The Mitochondrial 2-Oxoglutarate Carrier Is Part of a Metabolic Pathway That Mediates Glucose- and Glutamine-stimulated Insulin Secretion
| Autor: | Mette V. Jensen, Christopher B. Newgard, Matthew L. Odegaard, Danhong Lu, Thomas C. Becker, Jamie W. Joseph, Olga Ilkayeva, Sarah M. Ronnebaum |
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| Rok vydání: | 2010 |
| Předmět: |
Glutamine
medicine.medical_treatment Pyruvate cycling Mitochondrion Carbohydrate metabolism Biology Models Biological Biochemistry Rats Sprague-Dawley Islets of Langerhans Cytosol Insulin Secretion medicine Animals Insulin Molecular Biology Mitochondrial transport Reverse Transcriptase Polymerase Chain Reaction Glutamate dehydrogenase Membrane Transport Proteins Cell Biology Mitochondria Rats Metabolic pathway Metabolism Glucose Ketoglutaric Acids NADP |
| Zdroj: | Journal of Biological Chemistry. 285:16530-16537 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m109.092593 |
| Popis: | Glucose-stimulated insulin secretion from pancreatic islet beta-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic alpha-ketoglutarate, also known as 2-oxoglutarate (2OG). Here, we have investigated if mitochondrial transport of 2OG through the 2-oxoglutarate carrier (OGC) participates in control of nutrient-stimulated insulin secretion. Suppression of OGC in clonal pancreatic beta-cells (832/13 cells) and isolated rat islets by adenovirus-mediated delivery of small interfering RNA significantly decreased glucose-stimulated insulin secretion. OGC suppression also reduced insulin secretion in response to glutamine plus the glutamate dehydrogenase activator 2-amino-2-norbornane carboxylic acid. Nutrient-stimulated increases in glucose usage, glucose oxidation, glutamine oxidation, or ATP:ADP ratio were not affected by OGC knockdown, whereas suppression of OGC resulted in a significant decrease in the NADPH:NADP(+) ratio during stimulation with glucose but not glutamine + 2-amino-2-norbornane carboxylic acid. Finally, OGC suppression reduced insulin secretion in response to a membrane-permeant 2OG analog, dimethyl-2OG. These data reveal that the OGC is part of a mechanism of fuel-stimulated insulin secretion that is common to glucose, amino acid, and organic acid secretagogues, involving flux through the pyruvate/isocitrate cycling pathway. Although the components of this pathway must remain intact for appropriate stimulus-secretion coupling, production of NADPH does not appear to be the universal second messenger signal generated by these reactions. |
| Databáze: | OpenAIRE |
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