Skeletal Muscle Mitochondrial Capacity and Insulin Resistance in Type 2 Diabetes

Maximal mitochondrial ATP synthesis, measured by dynamic 31P magnetic resonance spectroscopy, is reduced in type 2 diabetes but is not associated with insulin resistance. Objective: The objective of this study was to determine the role of maximum mitochondrial capacity on the variation in insulin sensitivity within a population of patients with type 2 diabetes mellitus (T2DM). Research Design and Methods: Fifty-eight participants enrolled in a cross-sectional design: eight active controls [maximum aerobic capacity (VO2max) > 40 ml/kg · min], 17 healthy sedentary controls without a family history (FH−) and seven with a family history (FH+) of diabetes, four obese participants, and 21 patients with T2DM. Mitochondrial capacity was measured noninvasively using 31P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATPmax) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise. Results: ATPmax was lower (P < 0.001) in T2DM and higher (P < 0.001) in active as compared with healthy sedentary FH− (active, 1.01 ± 0.2; FH−, 0.7 ± 0.2; FH+, 0.6 ± 0.1; obese, 0.6 ± 0.1; T2DM, 0.5 ± 0.2 mm ATP/sec; ANOVA P < 0.0001). Insulin sensitivity, measured by euglycemic-hyperinsulinemic (80 mIU/m2 · min) clamp was also reduced in T2DM (P < 0.001) (active, 12.0 ± 3.2; FH−, 7.8 ± 2.2; FH+, 6.8 ± 3.5; obese, 3.1 ± 1.0; T2DM, 3.4 ± 1.6; mg/kg estimated metabolic body size · min; ANOVA P < 0.0001). Unexpectedly, there was a broad range of ATPmax within the T2DM population where 52% of subjects with T2DM had ATPmax values that were within the range observed in healthy sedentary controls. In addition, 24% of the T2DM subjects overlapped with the active control group (range, 0.65–1.27 mm ATP/sec). In contrast to the positive correlation between ATPmax and M-value in the whole population (r2 = 0.35; P < 0.0001), there was no correlation between ATPmax and M-value in the patients with T2DM (r2 = 0.004; P = 0.79). Conclusions: Mitochondrial capacity is not associated with insulin action in T2DM.