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The Effects of Recombinant Human Leptin on Visceral Fat, Dyslipidemia, and Insulin Resistance in Patients with Human Immunodeficiency Virus-Associated Lipoatrophy and Hypoleptinemia

Department of Medicine, University of California, San Francisco (K.M., H.K., J.-M.S., G.K.S., V.W.T., M.J.W., G.A.L., C.G., M.S.), San Francisco, California 94143; San Francisco General Hospital (K.M., H.K., J.-M.S., G.K.S., V.W.T., M.J.W., M.S.), San Francisco, California 94110; Department of Basic Sciences, Touro University (J.-M.S.), Vallejo, California 94592; Amgen Inc. (A.M.D.), Thousand Oaks, California 91320; and San Francisco Veterans Affairs Medical Center (G.A.L., C.G.) , San Francisco, California 94121

Address all correspondence to: Kathleen Mulligan, Ph.D., Division of Endocrinology, San Francisco General Hospital, Building 30, Room 3501K, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: kathleen.mulligan{at}ucsf.edu.

Context: Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities.

Objective: The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia.

Design: This was a 6-month, open-label, proof-of-principle pilot study.

Setting: Metabolic ward studies were performed before and 3 and 6 months after leptin treatment.

Participants: Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml.

Intervention: Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods).

Outcome Measures: Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety.

Results: Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass.

Conclusions: Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.

This article has been cited by other articles:

				C. S. Mantzoros Whither Recombinant Human Leptin Treatment for HIV-Associated Lipoatrophy and the Metabolic Syndrome? J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1089 - 1091. [Full Text] [PDF]