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Diabetes Publish Ahead of Print published online ahead of print February 7, 2007
DOI: 10.2337/db06-0783
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Original Research

Impaired Mitochondrial Substrate Oxidation in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic Patients

Douglas E Befroy1, Kitt Falk Petersen1, Sylvie Dufour4, Graeme F Mason2, Robin A. de Graaf2, Douglas L. Rothman2, and Gerald I. Shulman1,,3,,4

1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536
2Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT 06536
3Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536
4Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06536

Correspondence: gerald.shulman{at}yale.edu

Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased mitochondrial ATP synthesis and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type 2 diabetics. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes. To further explore this hypothesis we assessed rates of substrate oxidation in the muscle of these same individuals using 13C Magnetic Resonance Spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetics and insulin-sensitive control subjects underwent 13C-MRS studies to non-invasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13C label into C4 glutamate during a [2-13C]acetate infusion. Using this approach we found that rates of muscle mitochondrial substrate oxidation were decreased by 30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol/g/min, p=0.02) as compared to insulin-sensitive control subjects (96.1 ± 16.3 nmol/g/min). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly due to an inherited defect in the activity of mitochondrial oxidative-phosphorylation.


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