Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity.
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.
Shimabukuro
M
M
Gifford Laboratories for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Koyama
K
K
Lee
Y
Y
Unger
R H
RH
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000517:prevention & control; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D018014:Gene Transfer Techniques; D007375:Interleukin-1 / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin; D008055:Lipids / Q000172:deficiency*; D009569:Nitric Oxide / Q000096:biosynthesis; D009765:Obesity / Q000150:complications / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000032:analysis; D000077288:Troglitazone
D002839:Chromans; D005230:Fatty Acids, Nonesterified; D007375:Interleukin-1; D020738:Leptin; D008055:Lipids; D011506:Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D009569:Nitric Oxide; D000077288:Troglitazone