Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes.
Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasia) followed by decompensation (>50% loss of beta cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3- and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokine-induced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C2-Ceramide without FFA induced DNA laddering, but fumonisin B1, a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [3H]Palmitate incorporation in [3H]ceramide in ZDF islets was twice that of controls, but [3H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, beta cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.
Shimabukuro
M
M
Gifford Laboratories for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Zhou
Y T
YT
Levi
M
M
Unger
R H
RH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis*; D002839:Chromans / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000096:biosynthesis; D053938:DNA Fragmentation; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009765:Obesity; D019308:Palmitic Acid / Q000378:metabolism; D011236:Prediabetic State / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011924:Rats, Zucker; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014158:Transcription, Genetic; D014226:Triazenes / Q000494:pharmacology; D000077288:Troglitazone; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D002518:Ceramides; D002839:Chromans; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D006146:Guanidines; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D014226:Triazenes; D019308:Palmitic Acid; C034613:triacsin C; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D000077288:Troglitazone; C004479:pimagedine