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| Research Presentation |
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.
Collaborations
This project is carried out in collaboration with Drs Christopher Rhodes (University of Chicago); Raghu Mirmira (University of Indiana); Roland Stein (Vanderbilt University); Tom Jetton (University of Vermont); Marc Prentki (University of Montreal); Sonia Najjar (University of Toledo); Jared Rutter (University of Utah); and Allen Volchuk (University of Toronto).
Funding
This project is funded by theUS National Institutes of Health.
References
1. Poitout V, Robertson RP: Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 29:351-366, 2008
2. Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V: Inhibition of insulin gene expression by long-term exposure of pancreatic beta-cells to palmitate is dependent upon the presence of a stimulatory glucose concentration. Metabolism 49:532-536, 2000
3. Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V: Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315-321, 2001
4. Kelpe CL, Moore PC, Parazzoli SD, Wicksteed B, Rhodes CJ, Poitout V: Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem 278:30015-30021, 2003
5. Moore PC, Ugas MA, Hagman DK, Parazzoli SD, Poitout V: Evidence against the involvement of oxidative stress in Fatty Acid inhibition of insulin secretion. Diabetes 53:2610-2616, 2004
6. Hagman DK, Hays LB, Parazzoli SD, Poitout V: Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J Biol Chem 280:32413-32418, 2005
7. Hagman DK, Latour MG, Chakrabarti SK, Fontes G, Amyot J, Tremblay C, Semache M, Lausier JA, Roskens V, Mirmira RG, Jetton TL, Poitout V: Cyclical and alternating infusions of glucose and intralipid in rats inhibit insulin gene expression and Pdx-1 binding in islets. Diabetes 57:424-431, 2008
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