aston-fructoseone-2008.pdf (401.31 kB)
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
journal contribution
posted on 2008-07-01, 00:00 authored by M Kebede, J Favaloro, J Gunton, D Laybutt, M Shaw, N Wong, B Fam, Kathryn Aston-MourneyKathryn Aston-Mourney, C Rantzau, A Zulli, J Proietto, S AndrikopoulosFructose-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.
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.
History
Journal
DiabetesVolume
57Issue
7Pagination
1887 - 1895Publisher
American Diabetes AssociationLocation
Alexandria, VaPublisher DOI
ISSN
0012-1797eISSN
1939-327XLanguage
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2008, by the American Diabetes AssociationUsage metrics
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