The mechanisms of inhibition of pancreatic beta-cell function by chronic exposure to fatty acids
Summary
Pancreatic beta-cell function inexorably declines after the onset of type 2 diabetes. The combination of excessive levels of glucose and fatty-acids, so-called glucolipotoxicity, is proposed to mediate, at least in part, the deterioration of glucose homeostasis (1). Our research project is aimed at unravelling the molecular and cellular basis of glucolipotoxicity in the pancreatic beta-cells. In vitro, we have shown that prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids and glucose impairs insulin gene expression (2; 3) via transcriptional mechanisms that involve de novo synthesis of ceramide (4; 5). Inhibition of insulin gene transcription involves reduction of MafA expression as well as exclusion of PDX-1 from the nuclear compartment (6). In vivo, we have shown that prolonged infusion of glucose and Intralipid in rats also leads to a decrease in insulin gene expression and nuclear exclusion of PDX-1 (7). We are presently investigating whether these early changes in insulin gene expression result in reduced insulin biosynthesis and secretion. Our current projects are aimed at examining the role of aging and genetic susceptibility on the occurrence of beta-cell failure upon nutrient excess and understanding the signalling pathway involved in the mechanisms of glucolipotoxicity. (More) |
