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Muscle-Specific Overexpression of CD36 Reverses the Insulin Resistance and Diabetes of MKR Mice

Diabetes Branch (L.H.-M., M.H., S.Y., O.G., S.P., W.C.J., H.K., D.H., D.L.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Mouse Metabolic Core Facility (O.G., S.P., W.C.J.), Université Sidi Mohammed Ben Abdellah (A.I.), Centre d’Etudes Universitaires de Taza, Taza 1223, Morocco; Endocrine and Diabetes Research Group (D.Y., Z.A., J.J., M.B.W.), Department of Physiology, University of Toronto, Toronto, Canada M5S 1AB; and Department of Physiology and Biophysics (N.A.A.), State University of New York, Stony Brook, New York 11794

Address all correspondence and requests for reprints to: Derek LeRoith, M.D., Ph.D., Diabetes Branch, NIDDK, Room 8D12, Building 10, National Institutes of Health, Bethesda, Maryland 20892-1758. E-mail: Derek{at}helix.nih.gov.

Insulin resistance is one of the primary characteristics of type 2 diabetes. Mice overexpressing a dominant-negative IGF-I receptor specifically in muscle (MKR mice) demonstrate severe insulin resistance with high levels of serum and tissue lipids and eventually develop type 2 diabetes at 5–6 wk of age. To determine whether lipotoxicity plays a role in the progression of the disease, we crossed MKR mice with mice overexpressing a fatty acid translocase, CD36, in skeletal muscle. The double-transgenic MKR/CD36 mice showed normalization of the hyperglycemia and the hyperinsulinemia as well as a marked improvement in liver insulin sensitivity. The MKR/CD36 mice also exhibited normal rates of fatty acid oxidation in skeletal muscle when compared with the decreased rate of fatty acid oxidation in MKR. With the reduction in insulin resistance, ß-cell function returned to normal. These and other results suggest that the insulin resistance in the MKR mice is associated with increased muscle triglycerides levels and that whole-body insulin resistance can be, at least partially, reversed in association with a reduction in muscle triglycerides levels, although the mechanisms are yet to be determined.

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