Mitochondrial oxidative function and type 2 diabetes.
The cause of insulin resistance and type 2 diabetes is unknown. The major part of insulin-mediated glucose disposal takes place in the skeletal muscle, and increased amounts of intramyocellular lipid has been associated with insulin resistance and linked to decreased activity of mitochondrial oxidative phosphorylation. This review will cover the present knowledge and literature on the topics of the activity of oxidative enzymes and the electron transport chain (ETC) in skeletal muscle of patients with type 2 diabetes. Different methods of studying mitochondrial function are described, including biochemical measurements of oxidative enzyme and electron transport activity, isolation of mitochondria for measurements of respiration, and ATP production and indirect measurements of ATP production using nuclear magnetic resonance (NMR) - spectroscopy. Biochemical markers of mitochondrial content are also discussed. Several studies show reduced activity of oxidative enzymes in skeletal muscle of type 2 diabetics. The reductions are independent of muscle fiber type, and are accompanied by visual evidence of damaged mitochondria. In most studies, the reduced oxidative enzyme activity is explained by decreases in mitochondrial content; thus, evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing. These impairments in oxidative function and mitochondrial morphology could reflect the sedentary lifestyle of the diabetic subjects, and the influence of physical activity on oxidative activity and mitochondrial function is discussed. The studies on insulin-resistant offspring of type 2 diabetic parents have provided important insights in the earliest metabolic defects in type 2 diabetes. These defects include reductions in basal ATP production and an attenuated response to insulin stimulation. The decreased basal ATP production does not affect overall lipid or glucose oxidation, and no studies linking changes in oxidative activity and insulin sensitivity in type 2 diabetes have been published. It is concluded that evidence of a functional impairment in mitochondria in type 2 diabetes is not convincing, and that intervention studies describing the correlation between changes in insulin resistance and mitochondrial function in type 2 diabetes are lacking. Specific effects of regular physical training and muscular work on mitochondrial function and plasticity in type 2 diabetes remain an important area of research.
Rabøl
Rasmus
R
The Copenhagen Muscle Research Centre, The Panum Institute, Department of Medical Physiology, University of Copenhagen, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark. rasmusr@mfi.ku.dk
Boushel
Robert
R
Dela
Flemming
F
D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D010085:Oxidative Phosphorylation