Deletion of ARNT/HIF1β in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo

Abstract

Aims/hypothesis: It has been suggested that the transcription factor ARNT/HIF1β is critical for maintaining in vivo glucose homeostasis and pancreatic beta cell glucose-stimulated insulin secretion (GSIS). Our goal was to gain more insights into the metabolic defects seen after the loss of ARNT/HIF1β in beta cells. Methods: The in vivo and in vitro consequences of the loss of ARNT/HIF1β were investigated in beta cell specific Arnt/Hif1β knockout mice (β-Arntfl/fl/Cre mice). Results: The only in vivo defects found in β-Arntfl/fl/Cre mice were significant increases in the respiratory exchange ratio and in vivo carbohydrate oxidation, and a decrease in lipid oxidation. The mitochondrial oxygen consumption rate was unaltered in mouse β-Arntfl/fl/Cre islets upon glucose stimulation. β-Arntfl/fl/Cre islets had an impairment in the glucose-stimulated increase in Ca2+ signalling and a reduced insulin secretory response to glucose in the presence of KCl and diazoxide. The glucose-stimulated increase in the NADPH/NADP+ ratio was reduced in β-Arntfl/fl/Cre islets. The reduced GSIS and NADPH/NADP+ levels in β-Arntfl/fl/Cre islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1β in human islets also inhibited GSIS. These results suggest that the regulation of GSIS by the KATP channel-dependent and -independent pathways is affected by the loss of ARNT/HIF1β in islets. Conclusions/interpretation: This study provides three new insights into the role of ARNT/HIF1β in beta cells: (1) ARNT/HIF1β deletion in mice impairs GSIS ex vivo; (2) β-Arntfl/fl/Cre mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1β is required for GSIS in human islets.