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Ann N Y Acad Sci. Author manuscript; available in PMC 2016 June 01.
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Published in final edited form as:

Ann N Y Acad Sci. 2015 June ; 1346(1): 4556. doi:10.1111/nyas.12757.

Personalized medicine in diabetes mellitus: current

opportunities and future prospects
Jeffrey W. Kleinberger and Toni I. Pollin
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition and Program in
Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore,
Maryland
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Abstract
Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause
of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1
and type 2 diabetes, respectively, have been identified. Additionally, there is emerging evidence
that some genetic variants help to predict response to treatment. Other variants confer apparent
protection from diabetes or its complications and may lead to development of novel treatment
approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of
diabetic individuals who have monogenic diabetes (e.g., maturity onset diabetes of the young and
KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of
diabetes enables personalized treatment, resulting in improved and less invasive glucose control,
better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate
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of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should
set the stage for effective clinical translation of current genetic, pharmacogenetic, and
pharmacogenomic research of more complex forms of diabetes.

Keywords
monogenic diabetes; type 2 diabetes; pharmacogenetics, geneenvironment interaction;
pharmacogenomics

Introduction
Currently, there are 382 million people living with diabetes mellitus around the world, and
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the total number is predicted to increase by over 50% over the next 20 years. Diabetes
mellitus is a spectrum of metabolic disorders characterized by hyperglycemia. Poorly
controlled diabetes mellitus can lead to microvascular and macrovascular complications,
including kidney failure, blindness, amputation, and cardiovascular disease. Fortunately,
medical advances have increased the number of treatment options for diabetes and improved
outcomes for many individuals. However, there remains a need to determine the appropriate
therapy for each individual, since a significant number of monotherapy treatments fail

Address for correspondence: Toni I. Pollin, MS, PhD, University of Maryland School of Medicine, 660 West Redwood Street, Room
445C, Baltimore, MD 21201. tpollin@medicine.umaryland.edu.
 Kleinberger and Pollin Page 2

within 3 years and diabetes-related morbidity and mortality continue.1,2 Additionally,

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inappropriate therapies can subject patients to increased risk of hypoglycemic events.

Personalizing diabetes treatment based on patient genetics can improve patient care by
decreasing the number of therapy failures and reducing the complications associated with
diabetes mellitus.

Currently, there is little widespread implementation of personalized medicine in diabetes

mellitus treatment. Diabetes mellitus encompasses a range of hyperglycemic conditions,
which the American Diabetes Association (ADA) divides into four categories. The first
category, type 1 diabetes mellitus (T1DM), is classified as an autoimmune disease with
progressive cell destruction, leading to polyuria, polydipsia, weight loss, and
hyperglycemia. Individuals with type 1 diabetes eventually become completely reliant on
non-endogenous insulin.3 In the case of true type 1 diabetes, glucose levels must be closely
monitored and insulin levels individualized to maintain glucose homeostasis. It could be said
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that making a proper diagnosis of type 1 diabetes, including obtaining clear evidence of
cell destruction through the presence of auto-islet antibodies, and then prescribing
endogenous insulin, represents a form of well-established personalized medicine that will
not be discussed further in this review. There is also emerging evidence that oral
medications including those used to treat type 2 diabetes may be effective adjunct therapies
for individuals with insulin-requiring type 1 diabetes.4 Thus, some of the findings discussed
in this review may ultimately have relevance for type 1 diabetes. Finally, there are some 40
genes implicated in the complex etiology of type 1 diabetes, with currently unknown
practical clinical implications.5

Most diabetes is classified in the second category, type 2 diabetes mellitus (T2DM), a
heterogeneous group of disorders caused by some combination of insulin resistance and
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impairment of insulin secretion.6 T2DM has a range of risk factors, etiologies, and clinical
presentations. Progress has been made in understanding the genetic etiology of T2DM, with
nearly 80 susceptibility loci identified,7 but the use of molecular testing to customize
treatment is not yet possible. Other risk factors (many of which themselves are partially
influenced by genetics) include obesity, low activity, and poor diet, sometimes referred to as
lifestyle or environmental risk factors. As the knowledge base increases, the ideal
implementation would use genetic testing and variant analysis to help clarify the etiology of
T2DM, the appropriate therapy for the patient, and, possibly, susceptibility testing for at-risk
relatives and members of the general population. Future genetic testing may help to identify
which patients with diabetes and prediabetes (elevated glucose not in the diabetic range)
may benefit from specific lifestyle interventions and which may need pharmaceutical
treatment as an adjunct to a healthy lifestyle. Results of studies examining genetic influences
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on response to both behavioral and pharmaceutical interventions to prevent, delay, or treat

diabetes will be examined in this review.

A third category of diabetes encompasses forms with specific known genetic and non-
genetic etiologies, including the at least 1% of all diabetes cases which are caused by a
defect in a single gene. These varieties of monogenic diabetes are highly penetrant and often
have similar clinical presentations to T1DM or T2DM. Monogenic forms of diabetes
mellitus are the low-hanging fruit in which genetic testing has already proven the ability to

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improve treatment,8 but they are currently underdiagnosed. Clinical implementations for
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genetic diagnosis and treatment of monogenic diabetes can provide a template for translating
genetic findings of T2DM into clinical practice in the future, and will be discussed in that
context. The fourth category of diabetes, gestational diabetes, may have etiology in common
with other types of diabetes and represent expression of underlying susceptibility enabled by
pregnancy-induced insulin resistance.9

There is still a great deal of progress to be made in the field of personalized diabetes mellitus
therapy. This review will focus on the current opportunities for implementations of
genetically personalized medicine in diabetes mellitus, specifically monogenic diabetes, as
well as the state of current research and potential prospects for future implementation in
T2DM.

Monogenic diabetes mellitus: current implementation of personalized

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medicine
Some forms of monogenic diabetes already present the opportunity for implementation of
personalized medicine. The most well-known and well-studied form of monogenic diabetes
is maturity-onset diabetes of the young (MODY). There are currently 13 different types of
MODY, classified by the dysfunctional gene causing the phenotype. MODY, by its classical
definition, presents in lean individuals before the age of 25 and is inherited in an autosomal
dominant manner while the patient still has signs of pancreatic cell function.10
Epidemiological studies conducted since MODY was initially defined suggest that the
original criteria do not capture all cases.11 It is predicted that MODY makes up 12% of
diabetes mellitus cases.12 However, because the presentation contains characteristics of both
type 1 (early onset, lean body type) and type 2 (family history of diabetes, maintained
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pancreatic cell function), it is often misdiagnosed. Misdiagnosis is especially troubling

because the most prevalent types of MODY have specific pharmacogenetic
recommendations based on the gene etiology.

MODY3 is the most common form of MODY, comprising 52% of cases in the well-
characterized United Kingdom,12 though prevalence varies by ethnicity and geographic
region. It is caused by a mutation in HNF1A, which encodes the transcription factor hepatic
nuclear factor 1- (HNF1-), which promotes transcription of multiple genes related to
glucose metabolism, insulin secretion, and insulin production. HNF1- has 55% amino acid
similarity with hepatic nuclear factor 4- (HNF4-), which is mutated in MODY1. MODY1
makes up about 10% of MODY cases in the United Kingdom.12 HNF1- and HNF4- have
also been shown to interact with each other in an epistatic manner.13 Diagnosis of MODY1
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or MODY3 is important for proper clinical therapy because those patients have been found
to be hypersensitive to sulfonylureas.8,14,15 This hypersensitivity is due to decreased
expression of HNF1- and HNF4- target genes in the liver, which leads to decreased
uptake of sulfonylureas, resulting in sustained increased circulating levels of
sulfonylureas.16 As a result, MODY1 and MODY3 patients need approximately one-tenth of
the sulfonylurea dose, although this varies depending on the patient. The high sensitivity to
sulfonylureas makes them a first-line treatment for MODY1 and MODY3.10 Patients with
these two types of MODY remain insulin-sensitive, since the genetic etiology causes

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dysfunction of pancreatic cells. It has been demonstrated that genetic diagnosis of

