Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans

Several common genetic variants have been reliably associated with type 2 diabetes and
related glycemic traits. Study investigators hypothesize that variants in genes that are
reproducibly associated with type 2 diabetes or related glycemic traits may impact the
effect of anti-diabetic medications. In particular, sulfonylureas may have differential
effects on individuals depending on the allelic variant they carry at KCNJ11 E23K;
conversely, because TCF7L2 is postulated to influence insulin secretion by regulating the
action of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a different step in the
insulin secretion pathway, the effect of sulfonylureas on insulin secretion could be
independent of genetic variation at TCF7L2. In addition, physiological responses to an
insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of
reported genetic associations.

Despite the convincing associations of several genetic variants with type 2 diabetes and
their involvement in physiological pathways involved in drug response, their impact on
pharmacological interventions has not been systematically examined. The completion of the
Human Genome Project and the high-density characterization of common human variation in four
different ethnic groups highlight the promise of genomic medicine. The elucidation of the
genetic architecture of complex phenotypes may help clinicians understand disease
heterogeneity, uncover new pathophysiological mechanisms, open the opportunity for novel
therapeutic interventions, provide predictive diagnostic and prognostic information, and
allow for individually tailored therapy that takes into account both the probability of
response and the incidence of drug-induced complications.

Inclusion Criteria:

- Male or non-pregnant female > 18 years of age

- Investigators will target preferentially people at risk of diabetes or requiring
diabetes meds

- The first tier of risk will be illustrated by one of the following variables (e.g.
established type 2 diabetes on diet therapy alone, elevated random glucose in
electronic medical record, PCOS, metabolic syndrome, obesity, history of gestational
diabetes, etc.)

- The second tier of risk will be illustrated by other features that correlate with
diabetes risk, such as a history of hypertension or dyslipidemia

- Otherwise healthy subjects may also be candidates for the study.

- Able and willing to give consent relevant to genetic investigation

Exclusion Criteria:

- Pregnant, nursing or at risk of becoming pregnant

- Currently taking any medications for the treatment of diabetes

- Currently on metformin for any other indication (e.g. PCOS)

- Onset of diabetes in a family member before age 25, with autosomal transmission of
diabetes across three generations

- History of liver or kidney disease

- Known severe allergic reactions to sulfonamides

- History of porphyria

- Documented estimated glomerular filtration rate (GFR) < 60 ml/min/1.73 m2, based on
the most recent serum creatinine measurement available in the electronic medical
record, and calculated by the Modification of Diet in Renal Disease equation (49)
available at http://www.nephron.com/cgi-bin/MDRD_GFR.cgi

- Currently taking medications known to affect glycemic parameters, such as
glucocorticoids, growth hormone or fluoroquinolones

- Planned radiologic or angiographic study requiring contrast within one week of
completion of this study

- Established coronary artery disease (CAD), defined as:

- History of myocardial infarction.

- History of revascularization (coronary artery bypass grafting, percutaneous coronary
intervention (e.g. stenting or balloon angioplasty).

- Evidence of ischemia on cardiac stress test.

- Enrolled in any other interventional study at time of screening through completion of
study protocol

- History of bariatric surgery

- History of seizures

- History of stroke/CVA