Official websites use. Share sensitive information only on official, secure websites. Prolonged exposure of pancreatic beta-cells to elevated levels of glucose and fatty acids adversely affects insulin secretion and gene expression.
Wistar rats were infused alternatively with glucose or Intralipid for cycles of 4h each for a total of 72h. Plasma glucose, fatty acids, insulin and C-peptide levels were unaffected by exenatide or sitaglitpin treatment during the infusion period. 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.
Type 2 diabetes mellitus is due to defective insulin secretion and peripheral insulin resistance. Whereas the initial beta-cell defect underlying the etiology of T2DM is unknown, it has been clearly demonstrated that insulin secretion declines after the onset of the disease 1.
Chronic hyperglycemia glucotoxicity 2 , chronic dislipidemia lipotoxicity 3 , and the association of both glucolipotoxicity 4 ; 5 , have been proposed to contribute to the deterioration of beta-cell function after the onset of type 2 diabetes. In vitro studies have shown that chronically elevated levels of fatty acids, in conjunction with high glucose, inhibit insulin secretion and insulin gene expression and promote beta-cell death reviewed in 6.
Under glucolipotoxic conditions, we have shown that palmitate inhibition of insulin gene expression in isolated rat islets is mediated at the transcriptional level 7 via decreased function of the transcription factors PDX-1 and MafA 8.
