiology to predict susceptibility loci is
difficult. The complex genetic pattern of T2DM, including the variable age of onset, reduced
penetrance (not everyone with the genes will get T2DM), locus and allelic heterogeneity, and
the likelihood of phenocopies (multiple different genetic causes and nongenetic causes), as
well as the likelihood that many genes interacting with the environment contribute to T2DM
have conspired to confound the search for T2DM susceptibility loci. Thus, T2DM remains as
geneticist’s “Gordian knot”.
Two broad approaches have been used to define the genetic predisposition of T2DM. First,
molecular events in diabetes pathogenesis have been examined directly by testing the role of
sequence variants of specific candidate genes. The candidate gene approach focuses on the
search for an association between T2DM and sequence variants in or near biologically defined
candidate genes which have been chosen based on their known physiological function. The
importance of these variants or other nearby variants is tested by comparing the frequency in
T2DM subjects and control individuals. Despite of the apparent simplicity of study design and
power of the study, candidate gene studies are necessarily limited to the investigation of known
genes that are already considered important in glucose homeostasis. Our partial knowledge of
the mechanisms contributing to T2DM and the complicated pathways involved in those known
mechanisms make the candidate gene approach even more daunting. Although the wealth of
information on pathways involved in T2DM pathophysiology is accumulating, and new
bioinformatics approaches may guide the selection of potential susceptibility genes, novel
genes and pathways cannot be identified by this approach.
To overcome the shortcomings of the candidate gene studies, investigators have applied a
genome-wide linkage scan strategy in which regularly spaced markers are traced in families
and sibling pairs for segregation with T2DM. No prior knowledge of gene or gene effects is
necessary, but the genetic locus must have sufficient impact on the disease susceptibility to be
detectable. The susceptibility locus is first localized to a chromosomal region. The specific
gene and sequence variant are then identified within this region by a positional candidate gene

approach in which genes are selected within the region for a physiologic impact. Alternatively,
an unbiased approach of testing a dense map of markers in cases and controls across the region
of linkage may be used. Most recently, technological advances have made a new approach
possible which combines the power to detect small effects that characterizes candidate gene
studies with the unbiased approach of the linkage study. This approach, known as the genome-
wide association, has been applied in a limited fashion. For example, a recent study (82)
identified a variant in the insulin induced gene 2 (INSIG2) that was associated with obesity in
children and adults in several populations using the genome-wide association approach.
Over 27 genome wide linkage scans have been published in multiple ethnic groups including
Mexican-American, Caucasian, Native American, Chinese, Japanese, Indian and African based
populations, and in both founder and out-bred populations. Family configurations have
included extended pedigrees, nuclear families, and simple affected (diabetic) sib pairs, and
both definitions of “affected” and the analytical approaches have varied. Other scans have
examined intermediate traits related to T2DM. The scans and best replicated regions are
summarized in Table 1. Despite such differences, at least 8 susceptibility regions show at least
some evidence for replication in our opinions and appear likely to harbor one or more
susceptibility genes. Many other regions with some evidence of linkage can be defined (see
Table 1), with much of the genome potentially identified. In consideration of brevity, we restrict
our review to those regions with the best evidence for replication.
Chromosome 2q
The first locus for T2DM was mapped by Hanis et. al. in 1996 (83) to the telomeric region of
chromosome 2q (2q33–q37) in 330 Mexican American sib pairs and called NIDDM1. Further
fine mapping placed NIDDM1 near D2S140 (263.6 cM; multipoint lod score=4.03) with a 1-
lod support interval from 257 to 269 cM, a 12-cM region that included marker D2S125. In
subsequent studies, Cox and colleagues (84) used a two–locus conditional search strategy to
show that NIDDM1 interacted with a chromosome 15 locus near CYP19, with an increase in
the evidence for linkage from a logarithm of odds ratio of linkage to chance segregation (LOD)
of 1.3 to 4.0 when NIDDM1 was taken into account. Similarly, evidence for linkage at
NIDDM1 increased from 4.03 to 7.28 by conditioning on chromosome 15 linkage and
decreased the 1-lod support interval (the size of the probable region harboring the susceptibility
gene) from 12 cM to 7 cM (from 257–269 cM to 259–266 cM). Studies to identify a
susceptibility gene in this region (calpain 10) are reviewed below. Other studies, including
those from our laboratory (85) and the original Mexican American linkage study (83), have
found suggestive evidence for linkage of T2DM to chromosome 2q in a second, more
centromeric region from the CAPN10 gene. Other studies with some evidence for linkage have
included Han Chinese (86) at marker D2S126 (221 cM), Japanese families selected for a BMI<
30 kg/m2 at 2q34 (223 cM) (87), and indigenous Australian families at 2q24.3 (177 cM; LOD
score 3.9, 88). The gene or geness responsible for these observations are unknown.
Chromosome 20
Chromosome 20 was among the first regions with evidence for linkage in multiple studies
(89–91). A large genome scan in 716 affected sib pairs from 477 Finnish families (The Finland–
U.S. Investigation of Non-Insulin- Dependent Diabetes Mellitus Genetics or FUSION study)
provided considerable additional evidence (92), and subsequent studies have added to the
replication in Ashkenazy Jewish families (93) and in African sib pairs (94). In the large
FUSION study, the evidence for linkage was observed on both the long and short arms, with
multipoint lod scores of 3.08 on 20p (19.5cM) and 2.06 on 20q (57cM). Further high resolution
mapping and conditioning on a chromosome 2p locus (8.5cM) provided further support for a
locus on 20q at 69 cM (lod 5.50, 95). Linkage in the 472 sib pairs of Ashkenazy Jewish descent
was similarly in the region form 51 cM to 62 cM, with a much weaker signal on 20p (2 cM,

