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Pyruvate dehydrogenase kinase 1 controls mitochondrial metabolism and insulin secretion in INS-1 832/13 clonal β- cells

Abstract : Tight coupling between cytosolic and mitochondrial metabolism is key for glucose-stimulated insulin secretion (GSIS). Here, we examined the regulatory contribution of pyruvate dehydrogenase (PDH) kinase 1, a negative regulator of PDH, to metabolic coupling in 832/13 clonal b-cells. Knocking down PDH kinase 1 with siRNA reduced its mRNA (<80%) and protein level (<40%) after 72 h. PDH activity, glucose-stimulated cellular oxygen consumption and pyruvate-stimulated mitochondrial oxygen consumption increased 1.7- (P<0.05), 1.6- (P<0.05) and 1.6-fold (P<0.05), respectively. Gas chromatography/mass spectrometry revealed an altered metabolite profile upon silencing of PDH kinase 1, determined by increased levels of the TCA cycle intermediates malate, fumarate, and a-ketoglutarate. These metabolic alterations were associated with exaggerated GSIS (5-fold vs. 3.1-fold in control cells; P<0.01). Insulin secretion provoked by leucine and dimethylsuccinate, which feed into the TCA cycle bypassing PDH, was unaffected. The oxygen consumption and metabolic data strongly suggest that knocking down PDH kinase 1 in β-cells permits increased metabolic flux of glucose-derived carbons into the TCA cycle via PDH. Enhanced insulin secretion is likely caused by increased generation of TCA cycle-derived reducing equivalents for mitochondrial electron transport to generate ATP and/or stimulatory metabolic intermediates. Based on these findings, we suggest that PDH kinase 1 is an important regulator of PDH in clonal b-cells and that PDH kinase 1 and PDH are important for efficient metabolic coupling. Maintaining low PDH kinase 1 expression/activity, keeping PDH in a dephosphorylated and active state, may be important for b-cells to achieve the metabolic flux rates necessary for maximal GSIS.
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Submitted on : Monday, June 14, 2010 - 2:50:42 AM
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Ulrika Krus, Olga Kotova, Peter Spégel, Elna Hallgard, Vladimir V. Sharoyko, et al.. Pyruvate dehydrogenase kinase 1 controls mitochondrial metabolism and insulin secretion in INS-1 832/13 clonal β- cells. Biochemical Journal, Portland Press, 2010, 429 (1), pp.205-213. ⟨10.1042/BJ20100142⟩. ⟨hal-00491631⟩

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