title: Revisiting the mechanisms of metformin action in the liver.
abstract: Although considerable efforts have been made since the 1950s to better understand the action of metformin, the first line therapeutic for type 2 diabetes, its mechanisms of action has not been fully elucidated. The main antidiabetic effect of this drug is to decrease hepatic glucose production. A plausible molecular mechanism of action now emerges from recent breakthroughs that place metformin at the control of energy homeostasis. Metformin was shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex 1. The resulting decrease in hepatic energy state activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, and provided a generally accepted mechanism for metformin action on hepatic gluconeogenic program. However, the role of AMPK activation in metformin action has recently been challenged by loss-of-function experiments. Recent evidence showed that metformin-induced inhibition of hepatic glucose output is mediated by reducing cellular energy charge rather than direct inhibition of gluconeogenic gene expression. Furthermore, recent data support a novel mechanism of action for metformin involving antagonism of glucagon signaling pathways by inducing the accumulation of AMP, which inhibits adenylate cyclase and reduced levels of cAMP.
authors.affiliation: Département endocrinologie, métabolisme et cancer, Inserm, U1016, Institut Cochin, 24, rue du Faubourg-Saint-Jacques, 75014 Paris, France. benoit.viollet@inserm.fr
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D029881:Galega / Q000737:chemistry; D049673:History, 20th Century; D049674:History, 21st Century; D049691:History, Medieval; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008517:Phytotherapy / Q000266:history
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin