REVIEW OF THERAPEUTICS

Using Personalized Medicine in the Management of

Diabetes Mellitus

Nina Elk1* and Otito F. Iwuchukwu2

1
Division of Pharmacy Practice, Fairleigh Dickinson University School of Pharmacy, Florham Park, New Jersey;
2
Division of Pharmaceutical Sciences, Fairleigh Dickinson University School of Pharmacy, Florham Park, New
Jersey

Diabetes mellitus is a worldwide problem with an immense pharmacoeconomic burden. The multifac-
torial and complex nature of the disease lends itself to personalized pharmacotherapeutic approaches
to treatment. Variability in individual risk and subsequent development of diabetes has been reported
in addition to differences in response to the many oral glucose lowering therapies currently available
for diabetes pharmacotherapy. Pharmacogenomic studies have attempted to uncover the heritable com-
ponents of individual variability in risk susceptibility and response to pharmacotherapy. We review
the current pharmacogenomics evidence as it relates to common oral glucose lowering therapies and
how they can be utilized in the management of polygenic and monogenic forms of diabetes. Evidence
supports the use of genetic testing and personalized approaches to the treatment of monogenic dia-
betes of the young. The data are not as robust for the current application of pharmacogenetic
approaches to the treatment of polygenic type 2 diabetes mellitus, but there are suggestions as to
future applications in this regard. We reviewed pertinent primary literature sources as well as current
evidence-based guidelines on diabetes management.
KEY WORDS pharmacogenomics, diabetes, monogenic diabetes syndrome, maturity-onset diabetes of
the young, oral glucose lowering agents.
(Pharmacotherapy 2017;37(9):1131–1149) doi: 10.1002/phar.1976

Diabetes mellitus (DM) presents a significant
public health problem worldwide and is recog-
nized as a cause of premature death and disabil-
ity.1 According to the World Health Organization’s
The authors, employees of Fairleigh Dickinson Univer-
sity School of Pharmacy, certify that they have no affilia-
tions with or involvement in any organization or entity
with any financial interest (such as honoraria; educational
grants; participation in speakers’ bureaus; membership,
employment, consultancies, stock ownership, or other
equity interest; and expert testimony or patent-licensing
arrangements), or nonfinancial interest (such as personal or
professional relationships, affiliations, knowledge or beliefs)
in the subject matter or materials discussed in this manu-
script.
*Address for correspondence: Nina Elk, School of Phar-
macy, Fairleigh Dickinson University, 230 Park Avenue,
M-SP1-01, Florham Park, NJ 07932; e-mail: NinaElk@fdu.edu.
Ó 2017 Pharmacotherapy Publications, Inc.
Global Report, the number of people diagnosed
with DM worldwide has been increasing, reaching
422 million adults in 2014 and causing 1.5 million
deaths.2 In the United States, although newly diag-
nosed cases of DM are declining, DM remains at
an all-time high with 29 million diagnoses
reported for 2016 (https://www.cdc.gov/chronicdis
ease/resources/publications/aag/diabetes.htm). DM
was the seventh leading cause of death in 2013,
and data indicate that patients with diabetes are
twice as likely to develop cardiac complications at
a younger age compared with people who do not
have the disease.3 The economic burden of DM
remains high. Direct and indirect costs stand at
$245 billion and cost of medical expenditures for
individuals with DM at $17,000 annually, which is
reportedly 2.3 times greater than for those without
DM.4
1132 PHARMACOTHERAPY Volume 37, Number 9, 2017
Prevention of DM, early diagnosis, and delay
of disease progression are critical measures to
avoid life-threatening complications. Current
guidelines emphasize the importance of personal-
ized care for patients with DM and recommend
use of patient-specific pharmacotherapy
approaches to treatment.5 An algorithmic
approach to the management of DM incorporates
steps such as identification of diabetes type, gly-
cemic target selection, use of medications based
on proven efficacy, and side-effect profiles.5
In addition, addressing comorbidities attributing
to cardiovascular diseases and counseling
patients on a healthy lifestyle are components of
personalized care for diabetes management.
Genetic findings in DM risk assessment, patho-
physiology, disposition, and efficacy of drugs
used in DM allow expanding the definition of
patient-specific therapy (Figure 1). This article
reviews the genetic findings in pathophysiology
and risk association of DM and pharmacogenet-
ics of common oral glucose lowering agents, fol-
lowed by a discussion of a pharmacogenomic
contribution to personalized therapy.
Pharmacogenomic Landscape of Diabetes
Mellitus
Although DM is classified into four general
categories based on pathophysiology, further
differentiation based on genetic components is
possible (Table 1). For the remainder of this
section, we focus on the polygenic type 2 DM
(T2DM) with some discussion on the monogenic
forms of diabetes that include maturity-onset
diabetes of the young (MODY) and neonatal dia-
betes mellitus (NDM).
Figure 1. Factors to consider when designing diabetes
mellitus (DM) treatment regimen.
Type 2 Diabetes Mellitus: A Polygenic,
Multifactorial Disease
T2DM is the most prevalent type of diabetes,
and its polygenicity is supported by many lines
of evidence showing both a distinct familial
aggregation and a lack of Mendelian segrega-
tion.6 Pathophysiology of T2DM involves multi-
ple abnormalities in the regulation of glucose
homeostasis (Figure 2). The search for suscepti-
bility risk genes involved in the pathophysiology
of T2DM and its observed phenotypes has been
ongoing for decades. Several strategies that have
been used include linkage, candidate gene, gen-
ome, and exome-wide association studies.9
Newer approaches, such as the reverse genetics
phenome-wide approach of surveying clinically
validated phenotypes with variants in known
susceptibility genes, have also been used to vali-
date diabetes-linked genes and pathways.10
Candidate gene studies (CGS) focus on genes
related to the disease in question and a priori
knowledge of any mechanistic roles in the dis-
ease pathway. Genes involved in glucose home-
ostasis, specifically those encoding pathways of
insulin production, secretion, and response
(such as the insulin receptor [INSR], glycogen
synthase 1 [GYS1], glucose transporter 4
[GLUT4], and insulin receptor site-1 [IRS-1])
were the main focus of T2DM CGS.11, 12 Overall,
CGS contribution to valid genetic associations in
T2DM was limited and sometimes not repro-
ducible due to the pleiotropic nature of the dis-
ease, small sample sizes, high genotyping costs,
and low genetic signal throughput. Despite these
shortcomings, CGS led to the identification of
common variants in confirmed susceptibility
genes such as peroxisome proliferator-activated
receptor gamma (PPAR-c) and KCNJ11 encoding
the inwardly rectifying Kir6.2 component of the
b-cell adenosine triphosphate (ATP)-sensitive
potassium channel (KATP channel).13
Genome-wide association studies (GWAS) are
comprehensive studies that use an unbiased and
hypothesis-free approach to interrogate the
whole genome for associations between genetic
variants and observed phenotypes.7 Because
GWAS are a special type of case-control studies
where individual genomes of subjects with dis-
ease (cases) are scanned for genetic markers dif-
fering in frequency from control subjects, there
is potential power to discover novel genetic loci
underlying predisposition to and development of
T2DM.7 Some limitations (small sample size,
low throughput) of diabetes CGS were overcome
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu 1133
Table 1. Differentiation of Diabetes Mellitus Types5–8
DM type Prevalence Pathophysiology Genetic component
Type 1 5–10% Autoantibodies to pancreatic Mostly associated with genetic
islet cells and insulin are variation of HLA association
present that cause pancreatic genes responsible for immune
b-cell destruction leading to system response and pancreatic
insulin deficiency. b-cell function. Other genes are
linked to type 1 DM.a
Type 2 90–95% Increase in glucose production Mutations in specific genes
by the liver, insulin resistance associated with disorders
in target tissues, and dysfunction of glucose homeostasis.
of pancreatic b cells in the
pancreas causing impairment
of insulin secretion.
Monogenic diabetes <5% Insulin is produced but not Mutations in a gene that
syndrome: NDM secreted through KATP channels encodes KATP channels in
in pancreatic b cells. pancreatic b cells.
Monogenic diabetes <5% In MODY 1 and MODY 3, Mutations in the gene that
syndrome: MODY hyperglycemia is present due encodes HNF4a in MODY 1
to partial pancreatic b-cell dysfunction. and HNF1a in MODY 3
In MODY 2, hyperglycemia Mutations in the gene that
is due to dysfunction of encodes GCK and several
glucose-level monitoring by transcription factors relevant
pancreatic b cells. to pancreatic b-cell development.
DM = diabetes mellitus; GCK = glucokinase; HLA = human leukocyte antigen; HNF = hepatocyte nuclear factor; KATP channel = ATP-sensi-
tive K+ channel; MODY = maturity-onset diabetes of the young; NDM = neonatal diabetes mellitus.
a
For a complete list of genes associated with type 1 DM, visit https://ghr.nlm.nih.gov/condition/type-1-diabetes#.

with GWAS, and due to the high-powered nat-
ure of this approach, many genetic loci were
both discovered and/or validated.11, 14 The initial
set of GWAS studies on diabetes was published
a decade ago, and about a dozen loci were
strongly associated with T2DM risk across these
studies.15 Indeed, the strongest genetic signal(s)
associated to date with diabetes susceptibility
was found with single nucleotide polymorphisms
(SNPs) in the transcription factor 7-like 2
(TCF7L2) gene. This loci was discovered by
whole-genome microsatellite marker analysis in
a cohort of ~1000 Icelandic subjects16 and sub-
sequently validated and replicated in T2DM
GWAS.14, 17 The protein encoded by TCF7L2 is
a high-mobility group box containing transcrip-
tion factor postulated to affect diabetes risk
through pancreatic b-cell dysfunction via the
Wnt signaling pathway.16 Other validated signals
reported include SNPs in the KCNJ11, PPAR-c,
Fat Mass and Obesity (FTO) associated genes15
(Table 2). At the time of last access, the publicly
available NHGRI-EBI Catalog of published
GWAS18 lists over 157 studies on diabetes with
more than 1500 associations at genome-wide
significance levels (p=5 9 10
8). One limiting
assumption of the GWAS approach is that
genetic variants conferring disease susceptibility
are common (more than 5% frequency) in the
studied populations,14 an assumption that has
not held true with T2DM. It was postulated that
only a fraction of heritability was attributable to
common variants and that combinations of rare
alleles of small effect size were more likely to
explain a greater fraction of T2DM heritability.19
This rare variant hypothesis is still unproven. A
very recent study by two of the largest diabetes
GWAS consortia concluded that large-scale
sequencing did not support the idea of a major
role of lower frequency rare variants in predis-
position to T2DM.17
Monogenic Diabetes Syndrome
The monogenic diabetes syndrome covers a
heterogeneous group of single-gene autosomally
inherited diabetes that cannot be classified as
type 1 or type 2 DM. The syndrome can be fur-
ther divided into two main forms, MODY and
NDM.
Maturity-Onset Diabetes of the Young
MODY (unlike polygenic T2DM) arises from
monogenic defects in pancreatic b-cell function
with little or no defect in insulin action. The clini-
cal features of MODY include autosomal domi-
nant inheritance, early onset (before age 25),
absence of obesity, and evidence of b-cell function
as seen with endogenous insulin secretion.20 Cur-
rently ~13 different types of MODY (1–14) exist,
associated with abnormalities in more than six
1134 PHARMACOTHERAPY Volume 37, Number 9, 2017

Figure 2. Schematic presentation of type 2 diabetes mellitus (T2DM) pathophysiology. Pathophysiology of T2DM involves
deficiency of insulin action that leads to hyperglycemia and inability to maintain glucose homeostasis. Deficiency of insulin
action may be due to decrease in amount of insulin secreted by islet cells of the pancreas, insulin resistance with skeletal
muscles’ inability to uptake glucose for utilization, or a combination of both. Decreased insulin secretion results from b-cell
dysfunction, decrease in b-cell mass, and reduced action of glucagon-like peptide 1 hormone that is involved in insulin
secretion. Insulin resistance linked to obesity is due to a decreased number of insulin receptors, increased fatty acids, and
triglycerides in adipose tissue interfering with insulin action, as well as causing an increase in production of glucose by the
liver. Disease progresses with unresolved hyperglycemia, increase in gluconeogenesis, and loss of b-cell function.

different loci on different chromosomes and sub-
classified by the deficient gene causing the
observable phenotype.21 MODY makes up ~1–4%
of all pediatric DM cases, and because presenting
characteristics include those associated with
either T1DM (early onset, lean body mass) or
T2DM (preserved b-cell function, familial aggre-
gation), misdiagnosis is common.22, 23
MODY 1, 2, and 3 are the most well character-
ized of all MODY subtypes. MODY 1 makes up
~10% of cases in characterized cohorts of MODY
subjects.21 It is caused by mutations in HNF4a,
encoding the transcription factor hepatocyte
nuclear factor 4-a.22 A defect in a similar modi-
fier gene, HNF1a, is responsible for the most
common subtype MODY 3 that together with
MODY 2 makes up ~50% of all cases.21 These
hepatic transcription factors promote the tran-
scription of multiple genes related to glucose
metabolism and insulin production and secretion.
MODY 2 is due to mutations in the glucoki-
nase (GCK) gene, causing decreased function of
glucokinase, the enzyme responsible for blood
glucose level homeostasis in pancreatic b cells.20
The resultant impaired hepatic cell glucose
phosphorylation is responsible for the very mild
hyperglycemia observed in patients with
MODY 28, 22 (Table 3).
Neonatal Diabetes Mellitus Syndrome
NDM syndrome is a rare form of diabetes pre-
senting within the first 6 months of life. Infants
with NDM do not produce enough insulin, lead-
ing to increased blood glucose levels. In about
half of presenting patients, the condition persists
and is termed permanent neonatal diabetes mel-
litus (PNDM). In the other half of cases, the
condition disappears during infancy and is ter-
med transient neonatal diabetes mellitus
(TNDM). NDM has a number of genetic causes
attributed to it including variations in genes
such as KCNJ11, ABCC8, GCK, INS, and
ZFP57.23–26 The most common causes are muta-
tions in KCNJ11 and ABCC8, the two genes
encoding different subunits of the ATP-depen-
dent potassium channel in pancreatic islet b
cells. These mutations serve to decrease insulin
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu 1135
Table 2. Selected Genes and Single Nucleotide Polymorphisms Associated with Insulin Action or b-Cell Function in
T2DM Risk/Susceptibility GWAS
Overall Postulated
Gene Chromosome rs number odds ratio Function mechanism Year
ADAMTS911, 14
3 rs4607103 1.09 Secreted Insulin action 2008
metalloproteinase
ADCY514 3 rs11708067 1.12 Adenylyl cyclase Insulin action 2010
BCAR114, 17
16 rs7202877 1.12 Docking protein Regulation of 2012
b-cell function
BCL11A14, 17
2 rs243021 1.08 Zinc finger protein Regulation of 2010
b-cell function
CCND217 12 rs76895963 0.53 Cyclin D2 Cell cycle 2014
regulator/Enhanced
insulin secretion
CDKAL19, 11, 14, 17
6 rs7754840 1.15 Methylthiotransferase Regulation of 2007
b-cell function
CDKN2A/B9, 11, 14, 17
9 rs7754840 1.20 Cyclin-dependent Regulation of 2007
kinase inhibitor b-cell function
FTO9, 11, 14, 17
16 rs8050136 1.27 Fat Mass and Obesity Insulin action 2007
Associated/Nucleic
acid demethylase
GCKR11, 17
2 rs780094 1.08 Glucokinase Insulin action 2007
regulator protein
HHEX/IDE 9, 11, 14, 17
10 rs1111875 1.15 Transcriptional repressor Intracellular 2007
insulin degradation
IGF2BP29, 11, 14, 17
3 rs4402960 1.17 Insulinlike growth factor Regulation of 2007
II mRNA-binding protein b-cell function
IRS111, 14, 17 2 rs2943640 1.12 Docking/binding protein Insulin action 2009
JAZF19, 11, 14, 17
7 rs864745 1.10 Zinc finger protein Regulation of 2008
b-cell function
KCNJ1111, 17
11 rs5219 1.14 Inwardly rectifying Regulation of 2003
potassium channel Kir6.2 insulin secretion
KCNQ1 9, 11, 14, 17 11 rs2237892 1.23 Potassium channel b-cell function 2008
NOTCH2 9, 11, 14, 17 1 rs10923931 1.13 Transmembrane receptor Pancreatic 2008
cell development
9, 11, 14, 15, 17
PPAR-c 3 rs1801282 1.11 Peroxisome Regulation 2000
proliferator-activated of insulin action
receptor
SLC30A8 9, 11, 14, 17
8 rs13266634 1.15 b-cell zinc efflux transporter Insulin storage 2007
and secretion
TCF7L214, 15
10 rs7903146 1.4 T-cell transcription factor b-cell function 2006
TSPAN8 9, 11, 14, 17
12 rs7961581 1.09 Cell surface glycoprotein b-cell function 2008
GWAS = genome-wide association study; rs = reference sequence. Note: The rs numbers indicate the reference single nucleotide polymor-
phism (SNP) cluster ID used for identification within the SNP public archive database (https://www.ncbi.nlm.nih.gov/projects/SNP/). All
GWAS are documented in the Catalog of Published Genome-Wide Association Studies (http://www.ebi.ac.uk/gwas).

secretion by preventing membrane depolariza- Metformin

tion (Table 3).
Pharmacogenetic-Based Associations for
Common Oral Glucose Lowering Therapies
Various agents are available for the treatment
of DM. They differ in their mechanisms of action
and efficacy, and ability to attain DM treatment
goals such as prevention of macrovascular and
microvascular complications. In addition, antihy-
perglycemic agents are classified by their propen-
sity to cause side effects that have a negative
impact on DM disease state treatment5, 27
(Table 4).
Metformin belongs to the biguanide class of
oral glucose lowering therapies (OGLTs).
Although many aspects of metformin’s action are
still not well established, it has been postulated
to exert its glucose-lowering effects by many
pleiotropic mechanisms.28 One major hypothesis
is metformin-induced activation of AMP-acti-
vated protein kinase (AMPK).29 In addition,
metformin prevents hyperglycemia by decreasing
intestinal glucose absorption and increasing
peripheral glucose uptake and utilization.30 The
glucose-lowering effect of metformin is highly
variable, with 35% of patients failing to achieve
initial decreases in hemoglobin HbA1c.31 About
 1136

Table 3. Common MODY Subtypes, Phenotypes, and Select Associated Genetic Mutations
Implicated gene Frequency in
Subtypea (affected protein) Mutationsb Chromosome MODY patients Age at diagnosis Pathophysiology Phenotype
MODY 120–23 HNF-4a Naturally occurring, 20 5% Adolescence/Early Transcription Neonatal
(Hepatocyte Heterozygous (Q268X, adulthood factor (b-cell hyperinsulinism,
Nuclear Factor 4a) R154X, R127W) function in pancreas) diabetes
20–23
MODY 28, GCK (Glucokinase) Heterozygous (A378T, 7 10–60% Birth to early Hexokinase (glucose Mild hyperglycemia
E339K) childhood sensor in pancreas
and liver)
MODY 320–23 TCF1 or HNF-1a Heterozygous (291 + C) 12 30–60% Adolescence/Early Transcription factor Diabetes
(Hepatocyte adulthood (b-cell function in
Nuclear Factor 1a) pancreas and kidney)
MODY 420–23 IPF1 or PDX1 Heterozygous 13 <1% Early adulthood Transcription factor Diabetes
(Insulin Promoter (Pro63fsdelC) (b-cell function
Factor 1) in pancreas)
MODY 520 TCF1 or HNF-1b Heterozygous 17 3–10% Adolescence/Early Transcription factor Diabetes
(Hepatocyte (E101X, delT) adulthood (b-cell function
Nuclear Factor 1b) in pancreas)
MODY 620 NEUROD1 Heterozygous 2 Very rare Later in life Transcription factor Diabetes
(Neurogenic (206 + C) (b cell function in
Differentiation factor 1) pancreas and kidney)
23–26
TNDM20, ZAC, ABCC8, Heterozygous Rare Birth to 6 mo Transient
KCNJ11, HNF-1b diabetes
23–26
PNDM20, KCNJ11, ABCC8, Heterozygous, Rare Birth to 6 mo Permanent
GCK*, IPF1*, *Homozygous diabetes
MODY = maturity-onset diabetes of the young.
a
PHARMACOTHERAPY Volume 37, Number 9, 2017

MODY subtypes 1–14 have been characterized at the genetic level, but only subtypes 1–6 have clinically defined phenotypes. MODY 7–14 are very rare heterozygous single-point mutations
typically occurring in early childhood/adolescence.
b
Mutations are select representative variants listed for studies of affected patients in the Online Mendelian Inheritance in Man database at https://www.omim.org. Because MODY is a relatively
rare type of diabetes, not all mutations listed in the table are represented in all MODY patients.
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu 1137
Table 4. Classification of Oral Medications Used in Diabetes Mellitus Treatment5, 27

Mechanism of Mechanism of HbA1c % Hypoglycemia Weight

Drug class Drugs action: cellular action: physiologic decrease risk effect
Biguanides* Metformin Activate AMPK, which Cause decrease in 1.0–1.5 Neutral Slight
then increase hepatic glucose loss
intracellular AMP production and intestinal
absorption of glucose;
improve insulin sensitivity
Sulfonylureas* Glyburide Close KATP channels Stimulate insulin release 0.8 Moderate Gain
Glipizide on pancreatic b-cell from b cells; reduce to severe
Glimepiride plasma membranes glucose output from
the liver, increase
insulin sensitivity
Meglitinides Repaglinide Close KATP channels Stimulate insulin release 0.7 Mild to Gain
Nateglinide on pancreatic b-cell from pancreatic b cells moderate
plasma membranes
Thiazolidinedione* Pioglitazone Activate the nuclear Improve target cell 0.8 Neutral Gain
Rosiglitazone transcription factor response to insulin
PPAR-c
a-Glucosidase Acarbose Inhibit intestinal Slow intestinal 0.6 Neutral Neutral
inhibitors Miglitol alpha-glucosidase carbohydrate
enzyme digestion/Absorption
DPP-4 inhibitors Sitagliptin Inhibit DPP-4 Glucose-dependent 0.7 Neutral Neutral
Saxagliptin activity, increasing increase in insulin
Linagliptin postprandial secretion and
Alogliptin active incretin decrease in glucose
(GLP-1, GIP) production
concentrations
SGLT2 inhibitors Canagliflozin Inhibit SGLT2 in the Block glucose 0.7–1.0 Neutral Loss
Empagliflozin proximal nephron reabsorption
in kidneys
GLP-1 Exenatide Activate GLP-1 Glucose-dependent 1 Neutral Loss
receptor agonists Liraglutide receptors increase in insulin
Albiglutide secretion and
Dulaglutide decrease in glucagon
secretion; slow gastric
emptying and increase
satiety
Amylin mimetics Pramlintide Activate amylin Decrease in glucagon 0.3 Severe Loss
receptors secretion; slow down
gastric emptying
and increase satiety
AMPK = AMP-activated protein kinase; DPP-4 = dipeptidyl peptidase-4; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide
1; KATP = ATP-sensitive K+ channel; PPAR-c = peroxisome proliferator-activated receptor gamma; SGLT2 = sodium-glucose cotransporter-2.
*Medications marked with an asterisk have evidence of a pharmacogenetic component.

a third of patients fail to achieve adequate glyce-
mic control on initial metformin monotherapy,
and over time many patients become less sensi-
tive (responsive) to its glucose-lowering
effects.32 The genetic contribution to this vari-
ability in response has been studied with a focus
on the pharmacokinetics (PK) and pharmacody-
namics (PD) of metformin.
Metformin: Pharmacokinetics/Pharmacodynamics
Metformin is not metabolized upon ingestion;
rather, it is actively transported into various tis-
sues and cleared by renal excretion. Metformin
is taken up into the intestinal cells by plasma
monoamine transporters, or PMAT (SLC29A4),
taken up into the bloodstream by the organic
cation transporter OCT1 (SLC22A1) that is also
responsible for its active hepatic uptake.28 Sub-
sequent secretion from the blood into the renal
tubular cells is mediated by another organic
cation transporter, OCT2 (SLC22A2). Final
excretion into the urine is mediated by two
transporters in the multidrug and toxin extru-
sion family, MATE1 and MATE2 (SLC47A1 and
SLC47A2) (Figure 3).28
Metformin: Evidence of Pharmacogenetic Associa-
tions
Although PD targets of metformin are not
well established, the pharmacogenetics of the
1138 PHARMACOTHERAPY Volume 37, Number 9, 2017

Figure 3. Schematic presentation of pharmacogenomics of metformin. Metformin is absorbed in the small intestine via
plasma monoamine transporters (PMATs) encoded by SLC29A4 and is taken up into the bloodstream by an organic cation
transporter (OCT1) encoded by the SLC22A1 gene that is also responsible for active hepatic uptake. Metformin is secreted
from the blood to tubular cells by the organic cation transporter (OCT2) encoded by the SLC22A2 gene. Finally, metformin
is excreted into the urine via multidrug and toxin extrusion family transporters MATE1 and MATE2 that are encoded by
genes SLC47A1 and SLC47A2, respectively.

metformin PD-based response have been
explored using both CGS and GWAS
(Table 5).33 One of the most promising results
was seen in the Genetics of DARTS (GoDARTS)
study. GoDARTs was a large-scale study with
1024 T2DM patients on metformin, a subset
from 3200 metformin-treated patients from the
parent U.K. Diabetes Audit and Research in
Tayside Scotland (DARTS) study.53 DARTS
aimed to identify all diabetes patients in the
Tayside community using electronic record
linkage of multiple data sources and compare
ascertainment of cases with that of primary care
registers.53 Subjects in the GoDARTs substudy
consented to have their genomes interrogated.39 In
this GWAS, the strongest association with
metformin response was found with an intronic
variant (rs11212617) near a candidate gene,
ATM, or the ataxia telangiectasia mutated gene
that encodes a serine/threonine kinase.39 The
minor C allele of rs11212617 was associated
with successful treatment outcomes on met-
formin, defined as a reduction in HbA1c and an
ability to reach treatment target HbA1c values
of 7% or lower.39 It has been postulated that
mutations in the ATM gene may affect
upstream regulation of AMPK and alter glyce-
mic response to metformin.39
The rs11212617 when studied in three other
different cohorts supported the positive
association between the minor C allele and met-
formin response,37 an association further con-
firmed in meta-analyses of the three cohorts
alone and in combination with two previously
published studies.37 The Diabetes Prevention
Program (DPP), another large T2DM cohort
study, failed to show an association between this
top ATM variant and metformin effect in delay-
ing progression to diabetes from impaired glu-
cose tolerance.40 These differences are most
likely due to the different phenotypes (predia-
betes and overt diabetes) and study outcomes
(impact on diabetes incidence and ability to
reach treatment goals) in DPP and the other
studies.
PK studies seeking to explain differences in
metformin exposure and response mainly focused
on variations in genes coding for OCT1, OCT2,
and MATE1.30, 33, 38, 54 Multiple genetic variants
in SLC22A1 have been associated with decreased
metformin efficacy and increased renal clear-
ance.34, 54 The GoDARTS study did not replicate
associations between two common SLC22A1 vari-
ants (rs12208357, rs72552763) and glycemic
response.35 The DPP study discovered a novel
SLC22A1 variant (rs683369) associated with a
31% decrease in diabetes incidence risk in met-
formin-treated patients and also validated
SLC47A1 variants that were previously associated
with increased response to metformin (Table 5).33
Table 5. Select PK-PD Based Genotype-Phenotype Associations for Most Commonly Studied Oral Glucose Lowering Therapies in T2DM Patients
Drug Gene Variant Study outcomes Effect
Biguanides SLC22A1 (OCT1)33–36 rs622342 HbA1c 0.58% reduction in HbA1c for CC
(metformin) homozygotes
rs628031 (M408V) HbA1c No significant effect
rs35167514 (M420del) HbA1c No effect
rs12208357 (R61C) HbA1c No effect
metformin steady-state Gene dose effect: Decreasing AUC and
levels and decrease in pharmacodynamic effects at 6 and
HbA1c 24 mo corresponding
to number of OCT1 reduced function
alleles
rs12208357 (R61C), Gastrointestinal side 2-fold higher odds of gastrointestinal
rs35167514 (M420del) effects effects in individuals with OCT1
reduced function alleles
rs683369 T2DM prevention Nominal association with diabetes
prevention
rs622342 HbA1c No effect
37, 38
SLC22A2 (OCT2)33, rs316019 (G808T) Metformin steady-state No effect
levels and decrease in
HbA1c
rs662301 T2DM prevention Nominal association with diabetes
prevention
36, 37
SLC47A1 (MATE1)33, rs2289669 HbA1c Increased reduction in HbA1c levels
rs2252281 HbA1c Increased reduction inHbA1c levels for
homozygous CC patients
rs12943590 HbA1c Decreased in HbA1c reduction for
AA homozygotes
rs34399035 Metformin steady-state No effect
levels and decrease
in HbA1c
39, 40
ATM37, rs11212617 HbA1c Increased reduction in HbA1c and
increased treatment success
T2DM prevention No effect on time to progression to
diabetes

(continued)
PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu
1139
Table 5 (continued) 1140

Drug Gene Variant Study outcomes Effect

41–44
Sulfonylureas CYP2C9 rs1057910 Hypoglycemia Increased risk of hypoglycemia with
variant allele
rs1057910, rs1799853 Hypoglycemia Heterozygous and homozygous variants
more common in SU-treated patients
with hypoglycemia
rs1057910, rs1799853 Fasting blood glucose, Increased lowering of fasting plasma
SU dose requirements glucose, increased tolbutamide dose
reduction between dose 1 and 10 for
variant alleles
rs1057910, rs1799853 HbA1c Increased reduction in absolute HbA1c
levels
rs1057910, rs1799853 Hypoglycemia No overrepresentation of variant alleles
in SU-treated patients with
hypoglycemia
rs1057910, rs1799853 Time to stable dose No significant effects with variant alleles
37, 45–47
ABCC836, rs757110 HbA1c, fasting plasma G allele carriers had greater HbA1c
glucose reductions compared to the TT
homozygotes
HbA1c, fasting plasma Greater reductions in fasting plasma
glucose glucose and HbA1c with heterozygous
and homozygous variant alleles
Severe hypoglycemia No effect
KCNJ1141–44 rs5219 HbA1c, fasting plasma Significantly associated with greater
glucose decreases in fasting plasma glucose
HbA1c Greater HbA1c reduction in variant
allele carriers vs wild-type
homozygotes
Secondary failure
HbA1c, severe Variant allele associated with increased
hypoglycemia HbA1c levels and was less frequent in
SU-treated patients with severe
hypoglycemia vs controls
PHARMACOTHERAPY Volume 37, Number 9, 2017

SU response No effect
49
TCF7L248, rs12255372, rs7903146 HbA1c <7% Increased risk of treatment failure with
variants alleles
rs7903146 HbA1c <7% Increased risk of treatment failure with
variant allele
HbA1c and fasting Less HbA1c reduction and fasting plasma
plasma glucose glucose levels with variant alleles
reduction compared with wild-type alleles

(continued)
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu 1141

Sulfonylureas

both SNPs, Less reduction in HbA1c for

decreases in fasting plasma glucose and

Greater HbA1c reduction but not weight

gain after rosiglitazone. No association

gain after rosiglitazone. No association

plasma levels of rosiglitazone, reduced
therapeutic response, and a lower risk

Decrease in fasting plasma glucose for

Less reduction in HbA1c, less weight
Sulfonylureas (SUs) are insulin secretagogues

Variant alleles associated with lower

homozygote variants of rs2241766

shown to be efficacious in the treatment of
Variant allele carriers had greater

T2DM by producing favorable lowering effect of

HbA1c and are recommended to be used in com-
bination with other agents for better blood glu-
Effect

of developing edema cose control.55 SUs bind to their target site on

AUC = area under the curve; Hb = hemoglobin; rs = reference sequence; SNP = single nucleotide polymorphism; SU = sulfonylurea; T2DM = type 2 diabetes mellitus.
pancreatic b islet cells, the sulfonylurea receptor
with pioglitazone

with pioglitazone
type 1 (SUR1), encoded by ABCC8, a member of
the ATP binding cassette gene superfamily.56, 57
When SUs bind to SUR1, it results in closing of
HbA1c

the pancreatic b-cell KATP channel, causing

membrane depolarization and triggering calcium
influx with subsequent exocytosis of insulin-
containing vesicles and increased insulin
secretion.57
Fasting plasma glucose,

HbA1c, fasting plasma

Rosiglitazone steady-
state levels, HbA1c,
Study outcomes

HbA1c, weight gain

HbA1c, weight gain

HbA1c reduction

Sulfonylureas: Pharmacokinetics/Pharmacodynamics
edema risk

The PK and PD responses of SUs are well

characterized. SUs undergo extensive and vari-
glucose

able hepatic metabolism by cytochrome P450

2C9 (CYP2C9). Polymorphisms in CYP2C9 were
shown to be one of the reasons behind the vari-
ability in elimination rates for most SUs.58 Two
CYP2C9 reduced function variants of interest,
rs11572080, rs10509681

CYP2C9*2 (rs1799853) and CYP29*3

rs2241766, rs1501299

(rs1057910), are associated with decreased clear-

ance and increased area under the curve (AUC)
Variant

of SUs in healthy volunteers.36

Response to SU therapy depends on b-cell
rs11572080
rs1801282

rs4149056

function, PK differences among patients, and

current T2DM status. Interpatient variability in
response to SU treatment is observed with fail-
ure of therapy and the incidence of hypo-
glycemia. Primary failure with SUs is reported in
10–20% of patients and secondary failure in 5–
7% of patients.56 Evidence from trials shows that
hypoglycemia develops in 31% of patients within
the first year of starting SU, progressing to 38%
of patients at 5 years of therapy.31, 59 Accord-
Gene

ing to one meta-analysis, the incidence of severe

SLCO1B151

hypoglycemia in SU-treated patients was 0.8%.60

ADIPOQ52
CYP2C851
50
PPAR-c

Sulfonylureas: Evidence of Pharmacogenetic Associ-

ations
The largest pharmacogenetics-based clinical
Table 5 (continued)

Thiazolidinediones

study to date was the GoDARTS study with

1073 patients, half of whom were on SU
monotherapy and half on dual therapy (SU and
metformin).41 In this study, patients with two
copies of the CYP2C9*2 or *3 alleles were 3.4
Drug

times more likely to achieve target treatment

1142 PHARMACOTHERAPY Volume 37, Number 9, 2017

HbA1c levels of less than 7% compared with
patients with two copies of the wild-type
CYP2C9*1 allele. Variant allele carriers were less
likely to experience treatment failure with SU
monotherapy.41 Reports were published on asso-
ciations between CYP2C9 genotypes and the risk
of hypoglycemia.42, 43 An initial study showed
an odds ratio of 5.2 for the *2/*3 and the *3/*3
genotypes for risk of SU-induced severe hypo-
glycemia,43 but a subsequent 10-year follow-up
study did not corroborate these findings.44
Although confirming the role of CYP2C9 in SU
metabolism, the GoDARTS study and other stud-
ies41, 43, 44 also emphasize that determination of
CYP2C9 genotype may not be sufficient itself to
predict SU response. Translating these PK gene-
based studies to clinical outcomes, such as fast-
ing serum glucose levels and hypoglycemia,
showed only modest effects due most likely to
limited sample size and lack of statistical power.
For the PD of SUs, initial CGS studies focused
on the ABCC8 and KCNJ11 genes encoding
SUR1 and Kir6.2, the different subunits of the
pancreatic b-cell KATP channels based on a
priori knowledge of their association with dia-
betes (Figure 4).45, 46, 61 Results were consistent
for variants previously associated with T2DM:
E23K (rs5219) in KCNJ11 and S1369A
(rs757110) in ABCC8, two tightly linked vari-
ants occurring together as a haplotype due to
linkage.62 This haplotype was shown to be less
sensitive to SU treatment in vitro.62 Clinical
studies probing associations of these variants
with either therapeutic response or occurrence
of hypoglycemia have proven equivocal with
some studies showing a positive association and
others showing no association.45, 47, 61, 63, 64 Of
note is the fact that studies differed with respect
to SUs used, dose, study outcomes, ethnicities,
cohort characteristics, and sample size.
With the advent of whole-genome sequencing
technologies, novel genetic loci associated with
T2DM and SU response have been discovered;
the most replicated is the TCF7L2 loci.16, 48, 49
In 901 SU-treated T2DM patients identified from
GoDARTS, an intronic SNP, rs12255732, in
TCF7L2 was strongly associated with SU
response.48 TCF7L2 is expressed in pancreatic b
cells, and reduced function alleles have been
associated with lower insulin secretion sugges-
tive of a direct or indirect role on b-cell func-
tion.48 Individuals with two copies of the variant
T allele were two times less likely to reach target
HbA1c levels below 7% within 1 year of treat-
ment compared with those with two copies of
the G variant of rs12255732.48 These findings

