title: Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes.
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.
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shannon
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Daniele
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Galindo
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Abdul-Ghani
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: Diabetes Division, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Norton
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D027321:Anion Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D002460:Cell Line; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D019289:Pyruvic Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D027321:Anion Transport Proteins; D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D033681:Mitochondrial Membrane Transport Proteins; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D000077205:Pioglitazone
keywords: MPCs; gluconeogenesis; mitochondria; pioglitazone; pyruvate