Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes

• Published in: The FEBS journal 2017-02, Vol.284 (3), p.451-465
• Main Authors: Shannon, Christopher E., Daniele, Giuseppe, Galindo, Cynthia, Abdul‐Ghani, Muhammad A., DeFronzo, Ralph A., Norton, Luke
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - antagonists & inhibitors; Adenosine Triphosphate - biosynthesis; Animals; Anion Transport Proteins - antagonists & inhibitors; Anion Transport Proteins - genetics; Anion Transport Proteins - metabolism; ATP; Biological Transport - drug effects; Carbon Radioisotopes; Cell Line; Dependence; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Gene expression; Gene silencing; gluconeogenesis; Gluconeogenesis - drug effects; Glucose; Glucose - antagonists & inhibitors; Glucose - biosynthesis; Glucose metabolism; Glycolysis - drug effects; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Homeostasis; Hypoglycemic Agents - pharmacology; Insulin; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mode of action; MPCs; Muscles; Oxidation; Oxidation-Reduction; Oxidative Phosphorylation - drug effects; Oxygen consumption; Pathogenesis; Pioglitazone; pyruvate; Pyruvic acid; Pyruvic Acid - metabolism; Rats; Regulators; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; siRNA; Skeletal muscle; Synthesis; Thiazolidinediones - pharmacology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13992

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. The thiazolidinedione drug pioglitazone inhibits multiple pathways of pyruvate metabolism in cultured hepatocytes, providing a direct mechanism through which it may exert its antidiabetic effects in the liver. These effects occur independently from the putative mitochondrial pyruvate carrier proteins MPC1 and MPC2, raising new speculation about the role of these proteins in pyruvate metabolism and TZD action.