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Diabetologia. 2006 Sep;49(9):2120-30. Epub 2006 Jul 26.

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

Author information

1
Molecular Nutrition Unit and Montreal Diabetes Research Center, University of Montreal and Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada. christopher.nolan@anu.edu.au

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.

PMID:
16868750
DOI:
10.1007/s00125-006-0305-5
[Indexed for MEDLINE]

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