Role of Mitochondrial Function in Insulin Resistance

The obesity pandemic increases the prevalence of type 2 diabetes (DM2). DM2 develops when pancreatic beta-cells fail and cannot compensate for the decrease in insulin sensitivity. How excessive caloric intake and weight gain cause insulin resistance has not completely been elucidated. Skeletal muscle is responsible for a major part of insulin stimulated whole-body glucose disposal and, hence, plays an important role in the pathogenesis of insulin resistance. It has been hypothesized that skeletal muscle mitochondrial dysfunction is involved in the accumulation of intramyocellular lipid metabolites leading to lipotoxicity and insulin resistance. However, findings on skeletal muscle mitochondrial function in relation to insulin resistance in human subjects are inconclusive. Differences in mitochondrial activity can be the result of several factors, including a reduced mitochondrial density, differences in insulin stimulated mitochondrial respiration, lower energy demand or reduced skeletal muscle perfusion, besides an intrinsic mitochondrial defect. The inconclusive results may be explained by the use of different techniques and study populations. Also, mitochondrial capacity is in far excess to meet energy requirements and therefore it may be questioned whether a reduced mitochondrial capacity limits mitochondrial fatty acid oxidation. Whether reduced mitochondrial function is causally related to insulin resistance or rather a consequence of the sedentary lifestyle remains to be elucidated.