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MODY1 followed by switching of treatment from insulin to sulfonylureas improved

glycemic control as measured by %HbA1c.8

Another common cause of MODY is mutation in GCK, which encodes the enzyme
glucokinase, causing MODY2.17 MODY2 makes up 32% of MODY diagnoses in the United
Kingdom.12 The damaging GCK mutations cause decreased function in the glucokinase
enzyme, which is crucial for pancreatic cell monitoring of blood glucose levels. As a
result, MODY2 patients present with mild hyperglycemia. Interestingly, MODY2 patients
generally do not progress to the microvascular and macrovascular complications associated
with diabetes mellitus at a rate greater than non-diabetic populations. As a result, MODY2
patients do not need pharmaceutical therapy.18 However, some evidence has shown that the
mild hyperglycemia can lead to insulin resistance,19 and gestational diabetes mellitus is
frequent among GCK mutation carriers.20,21 In particular, the carrier status of GCK
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mutations of the mother and fetus appears important for ideal glycemic control during
pregnancy, given that maternal GCK mutations can lead to high birth weight and,
conversely, fetal GCK mutations can restrict birthweight.22

Another type of actionable monogenic diabetes is neonatal diabetes mellitus (NDM). NDM
is diagnosed within the first 6 months of life in a transient or permanent form, which can
have a number of gene etiologies including, KCNJ11, ABCC8, GCK, INS, ZFP57 and
chromosome 6q24 paternal duplication or hypomethylation, as well as several others, such
as EIF2AK3 and PTF1A, that cause syndromic forms. NDM is most commonly caused by
activating mutations in KCNJ11 or ABCC8, the two genes encoding the subunits that make
up the ATP-sensitive potassium channel in pancreatic cells. These mutations prevent
membrane depolarization in response to a decreased ATP:ADP ratio, resulting in decreased
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insulin secretion.23 Most patients with these mutations can be treated successfully with high-
dose sulfonylureas instead of the insulin that is the default treatment for neonatal diabetes
and is more expensive, more invasive, less effective, and places individuals with these
mutations at a greater risk for hypoglycemic episodes.2426 Sulfonylureas close the same
channels that become constitutively open owing to NDM mutations.

These cases demonstrate the value of a proper diagnosis of monogenic forms of diabetes. In
the SEARCH for Diabetes in Youth study, it was discovered that 47 study participants
(8.0% of those who did not have type 1related antibodies and had endogenous insulin
production as measured by C-peptide) had mutations in one of the three most common
MODY genes, although only three of those individuals had a MODY diagnosis before the
study.27 Consequently, 79% of MODY patients were on suboptimal treatment rather than
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the treatment indicated by their diagnosis. The advent and advances of next-generation
sequencing techniques have provided the opportunity for accurate diagnoses of these genetic
disorders. Multiple studies have demonstrated the capabilities of different sequencing
platforms to accurately detect pathogenic variants.28,29 Before next-generation sequencing,
most monogenic diabetes studies focused on the prevalence and characteristics of MODY1,
MODY2, and MODY3. Although this method covers the majority of monogenic diabetes
cases, it does not address the prevalence or characteristics of less common forms of
monogenic diabetes. Besides MODY and NDM caused by less-common genetic etiologies,

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there are also many other syndromic and non-syndromic forms of diabetes with monogenic
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etiologies.

Identifying individuals who can benefit from genetic testing for monogenic diabetes is
challenging, owing to clinical overlap with other types of diabetes, incomplete knowledge of
the full phenotypic spectrum of monogenic diabetes, and the lack of a standard accepted
screening and diagnostic algorithm. Other challenges to patients receiving an accurate
diagnosis are the expense of testing and lack of awareness of many providers. The American
Diabetes Association recommends that genetic testing for monogenic diabetes be considered
in children in four situations: (1) diabetes diagnosed in the first 6 months of life; (2) strong
family history of diabetes without risk factors for type 2 diabetes (obesity, certain
ethnicities); (3) mild fasting hyperglycemia (100150 mg/dl), especially without obesity;
and (4) diabetes without autoantibodies, obesity, or insulin resistance.6 These criteria are not
all straightforward to apply in practice and are likely too narrow because, for example, it is
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possible for monogenic diabetes to coexist with obesity, especially where obesity prevalence
is high.

