Original Article Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle

Insulin resistance is associated with metabolic inflexibil-ity, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Impaired switching to fat oxidation in response to a high-fat diet (HFD) is hypothesized to contribute to insulin resistance. The ob-jective of this study was to test the hypothesis that defects in substrate switching in response to insulin and a HFD are linked to reduced mitochondrial biogenesis and occur be-fore the development of diabetes. Metabolic flexibility was measured in young sedentary men with (n 16) or without (n 34) a family history of diabetes by euglycemic-hyperinsulinemic clamp. Flexibility correlated with fat ox-idation measured in a respiratory chamber after a 3-day HFD. Muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a HFD and contrib