A New Mechanism for an Old Therapy: Metformin and Glucagon Signaling

摘要

Metformin is the most commonly prescribed pharmaceutical for reducing hepatic glucose production for treatment of type 2 diabetes. Metformin and phenformin are members of the biguanide class of therapeutics whose mechanism of action is poorly understood. Based on the observation that glucagon increases hepatic glucose production, a new report by Miller et al. focused on the potential link between biguanide action and glucagon. Glucagon binds to plasma membrane receptors, causing adenylyl cyclase activity, an increase in cAMP, activation of PKA, and phosphorylation of proteins that stimulate glucose output. Studies in primary mouse hepatocytes and in mice in vivo demonstrated that biguanides disrupted the hepatic glucagon signaling cascade. In primary mouse hepatocytes, phenformin and metformin inhibited glucagon-induced accumulation of cAMP and subsequent phosphorylation of PKA cellular protein targets.