Multiple diagnostic algorithms have been proposed to accurately predict the presence of
monogenic diabetes.3032 Two centers with extensive experience in the diagnosis and
treatment of monogenic diabetes provide criteria for consideration of a monogenic diabetes
diagnosis on their websites: the University of Exeter Medical School (diabetesgenes.org,
which includes a link to the current International Society of Pediatric and Adolescent
Diabetes (ISPAD) guidelines, which are cited by the ADA and are more extensive), and the
University of Chicago Kovler Diabetes Center (http://monogenicdiabetes.uchicago.edu/).
One of the authors of this paper (TIP), with colleagues, published a review and a suggested
algorithm for utilizing genetic family history session to detect potential cases of monogenic
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diabetes.33

Genetic testing for monogenic diabetes should be performed using a Clinical Laboratory
Improvement Amendments (CLIA)-certified laboratory to assure proper regulations and
quality control metrics are observed. There are multiple testing centers available in the
online databases available at Genetests (www.genetests.org) and the Genetic Testing
Registry (http://www.ncbi.nlm.nih.gov/gtr/). Upon receipt of genetic results, the requesting
physician should ensure proper result interpretation by consulting with experts in the field of
monogenic diabetes.34 The most well-established treatment changes that can result from a
genetic diagnosis are high-dose sulfonylureas rather than insulin for KCNJ11/ABCC8-
related diabetes (usually neonatal),26 low-dose sulfonylureas rather than insulin (especially
at early stages) for MODY1 (HNF4A) and MODY3 (HNF1A), and no treatment for
MODY2 (GCK).34 An exciting new progression in testing for diabetes is the incorporation
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of next-generation sequencing. Next-generation sequencing allows multiple genes to be

sequenced in a single assay in a cost-effective manner and should provide more information
about a broader range of gene etiologies of monogenic diabetes. This will hopefully provide
insights into clinical indications for other forms of monogenic diabetes.

The University of Maryland Center for Diabetes and Endocrinology is implementing a

Personalized Diabetes Medicine Program (PDMP) comprising a simple screening process

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followed by next-generation sequencing using a multi-gene panel to find and diagnose

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patients with monogenic diabetes, an effort led by one of the authors of this paper (TIP) and
being evaluated and disseminated as part of the National Human Genome Research Institute
(NHGRI)-funded Implementing Genomics in Practice (IGNITE) Network (ignite-
genomics.org). Patients referred by providers or screening positive on the questionnaire with
one of the following profiles are selected for further evaluation: (1) diabetes diagnosed at <
1 year of age; (2) diagnosed with T1DM and having a parent or child with T1DM; (3)
diagnosed with T2DM at <30 years old; (4) diagnosed with T2DM at < 45 years of age and
two or more first- or second-degree relatives diagnosed at < 50 years of age, or (5) presence
of diabetes plus an extrapancreatic feature that may be indicative of a syndrome. Further
evaluation using a combination of laboratory testing (C-peptide and IA-2 antibodies35,36)
and family and medical history elicited by a genetic counselor is used to determine
eligibility for testing using a 40-gene next-generation sequencing panel. Variants detected
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by the sequencing panel are confirmed clinically, and a report is generated and incorporated
into the electronic medical record. Guidance is provided to clinicians regarding treatment
implications, and participants are encouraged to share results and opportunities to be
counseled and tested with at-risk family members. 33

Pharmacogenetics of oral T2DM medications

Individuals with type 2 diabetes make up by far the greatest proportion of the population
with diabetes mellitus. The first-line medication for T2DM is metformin, a biguanide
medication that functions by decreasing gluconeogenesis in the liver. Secondary oral
medications include sulfonylureas, meglitinides, thiazolidinediones, glucose-like peptide-1
(GLP-1) analogs, and dipeptidyl peptidase-4 (DPP4) inhibitors.37 Each of these medication
classes has a different mechanism of action and different molecular interactions, and
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consequently, different genetic variants that affect function. Studies of the genetic variants
that can alter response to oral diabetes medications have generally shown modest effects,
some of which are contradictory. Regardless, these studies represent findings that could
provide information about future pharmacogenetic recommendations for oral T2DM
medications. The etiology-specific treatment recommendations for monogenic diabetes
provide a current model of genetic diagnosis to pharmacological treatment that can be used
for future implementation of pharmacogenetic findings into clinical recommendations.
However, before any of these genetic associations can be implemented into clinical practice,
further studies need to be performed to analyze the effectiveness of a priori genetic testing
on the patient outcomes.

