RGD Reference Report - Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion. - Rat Genome Database

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Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion.

Authors: Stark, R  Pasquel, F  Turcu, A  Pongratz, RL  Roden, M  Cline, GW  Shulman, GI  Kibbey, RG 
Citation: Stark R, etal., J Biol Chem. 2009 Sep 25;284(39):26578-90. doi: 10.1074/jbc.M109.011775. Epub 2009 Jul 27.
RGD ID: 7242950
Pubmed: PMID:19635791   (View Abstract at PubMed)
PMCID: PMC2785346   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.011775   (Journal Full-text)

Pancreatic beta-cells couple the oxidation of glucose to the secretion of insulin. Apart from the canonical K(ATP)-dependent glucose-stimulated insulin secretion (GSIS), there are important K(ATP)-independent mechanisms involving both anaplerosis and mitochondrial GTP (mtGTP). How mtGTP that is trapped within the mitochondrial matrix regulates the cytosolic calcium increases that drive GSIS remains a mystery. Here we have investigated whether the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) is the GTPase linking hydrolysis of mtGTP made by succinyl-CoA synthetase (SCS-GTP) to an anaplerotic pathway producing phosphoenolpyruvate (PEP). Although cytosolic PEPCK (PEPCK-C) is absent, PEPCK-M message and protein were detected in INS-1 832/13 cells, rat islets, and mouse islets. PEPCK enzymatic activity is half that of primary hepatocytes and is localized exclusively to the mitochondria. Novel (13)C-labeling strategies in INS-1 832/13 cells and islets measured substantial contribution of PEPCK-M to the synthesis of PEP. As high as 30% of PEP in INS-1 832/13 cells and 41% of PEP in rat islets came from PEPCK-M. The contribution of PEPCK-M to overall PEP synthesis more than tripled with glucose stimulation. Silencing the PEPCK-M gene completely inhibited GSIS underscoring its central role in mitochondrial metabolism-mediated insulin secretion. Given that mtGTP synthesized by SCS-GTP is an indicator of TCA flux that is crucial for GSIS, PEPCK-M is a strong candidate to link mtGTP synthesis with insulin release through anaplerotic PEP cycling.




Biological Process

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Pck2Ratcellular response to glucose stimulus  IEP  RGD 
Pck2Ratpositive regulation of insulin secretion  IMP  RGD 
Pck2Ratpyruvate biosynthetic process  IMP  RGD 


Genes (Rattus norvegicus)
Pck2  (phosphoenolpyruvate carboxykinase 2 (mitochondrial))