ACTIV- Exercise Intervention in Healthy Young Men

Skeletal muscle mitochondrial defects are a sine qua non of insulin resistance in patients with type 2 diabetes mellitus (T2DM), obese and subjects with family history of T2DM (FH+). Exercise increases mitochondrial capacity whereas lipid infusion or high fat diet decreases genes involved in mitochondrial biogenesis. In this study 2 cohorts will be involved: Cohort I (athletes, T2DM and obese) and Cohort II (healthy with "FH+" or without "FH-" family history of T2DM). This randomized, parallel arm clinical trial will consist of 4 periods: screening, stabilization (3 days), baseline (for Cohort I and II) and exercise period (14 days, only for Cohort II). The overall objective of the study is to validate a paradigm for the evaluation of compounds and drugs that activate mitochondrial biogenesis in skeletal muscle. In Specific Aim 1 we will compare and contrast biopsy and MRS power to detect differences in mitochondrial capacity in 78 subjects: athletes (N=10), FH- (N=24), FH+ (N=24), obese (N=10) and T2DM (N=10). In Specific Aim 2 we will compare mitochondrial changes in response to exercise in subjects FH - vs. FH + subjects. In Specific Aim 3 we will determine if HFD impairs mitochondrial changes in response to exercise in FH+ subjects. In Specific Aim 4 we will determine the role of mitochondrial capacity in metabolic flexibility and insulin sensitivity in T2DM, obese, FH+, FH- and athlete subjects.

Inclusion criteria

T2DM group:

• Men aged 25-35
• BMI > 30 kg/m2
• Sedentary lifestyle determined by activity index questionnaire (not involved in regular exercise program) and accelerometer data.
• Are willing to eat only foods provided by Pennington for the study period
• Diagnosed with T2DM defined by one or more of the following:

• fasting plasma glucose > 126 mg/dL at entry
• a two-hour OGTT glucose > 200mg/dL
• current medication for T2DM

Obese group:

• Men aged 25-35
• BMI > 30 kg/m2
• Sedentary lifestyle activity index questionnaire (not involved in regular exercise program) and accelerometer data.
• Are willing to eat only foods provided by Pennington for the study period

FH+ group:

• Men aged 25-35
• One parent diagnosed with T2DM
• fasting insulin > 10mIU/ml (> 50th %tile)
• BMI between 22 and 30 kg/m2
• Sedentary lifestyle activity index questionnaire (not involved in regular exercise program) and accelerometer data.
• Are willing to exercise every day for the study period
• Are willing to eat only foods provided by Pennington for the study period

FH- group:

• Men aged 25-35
• Parents and grandparents were not diagnosed with T2DM
• Fasting insulin < 10mIU/ml (< 50th %tile)
• BMI between 22 and 30 kg/m2
• Sedentary lifestyle activity index questionnaire (not involved in regular exercise program) and accelerometer data.
• Are willing to exercise for the study period
• Are willing to eat only foods provided by Pennington for the study period

Athlete group:

• Men aged 25-35
• Maximal oxygen uptake > 60 ml/kg.min
• Are engaged in minimum of 1.5 h of aerobic exercise 3 times/ week
• Are willing to eat only foods provided by Pennington for the study period

Exclusion criteria

• Abnormal resting or exercise ECG
• Significant renal, cardiac, liver, lung, or neurological disease (controlled hypertension is acceptable if baseline bp < 140/90 on medications)
• Use of drugs known to affect energy metabolism or body weight: including, but not limited to: orlistat, sibutramine, ephedrine, phenylpropanolamine, corticosterone, etc
• Alcohol or other drug abuse
• Smoking
• Gait problems
• Unwilling or unable to abstain from caffeine (48h) prior to metabolic rate measurements
• Unwilling or unable to eat all study foods
• Increased liver function tests at baseline (AST/ALT/GGT/or alkaline phosphatase greater than 2.5 times the upper limit of normal)
• Metal objects that would interfere with the measurement of body composition /MRS such as implanted rods, surgical clips, etc
• NYHA class III/IV CHF is an exclusionary cardiac condition
• history of deep vein thrombosis (DVT) or pulmonary embolism (PE)
• varicose veins
• major surgery on the abdomen, pelvis, or lower extremities within previous 3 months
• cancer (active malignancy with or without concurrent chemotherapy)
• rheumatoid disease
• bypass graft in limb
• known genetic factor (Factor V Leiden, etc) or hypercoagulable state
• diagnosed peripheral arterial or vascular disease, or intermittent claudication
• family history of primary DVT or PE (pulmonary embolism)
• peripheral neuropathy