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- Title
The Mitochondrial Dicarboxylate Carrier (DIC) Plays a Regulatory Role in Glucose-Stimulated Insulin Secretion.
- Authors
Joseph, Jamie W.; Ronnebaum, Sarah M.; Odegaard, Matthew; Jensen, Mette V.; Newgard, Christopher B.
- Abstract
Mitochondrial metabolism of pyruvate derived from glycolysis plays an important role in glucose-stimulated insulin secretion (GSIS) in pancreatic βcells. Glucose stimulates anaplerosis and efflux of TCA cycle intermediates into the cytosol, where they can be recycled to pyruvate or metabolized to other products. We have previously described a strong correlation between pyruvate cycling and insulin secretion, and have demonstrated a particularly important role for a pyruvate-isocitrate cycling pathway involving the mitochondrial citrate/isocitrate carrier (CIC) and cytosolic NADP-dependent isocitrate dehydrogenase. CIC requires cytosolic malate as a counter-ion during citrate and isocitrate export, and an important source of cytosolic malate is the mitochondrial dicarboxylate carrier (DIC). We therefore investigated the potential role of DIC in control of GSIS. Butylmalonate, an inhibitor of malate transport, inhibited GSIS in a dose-dependent manner in 832/13 cells without affecting basal insulin secretion and insulin content. Transfection of cells with three different small interfering RNAs (siRNA) specific for DIC reduced DIC mRNA levels between 45.9 to 88.6% and caused a proportional decrease in DIC protein levels in 832/13 cells. Suppression of DIC expression resulted in inhibition of GSIS by 20.1 to 58.3% (P<0.001) relative to cells transfected with a control siRNA construct, and the extent of inhibition of insulin secretion was proportional to the level of DIC gene knockdown. This suppression of DIC expression did not alter insulin content. The most effective siRNA duplex against DIC did not affect glucose utilization, glucose oxidation, ATP/ADP ratio, or incorporation of glucose into lipids. These studies suggest that malate transport by DIC plays an important role in GSIS, possibly by producing an essential cytosolic counter-ion for citrate and isocitrate export from the mitochondria.
- Subjects
GLYCOLYSIS; GLUCOSE; INSULIN; CELL metabolism; PYRUVATES; PANCREATIC beta cells; MESSENGER RNA; LIPIDS
- Publication
Diabetes, 2007, Vol 56, pA442
- ISSN
0012-1797
- Publication type
Article