Physical Inactivity and Insulin Resistance in Skeletal Muscle.

In this project we will study two diverse groups of subjects. Group 1 will be subjects who
are sedentary, insulin resistant, and have the Metabolic Syndrome. These subjects will be
tested for insulin sensitivity at the whole body level, and for key changes in skeletal
muscle metabolism at baseline, following 12 weeks of exercise training, and during an acute
(1-3 days) period of time following the cessation of exercise training. The design allows us
to study the effects of exercise on improving insulin sensitivity and make direct
comparisons to a period when insulin sensitivity quickly decreases because of the removal of
exercise training. Metformin is a drug commonly prescribed to control insulin resistance and
type 2 diabetes. Metformin is thought to have exercise like effects on muscle metabolism and
is known to activate a molecule that is de-activated during inactivity. Thus, half of the
Metabolic Syndrome subjects will cease exercise training with no treatment while another
half will quite exercise training while taking the drug Metformin.

Group 2 subjects will be highly trained endurance athletes. Endurance athletes display high
levels of insulin sensitivity that can drop in the hours and days following the cessation of
exercise. Thus we will take the same measurements in endurance athletes at baseline during
their normal training regimen and in the acute (1-3 days) period following the cessation of
exercise training. Again, half of the subjects will be take Metformin during the cessation
of exercise in the same fashion as done in group 1.

Studies in both groups seek to determine the event(s) which cause insulin resistance in
skeletal muscle following a decrease in physical activity levels. Comparisons between
healthy, active individuals and sedentary Metabolic Syndrome subjects may provide additional
information about the underlying events that cause insulin resistance.

Inclusion Criteria:

- Selection of inclusion for Metabolic Syndrome Subjects :

Sedentary metabolic syndrome subjects will be 20-55 y of age, overweight to Class I or II
obese (BMI 25-39 kg/m2) men and women, who have a fasting glucose of 100 to 125 mg/dl, and
at least 2 of 4 other characteristics of the metabolic syndrome which are the following:
waist circumference greater than 102 cm in men and 88 cm in women, serum triglyceride
concentration greater than 150 mg/dl, HDL-C concentration greater than 40 mg/dl in men and
50 mg/dl in women, and blood pressure greater than 130/85 mmHG.

Selection for inclusion for Endurance Athlete Subjects:

Subjects who report training (running and/or biking) greater than 30 min a day, 4 days a
week for at least 1 year will be included. Final inclusion criteria will be a VO2max of
greater than 55 ml/kg/min.

To take part in the study, Women must currently be taking birth control or be
postmenopausal.

Exclusion Criteria:

- Subjects will be excluded from the study if they have or are:

Diagnosed cardiovascular disease or diabetes or disease symptoms that could alter their
ability to perform exercise, fasting blood glucose of greater than 126 mg/dl, smokers,
taking any medications or supplements (e.g., statins, fibrates, metformin,
thiazolidinediones, anti-hypertensives (ACE-inhibitors and angiotensin blockers) which
could affect blood lipids or insulin sensitivity.

Women who are pregnant or plan to become pregnant during the duration of the study For the
Metabolic Syndrome subjects only individuals exercising regularly (more than one 30 min
session per week) or have a physically active lifestyle (>8,000 daily steps as measured by
a pedometer) will be excluded.

Individuals with an orthopedic limitations for walking. Allergies to drugs used in the
study. Past or current liver and/or kidney problems of any nature.