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.

ABSTRACT: The metabolic pathways that are involved in regulating insulin secretion from pancreatic ?-cells are still incompletely understood. One potential regulator of the metabolic phenotype of ?-cells is the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1?. ARNT/HIF-1? 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 ?-cells that lack ARNT/HIF-1?. In this study, we confirm that siRNA-mediated knockdown of ARNT/HIF-1? inhibits glucose-stimulated insulin secretion. We next investigated the metabolic consequence of the loss of ARNT/HIF-1? knockdown. We demonstrate that ?-cells with reduced ARNT/HIF-1? expression levels exhibit a 31% reduction in glycolytic flux without significant changes in glucose oxidation or the ATP:ADP ratio. Metabolic profiling of ?-cells treated with siRNAs against the ARNT/HIF-1? 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? knockdown. Together, our data suggest an important role for ARNT/HIF-1? in anaplerosis, and it may play a critical role in maintaining normal secretion competence of ?-cells.

SUBMITTER: Pillai R 

PROVIDER: S-EPMC3020708 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature