title: Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling.
abstract: OBJECTIVE
  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.
  
  
  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
  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.
authors.affiliation: 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
authors.forename: C J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: J L
authors.initials: JL
authors.lastname: Leahy
authors.forename: V
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.forename: J
authors.initials: J
authors.lastname: Moibi
authors.forename: K
authors.initials: K
authors.lastname: Soni
authors.forename: M-L
authors.initials: ML
authors.lastname: Peyot
authors.forename: M
authors.initials: M
authors.lastname: Fortier
authors.forename: C
authors.initials: C
authors.lastname: Guay
authors.forename: J
authors.initials: J
authors.lastname: Lamontagne
authors.forename: A
authors.initials: A
authors.lastname: Barbeau
authors.forename: E
authors.initials: E
authors.lastname: Przybytkowski
authors.forename: E
authors.initials: E
authors.lastname: Joly
authors.forename: P
authors.initials: P
authors.lastname: Masiello
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: G A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: M
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000818:Animals; D001665:Binding Sites; D005576:Colforsin / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D008954:Models, Biological; D000077403:Orlistat; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007783:Lactones; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D000077403:Orlistat; D008049:Lipase; D005947:Glucose