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Deletion of ARNT/HIF1? 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/HIF1? 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/HIF1? in beta cells. METHODS:The in vivo and in vitro consequences of the loss of ARNT/HIF1? were investigated in beta cell specific Arnt/Hif1? knockout mice (?-Arnt (fl/fl/Cre) mice). RESULTS:The only in vivo defects found in ?-Arnt (fl/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 ?-Arnt (fl/fl/Cre) islets upon glucose stimulation. ?-Arnt (fl/fl/Cre) islets had an impairment in the glucose-stimulated increase in Ca(2+) 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 ?-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in ?-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1? 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/HIF1? in islets. CONCLUSIONS/INTERPRETATION:This study provides three new insights into the role of ARNT/HIF1? in beta cells: (1) ARNT/HIF1? deletion in mice impairs GSIS ex vivo; (2) ?-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1? is required for GSIS in human islets.

PROVIDER: S-EPMC6338330 | BioStudies |

REPOSITORIES: biostudies

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