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Glucose-induced O(2) consumption activates hypoxia inducible factors 1 and 2 in rat insulin-secreting pancreatic beta-cells


BACKGROUND: Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner. METHODOLOGY/PRINCIPAL FINDINGS: Isolated rat islets and insulin-secreting INS-1E cells were stimulated with nutrients at various pO(2) values or treated with the HIF activator CoCl(2). HIF-target gene mRNA levels and HIF subunit protein levels were measured by real-time RT-PCR, Western Blot and immunohistochemistry. The formation of pimonidazole-protein adducts was used as an indicator of hypoxia. In INS-1E and islet beta-cells, glucose concentration-dependently stimulated formation of pimonidazole-protein adducts, HIF1 and HIF2 nuclear expression and HIF-target gene mRNA levels to a lesser extent than CoCl(2) or a four-fold reduction in pO(2). Islets also showed signs of HIF activation in diabetic Lepr(db/db) but not non-diabetic Lepr(db/+) mice. In vitro, these glucose effects were reproduced by nutrient secretagogues that bypass glycolysis, and were inhibited by a three-fold increase in pO(2) or by inhibitors of Ca(2)(+) influx and insulin secretion. In INS-1E cells, small interfering RNA-mediated knockdown of Hif1alpha and Hif2alpha, alone or in combination, indicated that the stimulation of glycolytic enzyme mRNA levels depended on both HIF isoforms while the vasodilating peptide adrenomedullin was a HIF2-specific target gene. CONCLUSIONS/SIGNIFICANCE: Glucose-induced O(2) consumption creates an intracellular hypoxia that activates HIF1 and HIF2 in rat beta-cells, and this glucose effect contributes, together with the activation of other transcription factors, to the glucose stimulation of expression of some glycolytic enzymes and other hypoxia response genes.

Type Journal
ISBN 1932-6203 (Electronic) 1932-6203 (Linking)
Authors Bensellam, M.; Duvillie, B.; Rybachuk, G.; Laybutt, D. R.; Magnan, C.; Guiot, Y.; Pouyssegur, J.; Jonas, J. C.;
Garvan Authors A/Prof Ross Laybutt
Publisher Name PLoS ONE
Published Date 2012-12-01 00:00:00
Published Volume 7
Published Issue 1
Published Pages e29807
Status Published In-print
OpenAccess Link