Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes

Abstract

Aims/hypothesis: Mitochondrial respiration has been linked to insulin resistance. We studied mitochondrial respiratory capacity and substrate sensitivity in patients with type 2 diabetes (patients), and obese and lean control participants. Methods: Mitochondrial respiration was measured in permeabilised muscle fibres by respirometry. Protocols for respirometry included titration of substrates for complex I (glutamate), complex II (succinate) and both (octanoylcarnitine). Myosin heavy chain (MHC) composition, antioxidant capacity (manganese superoxide dismutase [MnSOD]), citrate synthase activity and maximal oxygen uptake (V̇O 2max) were also determined. Insulin sensitivity was determined with the isoglycaemic-hyperinsulinaemic clamp technique. Results: Insulin sensitivity was different (p<0.05) between the groups (patients <0.05) in lean controls than in patients and obese controls. When normalised for mitochondrial content by citrate synthase, mitochondrial respiratory capacity was similar in all groups. However, the half maximal substrate concentration (C50) for complex I was significantly lower (p=0.03) in patients (1.1±0.2 mmol/l [mean ± SE]) than in obese (2.0±0.3) and lean (1.8±0.3) controls. Likewise, C 50 for complex II was lower (p=0.02) in patients (3.5±0.2 mmol/l [mean ± SE]) than in obese controls (4.1±0.2), but did not differ from that in lean controls (3.8±0.4). Substrate sensitivity for octanoyl-carnitine did not differ between groups. Conclusions/interpretation: Increased mitochondrial substrate sensitivity is seen in skeletal muscle from type 2 diabetic patients and is confined to non-lipid substrates. Respiratory capacity per mitochondrion is not decreased with insulin resistance. © Springer-Verlag 2011.