PGC-1 & Muscle Mitochondrial Dysfunction in Diabetes

The goal of this study is to understand how and why insulin resistant individuals respond
differently to exercise as compared with insulin sensitive individuals at the skeletal
muscle and gene expression level. The study has four aims including testing if MZF1, NFKB1,
RELA, SP1/KLF and EGRI expression responses are outside of the normal range in insulin
resistant individuals and how insulin resistance changes the cell biosynthesis process/ post
translational modifications. It also aims to define the response of MiRNAs in healthy and
insulin resistant individuals and determine if treatment with Gemfibrozil inhibits
transcription processes.

Inclusion Criteria: Aims1-3

1. Age 30-59

2. BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30-40; type 2 diabetic,
BMI between 30-40.

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:

- Hematocrit ≥ 35 vol%

- Serum creatinine ≤ 1.6 mg/dl

- AST (SGOT) < 2 times upper limit of normal

- ALT (SGPT) < 2 times upper limit of normal

- Alkaline phosphatase < 2 times upper limit of normal

- Triglycerides < 150 mg/dl (except for Aim 4).

Aim 4

1. Age 30-59

2. BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30-40.

3. Patients may have normal or impaired glucose tolerance.

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

5. 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.

6. Subjects must have the following laboratory values:

- Hematocrit ≥ 35 vol%

- Serum creatinine ≤ 1.6 mg/dl

- AST (SGOT) < 2 times upper limit of normal

- ALT (SGPT) < 2 times upper limit of normal

- Alkaline phosphatase < 2 times upper limit of normal

- Triglycerides > 300 mg/dl for nondiabetics, > 250 mg/dl for impaired glucose
tolerance.

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 metformin or 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.