Revisiting the mechanisms of metformin action in the liver

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.