Journal
DIABETES & METABOLISM JOURNAL
Volume 39, Issue 3, Pages 188-197Publisher
KOREAN DIABETES ASSOC
DOI: 10.4093/dmj.2015.39.3.188
Keywords
Diabetes mellitus, type 2; Glucose metabolism; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase; Pyruvate dehydrogenase kinase inhibitor; Warberg effect
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Funding
- Catholic University of Daegu [2010 1227]
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Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases.
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