 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 N10, FH- N24, FH N24, obese N10 and T2DM N10. 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. 