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Pyruvate dehydrogenase E1α phosphorylation is induced by glucose but does not control metabolism-secretion coupling in INS-1E clonal β-cells

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Published in Biochimica et Biophysica Acta. 2012, vol. 1823, no. 10, p. 1815-24
Abstract Glucose-induced insulin secretion from pancreatic β-cells depends on mitochondrial activation. In the organelle, glucose-derived pyruvate is metabolised along the oxidative and anaplerotic pathway to generate downstream signals leading to insulin granule exocytosis. Entry into the oxidative pathway is catalysed by pyruvate dehydrogenase (PDH) and controlled in part by phosphorylation of the PDH E1α subunit blocking enzyme activity. We find that glucose but not other nutrient secretagogues induce PDH E1α phosphorylation in INS-1E cells and rat islets. INS-1E cells and primary β-cells express pyruvate dehydrogenase kinase (PDK) 1, 2 and 3, which mediate the observed phosphorylation. In INS-1E cells, suppression of the two main isoforms, PDK1 and PDK3, almost completely prevented PDH E1α phosphorylation. Under basal glucose conditions, phosphorylation was barely detectable and therefore the enzyme almost fully active (90% of maximal). During glucose stimulation, PDH is only partially inhibited (to 78% of maximal). Preventing PDH phosphorylation in situ after suppression of PDK1, 2 and 3 neither enhanced pyruvate oxidation nor insulin secretion. In conclusion, although glucose stimulates E1α phosphorylation and therefore inhibits PDH activity, this control mechanism by itself does not alter metabolism-secretion coupling in INS-1E clonal β-cells.
Keywords AnimalsCalcium/pharmacologyCell Survival/drug effectsClone CellsGlucose/pharmacology/toxicityInsulin/secretionInsulin-Secreting Cells/drug effects/enzymology/metabolism/secretionIsoenzymes/metabolismPhosphorylation/drug effectsProtein-Serine-Threonine Kinases/metabolismPyruvate Dehydrogenase (Lipoamide)/metabolismRNA, Small Interfering/metabolismRats
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PMID: 22809973
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AKHMEDOV, Dmitry et al. Pyruvate dehydrogenase E1α phosphorylation is induced by glucose but does not control metabolism-secretion coupling in INS-1E clonal β-cells. In: Biochimica et Biophysica Acta, 2012, vol. 1823, n° 10, p. 1815-24. https://archive-ouverte.unige.ch/unige:33354

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Deposited on : 2014-01-16

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