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|Title:||Fructose-1,6-bisphosphatase overexpression in pancreatic beta-cells results in reduced insulin secretion: a new mechanism for fat-induced impairment of beta-cell function.|
|Authors:||Kebede, Melkam;Favaloro, Jenny M;Gunton, Jenny E;Laybutt, D Ross;Shaw, Margaret;Wong, Nicole;Fam, Barbara C;Aston-Mourney, Kathryn;Rantzau, Christian;Zulli, Anthony;Proietto, Joseph;Andrikopoulos, Sofianos|
|Affiliation:||Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia|
|Citation:||Diabetes 2008; 57(7): 1887-95|
|Abstract:||Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic beta-cell lines exposed to high fat. However, whether specific beta-cell upregulation of FBPase can impair insulin secretory function is not known. The objective of this study therefore is to determine whether a specific increase in islet beta-cell FBPase can result in reduced glucose-mediated insulin secretion.To test this hypothesis, we have generated three transgenic mouse lines overexpressing the human FBPase (huFBPase) gene specifically in pancreatic islet beta-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin secretion, we made two pancreatic beta-cell lines (MIN6) stably overexpressing huFBPase.FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared with the untransfected parental MIN6, FBPase-overexpressing cells showed a decreased cell proliferation rate and significantly depressed glucose-induced insulin secretion. These defects were associated with a decrease in the rate of glucose utilization, resulting in reduced cellular ATP levels.Taken together, these results suggest that upregulation of FBPase in pancreatic islet beta-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.|
|Internal ID Number:||18375435|
Diabetes Mellitus, Type 2.enzymology.physiopathology
Enhancer Elements, Genetic
Gene Expression Regulation, Enzymologic
Polymerase Chain Reaction
Promoter Regions, Genetic
|Appears in Collections:||Journal articles|
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