Metformin
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Metformin is the first-line medication for T2DM because of its safety profile as an insulin-
sensitizing agent. However, it has a high variability of efficacy between patients, and it often
needs to be supplemented with secondary agents. Metformins mechanism of action has not
been well defined, and therefore its target molecules have not been analyzed for important
pharmacogenetic variants. However, a large-scale genome-wide association study (GWAS)
discovered that single nucleotide polymorphism (SNP) rs11212617 near the ATM locus was
associated with reduction in HbA1c in response to metformin.38 ATM encodes the ataxia-

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telangiectasia mutated gene, a member of the phosphatidylinositol 3-kinase family important

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for cell cycle control and DNA repair. In a meta-analysis replication of this study, the
association was confirmed, although one of the three cohorts showed no association.39
Finally, the Diabetes Prevention Program (DPP) found that there was no association
between rs11212617 and progression from impaired glucose tolerance to diabetes.40 This
SNP needs further confirmation and exploration for validation and future studies into
metformins mechanism of action.

On the other hand, metformins transport between cell types has been well characterized.
Metformin is actively transported between tissues, but it is not metabolized before excretion.
It is absorbed into the intestinal epithelium through the plasma membrane monoamine
transporter (PMAT encoded by SLC29A4) and the organic cation transporter 3 (OCT3
encoded by SLC22A3). Organic cation transporter 1 (OCT1) transports the metformin
through the basolateral membrane of the epithelium to the bloodstream, and OCT1 is also
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responsible for uptake into hepatocytes. Metformin is transported from the bloodstream into
the renal epithelium through organic cation transporter 2 (OCT2 encoded by SLC22A2).
From there, metformin is excreted into the urine through the multidrug and toxin extrusion
proteins 1 and 2 (MATE1 and MATE2 encoded by SLC47A1 and SLC47A2).41 These
transporters have provided targets for genetic analysis.

The OCT1 gene (SLC22A1) has multiple genetic variants that are associated with decreased
efficacy of metformin. The variants R61C (rs12208357), G401S (rs34130495), G456R
(rs34059508), and 420del (rs72552763) have all been shown to decrease the effectiveness of
metformin, as well as to increase renal clearance, in multiple studies.4245 However, another
study discovered no effects due to the R61C and 420del variants.45 The DPP discovered
another SLC22A1 polymorphism (rs683369 encoding L160F) that affected metformin
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efficacy. The major allele of this variant was associated with a 31% risk reduction in
diabetes incidence in metformin-treated participants, but not in those treated with placebo.46
Variants in SLC47A1 have demonstrated an enhancing effect of metformin treatment. Two
variants, rs2289669 and rs8065082, in linkage disequilibrium with each other, were
separately found to produce these effects. An association between rs2289669 and decreased
level of HbA1c in metformin users was initially observed in a pilot study.47 In another
finding by the DPP, rs8065082 was associated with decreased incidence of T2DM in the
metformin arm but not the placebo arm, validating the study by Becker et al.46 With further
validation, these genetic variants associated with metformin response could be used to
predict the efficacy of metformin treatment in patients before they take the drug.

Sulfonylureas
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Sulfonylureas are insulin secretagogues that act by binding the SUR1 subunit (encoded by
ABCC8) to close the ATP-sensitive potassium inward-rectifying channel, causing membrane
depolarization followed by calcium influx and insulin secretion. The other subunit of the
KATP channel is Kir6.2 (encoded by KCNJ11), which is located within close proximity to
ABCC8 on chromosome 11.48 High-dose sulfonylureas are used to treat NDM caused by
activating mutations in ABCC8 and KCNJ11 (and low-dose sulfonylureas are the first-line
treatment for MODY1 and MODY3). Studies of polymorphisms of these genes have

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discovered a common haplotype of E23K in KCNJ11 and S1369A in ABCC8, which is

