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Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance^1,2,3

¹ From the Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO.

² Presented at the symposium "The Emerging Interplay among Muscle Mitochondrial Function, Nutrition, and Disease,"held at Experimental Biology 2008, San Diego, CA, 5 April 2008

³ Reprints not available. Address correspondence to JO Holloszy, Washington University School of Medicine, 4566 Scott Avenue, Campus Box 8113, St Louis, MO 63110. E-mail: jhollosz{at}dom.wustl.edu.

Patients with type 2 diabetes, insulin-resistant obese individuals, and insulin-resistant offspring of patients with diabetes have 30% less mitochondria in their skeletal muscles than age-matched healthy controls. It has been hypothesized that this "deficiency" of mitochondria mediates insulin resistance by impairing the ability of muscle to oxidize fatty acids (FAs). However, a 30% decrease in mitochondria should not impair the ability of muscle to oxidize FAs because the capacity of muscle to oxidize substrate is far in excess of what is needed to supply energy in the basal state, ie, in resting muscle. In pathologic states in which mitochondrial content/function is so severely impaired as to limit substrate oxidation in resting muscle, glucose uptake and insulin action are actually enhanced. Recent studies have shown that feeding rodents high-fat diets and raising FA concentrations results in muscle insulin resistance despite an increase muscle mitochondria that enhances the capacity for fat oxidation. Furthermore, it was recently shown that skeletal muscle mitochondrial capacity for oxidative phosphorylation in Asian Indians with type 2 diabetes is the same as in nondiabetic Indians and higher than in healthy European Americans. In light of this evidence, it seems highly unlikely that "mitochondrial deficiency" causes muscle insulin resistance.

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