93). A genome wide scan on Han Chinse families also found evidence for linkage near marker
D20S196 on 20q in the subset of families with low BMI (86), and a similar subset analysis in
Japanese families with BMI <30kg/cm2 provided additional evidence for T2DM linkage at
20q12–q13 (D20S119 at 61.77 cM; MLS 2.32, 87). In 343 sibling pairs from West Africa,
highly suggestive linkage was found at 96 cM (D20S171, lod 2.63) (94). At least two strong
candidate genes (PTPN1 and HNF4A) show evidence for an association with T2DM, and are
reviewed below. However, additional susceptibility genes seem likely to explain this well
replicated linkage across a broad region of chromosome 20.
Chromosome12
A T2DM susceptibility loci on chromosome 12q near HNF1α was reported first by Mahtani
et al (96) in a subset analysis of families from Western Finland that had the lowest mean insulin
levels. In an extension of this initial study by using 32 additional families, for a total of 54
multiplex families, Lindgren et al replicated the initial findings at chromosome 12q24 (97),
and support a locus on 12q near 130–150cM. In the West African study of affected sibling
pairs, a T2DM susceptibility locus was also reported at 12q24 (D12S2070 at 125.31cM;
LOD=1.92, 94), and Ehm et al reported a locus on chromosome 12q in the Caucasian subset
of families collected under the American Diabetes Association’s Genetics of NIDDM
(GENNID) study, albeit somewhat centromeric to the earlier findings at 95 cM (lod 2.81, 98).
Other reports of linkage provide additional support, albeit many findings are to a more
centromeric region on chromosome 12 (50–100cM, 89,99–102). These findings suggest
substantial replication to chromosome 12, but the gene or genes responsible remain unknown
and the actual number of loci is uncertain.
Chromosome 1q
The best replicated locus at 1q21–q23 was initially identified independently by our laboratory
in North European Caucasians (85) and in Pima Indians with onset before age 25 years (103).
Subsequent replications of this region included Amish (104), French (105), United Kingdom
(106), US Caucasians (Framingham, 107), two Chinese populations (108,109) and Arkansas
African-American families (unpublished). In contrast to chromosomes 20 and 12, the
chromosome 1 linkage peaks overlap in a relatively narrow region extending from 165 cM to
200 cM (110). This well replicated region of T2DM linkage is characterized by an extraordinary
gene density, including a plethora of strong candidate genes. We recently reported that this
region encompasses at least two and possibly three linkage peaks (111). We have reported that
two genes in this region, liver pyruvate kinase (PKLR, 112) and calsequestrin1 (CASQ1, 113),
were associated with T2DM. Both have been observed in other populations (114), and support
a model of multiple susceptibility loci accounting for the chromosome 1 linkage signal. Work
is ongoing to identify additional susceptibility genes in this region as an international
collaborative effort.
Chromosome 18p
A locus on 18p (0–20cM) is likewise now well replicated. This region was suggestive in a scan
from our laboratory (85). A subgroup analysis of the 20% of the most obese subjects from a
study of 480 Finnish-Swedish Caucasian affected sib-pairs showed linkage to 18p11 (lod= 3.82
at D18S976 – D18S391, 115). Two subsequent studies from the Netherlands also suggested a
locus that interacted with obesity. Aulchenko et al (116) reported a lod score of 2.3 at marker
D18S63. When association was tested, the most significant findings were for subjects with
high BMI. In a study from van Tilburg and colleagues (117), the linkage was again for the 20%
of the most obese pedigrees at 18p11, between markers D18S471 and D18S843. Hence, the
putative T2DM susceptibility locus at 18p11 is replicating well, but may be of most importance
in interaction with obesity.