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associated with T2DM.49 This haplotype has been shown to be less sensitive to sulfonylurea
inhibition through patch-clamp analysis.50 Separately, both the E23K and S1369A
polymorphisms have disputed associations with T2DM and sulfonylurea efficacy.51,52 Other
genes have also been associated with response to sulfonylureas. TCF7L2, the gene with the
strongest association with T2DM, encodes transcription factor Tcf-4, which plays a role in
cell proliferation through the Wnt signaling pathway. The GoDARTs study found that TT
individuals at rs12255372 of TCF7L2 were less likely to respond to sulfonylurea therapy
than their GG counterparts.53 Likewise, carriers of the common rs1801278 variant in insulin
receptor substrate-1 (IRS-1) have an increased rate of secondary failure to sulfonylureas in
addition to the general increased risk of T2DM associated with the polymorphism.54 These
genetic variations could affect the pharmacological regimens for individuals known to be
carriers.
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In addition to the effects of genetic variants on target genes, variation in the enzymes
responsible for sulfonylurea metabolism also affect drug efficacy. CYP2C9 is the major
metabolizer of the drug class. Two polymorphisms, CYP2C9*2 (I359L) and CYP2C9*3
(R114C) are associated with increased serum sulfonylurea levels.55 There is a risk of
hypoglycemia in carriers of the CYP2C9*3 polymorphism, although studies have also
shown that carriers have an increased capability to reach target HbA1c levels.56 By having
knowledge of CYP2C9 polymorphisms, it may be possible to preemptively adjust
sulfonylurea dosage to avoid hypoglycemic events while still maintaining the effectiveness
of the medication.

Meglitinides
Meglitinides are another class of insulin secretagogues that also act by inhibiting the KATP
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channel to induce depolarization and insulin secretion. However, these medications act in a
much shorter timeframe than sulfonylureas and consequently confer less risk of
hypoglycemia. Meglitinides are rapidly metabolized by the liver.57 The transporter
SLCO1B1 is responsible for uptake into the liver, and the c.521T>C polymorphism has been
shown to decrease the rate of metabolism of meglitinides, but the altered pharmacokinetics
have little physiological effect on glucose levels.58,59 Another gene, KCNQ1, contains
intronic variant rs2237892 associated with repaglinide response. The individuals carrying a
TT phenotype showed improved HOMA-IR and 2-hour glucose response to 48-week
repaglinide therapy, although this effect was lost when accounting for age, gender, and body
mass index.60 Meglitinide metabolism differs between repaglinide (by CYP2C8 and
CYP3A4) and nateglinide (by CYP2C9). Although genetic variants in these metabolizing
enzymes may alter pharmacokinetics of the medications, it does not appear to have major
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effects on the glucose levels of patients.61,62

Thiazolidinediones
Thiazolidinediones (TZDs) are PPAR (peroxisome proliferatoractivating receptor)
activators that act by improving insulin sensitivity and decreasing hyperglycemia by
decreasing circulating free fatty acids. Troglitazone was withdrawn from the market due to
hepatotoxicity, but pioglitazone and rosiglitazone are still available.63 However, these

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medications have associated drug-specific increased risks of fluid retention, heart failure, or
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bladder cancer,64,65 indicating they should be prescribed with caution and careful
examination of the risk/benefit ratio. Individual genotype information may be of great
benefit for this examination, and genetic variants that predispose individuals to these side
effects have already been discovered. The rs296766 T allele of AQP2 (aquaporin 2) and the
rs12904216 G allele of SLC12A1 (sodium/potassium/chloride transporter) are both
associated with edema in patients taking rosiglitazone.66 Regarding the efficacy of TZDs,
the well-studied P12A variant in PPAR- has been associated with decreased fasting blood
glucose and decreased HbA1c in response to rosiglitazone.67 Additionally, carriers of the A
allele of rs6467136 in PAX4 showed improved response to rosiglitazone.68 This is
significant because PAX4 has been associated with T2D through GWAS, and mutations in
the gene can cause MODY type 9. These are also studies indicating that the *3 variant of
CYP2C8, the major metabolizer of TZDs, has decreased insulin response, but these studies
have generally been underpowered.69
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GLP-1 analogs/DPP4 inhibitors

The newest class of oral antidiabetic medications act through the incretin signaling pathway.
These medications include GLP-1 analogs that act as incretin mimetics and DPP4 inhibitors
that stop the degradation of endogenous GLP-1 and gastric inhibitory peptide (GIP).
Promoting incretin signaling induces insulin secretion, inhibits glucagon secretion, reduces
gastric emptying, and decreases appetite.70 Because these medications have been approved
for less than 10 years, there have been relatively few studies on the pharmacogenetics of
incretin mimetics. However, a study in non-diabetic individuals found that SNP rs7202877
regulates expression of the CTRB1 and CTRB2 genes for chymotrypsin, an important
regulator of the incretin pathway.71 There is still a great need for further exploration of
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pharmacogenetics of these new medications.

