This document discusses the role of pharmacogenetics in diabetes mellitus (DM) and its treatment. It provides background on DM, noting it is a leading cause of death and its complications include blindness, renal failure and cardiovascular disease. For type 2 DM (T2DM), current treatments aim to lower blood glucose but do not eliminate risk of complications. The document explores how genetic variants identified through genome-wide association studies can help elucidate biological mechanisms underlying T2DM and response to pharmacological interventions. It provides a review of pharmacogenetic investigations into specific anti-diabetes medications and how understanding these genetics can help develop individualized treatment strategies for optimal glucose control and reduced adverse events.

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Diabetes mellitus and role of pharmacogenetics
Maria Armie Ladores Pacheco
Rutgers the State University

2. DM AND PHARMACOGENETICS 2
Diabetes Mellitus and Role of Pharmacogenetics
Diabetes is one of the leading causes of death in the U.S. (Nat. Diabetes Statistics/2014).
The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of
morbidity and mortality that is attributable to the complications of chronic hyperglycemia. These
complications include blindness, renal failure and cardiovascular disease. Current therapeutic
options for chronic hyperglycemia reduce, but do not eradicate, the risk of these complications
(Takane, Miyate, Burioka, & Shimizu/2006). Success in defining new preventative and
therapeutic strategies hinges on an improved understanding of pharmaceutical agents and the
genetic processes involved.
Type 2 DM (T2DM) is a multifactorial, heterogeneous group of disorders characterized
by a deficiency or failure in maintaining glucose homeostasis (Marchetti, Lupi, &
Delguerra/2009). For the most part, T2D results from defects in insulin secretion and insulin
action. T2DM accounts for the majority of all cases of diabetes in adults, and is typically
associated with obesity, sedentary lifestyle, older age, family history of diabetes, and ethnicity.
T2DM is also a risk factor for microvascular complications leading to amputations, renal
failures, and blindness as well as other disorders like hypertension, cardiovascular diseases,
dyslipidemia, and infections (Zeggini, Scott, Saxena, & Voight/2008). A variety of treatment
modalities exist for individuals with type 2 DM. In addition to dietary and physical activity
interventions, T2DM is treated pharmacologically with nine major classes of approved drugs.
These medications include insulin and its analogues, incretin hormone mimetics, dipeptidyl
peptidase 4 (DPP4) inhibitors.

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Purpose
This paper explores the role of causal gene or polymorphism, and its impact on response
to anti-hyperglycemic medications. New genetic variants associated with DM identified using
genome-wide association studies has elucidated new biological mechanisms underlying not just
predisposition to diabetes , but also response to pharmacologic intervention for DM. This article
aims to provide a comprehensive review of pharmacogenetics investigations of specific anti-
diabetes medications namely, sulfonylureas, biguanides, and thiazolidinediones
Discussion.
Rapid advances in genomic technologies have revolutionized studies of human genetics.
Pharmacogenetic research studies attempts to understand the link between genetic variation and
response to drugs (Zeggini, Scott, Saxena, & Voight/2008). Characterization of drug response is
expected to substantially enhance the ability to provide patients the most effective treatment
strategies based on their individual backgrounds and genetic make-up. Furthermore, genome-
wide association studies specifically focused on drug response. Coupled with other advances in
biomedical research, pharmacogenetics has moved beyond the relative focus on
pharmacokinetics to pharmacodynamics (Florez, Jablonski, & McAteer/2008). The efficacy of
any pharmacologic therapy is due to a balance between drug action and clearance, coupled with a
minimal adverse effect profile. However, many times the specific biologic mechanism of action
for a given drug is unknown, resulting in a relative focus on pharmacokinetics, given the lack of
pharmacodynamics knowledge. Current therapies in the management of diabetes include
lifestyle intervention through diet modification and exercise, as well as oral and injected
hypoglycemic agents. Ultimately, the goal of all treatment strategies forT2DM is to lower blood

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glucose concentrations to levels that approximate those representing normal range.
Pharmacologically, T2DM is treated with nine major classes of approved drugs including insulin
and its analogues, sulfonylureas, biguanides, thiazolidinediones, meglitinides, a-glucosidase
inhibitors, amylin analogues, incretin hormone mimetics, and DPP4 inhibitors.
For many patients with T2DM, treatment with anti-hyperglycemic drugs is initially
successful, yet over time, monotherapy fails and either addition of a second drug or transition to
insulin becomes necessary to restore acceptable glycemic control (Dina, Sladek, Rocheleau,
Rung, et al/2012). The unfortunate reality is that very rarely is a given pharmacologic agent
100% efficacious in 100% of treated patients. Understanding the pharamacogenetics of anti-
diabetes medications will provide critical baseline information for the development and
implementation of genetic screening into therapeutic decision making, and lay the foundation for
individualized medicine for patients with T2DM and other diseases in general. Glycemic
response to oral diabetic agents is highly variable; there are a number of factors which contribute
to inter-individual differences in drug response including age, sex, disease, drug and food
interactions, co-morbidity, and genetic factors. Genome-wide associated studies have uncovered
a large number of genetic variants associated with type 2 diabetes or related phenotypes in
relation to specific treatment drug modalities. Pharamacogenetic research, which assesses the
role of genetic determinants of drug response, promises to yield information that may be used to
personalize treatment strategies to insure optimal glucose control in all patients, improve
treatment efficacy, and reduce the risk of adverse drug events in susceptible individuals. These
events brings closer the prospect of identifying genetic variation that may provide information
illuminating which drug at which dose may be most effective for a given individual. This raises

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the probability of bringing “personalized medicine” to fruition to reduce morbidity and mortality
and improve the quality of life of individuals with T2DM.
Nurse Practitioner’s Role
The care of a diabetic patient with uncontrolled hyperglycemia is costly and both
resource and time intensive. Its treatment is complex, involving numerous lifestyle adaptations
and requiring a great deal of teaching and support. Advances in technology have contributed to
the need for education and patient participation in care. Many procedures formerly performed by
health care professionals, such as blood glucose monitoring, are now routinely done at home by
patients. Nurse practitioners have been major contributors to the improvement in the quality of
care provided to people with diabetes. Working with professionals from other disciplines, APNs
are able to deliver quality, cost-effective care by applying all of the combined skills, knowledge,
and competence improving patient outcomes. Professional education that increases awareness of
the importance of diabetes management is a valuable tool in reducing and preventing the
complications of diabetes. Diabetes NPs can serve as role models and educators, offering
professional education in diabetes care and management to their colleagues in both primary care
and acute setting. With rapid advances in genomic technologies, the APN’s knowledge on
understanding the kinetics and dynamics of different drugs used for treatments in relation to the
patient’s unique genetic entities will most definitely benefit both providers and patients and
improve clinical outcomes.

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