title: Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass.
abstract: OBJECTIVE
  The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model.
  
  
  METHODS
  Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured.
  
  
  RESULTS
  ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression.
  
  
  CONCLUSIONS
  Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.
authors.affiliation: Molecular Nutrition Unit and the Montreal Diabetes Research Center, CR-CHUM, Montreal, QC, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.forename: C J
authors.initials: CJ
authors.lastname: Nolan
authors.forename: D
authors.initials: D
authors.lastname: Gupta
authors.forename: T L
authors.initials: TL
authors.lastname: Jetton
authors.forename: M G
authors.initials: MG
authors.lastname: Latour
authors.forename: M
authors.initials: M
authors.lastname: Peshavaria
authors.forename: S R Murthy
authors.initials: SR
authors.lastname: Madiraju
authors.forename: E
authors.initials: E
authors.lastname: Joly
authors.forename: M-L
authors.initials: ML
authors.lastname: Peyot
authors.forename: M
authors.initials: M
authors.lastname: Prentki
authors.forename: J
authors.initials: J
authors.lastname: Leahy
mesh_terms: D000818:Animals; D001835:Body Weight; D049109:Cell Proliferation; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000473:pathology*; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010180:Pancreatectomy; D011384:Proinsulin / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011384:Proinsulin