UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES
SCHAMBELAN, MORRIS, M.D. Department of Medicine |
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A major goal of my laboratory has been to understand the pathogenesis of HIV-associated metabolic and morphologic abnormalities and evaluate potential therapeutic options, using a paradigm based on intensive metabolic ward assessments in which each subject serves as his or her own control. In such studies, we found that a pharmacologic dose of growth hormone (GH) reduced total, trunk and visceral fat and improved lipid profiles in HIV-infected men with fat accumulation. However, GH also impaired insulin action in both muscle and liver, thus limiting its potential therapeutic value. In studies undertaken recently under the auspices of an investigator-initiated IND with funding from the NIH, we are evaluating a novel treatment strategy using insulin-like growth factor-I (IGF-I), which has been shown to reduce fat and enhance lipid oxidation while improving insulin sensitivity, in a formulation in which it is complexed to its major binding protein, IGFBP-3, to enhance bioavailability and safety. We have hypothesized that IGF-I/IGFBP-3 will achieve both fat-mobilizing and insulin-sensitizing effects in patients with HIV infection and thus provide a therapeutic advantage over GH. In this proof-of-principle study, we are performing intensive metabolic ward studies to evaluate the effect of three months of treatment with IGF-I/IGFBP-3 on body fat content and distribution and lean body and muscle mass (DEXA and MRI), intramyocellular lipid levels (proton spectroscopy), insulin-mediated glucose uptake and disposal (euglycemic hyperinsulinemic clamp with indirect calorimetry), oral glucose tolerance, integrated lipid and carbohydrate metabolism (stable isotope studies of glucose production, gluconeogenesis, lipolysis, de novo lipogenesis), and plasma lipid and lipoprotein levels.
An even more prevalent body composition abnormality in patients with HIV infection is peripheral lipoatrophy, characterized by striking depletion of fat depots in the arms, legs, buttocks and face. Depletion of fat stores is associated with insulin resistance, dyslipidemia, and hepatic steatosis in both non-HIV infected patients with congenital or acquired lipoatrophy and transgenic mice engineered to be virtually free of white fat. Since these patients and mice are markedly hypoleptinemic and since leptin administration ameliorates their metabolic abnormalities, we obtained funding to test the hypotheses that treatment with leptin will: improve hepatic and peripheral insulin sensitivity and overall carbohydrate metabolism; ameliorate abnormalities in lipid metabolism; and decrease visceral adiposity, hepatic volume, and intramyocellular lipid levels in HIV-infected patients with lipoatrophy. This open-label, proof-of-principle study will employ a metabolic ward approach and similar state-of-the art methods as described in our studies employing IGF-I/IGFBP-3. Should the results of either of these preliminary studies be positive, they would provide a rationale for further studies of these agents, including randomized, double-blind, placebo-controlled trials.
Selected References
Schwarz J-M, Mulligan K, Lee J, Lo JC, Wen M, Noor MA, Grunfeld C, Schambelan M. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 87:942-945, 2002.
Schambelan M, CA Benson, A Carr, JS Currier, MP Dube, JG Gerber, SJ Grinspoon, C Grunfeld, DP Kotler, K Mulligan, WG Powderly, MS Saag: Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society – USA panel. J Acquire Immune Defic Syndr 257-275, 2002.
Abrams DI, RJ Leiser, JF Hilton, SB Shade, TA Elbeik, FT Aweeka, NL Benowitz, BM Bredt, TF Mitchell, K Mulligan, JM McCune, M Schambelan: Short-term effects of cannabinoids in patients with HIV-1 infection. A randomized, placebo-controlled clinical trial. Ann Intern Med 139:258-266, 2003.
Zambon AC, EL McDearmon, N Salomonis, K Vranizan, K Johansen, D Adey, JS Takahashi, M Schambelan, BR Conklin: Time- and exercise-dependent gene regulation in human skeletal muscle. Genome Biol 4:R61, 2003.