Mitochondrial DNA copy number associates with insulin sensitivity and aerobic capacity, and differs between sedentary, overweight middle-aged males with and without type 2 diabetes

Background/objectives Increased risk of type 2 diabetes mellitus (T2DM) is linked to impaired muscle mitochondrial function and reduced mitochondrial DNA copy number (mtDNA(num)). However, studies have failed to control for habitual physical activity levels, which directly influences both mtDNA copy number and insulin sensitivity. We, therefore, examined whether physical conditioning status (maximal oxygen uptake, V?O-2max) was associated with skeletal muscle mitochondrial volume and mtDNA(num), and was predictive of T2DM in overweight, middle-aged men. Methods Whole-body physiological (ISI-insulin sensitivity index, HOMA-IR, V?O-2max) and muscle biochemical/molecular (vastus lateralis; mtDNA(num), mitochondrial and glycolytic enzymes activity, lipid content and markers of lipid peroxidation) measurements were performed in three groups of overweight, middle-aged male volunteers (n = 10 per group): sedentary T2DM (ST2DM); sedentary control (SC) and non-sedentary control (NSC), who differed in aerobic capacity (ST2DM < SC < NSC). Results mtDNA(num) was greater in NSC versus SC and ST2DM (P < 0.001; P < 0.001), and less in ST2DM versus SC (P < 0.01). Across all groups, mtDNA(num) positively correlated with ISI (P < 0.001; r = 0.688) and V?O-2max (normalised to free fat mass; r = 0.684, P < 0.001), and negatively correlated to HOMA-IR (r = -0.544, P < 0.01). The activity of mitochondrial enzymes (GluDH, CS and beta-HAD) was greater in NSC than ST2DM (P < 0.01, P < 0.001 and P < 0.05) and SC (P < 0.05, P < 0.01 and P < 0.05), but similar between ST2DM and SC. Intramuscular-free fatty acids, triglycerides and malondialdehyde contents were similar between ST2DM and SC. Conclusions Body composition and indices of muscle mitochondrial volume/function were similar between SC and ST2DM. However, mtDNA(num) differed and was positively associated with ISI, HOMA-IR and V?O-2max across all groups. Collectively, the findings support the contention that habitual physical activity is a key component of T2DM development, possibly by influencing mtDNA(num).