Deletion of ARNT/HIF1ß 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, 2015 Dec.
Article
em En
| MEDLINE
| ID: mdl-26409461
ABSTRACT
AIMS/HYPOTHESIS:
It has been suggested that the transcription factor ARNT/HIF1ß 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/HIF1ß in beta cells.METHODS:
The in vivo and in vitro consequences of the loss of ARNT/HIF1ß were investigated in beta cell specific Arnt/Hif1ß knockout mice (ß-Arnt (fl/fl/Cre) mice).RESULTS:
The only in vivo defects found in ß-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 ß-Arnt (fl/fl/Cre) islets upon glucose stimulation. ß-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 ß-Arnt (fl/fl/Cre) islets. The reduced GSIS and NADPH/NADP(+) levels in ß-Arnt (fl/fl/Cre) islets could be rescued by treatment with membrane-permeable tricarboxylic acid intermediates. Small interfering (si)RNA mediated knockdown of ARNT/HIF1ß 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/HIF1ß in islets. CONCLUSIONS/INTERPRETATION:
This study provides three new insights into the role of ARNT/HIF1ß in beta cells (1) ARNT/HIF1ß deletion in mice impairs GSIS ex vivo; (2) ß-Arnt (fl/fl/Cre) mice have an increased respiratory exchange ratio; and (3) ARNT/HIF1ß is required for GSIS in human islets.Palavras-chave
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Bases de dados:
MEDLINE
Assunto principal:
Células Secretoras de Insulina
/
Translocador Nuclear Receptor Aril Hidrocarboneto
/
Glucose
/
Homeostase
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Diabetologia
Ano de publicação:
2015
Tipo de documento:
Article