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Mitochondrial Dysfunction in Type 2 Diabetes – An Update

Published Online: June 6th 2011 European Endocrinology, 2009; 5:28-31; DOI: http://doi.org/10.17925/ee.2009.05.00.28
Authors: Ralph A DeFronzo, Muhammad A Abdul-Ghani
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Abstract
Insulin resistance is a characteristic feature of type 2 diabetes, obesity and the metabolic syndrome. The increase in intracellular fat content in skeletal muscle and liver associated with insulin resistance has led to the hypothesis that a mitochondrial defect in substrate oxidation exists in disorders of insulin resistance, leading to the accumulation of toxic lipid metabolites that impair insulin signalling. In vivo measurements (utilising NMR spectroscopy) of metabolic fluxes through both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation with magnetic resonance spectroscopy have demonstrated multiple defects in mitochondrial function in skeletal muscle. A decrease in mitochondrial density and mitochondrial copy number has also been reported in insulin-resistant individuals. However, these findings have not been a consistent observation in all studies. Similarly, an intrinsic functional defect in mitochondrial adenosine triphosphate (ATP) synthesis has been reported in some but not all studies. In this article we summarise the evidence that implicates a defect in mitochondrial oxidative phosphorylation and its relationship to insulin resistance in common metabolic diseases characterised by impaired insulin action.

Keywords
Mitochondrial dysfunction, mitochondrial adenosine triphosphate synthesis, type 2 diabetes, insulin resistance

Disclosure: The authors have no conflicts of interest to declare.
Received: 2 January 2009 Accepted: 6 February 2009
Correspondence: Muhammad A Abdul-Ghani, Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, US. E: abdulghani@uthscsa.edu

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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. Insulin-stimulated glucose disposal in skeletal muscle is reduced in insulin-resistant individuals due to impaired insulin signalling and multiple intracellular defects in glucose metabolism (reviewed in reference 5). Similar defects in insulin signalling have been reported in the liver and adipocytes and lead to impaired suppression of hepatic glucose production and lipolysis, respectively.

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. Insulin-stimulated glucose disposal in skeletal muscle is reduced in insulin-resistant individuals due to impaired insulin signalling and multiple intracellular defects in glucose metabolism (reviewed in reference 5). Similar defects in insulin signalling have been reported in the liver and adipocytes and lead to impaired suppression of hepatic glucose production and lipolysis, respectively.

Compelling evidence suggests an important role for intracellular deposition of fat in non-adipose tissues, e.g. liver, skeletal, and cardiac muscle, and β cells 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. Alternatively, 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) diacylglycerol (DAG) and ceramide produces insulin resistance through the activation of serine kinases, which interfere with the insulin signalling cascade and inhibit multiple intracellular steps involved in glucose metabolism, including glucose transport and glucose phosphorylation glycogen synthesis (glycogen synthase) and glucose oxidation (pyruvate dehydrogenase and Krebs cycle activity). In this article, we will summarise the evidence implicating a possible role for impaired mitochondrial function in the pathogenesis of insulin resistance.

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