The role of pyruvate dehydrogenase kinase in diabetes and obesity

Abstract

The pyruvate dehydrogenase complex (PDC) is an emerging target for the treatment of metabolic syndrome. To maintain a steady-state concentration of adenosine triphosphate during the feed-fast cycle, cells require efficient utilization of fatty acid and glucose, which is controlled by the PDC. The PDC converts pyruvate, coenzyme A (CoA), and oxidized nicotinamide adenine dinucleotide (NAD(+)) into acetyl-CoA, reduced form of nicotinamide adenine dinucleotide (NADH), and carbon dioxide. The activity of the PDC is up- and down-regulated by pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase, respectively. In addition, pyruvate is a key intermediate of glucose oxidation and an important precursor for the synthesis of glucose, glycerol, fatty acids, and nonessential amino acids.

Keywords: Diabetes mellitus; Obesity; Pyruvate dehydrogenase (acetyl-transferring) kinase.

Fig. 1

Schematic representation of the regulation of glucose metabolism by pyruvate dehydrogenase complex (PDC). The activity of PDC is strongly inhibited by phosphorylation of its dehydrogenase component by pyruvate dehydrogenase kinases (PDKs) and enhanced by dephosphorylation by pyruvate dehydrogenase phosphatases (PDPs). The main regulatory factors of PDKs and PDPs are shown as above. Pyruvate enters into mitochondria via the voltage-dependent anion channel (VDAC) and mitochondrial pyruvate carrier (MPC) and is then converted into either oxaloacetate by pyruvate carboxylase or acetyl-CoA by PDC. Acetyl-CoA then enters into the tricarboxylic acid cycle, yielding nicotinamide adenine dinucleotide (NADH) and favin adenine dinucleotide 2 (FADH2) and promoting oxidative phosphorylation. PEP, phosphoenolpyruvate; CoASH, coenzyme A-SH; PEPCK, phosphoenolpyruvate carboxykinase; cAMP, cyclic adenosine monophosphate; ADP, adenosine diphosphate; ATP, adenosine triphosphate.