| First Author | Pillai R | Year | 2015 |
| Journal | Diabetologia | Volume | 58 |
| Issue | 12 | Pages | 2832-42 |
| PubMed ID | 26409461 | Mgi Jnum | J:229034 |
| Mgi Id | MGI:5750258 | Doi | 10.1007/s00125-015-3768-4 |
| Citation | Pillai R, et al. (2015) Deletion of ARNT/HIF1beta in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo. Diabetologia 58(12):2832-42 |
| abstractText | AIMS/HYPOTHESIS: It has been suggested that the transcription factor ARNT/HIF1beta 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/HIF1beta in beta cells. METHODS: The in vivo and in vitro consequences of the loss of ARNT/HIF1beta were investigated in beta cell specific Arnt/Hif1beta knockout mice (beta-Arnt (fl/fl/Cre) mice). RESULTS: The only in vivo defects found in beta-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 beta-Arnt (fl/fl/Cre) islets upon glucose stimulation. beta-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 beta-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in beta-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1beta 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/HIF1beta in islets. CONCLUSIONS/INTERPRETATION: This study provides three new insights into the role of ARNT/HIF1beta in beta cells: (1) ARNT/HIF1beta deletion in mice impairs GSIS ex vivo; (2) beta-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1beta is required for GSIS in human islets. |
