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Differential Effects of Metformin and Exercise on Muscle Adiposity and Metabolic Indices in Human Immunodeficiency Virus-Infected Patients

Program in Nutritional Metabolism (S.D.D., G.E.M., K.L., C.H., S.G.), Neuroendocrine Unit (S.D.D., G.E.M., K.L., C.H., A.K., S.G.), and Division of Musculoskeletal Radiology (M.T.), Massachusetts General Hospital, and Department of Physical Medicine and Rehabilitation (W.R.F.), Spaulding Rehabilitation Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Program in Nutritional Metabolism, 55 Fruit Street, LON207, Boston, Massachusetts 02144-2696. E-mail: sgrinspoon{at}partners.org.

The HIV-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance (IR). The mechanisms and treatment strategies for IR in HIV-lipodystrophy are unclear, but data suggest that intramuscular lipids contribute to IR in this population. We previously showed that metformin and exercise improve hyperinsulinemia more than metformin alone in HIV-lipodystrophy. Now we investigate the effects of these treatment strategies on thigh muscle adiposity measured by computed tomography and additional body composition measures. Twenty-five HIV-infected patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution participated in a prospective, randomized, 3-month study of metformin alone or metformin and resistance training three times a week. Thigh muscle adiposity decreased significantly more as shown by increased muscle attenuation [2.0 (range, 0.5–5.0) vs. –1.0 (–3.5–0), P = 0.04] and sc leg fat tended to decrease more [–3.3 (–7.5–4.3) vs. 0.8 (–2.1–9.5), P = 0.06] in the combined treatment group in comparison with metformin alone. In multivariate analysis, change in thigh muscle adiposity remained a significant predictor of change in insulin (P = 0.04), controlling for changes in other body composition measurements. These data suggest that muscle adiposity, in addition to other fat depots, is an important determinant of hyperinsulinemia and that exercise has complex effects on regional fat depots in HIV-infected patients. Reduction in muscle adiposity may be an important mechanism by which exercise improves hyperinsulinemia in this population.

This work was funded in part by National Institutes of Health Grants DK49302, RR300088, and RR01066.

Abbreviations: BMI, Body mass index; CT, computed tomography; DEXA, dual-energy x-ray absorptiometry; FFA, free fatty acid; OGTT, oral glucose tolerance testing; PI, phosphatidyl inositol; WHR, waist-to-hip ratio.

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