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

Diabetologia. 2006 Sep;49(9):2120-30. doi: 10.1007/s00125-006-0305-5. Epub 2006 Jul 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Colforsin / pharmacology
  • Fatty Acids, Nonesterified / metabolism
  • Fatty Acids, Nonesterified / pharmacology
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucose / pharmacology
  • In Vitro Techniques
  • Insulin / metabolism*
  • Insulin Resistance*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Lactones / metabolism
  • Lactones / pharmacology
  • Lipase / metabolism
  • Lipid Metabolism / drug effects
  • Lipolysis / drug effects
  • Models, Biological
  • Orlistat
  • Oxidation-Reduction / drug effects
  • Rats
  • Rats, Zucker
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects


  • Fatty Acids, Nonesterified
  • Insulin
  • Lactones
  • Colforsin
  • Glucagon-Like Peptide 1
  • Orlistat
  • Lipase
  • Glucose