ACTIV- Exercise Intervention in Healthy Young Men

The study is designed to compare muscle energy capacity in men with obesity or diabetes as compared to athletes. This study will also enable researchers to determine whether MRS can replace muscle biopsy for this type of assessment.

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.

Eligibility Criteria:
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