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
- Melkam Kebede1,
- Jenny Favaloro1,
- Jenny E. Gunton23,
- D. Ross Laybutt2,
- Margaret Shaw1,
- Nicole Wong1,
- Barbara C. Fam1,
- Kathryn Aston-Mourney1,
- Christian Rantzau1,
- Anthony Zulli1,
- Joseph Proietto1 and
- Sofianos Andrikopoulos1
- 1Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia
- 2Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- 3Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
- Corresponding author: Sofianos Andrikopoulos, sof{at}unimelb.edu.au
Abstract
OBJECTIVE—Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated 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 overexpressing the human FBPase (huFBPase) 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 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 β-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 28 March 2008.
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- Accepted March 23, 2008.
- Received September 17, 2007.
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