SLC30A8 and zinc supplementation

An intriguing potential opportunity for translation of T2DM association data to
pharmacogenetic applications is the SNP rs13266634 (R325W) in zinc transporter-8
(encoded by SLC30A8). The zinc transporter was first associated with T1DM as an
autoimmunity antigen. Through candidate assays, it was discovered to also confer risk for
T2DM, which has since been verified through multiple studies.72 Other studies have found
that rs13266634 may confer its risk through geneenvironment interactions with decreased
serum levels of trans--carotene.73 However, a recent clinical trial has shown that
individuals carrying the variant could improve insulin response to glucose with daily zinc
supplementation for as little as 14 days.74 Interestingly, loss-of-function variants in
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SLC30A8 have protective effects from T2DM.75 Overall, SLC30A8 represents an appealing,
albeit complex, target for pharmacogenetic-directed therapy to reduce risk from disease-
associated variants.

Opportunities for Pharmacogenomics

Besides the pharmacogenetic studies determining how drug function is affected by genetic
variants, a complex disease like T2DM presents the opportunity to utilize

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pharmacogenomics for development of novel pharmacologic therapies. In particular, rare

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genetic variants can provide information about the protective or disease state physiology.
The discovery that nonsense mutations in SLC30A8 are protective against T2DM is an
example of a pharmacogenomic finding that could be utilized for pharmaceutical
development.75 By targeting SLC30A8 for downregulation therapeutically, it could confer
the T2DM-protective effects of nonsense variants. APOC3 nonsense variant R19X is
another example of a genetic variant that could lead to future diabetes treatment methods.
The nonsense variant decreases circulating levels of APOC3, leading to decreased levels of
serum triglycerides and protection from coronary disease.76,77 As a result, APOC3 has
become a target for pharmaceutical inhibition in order to prevent hypertriglyceridemia.
Since hypertriglyceridemia is common complication of diabetes and a risk factor for
coronary heart disease, this could a rewarding direction for diabetes drug development.78
These are just a couple examples of how pharmacogenomics can be important for
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developing diabetes pharmacotherapeutics.

The studies presented here represent the beginning phase of personalized diabetes treatment.
In contrast to the current opportunity for personalized medicine in treatment of monogenic
diabetes, the field of personalized diabetes therapeutics for T2DM still needs to mature
greatly before clinical implementation is possible. Currently observed pharmacogenetic
associations are promising but require expansion made possible by falling costs of large-
scale genotyping and sequencing and replication in well-designed clinical trials. Meanwhile,
expanding implementation of the available opportunities for clinical implementation in
monogenic diabetes will provide a model for future implementation of personalized T2DM
medicine.

Genetic interaction with lifestyle factors

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Geneenvironment interaction is the interplay of genetic factors and non-genetic factors to

influence a phenotypic outcome. The pharmaceutical interventions discussed previously are
an example of a non-genetic factor in such an interaction, but another important issue in the
field of diabetes mellitus is the relationship between diabetes-associated genetic variants and
lifestyle. Alteration of lifestyle through diet and exercise change is the first preventive
measure against diabetes onset.37 Some are able to stop the progression toward diabetes,
while others progress despite changing their lifestyle. It would be a powerful tool to
determine if genetic risk variants maintain their associations despite environmental changes
and which ones have altered risk associations due to non-genetic factors. Similarly, gene
environment interaction studies could be used to determine the most effective type of
lifestyle change based on an individuals profile of genetic risk variants. Some studies have
already begun to perform these analyses, as they examined at-risk individuals in their
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progression toward T2DM.

One of the leading studies for measuring geneenvironment interactions is the DPP. This
large multicenter trial studied whether lifestyle modification or metformin therapy was able
to prevent progression to T2DM in individuals with risk factors for the disease. One of the
primary discoveries determined that the environment altered the association with T2DM of
the rs12255372 and rs7903146 SNPs in strong linkage disequilibrium in the TCF7L2 locus.

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It was shown that the risk alleles conferred a stronger effect in the placebo group than in
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either the metformin-treated group or the lifestyle-intervention group.79 This provided

evidence that the genetic predisposition for T2DM could effectively be decreased through
either type of therapy, particularly lifestyle changes. Additionally, the DPP observed
nominally differential improvement of cell function due to troglitazone therapy or lifestyle
changes based on the presence of the protective rs10811661 SNP in the CDKN2A/B locus.80
The DPP study is unique in that it provided large enough sample sizes to have the power to
detect geneenvironment interactions in a prospective study that incorporated lifestyle
intervention.

