MiP2005: Session 10

Mitochondrial Physiology Network 10.9: 120 (2005) - download pdf


Reduced skeletal muscle mitochondrial O2 flux capacity in type 2 diabetes.

Flemming Dela,1 E Gnaiger,2 R Boushel3

1Medical Physiol. Inst., Panum Institute, Univ. Copenhagen; 2D. Swarovski Research Lab., Dept. Transplant Surgery, Innsbruck Medical Univ., Austria; 3Dept. Exercise Science, Concordia Univ., Montreal, Canada. - fdela@mfi.ku.dk

    Hyperglycemia in insulin-resistant type 2 diabetes is associated with mitochondrial dysfunction characterized by diminished mitochondrial oxidative capacity and proton uncoupling, elevated membrane potential, increased ROS production and impaired lipid metabolism. While mitochondria are considered a central locus of altered metabolic pathways leading to pathogenic processes in type 2 diabetes, the mechanisms underlying these factors remains to be elucidated. Evidence for reduced oxidative capacity of skeletal muscle in diabetes is based on markers of oxidative enzyme levels and gene expression defects, yet there is a paucity of data reporting direct measures of mitochondrial O2 flux capacity in cells. In this study, O2 flux capacity of permeabilized muscle fibers from biopsies of the quadriceps in healthy humans (n=5) and patients with type 2 diabetes (n=7) was measured at 37 °C using high resolution respirometry (OROBOROS Oxygraph-2k). Oxygen flux was expressed per mg muscle fresh weight. Diabetic and control subject characteristics were; age = 62 ± 2 and 56 ± 2 yrs; body mass index =  33 ± 2 and 29 ± 1 kg/m2; fasting glucose = 8.7 ± 0.8 and 5.3 ± 0.2 mM; lactate = 1.3 ± 0.1 and 1.5 ± 0.4 mM, respectively.

    In healthy controls and diabetics respectively, ADP-stimulated state-3 respiration with complex I substrate (glutamate) was 43±4 vs. 33±2 pmol O2∙s-1∙mg-1, and state-3 O2 flux with parallel electron input from complex I+II (glutamate+succinate) was 87±8 vs. 70±3 pmol∙s-1∙mg-1. Further increases in flux capacity were observed with uncoupling by FCCP, but were lower in type 2 diabetics (106±12 vs. 84±2 pmol∙s-1∙mg-1). Subsequent fluxes with rotenone were 73±9 vs. 58±3 allowing for an estimation of individual fluxes through complex I and II. The findings demonstrate serial blunting of state-3 O2 flux with electron flux through either complex I or II, and a similar reduction with parallel electron input through both complexes. Furthermore, on the basis of similar uncoupled responses relative to state 3 (glutamate+succinate) in both healthy (1.22) and diabetic subjects (1.2), the results reflect an attenuation of mitochondrial oxidative capacity in skeletal muscle of type 2 diabetic patients indicative of an impaired  electron transport capacity.

     Supported by the Lundbeck Foundation and Fonds de la Recherche en Sante Quebec. The authors acknowledge the excellent technical work of Regitze Kraunsøe.

1.  Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615-25.

2.  Schrauwen P, Hesselink MK (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53: 1412-1417.


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