Genetic Inactivation of Pyruvate Dehydrogenase Kinases Improves Hepatic Insulin Resistance Induced Diabetes

Rongya Tao, Xiwen Xiong, Robert Harris, Morris F. White, X. Dong

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes.

Original languageEnglish
Article numbere71997
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 5 2013

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pyruvate dehydrogenase (acetyl-transferring) kinase
Insulin Receptor Substrate Proteins
Medical problems
insulin resistance
diabetes
Insulin Resistance
inactivation
Genes
Insulin
liver
Liver
Gene Knockdown Techniques
Gluconeogenesis
Gene Deletion
genes
gluconeogenesis
Glucose
gene deletion
Hyperglycemia
glucose tolerance

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Genetic Inactivation of Pyruvate Dehydrogenase Kinases Improves Hepatic Insulin Resistance Induced Diabetes. / Tao, Rongya; Xiong, Xiwen; Harris, Robert; White, Morris F.; Dong, X.

In: PLoS One, Vol. 8, No. 8, e71997, 05.08.2013.

Research output: Contribution to journalArticle

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