Erschienen in:
01.12.2015 | Article
Deletion of ARNT/HIF1β in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo
verfasst von:
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
Erschienen in:
Diabetologia
|
Ausgabe 12/2015
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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-Arnt
fl/fl/Cre mice).
Results
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 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-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.
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-Arnt
fl/fl/Cre mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1β is required for GSIS in human islets.