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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.

SUBMITTER: Pillai R

PROVIDER: S-EPMC6338330 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Pillai Renjitha R Paglialunga Sabina S Hoang Monica M Cousteils Katelyn K Prentice Kacey J KJ Bombardier Eric E Huang Mei M Gonzalez Frank J FJ Tupling A Russell AR Wheeler Michael B MB Joseph Jamie W JW

Diabetologia 20150926 12

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>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).<h4>Re ...[more]

PMID: 26409461

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Project description:17?-Estradiol (17?E) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17?E modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17?E availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs).These hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17?E seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed.The response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17?E. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17?E application.These data suggest that physiological fluctuations in circulating 17?E levels across the estrous cycle lead to changes in hypothalamic glucose sensing and the response to IIH.

Dataset Information

Deletion of ARNT/HIF1? in pancreatic beta cells does not impair glucose homeostasis in mice, but is associated with defective glucose sensing ex vivo.

Publications

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

Similar Datasets

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