Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy

J Clin Endocrinol Metab. 2006 Jul;91(7):2605-11. doi: 10.1210/jc.2005-1545. Epub 2006 Apr 24.

Abstract

Context: Highly active antiretroviral therapy (HAART) for HIV-1 infection has been associated with a metabolic syndrome characterized by insulin resistance, hyperlipidemia, and redistribution of body fat (lipodystrophy). A subset of patients with predominant lipoatrophy has low levels of the adipocyte-secreted hormone leptin.

Objective: The objective of the study was to assess whether administration of recombinant methionyl human leptin (r-metHuLeptin) improves insulin resistance and other metabolic abnormalities in HIV+ leptin-deficient subjects with HAART-induced lipoatrophy.

Design, setting, patients, and intervention: We conducted a randomized, placebo-controlled, double-blinded, crossover study from 2002 to 2004 in seven HIV+ men with HAART-induced lipoatrophy, serum leptin level less than 3 ng/ml, and fasting triglyceride level greater than 300 mg/dl, who were administered placebo for 2 months before or after administration of r-metHuLeptin at physiological doses for an additional 2 months.

Main outcome measures: Insulin resistance, lipid levels, inflammatory markers, body composition, and HIV control were measured.

Results: Compared with placebo, r-metHuLeptin therapy improved fasting insulin levels, insulin resistance (as expressed by the homeostasis model assessment index and an insulin suppression test), and high-density lipoprotein. Body weight and fat mass decreased on r-metHuLeptin, mainly due to a decrease in truncal fat but not peripheral fat or lean body mass. r-metHuLeptin was well tolerated, and HIV control was not adversely affected.

Conclusions: r-metHuLeptin replacement at physiological doses in HIV+ leptin-deficient patients with HAART-induced lipoatrophy improves insulin resistance, high-density lipoprotein, and truncal fat mass. Future larger and more long-term studies in HAART-induced lipoatrophy, including patients with more severe metabolic abnormalities, are warranted to evaluate the physiological and potentially therapeutic role of r-metHuLeptin for this condition and to fully clarify the underlying mechanisms of action.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy
  • Adolescent
  • Adult
  • Antiretroviral Therapy, Highly Active / adverse effects*
  • Body Composition
  • Body Mass Index
  • Cross-Over Studies
  • Double-Blind Method
  • HIV-1
  • HIV-Associated Lipodystrophy Syndrome / chemically induced*
  • HIV-Associated Lipodystrophy Syndrome / metabolism
  • Humans
  • Insulin / blood
  • Insulin Resistance*
  • Interleukin-6 / blood
  • Leptin / analogs & derivatives*
  • Leptin / deficiency*
  • Leptin / therapeutic use
  • Lipids / blood
  • Lipoproteins, HDL / blood
  • Male
  • Metabolic Syndrome / chemically induced*
  • Metabolic Syndrome / metabolism
  • Placebos
  • Recombinant Proteins / therapeutic use

Substances

  • Insulin
  • Interleukin-6
  • Leptin
  • Lipids
  • Lipoproteins, HDL
  • Placebos
  • Recombinant Proteins
  • recombinant methionyl human leptin