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

• DOI: 10.1007/s00125-015-3768-4
• Publication Date: 2015-09-26T17:48:54Z
• Authors: Renjitha Pillai; Sabina Paglialunga; Monica Hoang; Katelyn Cousteils; Kacey J. Prentice; Eric Bombardier; Mei Huang; Frank J. Gonzalez; A. Russell Tupling; Michael B. Wheeler; Jamie W. Joseph
• Keywords: Membrane Potential, Mitochondrial; Mice, Knockout; 0303 health sciences; Human Growth Hormone; Pulmonary Gas Exchange; Aryl Hydrocarbon Receptor Nuclear Translocator; Glucose Tolerance Test; Mice; 03 medical and health sciences; Glucose; Oxygen Consumption; Insulin-Secreting Cells; Insulin Secretion; Animals; Homeostasis; Humans; Insulin; NADP

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.The in vivo and in vitro consequences of the loss of ARNT/HIF1β were investigated in beta cell specific Arnt/Hif1β knockout mice (β-Arnt (fl/fl/Cre) mice).The only in vivo defects found in β-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 β-Arnt (fl/fl/Cre) islets upon glucose stimulation. β-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 β-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in β-Arnt (fl/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.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-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1β is required for GSIS in human islets.