Leptin- Or Troglitazone-Induced Lipopenia Protects Islets From Interleukin 1beta Cytotoxicity

J Clin Invest. 1997 Oct 1;100(7):1750-4. doi: 10.1172/JCI119700.

Abstract

Interleukin 1beta (IL-1beta)-induced beta cell cytotoxicity has been implicated in the autoimmune cytotoxicity of insulin-dependent diabetes mellitus. These cytotoxic effects may be mediated by nitric oxide (NO). Since long-chain fatty acids (FFA), like IL-1beta, upregulate inducible nitric oxide synthase and enhance NO generation in islets, it seemed possible that islets might be protected from IL-1beta-induced damage by lowering their lipid content. We found that IL-1beta-induced NO production varied directly and islet cell viability inversely with islet triglyceride (TG) content. Fat-laden islets of obese rats were most vulnerable to IL-1beta, while moderately fat-depleted islets of food-restricted normal rats were less vulnerable than those of free-feeding normal rats. Severely lipopenic islets of rats made chronically hyperleptinemic by adenoviral leptin gene transfer resisted IL-1beta cytotoxicity even at 300 pg/ml, the maximal concentration. Troglitazone lowered islet TG in cultured islets from both normal rats and obese, leptin-resistant rats and reduced NO production and enhanced cell survival. We conclude that measures that lower islet TG content protect against IL-1beta-induced NO production and cytotoxicity. Leptin or troglitazone could provide in vivo protection against insulin-dependent diabetes mellitus.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Chromans / pharmacology*
  • Diabetes Mellitus, Type 1 / etiology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Fatty Acids, Nonesterified / pharmacology
  • Gene Transfer Techniques
  • Interleukin-1 / toxicity*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Leptin
  • Lipids / deficiency*
  • Nitric Oxide / biosynthesis
  • Obesity / complications
  • Obesity / metabolism
  • Proteins / genetics
  • Proteins / pharmacology*
  • Rats
  • Rats, Zucker
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Triglycerides / analysis
  • Troglitazone

Substances

  • Chromans
  • Fatty Acids, Nonesterified
  • Interleukin-1
  • Leptin
  • Lipids
  • Proteins
  • Thiazoles
  • Thiazolidinediones
  • Triglycerides
  • Nitric Oxide
  • Troglitazone