title: Skeletal muscle lactate overproduction during metformin intoxication: An animal study with reverse microdialysis.
abstract: Lactic acidosis during metformin intoxication is classically mainly attributed to diminished lactate clearance through liver gluconeogenesis. Here we studied 6 healthy, sedated and mechanically ventilated pigs to clarify whether high dose of metformin also increases skeletal muscle lactate production. Each animal had two microdialysis catheters inserted in gluteus muscles, one per side. One catheter was infused with saline (control) while the other one was infused with metformin diluted in saline (1M), both at a rate of 0.3μl/min. Dialysate lactate concentration and lactate-to-pyruvate ratio, a marker of the balance between anaerobic glycolysis and aerobic (mitochondrial) metabolism, were measured every 3h, for 12h. Continuous infusion of metformin caused a progressive rise in dialysate lactate level (p=0.007) and lactate-to-pyruvate ratio (p<0.001) compared to that of saline, as for mitochondrial "poisoning". These findings suggest that skeletal muscle lactate overproduction contributes to the development of metformin-induced lactic acidosis.
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: alessandro.protti@policlinico.mi.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Protti
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Properzi
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Magnoni
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Santini
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.affiliation: Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guenzani
authors.affiliation: U.O.C. Anatomia Patologica, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy; Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Centro di Ricerche Chirurgiche Precliniche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bassani
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy; Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi, Milan, Italy.
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
authors.affiliation: Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy; Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi, Milan, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Gattinoni
mesh_terms: D000140:Acidosis, Lactic / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D006019:Glycolysis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D007263:Infusions, Parenteral; D019344:Lactic Acid / Q000378:metabolism*; D008687:Metformin / Q000008:administration & dosage / Q000633:toxicity*; D017551:Microdialysis; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013552:Swine; D013997:Time Factors
chemical_list: D007004:Hypoglycemic Agents; D019344:Lactic Acid; D019289:Pyruvic Acid; D008687:Metformin
keywords: Diabetes; Lactic acidosis; Metformin; Microdialysis; Mitochondria