Chromosomes 3q, 11q and 8p

Several other loci show reasonable evidence for replication, and many cross ethnic groups. A
locus at 3q22–q27 near the adiponectin locus (165–220cM) has replicated well, and
adiponectin itself may be partially responsible (88,105,118). A broad region of 11q has been
implicated in several studies, and obesity also maps to this region (95,103,119,120). In Pima
Indians, the strongest 11q linkage was for a bivariate trait of obesity (BMI) and T2DM (103).
Finally, studies in British families, Utah families of European descent, and indigenous
Australian populations suggest an 8th possible locus at 8p21–p23 (85,88,106). With the
exception of adiponectin, genes accounting for these linkage signals have not been identified.
Established T2DM Susceptibility Genes

Genes Identified by Linkage Studies
Horikawa Y and colleagues (121) used a relatively sparse linkage disequilibrium map of SNPs
in the region of linkage on chromosome 2q to identify 3 common intronic variants of a
previously unknown gene. The gene, calpain 10 (CAPN10), belonged to the family of calcium-
activated, non-lysosomal thiol proteinases. Both a single intronic variant (UCSNP-43: G to A)
and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and
-63) were associated with T2DM in Mexican Americans, with lesser evidence of an association
in a Northern European population from the Botnia region of Finland (121). Surprisingly,
individuals with a combination of two different haplotypes (121/112) were at the highest risk
of T2DM. In further support of CAPN10 as a susceptibility gene, Baier and colleagues (122)
showed altered gene transcription and reduced muscle mRNA levels in muscle biopsies from
Pima Indians with T2DM. Recent studies provide further support for a role of CAPN10 in
T2DM, even among European derived populations (123). SNP-44 (designated “CAPN10-
g4841TtoC”; minor allele frequency 16%), located in intron 3 and 11 bp from SNP-43, was
independently associated with T2DM in several populations, and was in linkage disequilibrium
with the missense mutation Thr504Ala and two 5′-UTR variants (SNP-134 and SNP-135). An
initial meta-analysis also supported an association with T2DM (124), but a subsequent meta-
analysis of over 5000 cases and 5000 controls suggested an effect size that was clearly less
than suggested in the first studies (125) and raised questions about the role in T2DM.
Nonetheless, we and others have found support for a role of CAPN10 in the association with
intermediate, quantitative traits (126;127). Furthermore, CAPN10 variants were valuable along
with traditional risk factors in predicting the onset of T2DM in a prospective study of Botnian
Finnish individuals (128).
Although initial studies of the HNF4α gene, an obvious candidate on chromosome 20, failed
to find any association with T2DM (92), subsequent studies based on the discovery of an
upstream, β-cell specific promoter and first exon prompted a reevaluation. Two studies found
evidence for association with T2DM that could partially explain the linkage signal (129,130).
HNF4A has a complex expression pattern, which includes elaborate alternative splicing, and
is expressed in many tissues, including the liver and pancreas. Three of the isoforms are
transcribed by an alternative P2 promoter, located ~46 kb upstream of the P1 promoter and the
rest of the coding exons. Transcripts from both the P1 and P2 promoters have been detected
in pancreatic β-cells, but the P2 promoter is suggested to be the primary transcription start site
in these cells. In total, 4 SNPs flanking the P2 promoter were associated with T2DM in both
populations. Subsequent replication has been inconsistent. Vaxillaire et al failed to replicate
in a French case control study (131). Hansen and colleagues found only modest evidence for
one of 4 SNPs originally reported (p=0.02, OR=1.15) in a large Danish study (132), and
Weedon et al found a similar effect in a large British study (5256 subjects; p=0.02, OR=1.15,
133). Damcott et al reported replication in the Old Order Amish (134), and Muller and
colleagues reported replication in Pima Indians with OR 1.3 (135). Winckler and colleagues,

on the other hand, found no replication in 7883 Caucasians from several populations (136).
Although these SNPs appear to have a role in T2DM susceptibility, the effect is likely much
smaller than originally reported, and likely similar to that of CAPN10.
The PTPN1 gene (chromosome 20q13) codes for protein tyrosine phosphatase 1B (PTP1B),
which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine
residues of the insulin receptor kinase activation domain. Multiple noncoding SNPs in the
PTPN1 gene (PTP1B) on chromosome 20q13 were recently implicated in T2DM in Caucasian
and Mexican-American populations (137,138). The association was observed between
multiple SNPs and T2DM, with the most consistent evidence for association occurring with
SNPs spanning the 3′ end of intron 1 of PTPN1 through intron 8 (p values ranging from 0.043
to 0.004 in one case-control set and 0.038–0.002 in a second case-control set). All of the
associated SNPs were present in a single 100-kb haplotype block that encompassed the
PTPN1 gene. Haplotype frequencies were significantly different between T2DM case and
control subjects (p=0.0035–0.0056), with a single common haplotype (36%) contributing
strongly to the evidence for association, with OR 1.3. Furthermore, the same haplotypes were
associated with glucose homeostasis measures in 811 Hispanic subjects (138). However, Florez
et al failed to replicate the findings in a large Caucasian study (139). Further study is needed
to determine the role of the strong candidate in a region of replicated linkage.
The search for diabetes susceptibility genes on most other chromosomes is ongoing. On
chromosome 1, we initially described an association of polymorphisms of the liver pyruvate

