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Diabetes Publish Ahead of Print published online ahead of print March 28, 2008
DOI: 10.2337/db07-1326
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Original Research

FRUCTOSE-1,6-BISPHOSPHATASE OVER-EXPRESSION IN PANCREATIC β-CELLS RESULTS IN REDUCED INSULIN SECRETION: A New Mechanism For Fat-Induced Impairment Of β-Cell function.

Melkam Kebede, PhD1, Jenny Favaloro, PhD1, Jenny E. Gunton, MBBS, FRACP, PhD2,,3, D. Ross Laybutt, PhD2, Margaret Shaw, PhD1, Nicole Wong, BSc,Honours1, Barbara C. Fam, PhD1, Kathryn Aston-Mourney, PhD1, Christian Rantzau, CAppSc1, Anthony Zulli, PhD1, Joseph Proietto, MBBS, FRACP, PhD1, and Sofianos Andrikopoulos, PhD1

1University of Melbourne, Department of Medicine (AH/NH), Heidelberg Repatriation Hospital, Heidelberg Heights, Victoria 3081 Australia
2Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010 Australia
3Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW 2045 Australia

Objective: Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is up-regulated 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 over-expressing the human FBPase 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 over-expressing human FBPase.

Results: FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared to the untransfected parental MIN6, FBPase over-expressing 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 up-regulation of FBPase in pancreatic islet β-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.

Correspondence: sof{at}unimelb.edu.au


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