Impaired substrate switching and reduced muscle mitochondrial content in subjects with a family history of type 2 diabetes

The study was aimed at testing the hypothesis that defects in substrate switching in response to insulin (metabolic inflexibility, i.e. the ability to switch from muscle lipid oxidation in the fasting state to glucose oxidation in response to insulin) and a high-fat diet (HFD) are associated with reduced mitochondrial biogenesis and decreased levels of PPAR-gamma coactivator-1alpha (PGC-1alpha). To this end, metabolic flexibility was determined by euglycaemic-hyperinsulinaemic clamp in 16 young sedentary men with a family history of diabetes and in 34 control subjects without such a history. Flexibility was correlated with fat oxidation measured in a respiratory chamber after a 3-day HFD. In flexible subjects with high HFD-induced fat oxidation, muscle mitochondrial content was higher, contributing 49% of the variance. Although subjects with a family history of diabetes did not differ in the amount of body fat or visceral fat, they were inflexible and exhibited reduced HFD-induced fat oxidation. In conclusion, metabolic inflexibility, impaired substrate switching and reduced muscle mitochondrial content appear to cluster in subjects with a family history of type 2 diabetes.

Abstract