31 Nolan, C. J. Leahy, J. L. Delghingaro-Augusto, V. Moibi, J. Soni, K. Peyot, M. L. Fortier, M. Guay, C. Lamontagne, J. Barbeau, A. Przybytkowski, E. Joly, E. Masiello, P. Wang, S. Mitchell, G. A. Prentki, M. 2006 Diabetologia 49 9 2120-30 Sep 0012-186X (Print) 16868750 Forskolin/pharmacology Fatty Acids, Nonesterified/metabolism/pharmacology Binding Sites Animals Signal Transduction/drug effects Reverse Transcriptase Polymerase Chain Reaction Rats, Zucker Rats Oxidation-Reduction/drug effects Models, Biological Lipolysis/drug effects Lipid Metabolism/drug effects Lipase/metabolism Lactones/metabolism/pharmacology Islets of Langerhans/cytology/drug effects/*metabolism Insulin-Secreting Cells/drug effects/*metabolism *Insulin Resistance Insulin/*secretion Glucose/pharmacology Glucagon-Like Peptide 1/pharmacology Gene Expression Regulation/drug effects Fatty Acids Zucker Models Biological Nonesterified/metabolism/pharmacology AIMS/HYPOTHESIS: The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes. MATERIALS AND METHODS: NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats. RESULTS: Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent. CONCLUSIONS/INTERPRETATION: The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity. DK-63356/DK/NIDDK NIH HHS/United StatesDK56818/DK/NIDDK NIH HHS/United StatesIn VitroJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tGermany http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16868750