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Flexibility in regulation of PDC is dependent on rapid changes in the phosphorylation state of PDC determined by the relative activities of the pyruvate dehydrogenase kinases (PDKs) and the pyruvate dehydrogenase phosphatases. Inactivation of the PDC by overexpression of PDK4 contributes to hyperglycemia, and therefore the serious health problems associated with diabetes. Loss of regulatory flexibility of PDC occurs in other disease states and pathological conditions that have received less attention than diabetes. These include cancers, non\u2010alcoholic fatty liver disease, cancer\u2010induced cachexia, diabetes\u2010induced nephropathy, sepsis and amyotrophic lateral sclerosis. Overexpression of PDK4, and in some situations, the other PDKs, as well as under expression of the pyruvate dehydrogenase phosphatases, leads to inactivation of the PDC, mitochondrial dysfunction and deleterious effects with health consequences. The possible basis for this phenomenon, along with evidence that overexpression of PDK4 results in phosphorylation of \u201coff\u2010target\u201d proteins and promotes excessive transport of Ca<jats:sup>2+<\/jats:sup> into mitochondria through mitochondria\u2010associated endoplasmic reticulum membranes are discussed. Recent efforts to find small molecule PDK inhibitors with therapeutic potential are also reviewed.<\/jats:p>","DOI":"10.1111\/jdi.13345","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T15:25:34Z","timestamp":1594049134000},"page":"21-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases"],"prefix":"10.1111","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9217-968X","authenticated-orcid":false,"given":"Jae\u2010Han","family":"Jeon","sequence":"first","affiliation":[{"name":"Department of Internal Medicine School of Medicine Kyungpook National University Kyungpook National University Hospital Daegu Korea"},{"name":"Leading\u2010Edge Research Center for Drug Discovery and Development for 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