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