Mechanism of Insulin-Resistant in Lean Non-Diabetics

The study is designed to test the following primary hypothesis: Aerobic exercise training will improve insulin sensitivity in insulin resistant subjects through changes in the major cellular signaling pathways and and/or their regulators. Accordingly, the proposed study is designed to accomplish the following specific aims: Quantitate how exercise training improves insulin sensitivity and decreases cardiovascular risk factors in a general population of lean, nondiabetic, insulin resistant subjects. Effects on known cardiovascular risk factors including blood pressure and serum lipoproteins will be evaluated. Change in regional adiposity will also be measured Determine the effects of a program of regular aerobic exercise on in the insulin receptor signaling pathway. Biopsies of vastus lateralis muscle from insulin resistant subjects will be obtained before and after a hyperinsulinemic glucose clamp. This procedure will take place in the untrained state and after exercise training. The investigators will measure changes in the insulin receptor and the activity of the major components of the intracellular insulin signaling pathway. The investigators will also look intracellular proteins that regulate this signaling pathway.

Patients exercise under supervision on either a treadmill, Stair Master, or LifeCycle apparatus. Exercise frequency, duration, and intensity will be incrementally increased to minimize the risk of injury. During weeks 1-3, you will exercise for 30 minutes 3 days per week at 70- 80 % of your maximum heart rate (MHR); weeks 4-7 will consist of exercising for 40 minutes 4 days per week at 70-80% of your MHR; and weeks 7-12 will consist of exercising for 45 minutes 4 days per week at 80-85% MHR

subjects randomized to this group will not undergo exercise training for 12 weeks supervised by exercise specialist

Inclusion Criteria: Men and women aged 20-50 No regular exercise for past 2 years Exclusion Criteria: Diabetes, Cardiovascular disease, Pregnant or lactating females,BMI >27 Medications that may interfere with carbohydrate metabolism - glucocorticoids, adrenergic agonists, ACE inhibitors, alpha blockers, diuretics, beta blockers, oral contraceptives, HMG CoA reductase inhibitors History of epilepsy, cancer, hepatitis, active infection, active Graves' disease, cystic fibrosis, sickle cell anemia, peripheral vascular disease, cerebrovascular disease, asthma Any medical condition that in the opinion of the investigator will interfere with safe completion of the trial Inability to give informed consent Prior participation in a clinical trial that could potentially alter insulin sensitivity: e.g., use of new insulin sensitizers HIV seropositive Anemia (Hgb < 12 g/dl)