Pillai Renjitha, Paglialunga Sabina, Hoang Monica, Cousteils Katelyn, Prentice Kacey J, Bombardier Eric, Huang Mei, Gonzalez Frank J, Tupling A Russell, Wheeler Michael B, Joseph Jamie W
School of Pharmacy, University of Waterloo, Health Science Campus building A, room 4008, 10A Victoria Street South, Kitchener, ON, Canada, N2G 1C5.
Department of Physiology, University of Toronto, Toronto, ON, Canada.
Diabetologia. 2015 Dec;58(12):2832-42. doi: 10.1007/s00125-015-3768-4. Epub 2015 Sep 26.
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.
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.
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.
目的/假设：有研究表明，转录因子ARNT/HIF1β对于维持体内葡萄糖稳态以及胰岛β细胞葡萄糖刺激的胰岛素分泌（GSIS）至关重要。我们的目标是更深入地了解胰岛β细胞中ARNT/HIF1β缺失后出现的代谢缺陷。
在胰岛β细胞特异性Arnt/Hif1β基因敲除小鼠（β-Arnt (fl/fl/Cre) 小鼠）中研究ARNT/HIF1β缺失的体内和体外后果。
在β-Arnt (fl/fl/Cre) 小鼠中发现的唯一体内缺陷是呼吸交换率和体内碳水化合物氧化显著增加，以及脂质氧化减少。葡萄糖刺激后，小鼠β-Arnt (fl/fl/Cre) 胰岛中的线粒体氧消耗率未改变。β-Arnt (fl/fl/Cre) 胰岛在葡萄糖刺激下Ca(2+)信号增加受损，并且在存在氯化钾和二氮嗪的情况下对葡萄糖的胰岛素分泌反应降低。β-Arnt (fl/fl/Cre) 胰岛中葡萄糖刺激的NADPH/NADP(+)比值增加减少。用膜通透性三羧酸中间体处理可挽救β-Arnt (fl/fl/Cre) 胰岛中降低的GSIS和NADPH/NADP(+)水平。小干扰（si）RNA介导的人胰岛中ARNT/HIF1β的敲低也抑制了GSIS。这些结果表明，胰岛中ARNT/HIF1β的缺失会影响KATP通道依赖性和非依赖性途径对GSIS的调节。
结论/解读：本研究为ARNT/HIF1β在胰岛β细胞中的作用提供了三个新的见解：（1）小鼠中ARNT/HIF1β的缺失会损害离体GSIS；（2）β-Arnt (fl/fl/Cre) 小鼠的呼吸交换率增加；（3）人胰岛中的GSIS需要ARNT/HIF1β。
