Epigenetics of Muscle Insulin Resistance

Insulin resistance is defined as the decreased ability of insulin to perform its biological
function in the muscle, liver and fat. Genetic and environmental factors are known to
influence insulin sensitivity. It is not known how this is mediated. This study looks at the
role of epigenetics (modifications of proteins associated with DNA and methylation of DNA) in
alterations in insulin resistance. The investigators will study lean healthy people, obese
non-diabetic people and people with type 2 diabetes to characterize the DNA methylation
patterns in muscle in each group. The second aim of the study is to see how a single bout of
exercise affects the DNA methylation in the muscle. The third aim looks at the effect of 8
weeks of supervised exercise on the DNA methylation.

Inclusion Criteria

1. Age 21-55

2. BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30- 50; type 2 diabetic,
BMI between 30- 50.

3. Subjects must be able to communicate meaningfully with the investigator and must be
legally competent to provide written informed consent.

4. Subjects may be of either sex with age as described in each protocol. Female subjects
must be non-lactating and will be eligible only if they have a negative pregnancy test
throughout the study period.

5. Subjects must range in age as described in each specific protocol.

6. Subjects must have the following laboratory values:

1. Hematocrit ≥ 35 vol%

2. Serum creatinine ≤ 1.6 mg/dl

3. AST (SGOT) < 2 times upper limit of normal

4. ALT (SGPT) < 2 times upper limit of normal

5. Alkaline phosphatase < 2 times upper limit of normal

6. Triglycerides < 150 mg/dl for nondiabetics

7. Triglycerides <300 for diabetics

8. INR ≤ 1.3

Exclusion Criteria

1. Subjects must not be receiving any of the following medications: thiazide or
furosemide diuretics, beta-blockers, or other chronic medications with known adverse
effects on glucose tolerance levels unless the patient has been on a stable dose of
such agents for the past three months before entry into the study. Subjects may be
taking a stable dose of estrogens or other hormonal replacement therapy, if the
subject has been on these agents for the prior three months. Subjects taking systemic
glucocorticoids are excluded. Patients with type 2 diabetes will be excluded if they
are taking thiazolidinediones, but may be taking sulfonylureas or other medications
known to work through effects on insulin secretion.

2. Subjects receiving Gemfibrozil must not also be receiving a statin.

3. Subjects with a history of clinically significant heart disease (New York Heart
Classification greater than grade II; more than non-specific ST-T wave changes on the
EKG), peripheral vascular disease (history of claudication), or pulmonary disease
(dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation)
will not be studied.

4. Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy,
recent retinal hemorrhage, uncontrolled hypertension, systolic BP>180, diastolic
BP>105, autonomic neuropathy, resting heart rate >100, electrolyte abnormalities.