kinase gene with T2DM (112); subsequent preliminary reports have confirmed that association
in Older Order Amish (140) and in other populations with chromosome 1 linkage (141). The
region has extended linkage disequilibrium, such that several potential candidate genes are
included within the two associated haplotypes. Work is ongoing in our laboratory and by others
to identify the responsible variants. Closer to the most prominent chromosome 1 linkage peak,
we and Fu et al independently showed an association of noncoding variants of calsequestrin
gene (CASQ1) with T2DM in populations of European ancestry (113,114). The effect size is
likely similar to that of CAPN10 or HNF4A. The role of this muscle gene, which is not an
obvious candidate for T2DM, must await replication in other populations, however.
Adiponectin is a strong candidate for T2DM given the clear role of plasma adiponectin levels
in insulin sensitivity and the fall in adiponectin levels with obesity and T2DM. Adiponectin
maps to the region of replicated linkage on chromosome 3q. A very large number of studies
have examined adiponectin variants with metabolic traits, T2DM, and risk of conversion of
impaired glucose tolerance to T2DM. Multiple studies found evidence that promoter variants
in the APM1 gene were associated with T2DM in French and Swedish Caucasian and Japanese
populations, and some data support a role of the APM1 locus in controlling adiponectin levels
(142). However, APM1 variants did not appear to account for the 3q27 linkage in French
families (142). Zacharova and colleagues showed that APM1 variation at positions 45 (G allele)
in exon 2 and 276 in intron 2 (T allele) were associated with a 4.5 fold increased risk of
converting from impaired glucose tolerance to T2DM in the STOP-NIDDM trial (143). On the
other hand, no association was observed in Pima Indians (144). Larger studies are needed to
determine the magnitude of risk imparted by APM1 variation.
Grant and colleagues (145) searched for a T2DM susceptibility gene under the suggestive
linkage peak on chromosome 10q in an Icelandic population. They identified a 6 allele simple
tandem repeat (STR) polymorphism in intron 3 of the transcription factor 7 like 2 gene
(TCF7L2, formerly TCF4). Impressive associations were found in a Danish population and a
United States Caucasian population, with a relative risk of 1.45 for heterozygotes and 2.41 in
homozygotes. Although the exact role of TCF7L2 is unknown, it appears to act through the
Wnt pathway to regulate proglucagon gene expression in enteroendocrine cells. The authors
calculated a relatively high 27% population attributable risk (the proportion of T2DM that

would not be present if the gene could be removed from the population). Two additional
noncoding SNPs were closely correlated with the simple tandem repeat composite risk allele.
Additional replication is needed to determine the real role of this novel gene.
Despite initial identification through a linkage signal, which would be expected to select
relatively strong effects, each of these variants reviewed above has only modest individual
effect (Odds Ratio, OR<1.4). Indeed, each with further study has shown much smaller effect
than in the initial report – a phenomenon named the “winner’s curse”. Available data suggest
that 1) the effects of individual variants are likely small; 2) multiple variants probably
contribute to replicated linkage signals, as we have demonstrated on chromosome 1q; and 3)
most variants are noncoding and regulatory rather than altering protein structure. We predict
that each linkage region will in fact harbor multiple disease genes of small effect, and that no
single variant will explain the linkage peak.
Genes Discovered by the Candidate Gene Approach

Extensive studies have been conducted of genes identified through physiologic pathways.
Consistent with the very large numbers of studies, many have shown modest associations in
single populations, but these associations have not yet been replicated. We make no attempt
to provide a comprehensive review of the hundreds of genes examined by investigators around
the world, and instead focus on genes for which reasonable replication has been achieved
already. In each case, like those genes identified through linkage, the effect of these variants
is relatively small, with OR<1.4 and in most cases approaching 1.2 or less. Perhaps as a bias
of candidate gene studies, these variants are more often coding.
The peroxisome proliferator activated receptor gamma (PPARγ) is a member of nuclear

