Kebede, Melkam, Favaloro, Jenny, Gunton, Jenny E, Laybutt, D Ross, Shaw, Margaret, Wong, Nicole, Fam, Barbara C, Aston-Mourney, Kathryn, Rantzau, Christian, Zulli, Anthony, Prioietto, Joseph and Andrikopoulos, Sofianos (2008) Fructose-1,6-bisphosphatase overexpression in pancreatic β-cells results in reduced insulin secretion: a new mechanism for fat-induced impairment of β-cell function. Diabetes, 57 (7). pp. 1887-1895. ISSN 0012-1797

Abstract

OBJECTIVE—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. RESEARCH DESIGN AND METHODS—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. RESULTS—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. CONCLUSIONS—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.

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