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

被引:16
作者
Akhmedov, Dmitry [1 ]
De Marchi, Umberto [2 ]
Wollheim, Claes B. [1 ]
Wiederkehr, Andreas [2 ]
机构
[1] Univ Geneva, Dept Cell Physiol & Metab, CH-1211 Geneva 4, Switzerland
[2] Nestle Inst Hlth Sci, CH-1015 Lausanne, Switzerland
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2012年 / 1823卷 / 10期
关键词
Beta-cell; Insulin; Pyruvate dehydrogenase; Pyruvate dehydrogenase kinase; STIMULATED INSULIN-SECRETION; RAT PANCREATIC-ISLETS; NMR ISOTOPOMER ANALYSIS; MITOCHONDRIAL METABOLISM; CYTOSOLIC CA2+; AMINO-ACID; ACTIVATION; PHOSPHATASE; COMPLEX; ANAPLEROSIS;
D O I
10.1016/j.bbamcr.2012.07.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucose-induced insulin secretion from pancreatic beta-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 E1 alpha subunit blocking enzyme activity. We find that glucose but not other nutrient secretagogues induce PDH E1 alpha phosphorylation in INS-1E cells and rat islets. INS-1E cells and primary beta-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 E1 alpha 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 E1 alpha phosphorylation and therefore inhibits PDH activity, this control mechanism by itself does not alter metabolism-secretion coupling in INS-1E clonal beta-cells. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:1815 / 1824
页数:10
相关论文
共 49 条
[1]   Mitochondrial matrix pH controls oxidative phosphorylation and metabolism-secretion coupling in INS-1E clonal β cells [J].
Akhmedov, Dmitry ;
Braun, Matthias ;
Mataki, Chikage ;
Park, Kyu-Sang ;
Pozzan, Tullio ;
Schoonjans, Kristina ;
Rorsman, Patrik ;
Wollheim, Claes B. ;
Wiederkehr, Andreas .
FASEB JOURNAL, 2010, 24 (11) :4613-4626
[2]   Mitochondrial metabolism sets the maximal limit of fuel-stimulated insulin secretion in a model pancreatic beta cell - A survey of four fuel secretagogues [J].
Antinozzi, PA ;
Ishihara, H ;
Newgard, CB ;
Wollheim, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (14) :11746-11755
[3]   Regulation of Islet β-Cell Pyruvate Metabolism: Interactions of Prolactin, Glucose, and Dexamethasone [J].
Arumugam, Ramamani ;
Horowitz, Eric ;
Noland, Robert C. ;
Lu, Danhong ;
Fleenor, Donald ;
Freemark, Michael .
ENDOCRINOLOGY, 2010, 151 (07) :3074-3083
[4]   Glucose-Induced O2 Consumption Activates Hypoxia Inducible Factors 1 and 2 in Rat Insulin-Secreting Pancreatic Beta-Cells [J].
Bensellam, Mohammed ;
Duvillie, Bertrand ;
Rybachuk, Galyna ;
Laybutt, D. Ross ;
Magnan, Christophe ;
Guiot, Yves ;
Pouyssegur, Jacques ;
Jonas, Jean-Christophe .
PLOS ONE, 2012, 7 (01)
[5]   Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex [J].
Bowker-Kinley, MM ;
Davis, WI ;
Wu, PF ;
Harris, RA ;
Popov, KM .
BIOCHEMICAL JOURNAL, 1998, 329 :191-196
[6]   Mitochondria-derived glutamate at the interplay between branched-chain amino acid and glucose-induced insulin secretion [J].
Broca, C ;
Brennan, L ;
Petit, P ;
Newsholme, P ;
Maechler, P .
FEBS LETTERS, 2003, 545 (2-3) :167-172
[7]   13C NMR isotopomer analysis of anaplerotic pathways in INS-1 cells [J].
Cline, GW ;
LePine, RL ;
Papas, KK ;
Kibbey, RG ;
Shulman, GI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (43) :44370-44375
[8]   Saturated fatty acids synergize with elevated glucose to cause pancreatic β-cell death [J].
El-Assaad, W ;
Buteau, J ;
Peyot, ML ;
Nolan, C ;
Roduit, R ;
Hardy, S ;
Joly, E ;
Dbaibo, G ;
Rosenberg, L ;
Prentki, M .
ENDOCRINOLOGY, 2003, 144 (09) :4154-4163
[9]   Reduction of plasma membrane glutamate transport potentiates insulin but not glucagon secretion in pancreatic islet cells [J].
Feldmann, Nicole ;
Martin del Rio, Rafael ;
Gjinovci, Asllan ;
Tamarit-Rodriguez, Jorge ;
Wollheim, Claes B. ;
Wiederkehr, Andreas .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2011, 338 (1-2) :46-57
[10]   β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release [J].
Franklin, I ;
Gromada, J ;
Gjinovci, A ;
Theander, S ;
Wollheim, CB .
DIABETES, 2005, 54 (06) :1808-1815