Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: Potential mechanism contributing to increased lipid oxidation in insulin- resistant subjects

Martin Majer, Kirill M. Popov, Robert A. Harris, Clifton Bogardus, Michal Prochazka

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Oxidative metabolism of glucose is regulated by pyruvate dehydrogenase (PDH) that can be inhibited by isoforms of PDH kinase (PDK). Recently, increased PDK activity has been implicated in the pathogenesis of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) in obese subjects. Using quantitative RT-PCR, we measured mRNA of PDK2 and PDK4 isoforms in skeletal muscle biopsies from nondiabetic Pima Indians, a population with a high prevalence of NIDDM associated with obesity. PDK2 and PDK4 mRNAs were positively correlated with fasting plasma insulin concentration, 2-h plasma insulin concentration in response to oral glucose, and percentage body fat, whereas both isoforms were negatively correlated with insulin-mediated glucose uptake rates. Measurements of PDK2 and PDK4 mRNA during the hyperinsulinemic-euglycemic clamp and of PDK2 in cell culture indicated that both transcripts decrease in response to insulin. Increased fatty acid (FA) oxidation has been traditionally viewed as the cause for increased PDK activity contributing to insulin resistance in obese subjects. In contrast, our data indicate that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased FA oxidation.

Original languageEnglish (US)
Pages (from-to)181-186
Number of pages6
JournalMolecular Genetics and Metabolism
Volume65
Issue number2
DOIs
StatePublished - Oct 1998
Externally publishedYes

Keywords

  • Insulin regulation
  • Insulin resistance
  • PDK
  • Pima Indians
  • mRNA

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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