Skeletal muscle mitochondrial capacity and insulin resistance in type 2 diabetes

Abstract

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 (VO(2max)) > 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 (31)P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATP(max)) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise.

Results: ATP(max) 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/m(2) · 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 ATP(max) within the T2DM population where 52% of subjects with T2DM had ATP(max) 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 ATP(max) and M-value in the whole population (r(2) = 0.35; P < 0.0001), there was no correlation between ATP(max) and M-value in the patients with T2DM (r(2) = 0.004; P = 0.79).

Conclusions: Mitochondrial capacity is not associated with insulin action in T2DM.

Trial registration: ClinicalTrials.gov NCT00401791 NCT00402012.

Fig. 1.

Precision and validity of ATP_max measurement. A, Precision of ATP_max measurement is shown by a test-retest plot of MRS/ATP_max measurement on two different occasions; B–D, ATP_max is positively correlated to VO_2max (B), fiber type I (C), and total OXPHOS protein content (D).

Fig. 2.

Cross-sectional measurement of ATP_max (A) and GDR (B) in athletes, healthy young controls (FH− and FH+), and obese and T2DM subjects. **, P < 0.01; ***, P < 0.001 vs. healthy control FH−.

Fig. 3.

Correlation of maximal ATP synthesis rate (ATP_max) with glucose disposal rate measured during a euglycemic hyperinsulinemic clamp in the whole population (A), in patients with T2DM only (B), and in the nondiabetic population (C). Correlation of resting ATP turnover (ATPase) with glucose disposal rate in the whole population (D), in patients with T2DM only (E), and in the nondiabetic population (F).