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.
The metabolic pathways that are involved in regulating insulin secretion from pancreatic β-cells are still incompletely understood. One potential regulator of the metabolic phenotype of β-cells is the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor (HIF)-1β. ARNT/HIF-1β 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 β-cells that lack ARNT/HIF-1β. In this study, we confirm that siRNA-mediated knockdown of ARNT/HIF-1β inhibits glucose-stimulated insulin secretion. We next investigated the metabolic consequence of the loss of ARNT/HIF-1β knockdown. We demonstrate that β-cells with reduced ARNT/HIF-1β expression levels exhibit a 31% reduction in glycolytic flux without significant changes in glucose oxidation or the ATP:ADP ratio. Metabolic profiling of β-cells treated with siRNAs against the ARNT/HIF-1β 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-1β knockdown. Together, our data suggest an important role for ARNT/HIF-1β in anaplerosis, and it may play a critical role in maintaining normal secretion competence of β-cells.
School of Pharmacy, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.
Renjitha
R
Pillai
Peter
P
Huypens
Mei
M
Huang
Stephanie
S
Schaefer
Tanya
T
Sheinin
Shawn D
SD
Wettig
Jamie W
JW
Joseph
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007340:Insulinoma; D055432:Metabolomics; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms; D010427:Pentose Phosphate Pathway / Q000502:physiology; D034741:RNA, Small Interfering; D051381:Rats
C497398:ARNT protein, rat; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D034741:RNA, Small Interfering; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose