Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes

Christopher E. Shannon, Giuseppe Daniele, Cynthia Galindo, Muhammad A Abdul-ghani, Ralph A Defronzo, Luke Norton

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2-14C]-pyruvate oxidation and pyruvate-driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose-dependently inhibited pyruvate-driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate-driven ATP synthesis, but did not alter pyruvate-driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies.

Original languageEnglish (US)
Pages (from-to)451-465
Number of pages15
JournalFEBS Journal
Volume284
Issue number3
DOIs
StatePublished - Feb 1 2017

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Keywords

  • gluconeogenesis
  • mitochondria
  • MPCs
  • pioglitazone
  • pyruvate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shannon, C. E., Daniele, G., Galindo, C., Abdul-ghani, M. A., Defronzo, R. A., & Norton, L. (2017). Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS Journal, 284(3), 451-465. https://doi.org/10.1111/febs.13992