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.
OBJECTIVE
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.


METHODS
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.


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 beta-cells, as occurs in states of lipid oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.
Kebede
Melkam
M
Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia.
Favaloro
Jenny
J
Gunton
Jenny E
JE
Laybutt
D Ross
DR
Shaw
Margaret
M
Wong
Nicole
N
Fam
Barbara C
BC
Aston-Mourney
Kathryn
K
Rantzau
Christian
C
Zulli
Anthony
A
Proietto
Joseph
J
Andrikopoulos
Sofianos
S
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000503:physiopathology; D004742:Enhancer Elements, Genetic; D005227:Fatty Acids / Q000494:pharmacology; D006597:Fructose-Bisphosphatase / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051381:Rats; D014019:Tissue Donors
D005227:Fatty Acids; D007328:Insulin; D006597:Fructose-Bisphosphatase