title: The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Sarah W Stedman Nutrition and Metabolism Center, Durham, North Carolina 27704, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Odegaard
authors.forename: Jamie W
authors.initials: JW
authors.lastname: Joseph
authors.forename: Mette V
authors.initials: MV
authors.lastname: Jensen
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ronnebaum
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Becker
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
mesh_terms: D000818:Animals; D003600:Cytosol / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007328:Insulin; D007656:Ketoglutaric Acids; D026901:Membrane Transport Proteins; C021723:oxoglutarate translocator; D005973:Glutamine; D009249:NADP; D005947:Glucose