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Published online March 28, 2008
Diabetes 57:1887-1895, 2008
DOI: 10.2337/db07-1326
© 2008 by the American Diabetes Association
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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. Gunton2,3, D. Ross Laybutt2, Margaret Shaw1, Nicole Wong1, Barbara C. Fam1, Kathryn Aston-Mourney1, Christian Rantzau1, Anthony Zulli1, Joseph Proietto1, and Sofianos Andrikopoulos1

1 Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia
2 Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3 Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia

Corresponding author: Sofianos Andrikopoulos, sof{at}unimelb.edu.au

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.


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