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

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.

journal_name

Mol Genet Metab

authors

Majer M,Popov KM,Harris RA,Bogardus C,Prochazka M

doi

10.1006/mgme.1998.2748

subject

Has Abstract

pub_date

1998-10-01 00:00:00

pages

181-6

issue

2

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(98)92748-2

journal_volume

65

pub_type

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