Figure 4. Schematic diagram of pharmacogenomics of sulfonylureas. Sulfonylureas bind to sulfonylurea receptor type 1
(SUR1) located on the pancreatic b islet cell that is encoded by the ABCC8, a member of the ATP-binding cassette gene
superfamily. When SUs bind to SUR1, it results in closing of the pancreatic b-cell potassium channel (KATP), made up of
Kir6.2 subunits encoded by KCNJ11. KATP channel closing causes membrane depolarization and triggering calcium influx
with subsequent exocytosis of insulin-containing vesicles and increased insulin secretion, a process postulated to be regulated
by TCF7L2. Insulin binds to insulin receptor site (IRS-1) encoded by IRS-1 and located on the surface of insulin-sensitive
tissue. IRS-1 gets phosphorylated and regulates the function of insulin inside the cell.
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu
were confirmed by other independent stud-
ies.49, 65 Another intron variant in TCF7L2,
rs7903146, was associated with lower response
and increased risk of treatment failure for carri-
ers of the T allele compared with the CC geno-
types.48, 49 Other PD targets such as Insulin
receptor substrate-1 encoded by the IRS-1 gene
have been associated with T2DM and SU
response. The most common variant in IRS-1,
rs1801278, was associated with an increased risk
of secondary failure to SU therapy in two sepa-
rate cohorts of T2DM patients.66, 67
Thiazolidinediones
Although their use is limited due to risk of
severe adverse events such as heart failure,
myocardial infarction, and bladder cancer, thia-
zolidinediones (TZDs) still have a role in dia-
betes pharmacotherapy. Decision to use a TZD
in a patient is made after careful risk versus ben-
efit evaluation. TZDs are insulin sensitizers that
increase insulin-dependent glucose elimination,
reduce hepatic glucose production, and decrease
circulating free fatty acids. TZDs act by activat-
ing PPAR-c; the activated receptor then binds to
DNA response elements and controls the expres-
sion of genes involved in maintenance of meta-
bolic homeostasis.68 PPAR-c activation in
mature adipose cells induces expression of genes
involved in the insulin signaling cascade and as
a result improves insulin sensitivity in diabetic
patients. In addition, these genes were demon-
strated to reduce insulin resistance.69
As seen with the other OGLTs, there is pro-
nounced interindividual variability in response
to TZD treatment. Clinical studies of pioglita-
zone and rosiglitazone show that between 12%
and 45% of T2DM patients failed to achieve suf-
ficient reduction in either fasting plasma glucose
and/or HbA1c concentrations.70
Thiazolidinediones: Pharmacokinetics/Pharmacody-
namics and Evidence of Pharmacogenetic Associa-
tions
TZDs and the impact of variation in PK genes
on response has been evaluated. TZDs are lar-
gely metabolized by the polymorphic cyto-
chrome P450 2C8 (CYP2C8) and to a much
lesser extent by CYP2C9 and CYP3A4.71 Genetic
variation in CYP2C8 was reported to influence
the PK of rosiglitazone with significantly lower
AUC and higher oral clearance for *1/*3 sub-
jects compared with *1/*1 subjects.71 Although
1143
it was hypothesized that the lower metabolic
activity CYP2C8*2 and *3 variants would result
in decreased metabolism and increased drug
levels, clinical studies did not corroborate these
assumptions. Instead, they showed higher clear-
ance and lower AUC for subjects with two
copies of the *3 alleles compared with the wild
type.72 The CYP2C8*3 allele is relatively rare in
whites, and adjustments for baseline variables
may have reduced the impact of genetic variabil-
ity on rosiglitazone PK. Furthermore, TZDs are
substrates of OATP1B (SLCO1B1), the main
organic anion transporter protein responsible for
their active shuttling into hepatocytes.71 A joint
investigation on the effects of CYP2C8 and
SLCO1B1 polymorphisms was recently con-
ducted in 833 Scottish patients with T2DM trea-
ted with TZDs.51 Results showed that although
the CYP2C8*3 variant was associated with
reduced glycemic response to rosiglitazone, the
common SCLO1B1 521T>C variant, in contrast,
was associated with an enhanced glycemic
response.51 A subset of patients known as super-
responders based on combined CYP2C8 (*1/*1)
and SCLO1B1 (CC) genotypes had a 0.39%
greater HbA1c reduction with rosiglitazone com-
pared with poor responders.51
Studies on TZDs and PD targets have shown
some progress. Many studies to date have
focused on polymorphisms in the PPAR-c gene,
a logical first choice because it encodes the
binding site for TZD ligands (Figure 5). The
PPAR-c gene contains a common nonsynony-
mous SNP, rs1801282, that gives rise to a codon
12 proline to alanine substitution (Pro12Ala)
implicated in more than 50 studies on diabetes
susceptibility.73 Meta-analyses of these associa-
tions show an almost 20% reduction in T2DM
risk for Ala12 allele carriers compared with car-
riers of the Pro12 allele.73, 74 Clinical transla-
tional studies probed for associations with the
Ala12 allele and response to TZD therapy in at-
risk patients and patients with T2DM. Reports
on the Ala12 allele and TZD response in dia-
betes patients are conflicting. Whereas one study
showed no difference in frequency of subjects
with one copy of the Ala12 allele,75 another
study reported a higher frequency of the Ala12
allele in responders to pioglitazone.76 One study
reported a significantly higher response to
rosiglitazone at 12 weeks in Ala12 subjects com-
pared with homozygous Pro12 subjects (43.72%
vs 86.67%).50 Again, key differences among
studies that may have contributed to inconsis-
tent results include differences in TZD type,
1144 PHARMACOTHERAPY Volume 37, Number 9, 2017

Figure 5. Schematic presentation of pharmacogenomics of thiazolidinediones. (A) Thiazolidinediones (TZDs) are substrates
of OATP1B, the organic anion transporter protein encoded by SLCO1B1. OATP1B1 is the main hepatic transporter
responsible for the active shuttling of organic anion compounds like TZDs into hepatocytes. (B) TZDs act by activating the
PPAR-c receptor encoded by the PPAR-c gene; the activated receptor then binds to DNA response elements and controls the
expression of genes involved in maintenance of metabolic homeostasis. (C) Adiponectin encoded by the ADIPOQ gene is a
protein hormone expressed abundantly in adipose tissue where it promotes glucose uptake and fatty acid oxidation.
Adiponectin actions are controlled by PPAR-c receptor activation.

