title: The pyruvate carboxylase-pyruvate dehydrogenase axis in islet pyruvate metabolism: Going round in circles?
abstract: Pyruvate is the major product of glycolysis in pancreatic β-cells, and its ultimate metabolic fate depends on the relative activities of two enzymes. The first, pyruvate carboxylase (PC) replenishes oxaloacetate withdrawn from the tricarboxylic acid (TCA) cycle via the carboxylation of pyruvate to form oxaloacetate. Flux via PC is also involved in the formation of NADPH, one of several important coupling factors for insulin secretion. In most tissues, PC activity is enhanced by increased acetyl-CoA. The alternative fate of pyruvate is its oxidative decarboxylation to form acetyl-CoA via the pyruvate dehydrogenase complex (PDC). The ultimate fate of acetyl-CoA carbon is oxidation to CO2 via the TCA cycle, and so the PDC reaction results of the irreversible loss of glucose-derived carbon. Thus, PDC activity is stringently regulated. The mechanisms controlling PDC activity include end-product inhibition by increased acetyl-CoA, NADH and ATP, and its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDHKs 1-4). Here we review new developments in the regulation of the activities and expression of PC, PDC and the PDHKs in the pancreatic islet in relation to islet pyruvate disposition and glucose-stimulated insulin secretion (GSIS).
authors.affiliation: Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK. m.c.sugden@qmul.ac.uk
authors.forename: Mary C
authors.initials: MC
authors.lastname: Sugden
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holness
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002952:Citric Acid Cycle / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
chemical_list: D007328:Insulin; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A; D017346:Protein Serine-Threonine Kinases; D011766:Pyruvate Carboxylase; D005947:Glucose