hormone receptor superfamily of transcription factors, and the target of the widely used class
of insulin sensitizers, the thiazolidinediones. Multiple studies have examined a common amino
acid change in the PPARγ2 isoform in which alanine is substituted for proline at position 12
(P12A). Although smaller studies provided inconsistent results, larger studies have shown a
consistently protective effect of the rare, alanine allele (A/A) when compared with the common
proline allele. Hence, the common P12 allele consistently increases T2DM risk by an OR of
1.2–1.3 in cross sectional studies (146). Furthermore, in the Nurses Health Study, the OR of
carrying the Ala12 allele was 0.72, again suggesting a protective role (147). Several, but not
all studies suggest that the rare “A” allele protects against insulin resistance and obesity, but
the association with obesity has been inconsistent. In studies of families from Utah, we found
an association with several “metabolic syndrome” traits, including BMI, serum total cholesterol
levels, triglyceride levels, systolic and diastolic blood pressures, and glucose concentrations.
Gene-environment interactions have been suggested, and may explain the many inconsistent
results. Because the common allele is also the risk allele for T2DM, and this allele has a
frequency of at least 75% in most populations, the population attributable risk is again
extremely high at 25%. Hence, the small individual effect of this variant translates into a large
effect in the context of the population.
The β-cell potassium channel comprises two subunits, the potassium channel encoded by the
gene KCNJ11, and the regulatory subunit (SUR1 encoded by ABCC8) that binds sulfonylureas
and ATP. Variants in both subunits have been associated with T2DM. Two variants in
ABCC8 were initially associated in smaller studies (148–150), and larger subsequent studies
appeared to confirm the association (151,152). Other studies have not confirmed the
association, however (153,154). We (155) and others (156) have shown altered insulin
secretion associated with these variants. The adjacent KCNJ11 gene was initially noted to have
multiple nonsynonymous coding variants (157), but none were associated with T2DM in this
or other early studies (146,158). However, a coding glutamine to lysine at position 23 in the
single exon (E23K) was shown to lower the sensitivity of the potassium channel to ATP and

thus reduce insulin secretion in vitro (159). Gloyn et al subsequently showed a modest
association of the E23K variant with T2DM in nearly 2500 British case-control subjects
(153), and in a meta-analysis confirmed association with an OR of 1.16. More recently Florez
and colleagues (154) thoroughly examined the two subunits (KCNJ11, ABCC8), and tested
sufficient variants to completely tag all variation in this region. Again, the E23K variant was
associated with T2DM in 3,413 subjects, and the association was confirmed in a meta-analysis
that included over 5000 T2DM subjects and 4747 controls (p<10−5, OR 1.15). The E23K
variant is in nearly complete linkage disequilibrium (completely correlated) with a Serine to
Alanine change at position 1369 in exon 33 of the sulfonylurea receptor, and thus S1369A and
E23K cannot be distinguished genetically. Nonetheless, E23K appears to have a role
comparable to the PPARG P12A polymorphism. The appropriate genetic model is close to
recessive, in which the relatively rare K23 homozygotes have the highest risk, but E23K
heterozygotes are at some increased risk. Some (160) but not all (161) studies have found an
effect of the K allele on insulin secretion.
Other variants in candidate genes have been more difficult to establish. The insulin gene
variable tandem repeat polymorphism, which has clearly been associated with type 1 diabetes,
and been controversial for over 20 years in T2DM (162). Whereas considerable evidence
supports an association with obesity and birth weight (163–165), the association with T2DM
is inconsistent (165–167). Similarly, both physiologic and genetic data are inconsistent for the
glycine to arginine (G972R) variant of the insulin receptor substrate 1(IRS1) gene (168,169),
now more correctly referred to as G971R. Despite evidence that this variant alters insulin action
on IRS1 (169), the association with T2DM has been inconsistently replicated. Two recent large
studies have revisited this variant. Zeggini and colleagues (170) examined 971 cases and 1257
controls from the United Kingdom, and found no association. However, a meta-analysis of 31
studies that included 5104 cases and 7,418 controls showed a modest association (p=0.025)
with an OR of 1.15, suggesting that the effect size was similar to or smaller than that of
KCNJ11 and PPARG. Florez et al (171) three large Caucasian samples with 9000 total
individuals, including 4279 cases and 3532 controls, and found no evidence for an association
with T2DM. If the IRS1 G972R (G971R) variant has any role in T2DM, clearly the role is quite
small and of minimal clinical significance. Similarly, the association of a glycine to serine
variant at position 482 of the PGC1α?gene has been reported by several groups, but not yet
well replicated. PGC1α??as reviewed above, plays key roles in liver gluconeogenesis and was
implicated in array studies of diabetic and control muscle. Positive associations were reported
in JapaneseT2DM (172) and Danish cases and controls (173), and subsequently some
replication was seen in populations from India (174) and Korea (175). Other associations were
reported with insulin resistance (176) elevated glucose in nondiabetic offspring of diabetic
parents (177), and reduced insulin secretion (178), but not with metabolic syndrome (179).
Additional studies are required to determine the real role of this variant in diabetes
susceptibility.
Variants in the gene ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), also

known as plasma cell glycoprotein 1, were shown recently to be associated with both childhood
and adult obesity in a French population. A moderate excess of the risk haplotype was also
seen in adults with T2DM compared with controls (10.7% vs 7.1%, OR 1.44), and the
association was replicated in an Austrian cohort with similar frequencies. A Mantel-Haenszel
analysis of 2,569 European subjects supported the association, with OR 1.56 and p=0.00002
(180). The nonsynonymous variant lysine 212 to glutamine (K121Q) has been best studied,
and also shown to be associated with obesity but not diabetes in Caucasian and African
American subjects ascertained from the New York Cancer Project (181). Other investigators
found an association of K121Q with earlier T2DM onset and coronary disease among T2DM
patients (182). The association of K121Q with T2DM was replicated in three relatively small
populations, two of South Asian ancestry and one Caucasian (183). Although the K121Q

variant appears to associate with T2DM and obesity, additional work is needed to determine
the magnitude of the risk, the populations affected, and to confirm a role comparable to
KCNJ11 or PPARG.
Conclusions: Placing Genetic Susceptibility in Context

