31 Delghingaro-Augusto, V. Nolan, C. J. Gupta, D. Jetton, T. L. Latour, M. G. Peshavaria, M. Madiraju, S. R. Joly, E. Peyot, M. L. Prentki, M. Leahy, J. 2009 Diabetologia 52 6 1122-32 Jun 1432-0428 (Electronic) 19294363 Animals Body Weight Cell Proliferation Cells, Cultured Fatty Acids, Nonesterified/metabolism Hyperlipidemias/*metabolism/*pathology/physiopathology Immunohistochemistry Insulin/metabolism Insulin-Secreting Cells/cytology/metabolism/*pathology Islets of Langerhans/*pathology Lipid Metabolism/physiology Male Obesity/*metabolism/*pathology/physiopathology Pancreatectomy Proinsulin/metabolism Rats Rats, Zucker AIMS/HYPOTHESIS: 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/INTERPRETATION: 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. 418077/Medical Research Council/United KingdomDK56818/DK/NIDDK NIH HHS/United StatesDK59851/DK/NIDDK NIH HHS/United StatesDK66635/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tGermany http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19294363