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
Kebede, Melkam, Favaloro, Jenny, Gunton, Jenny E., Laybutt, D. Ross, Shaw, Margaret, Wong, Nicole, Fam, Barbara C., Aston-Mourney, Kathryn, Rantzau, Christian, Zulli, Anthony, Proietto, Joseph and Andrikopoulos, Sofianos 2008, 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, Diabetes, vol. 57, no. 7, pp. 1887-1895.
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.
Field of Research
119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective
970111 Expanding Knowledge in the Medical and Health Sciences