title: Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets.
abstract: OBJECTIVE
  The G-protein-coupled receptor GPR40 mediates fatty acid potentiation of glucose-stimulated insulin secretion, but its contribution to insulin secretion in vivo and mechanisms of action remain uncertain. This study was aimed to ascertain whether GPR40 controls insulin secretion in vivo and modulates intracellular fuel metabolism in islets.
  
  
  METHODS
  Insulin secretion and sensitivity were assessed in GPR40 knockout mice and their wild-type littermates by hyperglycemic clamps and hyperinsulinemic euglycemic clamps, respectively. Transcriptomic analysis, metabolic studies, and lipid profiling were used to ascertain whether GPR40 modulates intracellular fuel metabolism in islets.
  
  
  RESULTS
  Both glucose- and arginine-stimulated insulin secretion in vivo were decreased by approximately 60% in GPR40 knockout fasted and fed mice, without changes in insulin sensitivity. Neither gene expression profiles nor intracellular metabolism of glucose and palmitate in isolated islets were affected by GPR40 deletion. Lipid profiling of isolated islets revealed that the increase in triglyceride and decrease in lyso-phosphatidylethanolamine species in response to palmitate in vitro was similar in wild-type and knockout islets. In contrast, the increase in intracellular inositol phosphate levels observed in wild-type islets in response to fatty acids in vitro was absent in knockout islets.
  
  
  CONCLUSIONS
  These results indicate that deletion of GPR40 impairs insulin secretion in vivo not only in response to fatty acids but also to glucose and arginine, without altering intracellular fuel metabolism in islets, via a mechanism that may involve the generation of inositol phosphates downstream of GPR40 activation.
authors.affiliation: Montréal Diabetes Research Center, Research Centre of the Montréal University Hospital, University of Montréal, Montréal, QC, Canada.
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.forename: Martin G
authors.initials: MG
authors.lastname: Latour
authors.forename: Melkam
authors.initials: M
authors.lastname: Kebede
authors.forename: Christina M
authors.initials: CM
authors.lastname: Sorensen
authors.forename: Stephane
authors.initials: S
authors.lastname: Gesta
authors.forename: C
authors.initials: C
authors.lastname: Ronald Kahn
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jetton
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D005947:Glucose / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008055:Lipids / Q000302:isolation & purification / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics*
chemical_list: D005227:Fatty Acids; C473036:Ffar1 protein, mouse; D007295:Inositol Phosphates; D007328:Insulin; D008055:Lipids; D043562:Receptors, G-Protein-Coupled; D016718:Arachidonic Acid; D001120:Arginine; D005947:Glucose