Effect of Pioglitazone on Mitochondrial Function in Muscle and Adipose Tissue in Humans

1. Subjects must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent.
2. 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.
3. Subjects must range in age from 18-65.

4. Subjects must have the following laboratory values:

   • 2-hour OGTT plasma glucose 140-250 mg/dl
   • Hematocrit ≥ 35 vol%
   • Serum creatinine ≤ 1.6 mg/dl
   • AST (SGOT) \< 2.5 times upper limit of normal
   • ALT (SGPT) \< 2.5 times upper limit of normal
   • PT, PTT within the normal range

Exclusion Criteria:

1. Subjects must not be receiving any medications with known effects on glucose tolerance unless the subject has been on stable dose of such agents for the past three months before entry into the study. Subjects taking systemic glucocorticoids will be excluded. 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.
2. History of clinically significant heart disease, including ischemic heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG) and congestive heart failure
3. History of peripheral vascular disease (history of claudication)
4. History of pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
5. History of peripheral edema
6. Uncontrolled hypertension with systolic BP>160 mmHg, diastolic BP>100 mmHg
7. Resting heart rate >100 beats/min
8. Autonomic neuropathy
9. Heavy alcohol consumption (> 2 drinks/day)