The Finnish Diabetes Prevention Study (DPS), although not as large as the DPP, was also
able to determine interactions between genetics and environment in progression toward
T2DM. They showed that lower levels of moderate-to-vigorous physical activity in
individuals homozygous for common SNPs in SLC2A2 (rs5393, rs5394, or rs5404) or
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ABCC8 (rs3758947) were 2.63.7 times more likely to progress from impaired glucose
tolerance to T2DM. The DPS also discovered complex interplay of the ADRA2B
polymorphism 12Glu9. They found that carriers of the 12Glu polymorphism had decreased
risk of T2DM in response to increased leisure-time physical activity. However, homozygous
9Glu9 individuals had greater risk reduction due to dietary changes.81 These interesting and
intricate results illustrate the complexity of geneenvironment interactions.

Geneenvironment interactions hold a great deal of promise for explaining more of the
heritability of diabetes mellitus. However, strong studies focusing on this topic have not
been aggressively pursued. This is likely due to the fact that most studies would be
underpowered because of the stratification of sample size by addition of another variable
and multiple hypothesistesting correction. On top of the difficulty of attaining sufficient
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power, it is also extremely difficult to validate findings through replication in different

cohorts because of the difficulty of recreating the same geneenvironment interaction.
Finally, confounders and bias are widespread in attempts to collect large populations with
measured environmental contact, which can create false-positive results. Despite these
challenges, the field is moving forward with techniques such as joint meta-analysis,
selective sampling, and nested case-cohort studies. These topics are further explored in
excellent review articles.82,83

Future prospective
Well-characterized forms of monogenic diabetes already present underutilized opportunities
for personalized medicine. A complex disease such as T2DM presents challenges in
implementation of personalized medicine. There is a growing knowledge base regarding the
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role of genetic variation in T2DM etiology and treatment response; however, the complexity
of this disease (itself in reality a group of diseases), the number of treatment options, and the
limited number of clinical trials providing adequate design and power to detect and replicate
pharmacogenetic associations are obstacles to overcome. Ever-decreasing prices of genetic
sequencing and the growing number of large diabetes research consortia such as Go-T2D,
T2D-GENES, and DIAGRAM and emerging comparative effectiveness trials such as the
Glycemia Reduction Approaches in Diabetes (GRADE) Study (https://

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 Kleinberger and Pollin Page 12

portal.bsc.gwu.edu/web/grade) are expected to provide the necessary data. Once a scientific

Author Manuscript

evidence base is gathered for pharmacogenetic markers, implementation studies will be

needed to determine the most effective way to realistically incorporate testing into medical
care in the context of complex healthcare systems. These unfolding opportunities, in
addition to current implementation of genetic testing for monogenic diabetes, provide a
promising outlook of the future of personalized medicine in diabetes.

Conclusions
The incidence and prevalence of the diabetes mellitus epidemic around the world are
currently at all-time highs. Despite medical advances, many people still suffer high rates of
complications. Through pharmacogenetics, it is possible to usher personalized medicine into
the field of diabetes. Certain types of monogenic diabetes already present an excellent
opportunity to practice personalized medicine. Proper genetic diagnosis and appropriate
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pharmacological treatment of these patients often prevent unnecessary insulin therapy,

simplify and increase efficacy of treatment, and create opportunities for prediction and
personalized treatment of diabetes in family members. Current epidemiological studies are
also pushing forward the field of pharmacogenetics of more genetically complex forms of
T2DM. Although more work needs to be performed, there are already promising examples,
such as zinc supplementation for rs13266634 risk allele carriers in SLC30A8.
Pharmacogenomic discoveries, like the SLC30A8 and APOC3 loss-of-function mutations,
are providing physiological models that can be mimicked in the drug discovery process.
Finally, the emerging field of geneenvironment interactions will progress to provide
information about how individuals can tailor their environment to either complement or
subvert their genetic predispositions. Many of these exciting developments in the field of
personalized medicine for diabetes will likely translate into clinical practices to individualize
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therapy that will improve the patient experience and public health.

Acknowledgments
Funding provided by the NIH (U01 HG007775) as part of the IGNITE Network, and by NIH R01 DK72041 and
R01 NIH HL104193.

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