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- Title
The Mitochondrial 2-Oxoglutarate Carrier Plays an Important Role in Glucose- and Amino Acid-Stimulated Insulin Secretion.
- Authors
Odegaard, Matt; Joseph, Jamie W.; Ronnebaum, Sarah M.; Jensen, Mette V.; Ilkayeva, Olga; Newgard, Christopher B.
- Abstract
Glucose-stimulated insulin secretion (GSIS) from islet β-cells is dependent on mitochondrial glucose metabolism and has been linked to anaplerotic entry of pyruvate into the TCA cycle through pyruvate carboxylase (PC) and pyruvate cycling pathways. Although much remains unknown about the role that anaplerosis/pyruvate cycling plays in insulin secretion, manipulation of the pyrovate-isocitrate pathway has revealed substantial effects on GSIS. One key component of this pathway involves transport of 2-oxoglutarate (2OG) across the mitochondrial membrane, possibly via the 2-oxoglutarate carrier (OGC). To investigate the importance of this transporter in insulin secretion, two different siRNA duplexes were used to suppress OGC in 832/13 and 832/3 insulinoma cells. Transfection of cells with either of these duplexes resulted in a 76.5±3.5% (P<0.05) reduction of OGC gene expression and a 50±4% decrease in GSIS (P<0.05) with no effect on basal insulin secretion, compared to cells transfected with a duplex with no known sequence homology. The ability of glucose to stimulate an increase in glucose oxidation and glucose incorporation into lipids was not substantially affected by OGC suppression, suggesting that the effects on insulin secretion could not be ascribed to generalized metabolic dysfunction. We also tested the effects of OGC suppression on stimulation of insulin secretion by amino acids. Cells transfected with the control duplex exhibited a 21±4.8-fold increase in insulin secretion in response to 15 mM glutamine + 15 mM BCH (an activator of glutamate dehydrogenase (GDH)) as compared to stimulation with 15mM glutamine alone. Suppression of OGC expression caused a 60±10% reduction in glutamine plus BCH-stimulated insulin secretion (P<0.05). Given the mitochondrial localization of GDH, our findings suggest that OGC plays an important role in glucose- and amino-acid-stimulated insulin secretion via export of 2OG from the lumen of the mitochondria to the cytoplasm.
- Subjects
MITOCHONDRIAL membranes; GLUCOSE; AMINO acids; INSULIN; METABOLISM; PANCREATIC beta cells; PYRUVATES; ISLANDS of Langerhans tumors
- Publication
Diabetes, 2007, Vol 56, pA443
- ISSN
0012-1797
- Publication type
Article