Aryl Hydrocarbon Receptor Nuclear Translocator/Hypoxia-inducible Factor-1 beta Plays a Critical Role in Maintaining Glucose-stimulated Anaplerosis and Insulin Release from Pancreatic beta-Cells

作者：Pillai Renjitha; Huypens Peter; Huang Mei; Schaefer Stephanie; Sheinin Tanya; Wettig Shawn D; Joseph Jamie W^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286(2): 1014-1024.

DOI：10.1074/jbc.M110.149062

The metabolic pathways that are involved in regulating insulin secretion from pancreatic beta-cells are still incompletely understood. One potential regulator of the metabolic phenotype of beta-cells is the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1 beta. ARNT/HIF-1 beta levels are profoundly reduced in islets obtained from type 2 diabetic patients. However, no study to date has investigated key pathways involved in regulating insulin release in beta-cells that lack ARNT/HIF-1 beta. In this study, we confirm that siRNA-mediated knockdown of ARNT/HIF-1 beta inhibits glucose-stimulated insulin secretion. We next investigated the metabolic consequence of the loss of ARNT/HIF-1 beta knockdown. We demonstrate that beta-cells with reduced ARNT/HIF-1 beta expression levels exhibit a 31% reduction in glycolytic flux without significant changes in glucose oxidation or the ATP:ADP ratio. Metabolic profiling of beta-cells treated with siRNAs against the ARNT/HIF-1 beta gene revealed that glycolysis, anaplerosis, and glucose-induced fatty acid production were down-regulated, and all are key events involved in glucose-stimulated insulin secretion. In addition, both first and second phase insulin secretion in islets were significantly reduced after ARNT/HIF-1 beta knockdown. Together, our data suggest an important role for ARNT/HIF-1 beta in anaplerosis, and it may play a critical role in maintaining normal secretion competence of beta-cells.

• 出版日期2011-1-14