treatment duration, inclusion criteria, baseline
metabolic conditions, and ethnicity.
Another non-PPAR-c TZD target gene of inter-
est is the ADIPOQ gene that encodes adiponectin
(Figure 5). Low levels of adiponectin have been
associated with insulin resistance, and TZDs are
known to increase adiponectin levels that may
contribute in part to their insulin-sensitizing
effects.74 Common exonic (45T>G; rs16861194)
and intronic (276G>T; rs1501299) SNPs in ADI-
POQ have been studied. Carriers of the 45G
variant and the 276G wild-type alleles, whether
studied alone or in haplotype combinations, had
smaller decreases in fasting plasma glucose and
HbA1c compared with patients carrying the
other alleles.52 In addition to studies probing
drug response, occurrence of the many troubling
and limiting adverse effects with TZDs also led
to genetic explorations of any associated mecha-
nisms. One study reported an association
between weight gain and a SNP in the perilipin
gene.77 A genetic substudy of the Diabetes
Reduction Assessment with Ramipril and
Rosiglitazone Medication (DREAM) study
showed a significant association with rosiglita-
zone-induced edema and rs6123045 in the
nuclear factor of the activated T-cells cytoplas-
mic calcineurin-dependent 2 (NFATC2) gene in
subjects of European descent.78 Neither of these
studies have yet to be replicated. Other PD
genes linked to TZDs have been studied without
any significant replication reports.
Gliptins
Gliptins, also known as dipeptidyl peptidase
IV (DPP4) inhibitors, are classified as incretin
mimetics. They are newer agents that exert their
effects by inhibiting a key enzyme in the incretin
signaling pathway, preventing the degradation of
endogenous glucagon-like peptide-1 (GLP-1)
receptor agonist and gastric inhibitory peptide
(GIP).79 GLP-1 is secreted by the intestines after
intake of food and acts to induce insulin secre-
tion from pancreatic b cells, suppresses the
release of glucagon, inhibits gastric emptying,
and reduces appetite. Inhibiting the degradation
of GLP-1 leads to prolonged secretion of insulin
and inhibition of glucagon.79
Gliptins: Evidence of Pharmacogenetic Associations
In terms of their metabolic profile, DPP-4
inhibitors are not typical substrates for either
cytochrome P450 (except saxagliptin, metabo-
lized by CYP3A4/A5) or any major transporter
families because their main mode of clearance is
by renal excretion.7 Due to the relatively recent
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu
entry of these drugs into the market, very few
pharmacogenetic studies have been conducted.80
Studies on genetic influence on insulin secretion
after administration of human GLP-1 to healthy
individuals may be extrapolated to explain
observed differences in response to GLP-1 recep-
tor agonists and DPP-4 inhibitors. A recent
study showed a SNP, rs7202877, near the
CTRB1 and CTRB2 loci influenced the response
to DPP-4 inhibitor treatment in patients with
T2DM.81 The CRTB locus encodes for the diges-
tive enzyme chymotrypsin, an important regula-
tor of the incretin pathway.79 The G allele of
rs7202877 was previously associated with an
increased risk for T1DM and a decreased risk
for T2DM.14 In one study, the rs7202877G allele
was associated with enhanced GLP-1 secretion
in healthy individuals and reduced response to
DPP-4 inhibitor treatment in patients with
T2DM.
Personalized Treatment Strategy for DM
Managing patients with DM presents a chal-
lenge. Treatment failure, risk of hypoglycemia,
and selection of appropriate agents based on
pathogenesis of the disease creates a need for
using precision medicine in DM. With so many
different classes of medications available, the
guidelines recommend use of patient-specific
approaches when designing DM treatment
plans.55 Clinicians should select a treatment
strategy and goals of therapy that provide the
most benefit with the least harm. To address the
question of efficacy among commonly used dia-
betes medications in various patient populations,
a national randomized interventional study was
proposed.82 The Glycemia Reduction Approaches
in Diabetes: A Comparative Effectiveness Study
(GRADE) is currently enrolling adult patients
with a history of DM for less than 10 years and
currently on metformin monotherapy. Patients
are divided into four groups to receive met-
formin with either glimepiride, sitagliptin,
liraglutide, or basal insulin glargine. The primary
outcome measure is time to primary failure of
treatment defined by a HbA1c higher than 7%
over a period of 4–7 years. Investigators will
compare personalized response to treatment,
looking at adverse events, tolerability, microvas-
cular and macrovascular complications, quality
of life, and cost-effectiveness. Participants’ phe-
notypes will be studied to help guide selection of
optimal diabetic agent(s).82 The results of
GRADE should provide additional guidance
1145
when selecting a diabetic agent and using a per-
sonalized approach in DM management. Despite
the multiple factors that clinicians need to con-
sider when selecting a treatment strategy for DM
today, there is still room for incorporating phar-
macogenomics for a more personalized manage-
ment of DM (Figure 1).
Using Genetics for the Prediction of DM
Primary studies and meta-analyses of genetics
studies on diabetes risk have yielded many
genetic associations that increase our under-
standing of T2DM pathophysiology. Although
these explorations only explain a small fraction
of genetic contribution to phenotype, the associ-
ations can be used to improve disease classifica-
tion. One example of this is with the use of
genetic risk scores (GRS) to predict the risk of
diabetes incidence. GRS scores are typically
weighted by participants, and the number of risk
alleles per SNP are summed over the total num-
ber of representative SNPs associated with the
risk of diabetes. The Framingham Heart Study
(FHS) and the Diabetes Prevention Program
(DPP) are representative cohorts that have suc-
cessfully used this approach to predict diabetes
risk.83, 84 In the FHS, a GRS based on 18 risk
alleles predicted new cases of diabetes with a
slightly better prediction of risk than common
risk factors (such as body mass index, hyperten-
sion, family history of diabetes, ethnicity, and
age) alone.84 In the DPP, a high GRS (based on
34 risk alleles) was associated with an increased
risk of developing diabetes but was subsequently
attenuated by lifestyle interventions in the ana-
lytical model.83 Although these examples pro-
vide an illustration of how pharmacogenomics
can be incorporated into the risk prevention
paradigm, the challenge of selecting the most
relevant and clinically validated risk variants is
one that is yet to be overcome.
Applications of Pharmacogenomics in
Monogenic Diabetes Syndrome
For disease management, the most extensive
application of pharmacogenetics in DM to date
has been with the monogenic forms of the dis-
ease. Identification of the correct MODY subtype
has a tremendous impact on treatment. It is rec-
ommended that patients presenting with diabetes
in the first 6 months of life be tested for muta-
tions in KCNJ11 and ABCC8 to rule out
TNDM.23 The identification of the NDM subtype
1146 PHARMACOTHERAPY Volume 37, Number 9, 2017
is significant due to associated mutations occur-
ring in the pancreatic b-cell KATP channels and
their role in guiding treatment choice. SU action
on these channels causes increased insulin secre-
tion, making them the most ideal agents for
NDM management. TNDM patients compared
with those with PNDM are likely to have signifi-
cantly higher endogenous insulin production,
making them much more responsive to SUs.23
They can thus be successfully treated with low-
dose SUs in place of standard insulin therapy
versus higher SU doses for PNDM. The switch
from insulin to SU should only be made after a
molecular genetic diagnosis. There are estab-
lished translational research diagnosis and treat-
ment approach guidance/protocols for MODY
and NDM as well as a MODY probability calcu-
lator for clinicians’ reference.85
Patients with MODY 1 and 3 are prime targets
for personalized therapy as embodied by the
reported relatively safe transition from insulin to
SU monotherapy in these patients. The finding
that these patients are generally hypersensitive
to SUs makes such a transition possible. This
hypersensitivity to SUs has been attributed to
downregulation of HNF1-a and HNF4-a target
genes in the liver, leading to decreased hepatic
uptake of SUs and increased levels in the general
circulation.80
Personalized treatment strategy selection may
not always include pharmacotherapy, a paradigm
seen with the appropriate identification of
patients with MODY 2, a frequently misdiag-
nosed subset.8 These patients present with mild
hyperglycemia, which improves on its own, and
generally do not progress to overt diabetes with
associated macrovascular and microvascular
complications. Consequently, patients with
MODY 2 typically have no need for pharma-
cotherapy and can be managed by diet alone.8
Ideally, clinicians ought to be aware that
patients with an onset of diabetes before age of
25 should be referred for genetic testing to rule
out MODY and prevent misdiagnosis. The Inter-
national Society for Pediatric and Adolescent
Diabetes (ISPAD) guidelines provide very
detailed recommendations about when to sus-
pect the presence of MODY.23 The American
Diabetes Association guidelines also provide rec-
ommendations for the screening of MODY in
children and adolescents initially diagnosed with
DM within the first 6 months of life.5 Genetic
tests for MODY-related genes and CLIA-
approved labs for such testing are available on
the Genetic Testing Registry.86 The National
Monogenic Diabetes Registry of MODY patients
is useful for further guidance on current
research and treatment strategies.87
Pharmacogenomics in Predicting Response to
Therapy
With respect to the pharmacogenetics of
OGLTs, metformin is still the guideline-based
first-line monotherapy for diabetes. The variabil-
ity in response and treatment failure with met-
formin is clearly indicative of a differential effect
that may be genetically induced. Variants in
metformin PK and transporter genes have been
the most widely studied and have greatly
advanced our knowledge of metformin pharma-
cogenomics. Replicated SLC transporter variants
could play a role in guideline development for
metformin use in select patient populations
based on combined GRS. Pharmacogenomics-
guided therapy based on a greater understanding
of metformin genes and pathways could help
