Beta cell compensation for insulin resistance in Zucker fatty rats: Increased lipolysis and fatty acid signalling

C. J. Nolan*, J. L. Leahy, V. Delghingaro-Augusto, J. Moibi, K. Soni, M. L. Peyot, M. Fortier, C. Guay, J. Lamontagne, A. Barbeau, E. Przybytkowski, E. Joly, P. Masiello, S. Wang, G. A. Mitchell, M. Prentki

*Corresponding author for this work

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    Abstract

    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.

    Original languageEnglish
    Pages (from-to)2120-2130
    Number of pages11
    JournalDiabetologia
    Volume49
    Issue number9
    DOIs
    Publication statusPublished - Sept 2006

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