Lack of preservation of insulin gene expression by a Glucagon-Like Peptide 1 agonist or a Dipeptidyl Peptidase 4 inhibitor in an in vivo model of glucolipotoxicity

Prolonged exposure of pancreatic beta-cells to elevated levels of glucose and fatty acids adversely affects insulin secretion and gene expression. Aim: To examine whether the GLP-1 agonist exenatide or the inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase 4 (DPP-4) sitagliptin rescue insulin gene expression in rats infused for 72 h with glucose + Intralipid, independently from their glucose-lowering action. Methods: Wistar rats were infused alternatively with glucose or Intralipid for cycles of 4 h each for a total of 72 h. The animals received exenatide (5 mu g/kg/day IV) or sitagliptin (5 mg/kg/day IV) continuously starting 4 days prior to and continuing throughout the 3-day infusion period. Results: Plasma glucose, fatty acids, insulin and C-peptide levels were unaffected by exenatide or sitagliptin treatment during the infusion period. Insulin mRNA levels increased in response to the glucose infusion, but this increase was abolished in islets from rats receiving glucose + Intralipid. Neither exenatide nor sitagliptin administration rescued insulin mRNA in glucose + Intralipid infused rats. Conclusions: Neither a GLP-1 agonist nor a DPP-4 inhibitor, at doses that do not alter blood glucose levels, prevented the inhibition of insulin gene expression in this in vivo model of glucolipotoxicity. (C) 2010 Elsevier Ireland Ltd. All rights reserved.