, namely its phosphorylation by a family of pyruvate dehydrogenase kinases,5,6. The pyruvate dehydrogenase component catalyzes the physiologically irreversible step, and is the PDC component phosphorylated by the PDHKs5,6. Phosphorylation of serine-264 of E1 of PDC is of primary importance for acute modulation of the percentage of active PDC; whereas additional phosphorylation at serine-271 and serine-203 of E1 may retard reactivation by dephosphorylation by the pyruvate dehydrogenase phosphatases.7-9 All of the PDHKs phosphorylate sites 1 and 2 of E1, whereas site 3 of E1 is phosphorylated only by PDHK1.10,11 In the starved state PDC is inhibited, whereas the PDHKs and PC are activated by increased mitochondrial acetyl-CoA derived from FA -oxidation. This allows the entry of acetyl-CoA derived from FA oxidation into the first span of the TCA cycle to generate citrate, but the operation of the second span of the TCA cycle becomes dependent on re-oxidation of the NADH and FADH2 that is generated by FA -oxidation. Pancreatic islets contain PDHKs 1, 2 and 4.12,13 As in other oxidative tissues, the potential therefore exists for multisite phosphorylation of E1 and metabolic inflexibility in switching from FA to glucose as oxidative substrate in islets. Nevertheless, a recent study has demonstrated that -cellspecific PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19820119 PDH deficiency leads to decreased pancreatic insulin content and reduced GSIS demonstrating a key role of PDC in GSIS.15 This review will focus on new developments in our understanding of the roles of flux via PC and PDC in augmenting GSIS in the fed state and suppressing GSIS in starvation, and how relative flux through these two strategic pyruvatemetabolizing enzymes is regulated. Pyruvate Cycles in -Cells A number of pathways exist in the -cell that enable the generation of several important coupling factors for insulin secretion. The pyruvate cycles involve the generation of oxaloacetate via PC and the subsequent exit of TCA cycle intermediates from the mitochondria to the cytosol. Their further metabolism in the cytosol yields coupling or amplification factors for insulin secretion, with subsequent re-entry of the pathway products into the TCA cycle. Critically, while the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase are known to generate NAPDH, the ME and ICDH isoforms that are expressed in the mitochondria generate NADH rather than NADPH. Thus, it is crucial that the TCA cycle intermediates are exported to the cytosol for the formation of the coupling or amplification factors for insulin secretion. The pyruvate/malate pathway involves the generation of oxaloacetate from pyruvate by PC, formation of malate by mitochondrial malate dehydrogenase, followed by transport of malate into the cytosol by the dicarboxylate carrier. The coupling factor NADPH is then purchase BQ 123 formed by the conversion of malate to pyruvate by cytosolic ME. Pyruvate can then re-enter the mitochondria for conversion to oxaloacetate. Both citrate and isocitrate can be transported to the cytosol by the citrate-isocitrate carrier, where citrate can be converted to isocitrate by cytosolic aconitase. Cytosolic citrate can be cleaved by ATP-citrate lyase to acetyl-CoA and oxaloacetate. Oxaloacetate can be converted to malate by cytosolic MDH, also generating NADH, and then the coupling factor NADPH can be generated by conversion of malate to 
pyruvate by cME. Pyruvate can then re-enter the mitochondria completing the cycle. Since the pyruvate/ citrate
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