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Diabetes Pathophysiology and Genetics
Mitochondrial Dysfunction in Type 2 Diabetes – An Update
Muhammad A Abdul-Ghani
1
and Ralph A DeFronzo
2
1. Assistant Professor of Medicine; 2. Professor of Medicine, and Chief, Division of Diabetes, University of Texas Health Science Center at San Antonio
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
Insulin resistance in skeletal muscle and the liver is a central feature synthesis (glycogen synthase)
28
and glucose oxidation (pyruvate
of type 2 diabetes.
1
Insulin resistance is also believed to be the dehydrogenase and Krebs cycle activity).
28,29
In this article, we will
underlying mechanism responsible for the metabolic syndrome.
1–3
summarise the evidence implicating a possible role for impaired
Insulin-stimulated glucose disposal in skeletal muscle is reduced mitochondrial function in the pathogenesis of insulin resistance.
in insulin-resistant individuals due to impaired insulin signalling
3–5
and
multiple intracellular defects in glucose metabolism (reviewed in Free Fatty Acid Metabolism and
reference 5). Similar defects in insulin signalling have been reported Insulin Resistance
in the liver and adipocytes
6
and lead to impaired suppression of Due to its accessibility, most studies have examined the relationship
hepatic glucose production and lipolysis, respectively.
7,8
between fatty acid metabolism, mitochondrial function and insulin
resistance in skeletal muscle. In subjects with type 2 diabetes and
Compelling evidence suggests an important role for intracellular in obese insulin-resistant individuals without diabetes, muscle-
deposition of fat in non-adipose tissues, e.g. liver, skeletal, and fat oxidation is reduced, suggesting an abnormality in mitochondrial
cardiac muscle, and β cells
8–14
in the pathogenesis of insulin oxidative capacity in insulin-resistant individuals.
29–33
The ability of
resistance. Both increased exogenous fat intake (obesity) and insulin to suppress lipolysis in insulin-resistant individuals is also
excess endogenous fat input (accelerated lipolysis, as occurs in impaired
7
and leads to an increase in the plasma free fatty acid (FFA)
obesity and type 2 diabetes)
5
lead to increased lipid supply to concentration and enhanced FFA influx into the skeletal muscle. In the
insulin target tissues and excessive lipid accumulation. presence of impaired mitochondrial fat oxidation, an increased FFA
Alternatively, it can be argued that a decrease in oxidative capacity influx could explain the elevated intramyocellar fat content and
in insulin-responsive tissues is responsible for the increase in increase in intramyocellar long-chain FACoA, diacylglycerol (DAG),
intracellular fat content in non-adipose tissues. The intracellular and ceramide concentrations observed in type 2 diabetes and obese
lipid stores are in a state of constant turnover and the individuals without diabetes.
15–18
Increased levels of these toxic lipid
accumulation of toxic lipid metabolites, e.g. fatty acyl Co-A metabolites, through serine phosphorylation of major molecules in
(FACoA),
11,15,16
diacylglycerol (DAG)
17
and ceramide,
18
produces insulin the insulin signalling pathway, would impair insulin action and lead to
resistance through the activation of serine kinases, which interfere insulin resistance. Thus, an inherited or acquired mitochondrial
with the insulin signalling cascade
17–23
and inhibit multiple defect, in combination with increased fat supply to non-adipose
intracellular steps involved in glucose metabolism, including tissues, could explain the link between increased plasma FFA levels,
glucose transport and glucose phosphorylation,
24,27
glycogen the accumulation of intramyocellar lipids and insulin resistance.
20 © TOUCH BRIEFINGS 2009
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