Mitochondrial Dysfunction in Type 2 Diabetes—An Update

Mitochondrial Dysfunction in Type 2 Diabetes—An Update

Abdul-Ghani Muhammad A, DeFronzo Ralph A
US Endocrinology - Volume 4 - Issue II
Published: April 2009
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Insulin resistance in skeletal muscle and the liver is a central feature of type 2 diabetes.1 Insulin resistance is also believed to be the underlying mechanism responsible for the metabolic syndrome.1–3 Insulin-stimulated glucose disposal in skeletal muscle is reduced in insulin-resistant individuals due to impaired insulin signaling3–5 and multiple intracellular defects in glucose metabolism (reviewed in reference 5). Similar defects in insulin signaling have been reported in the liver and adipocytes6 and lead to impaired suppression of hepatic glucose production and lipolysis, respectively.7,8

Compelling evidence suggests an important role for intracellular deposition of fat in non-adipose tissues, e.g. liver, skeletal, and cardiac muscle, and β cells8–14 in the pathogenesis of insulin resistance. Both increased exogenous fat intake (obesity) and excess endogenous fat input (accelerated lipolysis, as occurs in obesity and type 2 diabetes)5 lead to increased lipid supply to insulin target tissues and excessive lipid accumulation. Alternately, it can be argued that a decrease in oxidative capacity in insulin-responsive tissues is responsible for the increase in intracellular fat content in non-adipose tissues. The intracellular lipid stores are in a state of constant turnover and the accumulation of toxic lipid metabolites, e.g. fatty acyl Co-A (FACoA),11,15,16 diacylglycerol (DAG),17 and ceramide,18 produces insulin resistance through the activation of serine kinases, which interfere with the insulin signaling cascade17–23 and inhibit multiple intracellular steps involved in glucose metabolism, including glucose transport and glucose phosphorylation,24,27 glycogen synthesis (glycogen synthase),28 and glucose oxidation (pyruvate dehydrogenase and Krebs cycle activity).28,29 In this article, we will summarize the evidence implicating a possible role for impaired mitochondrial function in the pathogenesis of insulin resistance.

Free Fatty Acid Metabolism and Insulin Resistance
Due to its accessibility, most studies have examined the relationship between fatty acid metabolism, mitochondrial function, and insulin resistance in skeletal muscle. In subjects with type 2 diabetes and in obese insulin-resistant individuals without diabetes, muscle-fat oxidation is reduced, suggesting an abnormality in mitochondrial oxidative capacity in insulin-resistant individuals.29–33 The ability of insulin to suppress lipolysis in insulin-resistant individuals is also impaired7 and leads to an increase in the plasma free fatty acid (FFA) concentration and enhanced FFA influx into the skeletal muscle. In the presence of impaired mitochondrial fat oxidation, an increased FFA influx could explain the elevated intramyocellar fat content and increase in intramyocellar longchain FACoA, diacylglycerol (DAG), and ceramide concentrations observed in type 2 diabetes and obese individuals without diabetes.15–18 Increased levels of these toxic lipid metabolites, through serine phosphorylation of major molecules in the insulin signaling pathway, would impair insulin action and lead to insulin resistance. Thus, an inherited or acquired mitochondrial defect, in combination with increased fat supply to non-adipose tissues, could explain the link between increased plasma FFA levels, the accumulation of intramyocellar lipids, and insulin resistance.

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