clinicians if outcomes (patient response and
probable treatment failures) could be determined
a priori. Alternative guideline-based recommen-
dations can then be used. This type of pharma-
cogenomics-guided approach could lead to
long-term dollar cost savings compared with a
“wait until treatment fails then switch”
approach.
Response to SU therapy depends on b-cell
function and its insulin production ability.
Results with clinical studies of the CYP2C9 gene
and SU response have been promising as seen in
the GoDARTs study. Variations in KCNJ11 and
ABCC8 genes were also identified as associated
with a high response to SU treatment in certain
patients with hyperglycemia.46 These critical
findings may potentially lead to testing/screening
patients for these polymorphisms. Advance
knowledge of these and other validated strong
genetic signals, such as those in TCF7L2, may
also assist in careful dose titration for SU-sensi-
tive versus SU-tolerant patients. On a pharmaco-
genetic basis, SU therapy can therefore be
initiated as the most effective choice in “high-
response” patients and avoided in “low/no-
response” patients similar to the current success
with some MODY patients.
With the TZDs, although results from many
of the pharmacogenomic studies conducted
were clinically significant, the current guideli-
nes stipulate consideration of risk versus benefit
before initiating use. It is doubtful there will
be any additional benefit to incorporation of
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu
pharmacogenomics based on their current role
in treatment.
It is our opinion that although there are cer-
tainly advances in genetic involvement and asso-
ciations with OGLTs, there are as yet no strong
clinical guidelines or recommendations for
genetic testing and application in clinical
practice.
Future Prospects of Using Genetics for Therapy
of DM
Common risk factors for T2DM include obe-
sity, dyslipidemia, family history, age, low physi-
cal activity, Hispanic and African-American
ethnicity, smoking, and unhealthy diet.5 Compos-
ite GRS may better predict diabetes risk in combi-
nation with other risk factors but would not be
expected to be an efficient discriminator due to
low effect sizes of single common variants in
models. However, GRS may be useful in younger
patients who have not developed obvious risk
factors and may also prove useful for newborn
diabetes susceptibility genetic screening and fol-
low-up.83, 84 Another utility for GRS would be in
ethnically focused screening and targeted treat-
ment based on the presence or absence of known
susceptibility genes because reports of popula-
tion-specific T2DM susceptibility variants con-
tinue to emerge from large consortia studies.17
Genetics-based association studies in OGLTs
and their role in DM treatment identified herita-
ble components of a patient’s response to therapy.
Although at this time not enough evidence for
clinical utility exists, future larger cohorts and
combinations from academic, practice, and indus-
try DM research groups may aid in identifying
more genes implicated in OGLT response. The
large evidence base generated from these high-
powered consortia studies may be an impetus for
development of guidelines for the use of genetic
information in diabetes pharmacotherapy.
Use of pharmacogenetics for the prediction
and prevention of side effects from OGLTs may
be an idea whose time is around the corner.
Metformin and SUs, although mainline agents
for therapy, are more prone to cause intolerant
gastrointestinal effects or hypoglycemia com-
pared with other agents. As such, testing
patients a priori for any implicated clinically val-
idated metformin or SU intolerance or low-
response susceptibility variants could be an
adjunct tool to maximizing their use in therapy.
The same extrapolations could also be made for
restricted OGLTs such as rosiglitazone. In the
1147
future, knowing which patients are likely to
develop severe side effects can help with strati-
fied medicine.
Conclusion
With so many different classes of medications
available for managing diabetes, the recommenda-
tion from the guidelines is to use a patient-speci-
fic approach and to select treatment strategies
providing the most benefit with the least harm.
Using personalized medicine in the treatment of
diabetes where patients’ diabetes types can be
precisely identified with respect to pathology fits
perfectly with the selection of agents that will best
treat specific pathologies of such stratified dia-
betes. To make it even more patient specific,
pharmacogenomics may be used to identify
variations in medication disposition. Based on the
evidence, attaining glycemic goal(s) is not enough
to prevent diabetes-related complications. Con-
trolling comorbidities and most importantly pre-
vention of diabetes onset and progression needs
to be addressed.
Overall, data from pharmacogenomics-based
studies may help present a clearer picture of any
implicated molecular mechanisms en route to
selecting pharmacoeconomically viable and rele-
vant treatment strategies for the complex multi-
factorial disease that is DM.
References
1. World Health Organization. Diabetes: Key Facts, November
2016. Available from www.who.int/mediacentre/factsheets/
fs312/en/. Accessed February 13, 2017.
2. World Health Organization. Diabetes: Global report on dia-
betes. Available from www.who.int/diabetes/global-report/en/.
Accessed February 13, 2017.
3. Centers for Disease Control and Prevention. Chronic Disease
Prevention and Health Promotion: Diabetes, July 2016. Avail-
able from www.cdc.gov/chronicdisease/resources/publications/
aag/diabetes.htm. Accessed February 13 2017.
4. American Diabetes Association. Economic costs of diabetes in
the U.S. in 2012. Diabetes Care 2013;36:1033–46.
5. American Diabetes Association. Standards of medical care in
diabetes. Diabetes Care 2016;39:S1–106.
6. Barroso I. Genetics of type 2 diabetes. Diabet Med 2005;22:
517–35.
7. Hupfeld CJ, Courtney H, Olefsky JM. Type 2 diabetes melli-
tus: etiology, pathogenesis, and natural history. In: Jameson JL,
De Groot LJ, eds. Endocrinology: adult and pediatric. Philadel-
phia, PA: Elsevier Health Sciences, 2010:765–87.
8. Carmody D, Naylor RN, Bell CD, et al. GCK-MODY in the
US National Monogenic Diabetes Registry: frequently misdiag-
nosed and unnecessarily treated. Acta Diabetol 2016;53:703–8.
9. Tan JT, Chia KS, Ku CS. The molecular genetics of type 2 dia-
betes: past, present and future. In: Encyclopedia of life
sciences. Chichester, UK: John Wiley & Sons, 2009. doi: 10.
1002/9780470015902.a0021994.
10. Denny JC, Ritchie MD, Basford MA, et al. PheWAS: demon-
strating the feasibility of a phenome-wide scan to discover
gene-disease associations. Bioinformatics 2010;26:1205–10.
1148 PHARMACOTHERAPY Volume 37, Number 9, 2017
11. Brunetti A, Chiefari E, FTI D. Recent advances in the molecu-
lar genetics of type 2 diabetes mellitus. World J Diabetes
2014;5:128–40.
12. Owen KR, McCarthy MI. Genetics of type 2 diabetes. Curr
Opin Genet Dev 2007;17:239–44.
13. Doria A, Patti M-E, Kahn CR. The emerging genetic architec-
ture of type 2 diabetes. Cell Metab 2008;8:186–200.
14. Morris AP, Voight BF, Teslovich TM, et al. Large-scale associ-
ation analysis provides insights into the genetic architecture
and pathophysiology of type 2 diabetes. Nat Genet 2012;44:
981–90.
15. The Wellcome Trust Case Control Consortium. Genome-wide
association study of 14,000 cases of seven common diseases
and 3,000 shared controls. Nature 2007;447:661–78.
16. Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of
transcription factor 7-like 2 (TCF7L2) gene confers risk of
type 2 diabetes. Nat Genet 2006;38:320–3.
17. Fuchsberger C, Flannick J, Teslovich TM, et al. The genetic
architecture of type 2 diabetes. Nature 2016;536:41–7.
18. GWAS Catalog. The NHGRI-EBI catalog of published gen-
ome-wide association studies, February 2017. Available from
www.ebi.ac.uk/gwas/. Accessed February 13, 2017.
19. Bonnefond A, Froguel P. Rare and common genetic events in
type 2 diabetes: what should biologists know? Cell Metab
2015;21:357–68.
20. Vaxillaire M, Froguel P. Genetic basis of maturity-onset dia-
betes of the young. Endocrinol Metab Clin North Am 2006;35:
371–84.
21. Chambers C, Fouts A, Dong F, et al. Characteristics of matu-
rity onset diabetes of the young in a large diabetes center.
Pediatr Diabetes 2016;17:360–7.
22. Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteris-
tics and clinical diagnosis of maturity onset diabetes of the
young due to mutations in HNF1A, HNF4A, and glucokinase:
results from the SEARCH for Diabetes in Youth. J Clin Endo-
crinol Metab 2013;98:4055–62.
23. Rubio-Cabezas O, Hattersley AT, Njølstad PR, et al. ISPAD
Clinical Practice Consensus Guidelines 2014. The diagnosis
and management of monogenic diabetes in children and ado-
lescents. Pediatr Diabetes 2014;15(Suppl 20):47–64.
24. Babenko AP, Polak M, Cave H, et al. Activating mutations in
the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med
2006;355:456–66.
25. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations
in the gene encoding the ATP-sensitive potassium-channel
subunit Kir6.2 and permanent neonatal diabetes. N Engl J
Med 2004;350:1838–49.
26. Colombo C, Delvecchio M, Zecchins C, et al. Transient
neonatal diabetes mellitus is associated with a recurrent
(R201H) KCNJ11 (KIR6.2) mutation. Diabetologia 2005;48:
2439–41.
27. Canadian Diabetes Association Clinical Practice Guidelines
Expert Committee. Pharmacologic management of type 2 dia-
betes: 2016 interim update. Can J Diabetes 2016;40:193–5.
28. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE.
Metformin pathways: pharmacokinetics and pharmacodynam-
ics. Pharmacogenet Genomics 2012;22:820–7.
29. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein
kinase in mechanism of metformin action. J Clin Invest
2001;108:1167–74.
30. Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez
JC. Metformin pharmacogenomics: current status and future
directions. Diabetes 2014;63:2590–9.
31. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of
rosiglitazone, metformin, or glyburide monotherapy. N Engl J
Med 2006;355:2427–43.
32. Riedel AA, Heien H, Wogen J, Plauschinat CA. Loss of glyce-
mic control in patients with type 2 diabetes mellitus who were
receiving initial metformin, sulfonylurea, or thiazolidinedione
monotherapy. Pharmacotherapy 2007;27:1102–10.
33. Jablonski KA, McAteer JB, De Bakker PIW, et al. Common
variants in 40 genes assessed for diabetes incidence and
response to metformin and lifestyle intervention in the dia-