In this review, we have restricted discussion to those genes with the best evidence for a role in
T2DM, and have not considered a multitude of other associations, many reported by our
laboratory and others (151), which suggest that the eventual genetic landscape of T2DM will
integrate a large number of genes, many with multiple variants. The completed work and the
few susceptibility genes that are now well validated suggest that these susceptibility variants
will have small effects, most with odds ratios below 1.4 and likely below 1.2. As these
susceptibility genes inhabit different pathways in the complex physiologic network that causes
T2DM, we expect many of the variants will interact. We propose that much as very small
changes in gene expression in the oxidative phosphorylation pathways appear to result in
decreased oxidative phosphorylation and mitochondrial function (52), multiple defects of
individually small effect will combine in a single pathway to have large physiologic effect. We
propose that broad linkage peaks, as found on chromosome 20 and chromosome 1q, in fact
represent multiple genes, many in either the same pathway or in interacting pathways. Sorting
out these complex gene-gene interactions will require sizeable populations, however.
Although we have focused on gene variation as the cause of T2DM, the role of environment
in the current diabetes pandemic is undeniable. Different environmental stresses, population
differences in activity, and different diets clearly cause some genes to manifest as a disease
phenotype. For example, fish oil may stimulate PPARγ in much the same fashion as the
thiazolidinedione class of drugs; studies of the interaction of the P12A variant with dietary
composition have not been performed. The spectacular rise in rates of diabetes among Pima
Indians and other populations as they adopt Western diets and life styles dramatically
demonstrates the key role of environment. Consequently, the effect of a common gene variant
between populations that have very different diets and exercise habits might be expected to be
totally different, thus explaining some instances of lack of replication.
In a recent study, Ioannidis et al (184), examined the genetic effects for 43 validated gene-
disease associations across 697 studies of varied ancestry. They argued that proposed racial
differences in genetic risk should be scrutinized cautiously, and that genetic effects are usually
consistent across human populations. Instead, they argued, small sample sizes, flawed study
designs, or other biases may be more common reasons than true ‘racial’ heterogeneity for the
observed discrepancies. Nonetheless, marked differences in allele frequencies are clearly
evident in known susceptibility genes, and ethnic differences in disease prevalence are also
common. We predict that ethnic “specific” risk factors will indeed be present, although
differences in the degree of risk, allele frequency, and gene-gene or gene-environment
interactions. Clearly much remains to be learned regarding these issues for complex disease.
Our tacit application of models derived from our understanding of monogenic disease may
retard our understanding of common complex diseases such as T2DM.
Whereas the focus on adult diseases such as T2DM is on the role of post-natal or post-pubertal
environment, considerable data that cannot be reviewed here suggest a role for genes that
control fetal growth and intrauterine environment in T2DM. For example, Beck-Nielsen
(185) demonstrated in a group of middle aged, monozygotic twins that the twin with T2DM
was consistently the lighter of the pair at birth. Hence, even in genetically identical individuals,
the intrauterine environment may influence fetal growth differentially with implications for
subsequent adult metabolic health. When considered in the context of numerous studies of birth
weight and the risk for diabetes and metabolic syndrome, this study suggests that gene-

environment interactions may need to consider intrauterine environment in addition to the

