FRUCTOSE-1,6-BISPHOSPHATASE OVER-EXPRESSION IN PANCREATIC β-CELLS RESULTS IN REDUCED INSULIN SECRETION: A New Mechanism For Fat-Induced Impairment Of β-Cell function.

Abstract

Objective: Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is up-regulated in islets or pancreatic β-cell lines exposed to high fat. However, whether specific β-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 β-cell FBPase can result in reduced glucose-mediated insulin secretion.

Research Design and Methods: To test this hypothesis we have generated three transgenic mouse lines over-expressing the human FBPase gene specifically in pancreatic islet β-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin secretion, we made two pancreatic β-cell lines (MIN6), stably over-expressing human FBPase.

Results: FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared to the untransfected parental MIN6, FBPase over-expressing 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.

Conclusions: Taken together these results suggest that up-regulation of FBPase in pancreatic islet β-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.