Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle

R Boushel, E Gnaiger, P Schjerling, M Skovbro, R Kraunsøe, F Dela, R Boushel, E Gnaiger, P Schjerling, M Skovbro, R Kraunsøe, F Dela

Abstract

Aims/hypothesis: Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content.

Materials and methods: The O(2) flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 +/- 2 years [mean+/-SEM]; BMI 28 +/- 1 kg/m(2); fasting plasma glucose 5.4 +/- 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 +/- 2 years; BMI 32 +/- 2 kg/m(2); fasting plasma glucose 9.0 +/- 0.8 mmol/l) was measured by high-resolution respirometry.

Results: O(2) flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 +/- 2 vs 43 +/- 3 pmol O(2) s(-1) mg(-1)) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 +/- 3 vs 85 +/- 6 pmol s(-1) mg(-1)). Further increases in O(2) flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 +/- 4 vs 109 +/- 8 pmol s(-1) mg(-1)). However, when O(2) flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects.

Conclusions/interpretation: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.

Figures

Fig. 1
Fig. 1
Glucose (a) and insulin (b) concentrations in venous plasma before (t = 0 min) and during an OGTT. The patients with type 2 diabetes had higher fasting glucose levels and were severely insulin resistant compared with healthy control subjects (*p < 0.05). Black and white symbols represent healthy control subjects and patients with type 2 diabetes, respectively
Fig. 2
Fig. 2
O2 flux in permeabilised skeletal muscle fibres from patients with type 2 diabetes and healthy control subjects. Data are shown as O2 flux per mg of tissue (a) and further normalised to the number of copies of mtDNA per μg of tissue ×10,000 (b). When data are expressed relative to mtDNA, any difference between the groups disappears. Data are means±SEM (*p < 0.05). Black and white bars represent healthy control subjects and patients with type 2 diabetes, respectively
Fig. 3
Fig. 3
a Respiratory control ratio for complex I (NADH supply from substrates glutamate + malate) measured as the ratio of O2 flux with (state 3) and without (state 2) ADP. b Electron transport capacity measured as O2 flux after FCCP-induced uncoupling relative to coupled O2 flux at state 3 with malate + glutamate + ADP + succinate (parallel electron input into both complex I and II). No significant difference between the groups was noted. Data are means±SEM

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