betes prevention program. Diabetes 2010;59:2672–81.
34. Shu Y, Sheardown SA, Brown C, et al. Effect of genetic varia-
tion in the organic cation transporter 1 (OCT1) on metformin
action. J Clin Invest 2007;117:1422–31.
35. Zhou K, Donnelly LA, Kimber CH, et al. Reduced-function
SLC22A1 polymorphisms encoding organic cation transporter
1 and glycemic response to metformin: a GoDARTS study.
Diabetes 2009;58:1434–9.
36. Becker ML, Pearson ER, Tkac I. Pharmacogenetics of oral
antidiabetic drugs. Int J Endocrinol 2013;2013: Article ID
686315. doi: 10.1155/2013/686315.
37. van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant
near ATM is significantly associated with metformin treatment
response in type 2 diabetes: a replication and meta-analysis of
five cohorts. Diabetologia 2012;55:1971–7.
38. Chen Y, Li S, Brown C, et al. Effect of genetic variation in the
organic cation transporter 2 on the renal elimination of met-
formin. Pharmacogenet Genomics 2009;19:497–504.
39. Zhou K, Bellenguez C, Spencer CC, et al. Common variants
near ATM are associated with glycemic response to metformin
in type 2 diabetes. Nat Genet 2011;43:117–20.
40. Florez JC, Barrett-Connor E, Jablonski KA, et al. The C allele
of ATM rs11212617 does not associate with metformin
response in the diabetes prevention program. Diabetes Care
2012;35:1864–7.
41. Zhou K, Donnelly L, Burch L, et al. Loss-of-function CYP2C9
variants improve therapeutic response to sulfonylureas in type
2 diabetes: a Go-DARTS study. Clin Pharmacol Ther 2010;87:
52–6.
42. Ragia G, Petridis I, Tavridou A, Christakidis D, Manolopou-
los VG. Presence of CYP2C9*3 allele increases risk for hypo-
glycemia in type 2 diabetic patients treated with sulfonylureas.
Pharmacogenomics 2009;10:1781–7.
43. Holstein A, Plaschke A, Ptak M, et al. Association between
CYP2C9 slow metabolizer genotypes and severe hypogly-
caemia on medication with sulphonylurea hypoglycaemic
agents. Br J Clin Pharmacol 2005;60:103–6.
44. Holstein A, Hahn M, Patzer O, Seeringer A, Kovacs P, Stingl
J. Impact of clinical factors and CYP2C9 variants for the risk
of severe sulfonylurea-induced hypoglycemia. Eur J Clin Phar-
macol 2011;67:471–6.
45. Feng Y, Mao G, Ren X, et al. Ser 1369Ala variant in sulfony-
lurea receptor gene ABCC8 Is associated with antidiabetic effi-
cacy of gliclazide in Chinese type 2 diabetic patients. Diabetes
Care 2008;31:1939–44.
46. Florez JC, Jablonski KA, Kahn SE, et al. Type 2 diabetes-asso-
ciated missense polymorphisms KCNJ11 E23K and ABCC8
A1369S influence progression to diabetes and response to
interventions in the Diabetes Prevention Program. Diabetes
2007;56:531–6.
47. Holstein JD, Kovacs P, Patzer O, Stumvoll M, Holstein A.
The Ser1369Ala variant of ABCC8 and the risk for severe sul-
fonylurea-induced hypoglycemia in German patients with type
2 diabetes. Pharmacogenomics 2012;13:5–10.
48. Pearson ER, Donnelly LA, Kimber C, et al. Variation in
TCF7L2 influences therapeutic response to sulfonylureas: a
GoDARTs study. Diabetes 2007;56:2178–82.
49. Holstein A, Hahn M, Korner A, Stumvoll M, Kovacs P.
TCF7L2 and therapeutic response to sulfonylureas in patients
with type 2 diabetes. BMC Med Genet 2011;12:30.
50. Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymor-
phism of peroxisome proliferator-activated receptor gamma2
gene on rosiglitazone response in type 2 diabetes. Clin Phar-
macol Ther 2005;78:202–8.
51. Dawed AY, Donnelly L, Tavendale R, et al. CYP2C8 and
SLCO1B1 variants and therapeutic response to thiazolidine-
diones in patients with type 2 diabetes. Diabetes Care
2016;39:1902–8.
52. Kang ES, Park SY, Kim HJ, et al. The influence of adiponectin
gene polymorphism on the rosiglitazone response in patients
with type 2 diabetes. Diabetes Care 2005;28:1139–44.
 PERSONALIZED MEDICINE IN DIABETES MANAGEMENT Elk and Iwuchukwu
53. Morris AD, Boyle DI, MacAlpine R, et al. The diabetes audit
and research in Tayside Scotland (DARTS) study: electronic
record linkage to create a diabetes register. DARTS/MEMO
Collaboration. BMJ 1997;315:524–8.
54. Shu Y, Brown C, Castro RA, et al. Effect of genetic variation
in the organic cation transporter 1, OCT1, on metformin phar-
macokinetics. Clin Pharmacol Ther 2008;83:273–80.
55. American Diabetes Association. 7. Approaches to glycemic
treatment. Diabetes Care 2016;39(Suppl 1):S52–9.
56. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mel-
litus. Ann Intern Med 1999;131:281–303.
57. Aquilante CL. Sulfonylurea pharmacogenomics in type 2 dia-
betes: the influence of drug target and diabetes risk polymor-
phisms. Expert Rev Cardiovasc Ther 2010;8:359–72.
58. Kirchheiner J, Roots I, Goldammer M, Rosenkranz B, Brock-
moller J. Effect of genetic polymorphisms in cytochrome p450
(CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral
antidiabetic drugs: clinical relevance. Clin Pharmacokinet
2005;44:1209–25.
59. Group UKPDS. Intensive blood-glucose control with sulpho-
nylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes. Lancet
1998;352:837–53.
60. Schopman J, Simon A, Hoefnagel S, Hoekstra J, Scholten R,
Holleman F. The incidence of mild and severe hypoglycaemia
in patients with type 2 diabetes mellitus treated with sulfony-
lureas: a systematic review and meta-analysis. Diabetes Metab
Res Rev 2014;30:11–22.
61. Li Q, Chen M, Zhang R, et al. KCNJ11 E23K variant is associ-
ated with the therapeutic effect of sulphonylureas in Chinese
type 2 diabetic patients. Clin Exp Pharmacol Physiol
2014;41:748–54.
62. Hamming KSC, Soliman D, Matemisz LC, et al. Coexpression
of the type 2 diabetes susceptibility gene variants KCNJ11
E23K and ABCC8 S1369A alter the ATP and sulfonylurea sen-
sitivities of the ATP-sensitive K+ channel. Diabetes
2009;58:2419–24.
63. Javorsky M, Klimcakova L, Schroner Z, et al. KCNJ11 gene
E23K variant and therapeutic response to sulfonylureas. Eur J
Intern Med 2012;23:245–9.
64. Sesti G, Laratta E, Cardellini M, et al. The E23K Variant of
KCNJ11 encoding the pancreatic b-cell adenosine 50 -tripho-
sphate-sensitive potassium channel subunit Kir6.2 is associated
with an increased risk of secondary failure to sulfonylurea in
patients with type 2 diabetes. J Clin Endocrinol Metab
2006;91:2334–9.
65. Kimber CH, Doney AS, Pearson ER, et al. TCF7L2 in the Go-
DARTS study: evidence for a gene dose effect on both diabetes
susceptibility and control of glucose levels. Diabetologia
2007;50:1186–91.
66. Sesti G, Marini MA, Cardellini M, et al. The Arg972 variant
in insulin receptor substrate-1 is associated with an increased
risk of secondary failure to sulfonylurea in patients with type
2 diabetes. Diabetes Care 2004;27:1394–8.
67. Prudente S, Morini E, Lucchesi D, et al. IRS1 G972R missense
polymorphism is associated with failure to oral antidiabetes
drugs in white patients with type 2 diabetes from Italy. Dia-
betes 2014;63:3135–40.
68. van Leeuwen N, Swen JJ, Guchelaar HJ, ’t Hart LM. The role
of pharmacogenetics in drug disposition and response of oral
glucose-lowering drugs. Clin Pharmacokinet 2013;52:833–54.
69. Della-Morte D, Palmirotta R, Rehni AK, et al. Pharmacoge-
nomics and pharmacogenetics of thiazolidinediones: role in
diabetes and cardiovascular risk factors. Pharmacogenomics
2014;15:2063–82.
1149
70. Aquilante CL, Zhang W, McCollum M. Race, ethnicity, and
use of thiazolidinediones among US adults with diabetes. Curr
Med Res Opin 2007;23:489–94.
71. Aquilante CL, Bushman LR, Knutsen SD, Burt LE, Rome LC,
Kosmiski LA. Influence of SLCO1B1 and CYP2C8 gene poly-
morphisms on rosiglitazone pharmacokinetics in healthy vol-
unteers. Hum Genomics 2008;3:7–16.
72. Kirchheiner J, Thomas S, Bauer S, et al. Pharmacokinetics
and pharmacodynamics of rosiglitazone in relation to CYP2C8
genotype. Clin Pharmacol Ther 2006;80:657–67.
73. Gouda HN, Sagoo GS, Harding A-H, Yates J, Sandhu MS, Hig-
gins JPT. The association between the peroxisome prolifera-
tor-activated receptor-gamma2 (PPARG2) Pro12Ala gene
variant and type 2 diabetes mellitus: a HuGE review and meta-
analysis. Am J Epidemiol 2010;171:645–55.
74. Aquilante CL. Pharmacogenetics of thiazolidinedione therapy.
Pharmacogenomics 2007;8:917–31.
75. Bluher M, Lubben G, Paschke R. Analysis of the relationship
between the Pro12Ala variant in the PPAR-gamma2 gene and
the response rate to therapy with pioglitazone in patients with
type 2 diabetes. Diabetes Care 2003;26:825–31.
76. Hsieh MC, Lin KD, Tien KJ, et al. Common polymorphisms
of the peroxisome proliferator-activated receptor-gamma
(Pro12Ala) and peroxisome proliferator-activated receptor-
gamma coactivator-1 (Gly482Ser) and the response to pioglita-
zone in Chinese patients with type 2 diabetes mellitus. Meta-
bolism 2010;59:1139–44.
77. Kang ES, Cha BS, Kim HJ, et al. The 11482G>A polymor-
phism in the perilipin gene is associated with weight gain with
rosiglitazone treatment in type 2 diabetes. Diabetes Care
2006;29:1320–4.
78. Bailey SD, Xie C, Do R, et al. Variation at the NFATC2 locus
increases the risk of thiazolidinedione-induced edema in the
Diabetes REduction Assessment with ramipril and rosiglita-
zone Medication (DREAM) study. Diabetes Care 2010;33:
2250–3.
79. Drucker DJ, Nauck MA. The incretin system: glucagon-like
peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibi-
tors in type 2 diabetes. Lancet 2006;368:1696–705.
80. Kleinberger JW, Pollin TI. Personalized medicine in diabetes
mellitus: current opportunities and future prospects. Ann N Y
Acad Sci 2015;1346:45–56.
81. ’t Hart LM, Fritsche A, Nijpels G, et al. The CTRB1/2 locus
affects diabetes susceptibility and treatment via the incretin
pathway. Diabetes 2013;62:3275–81.
82. Nathan DM, Buse JB, Kahn SE, et al. Rationale and design
of the glycemia reduction approaches in diabetes: a compara-
tive effectiveness study (GRADE). Diabetes Care 2013;36:
2254–61.
83. Hivert M-F, Jablonski KA, Perreault L, et al. Updated genetic
score based on 34 confirmed type 2 diabetes loci is associated
with diabetes incidence and regression to normoglycemia in
the diabetes prevention program. Diabetes 2011;60:1340–8.
84. Meigs JB, Shrader P, Sullivan LM, et al. Genotype score in
addition to common risk factors for prediction of type 2 dia-
betes. N Engl J Med 2008;359:2208–19.
85. Diabetes Genes. Genetic types of diabetes including maturity-
onset diabetes of the young (MODY). Available from www.di
abetesgenes.org. Accessed February 13, 2017.
86. Genetic Testing Registry. Available from www.ncbi.nlm.nih.
gov/gtr/. Accessed February 13, 2017.
87. Monogenic Diabetes Registry. Available from http://monogenic
diabetes.uchicago.edu/mody-registry/. Accessed February 13,
2017.