| 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. | |
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MedLine Citation:
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PMID: 21059654 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Renjitha Pillai; Peter Huypens; Mei Huang; Stephanie Schaefer; Tanya Sheinin; Shawn D Wettig; Jamie W Joseph |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-08 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-10 Completed Date: 2011-03-02 Revised Date: 2012-01-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1014-24 Citation Subset: IM |
Affiliation:
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School of Pharmacy, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Diphosphate
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metabolism Adenosine Triphosphate / metabolism Animals Aryl Hydrocarbon Receptor Nuclear Translocator / genetics, metabolism* Cell Line, Tumor Citric Acid Cycle / physiology Diabetes Mellitus, Type 2 / genetics, metabolism* Fatty Acids, Nonesterified / metabolism Gas Chromatography-Mass Spectrometry Gene Expression Profiling Glucose / metabolism*, pharmacology Insulin / metabolism* Insulin-Secreting Cells / cytology, metabolism* Insulinoma Metabolomics Oxidation-Reduction Pancreatic Neoplasms Pentose Phosphate Pathway / physiology RNA, Small Interfering Rats |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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0/ARNT protein, rat; 0/Fatty Acids, Nonesterified; 0/Insulin; 0/RNA, Small Interfering; 138391-32-9/Aryl Hydrocarbon Receptor Nuclear Translocator; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 58-64-0/Adenosine Diphosphate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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