external environment.
With the human genome sequence completed in 2003, new data are rapidly expanding on the
noncoding aspects of our genome. T2DM and most other complex diseases appear to be caused
primarily by noncoding rather than coding variants. Thus, KCNJ11, PPARG, IRS1, and
ENPP1 coding variants discussed above are likely the exception, and their prominence
reflecting a strong publication bias to report and validate changes in protein structure while
ignoring noncoding variants as silent. This bias is likely unfounded. Noncoding SNPs or
microsatellites are clearly the only explanation for a multitude of complex disease genes,
including HNF4A, PTPN1, CASQ1, PKLR, and CAPN10 reviewed above among many others.
Whereas not long ago such findings were viewed as implausible, recent studies (186–188) have
revolutionized our understanding of the genome, and suggest that much noncoding DNA is
indeed functional as long range enhancer elements controlling gene transcription, noncoding
RNA that may have regulatory functions, and small RNA species that have widespread
regulatory properties and are often derived from intronic sequences of coding genes.
Furthermore, over 70% of genes likely undergo alternative splicing and generate multiple
protein forms (186). The balance between those splice forms often correlates with noncoding
SNPs that may have profound effects on phenotype. Given the likely extensive role of intronic
and intergenic DNA in determining phenotype, a major role of sequence variants in noncoding
regions in T2DM pathogenesis should be anticipated. Ignoring this wealth of knowledge will
impede our continued quest to understand the role of genes in T2DM susceptibility. Our
increased understanding of such phenomena will open new doors to understanding how
common variants can alter disease susceptibility, and will be essential in understanding the
physiologic importance of the genetic associations that we uncover.
Clinical Implications
The molecular genetic definition of T2DM pathophysiology will certainly satisfy our
intellectual curiosity about this common disease, but will it impact health care? Our knowledge
to predict T2DM is currently limited. Pharmacological intervention rather than prevention
remains the primary approach to this disease. In a recent study, Lyssenko et.al.(128) combined
variants in only two genes, PPARG and CAPN10, both reviewed above, with traditional risk
factors. These investigators achieved a remarkable 21.2 –fold increased risk (estimated by
hazard ratio-HR) in obese carriers of the PPARG P12/P12 genotype and CAPN10 SNP43/44
GG/TT genotypes along with elevated fasting plasma glucose (FPG). This study is a landmark
in combining individually weak genetic risk factors with traditional risk factors to improve the
prediction of future T2DM. Although the combination of genetic risk factors in this model has
been challenged (189), the methods of Lyssenko and colleagues model the was in which
multiple small genetic risk factors can be combined to predict risk. Future predictive testing
might include testing a battery of common genetic variants, followed by computational joint
assessment of traditional environmental and lifestyle risk factors, which may assist physicians
and patient in choosing a preventive strategy. If personalized medicine is to be realized in the
future for complex diseases, such models will be required. The future challenges for the
genetics of T2DM will include not only the cataloging of what can now be recognized as likely
100 or more genetic susceptibility variants, but more importantly the synthesis of this catalog
with environmental risk factors, gene-gene, and gene-environment interactions. The utility of
genetic approaches will depend on a holistic understanding of the interactions of among genetic
variants, and between genetic variants and the environmental, lifestyle factors, treatments, and
perhaps even intrauterine environment. This integrated approach must replace the current
methods of using a reductionist approach to understand each component separately.

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Table 1
Summary of published Genome-wide Scans for T2DM
The table summarizes published genome wide scans for T2DM or related traits that are at least 10cM density.
Replicated regions are marked by red color. Regions are selected for reported LOD score of at least 2.0 or
equivalent, some regions represent subset analysis or below this threshold but replicate other findings. Locations
are presented according to current Marshfield Linkage Map, based on most significant marker or region.
Study Population Size and type Suggestive linkage (LOD>2 or

equivalent)
Hanis (1996) Mexican American 330 affected sib pairs 2q(260cM);15(45cM)

Mahtani (1996) Botanian Finn 26 extended families 12q(140cM)
Hanson (1998) Pima Indian 264 nuclear families 11q(139cM);1q(175–200cM);6
(130cM)
Duggirala (1999) Mexican American 32 extended families 10q(150cM);3p(70cM);4q(170cM);
9p(14cM)
Elbein (1999) US Caucasian 42 extended families 1q(165.62–170.84cM); 2q
(245.4cM); 18p(0cM)
Ghosh (1999, 2000) Finnish Caucasian (FUSION I) 477 families (716 affected sib 20p(20cM); 20q(60–85cM); 11q
pairs) (85cM)
Ehm (2000) US Caucasian 77 Caucasian families 5(78cM); 12(94cM); X(68.74cM) :
for Caucasian
[GENNID] African American 65 African-American families 10p(28cM) : for African American
Mexican American 53 Mexican American families 3p(58cM) : for Mexican American
Vionnet (2000) French Caucasian 143 families 1q21–q24(169.68cM); 3q
(207.73cM)
Permutt (2001) Ashkenazi Caucasian 267 families 4q(178cM);20q(50–63cM)
Parker (2001) Finnish Swedish Caucasian 353 families 18p11(18–30cM)
Wiltshire (2001) UK Caucasian 573 families (743 sib pairs) 1q21(181.49–191.52cM); 8p(33–
44cM); 10(120cM)
Francke (2001) Indo-Mauritian 99 families 1q44(318cM);3q22(165cM)
Luo (2001) Chinese Han 102 families 20q (75cM);9p21.3(42.73cM);
9q21.13(70.33cM); 2q36.1
(221.13cM)
Meigs (2002) Framingham Caucasian 330 families 1q21(192.05cM) HbA1c level;
1q42.2(247.23) Mean glucose
Mori (2002) Japanese 224 affected sib pairs 2q(194cM); 7p(7cM); 11p13(46cM);
15q13(42cM); 20q12(62cM)
Lindgren (2002) Botnian Finn 58 families 9q21(66.32cM)
Bushfield (2002) Indigenous Australian 1 extended families(232 2q24(171.04cM); 8p22
members) (31.73cM); 3q27(224.88cM)
Hsueh (2003) Amish Caucasian lextended family (691 member) 1q31(116cM); 1q21(166cM); 14q11
(7cM)
Van Tilburg (2003) Dutch Caucasian 178 families 12q12–q14(48–68cM);18p11(18–
28cM)
Aulchenko (2003) Dutch Caucasian 1 extended pedigree (79 nuclear 18p11(8cM)
families)
Reynisdottir (2003) Iceland Caucasian 227 families 5q34–q35.2(177.06cM)
Iwasaki (2003) Japanese 256 affected sib pairs 15q(45.8cM); 21q(48cM); 9q
(140cM) : in ordered subset analysis
Xiang (2004) Chinese Han 257 families 1q21(192cM);6q21(129cM)
Ng (2004) Chinese (Hong Kong) 64 families (126 sibpairs) 1q21–q25(173cM); 4q(135cM)
Silander (2004) Finnish Caucasian (FUSION II) 242 affected sib pairs 6q16–q22(113.03cM);14q23
(66.81cM)
Sale (2004) African American 247 families 6q25.3(164.78cM)
Rotimi (2004) West Africa 343 sib pairs 20q13.3(62–95cM); 19
(43.4cM); 12q(131cM)
Nawata (2004) Japanese 102 affected sib pairs 11p13–p12(99.01cM);6q15–q16
(51.95cM)
Hunt (2005) Mexican American (SAFDGS) 39 extended families 3p(102cM)
Zhao (2005) Chinese Han 34 Multiplex nuclear families 1p34.2(73.21cM);1q24.3
(188.85cM)

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Cellscience. 2006 April 30; 2(4): 100–131.

The Genetic Basis of Type 2 Diabetes

Swapan Kumar Das and Steven C Elbein

Type 2 Diabetes: A Prologue

T2DM Is a Genetic Disease: Classical Evidence

sensitivity and insulin secretion (12–14).

Pathophysiology of T2DM: Current status

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cytokines, Adipokines and Inflammation

Cellscience. Author manuscript; available in PMC 2006 August 3.

carboxykinase (PEPCK) and impaired insulin signaling in muscle.

Endoplasmic Reticulum Stress Response and Diabetes

Mitochondria and Reactive Oxygen Species

Cellscience. Author manuscript; available in PMC 2006 August 3.

resistance of TNFα or dexamethasone treated 3T3-L1 adipocytes to varying degrees.

progression of pancreatic β-cell dysfunction in T2DM.

Reduced mitochondrial oxidative phosphorylation has recently been demonstrated in several

glucose uptake in skeletal muscle (53).

Oxidative Metabolism and the Pancreatic β-Cell

impact on glucose-stimulated insulin secretion.

Glucose Homeostasis: The Central Nervous System

Cellscience. Author manuscript; available in PMC 2006 August 3.

Glucose Homeostasis: Liver

that TORC2 is a critical target of LKB1/AMPK signaling (67).

The β-Cell and Type 2 Diabetes

Cellscience. Author manuscript; available in PMC 2006 August 3.

through this ARNT-related pathway. ARNT is an obligate partner of several transcription

The Quest for T2DM Susceptibility Loci: A Linkage Approach

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

Chromosomes 3q, 11q and 8p

Established T2DM Susceptibility Genes

Cellscience. Author manuscript; available in PMC 2006 August 3.

chromosome 1, we initially described an association of polymorphisms of the liver pyruvate

Cellscience. Author manuscript; available in PMC 2006 August 3.

Genes Discovered by the Candidate Gene Approach

The peroxisome proliferator activated receptor gamma (PPARγ) is a member of nuclear

Cellscience. Author manuscript; available in PMC 2006 August 3.

Variants in the gene ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), also

Cellscience. Author manuscript; available in PMC 2006 August 3.

Conclusions: Placing Genetic Susceptibility in Context

Cellscience. Author manuscript; available in PMC 2006 August 3.

environment interactions may need to consider intrauterine environment in addition to the

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. NatMed

Cellscience. Author manuscript; available in PMC 2006 August 3.

and pancreatic-islet dysfunction in human type 2 diabetes. Cell 2005;122:337–349. [PubMed:

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

locus on 12q24. Diabetes 2004;53:855–860. [PubMed: 14988275]

Cellscience. Author manuscript; available in PMC 2006 August 3.

Cellscience. Author manuscript; available in PMC 2006 August 3.

128. Lyssenko V, Almgren P, Anevski D, Orho-Melander M, Sjogren M, Saloranta C, Tuomi T, Groop