Abstract
Metformin primarily gives rise to the hypoglycemic effect by reducing hepatic gluconeogenesis and activating glucose utilization in peripheral tissues. Inhibiting hepatic gluconeogenesis is important to the hypoglycemic effect of metformin, a medication whose molecular mechanisms of action are complex, diverse, and related to drug concentration. Metformin at pharmacologic concentrations directly inhibits mitochondria glycerophosphate dehydrogenase, resulting in NADH accumulation in the cytosol and reducing the pyruvate/lactate ratio, thus inhibiting gluconeogenesis. This effect is dependent on neither AMP nor AMPK. Metformin also promotes subunit assembly of AMPK to activate AMPK directly, thereby inhibiting hepatic gluconeogenesis. This effect is independent of AMP, but dependent on AMPK. At supra-pharmacologic concentrations, metformin inhibits mitochondrial complex I, decreasing the ATP/AMP ratio, thereby activating AMPK, inhibiting hepatic gluconeogenesis. The reduction of the ATP/AMP ratio also inhibits gluconeogenesis directly by the energy charge mechanism; the accumulation of AMP inhibits adenylate cyclase, reducing levels of cyclic AMP and protein kinase A (PKA) activity, abrogating phosphorylation of critical protein targets of PKA, and blocking hepatic glucagon signaling (AMP-dependent but AMPK-independent pathway). Metformin at supra-pharmacologic concentrations can also inhibit AMP deaminase and bypass the mitochondrial respiratory chain to increase AMP levels, which activates AMPK and inhibits gluconeogenesis (via the AMP-dependent and AMPK-dependent non-mitochondrial pathway). Metformin at supra-pharmacologic concentrations also inhibits hepatic gluconeogenesis by the PKCζ-LKB1-AMPK phosphorylation cascade. In addition, it activates intestinal mucosa (possibly L-cell) AMPK to increase GLP1 secretion. GLP1 acts on vagal afferent neurons to inhibit hepatic gluconeogenesis through the vagal efferent of the nucleus tractus solitarii (gut-brain-liver axis). (Am J Transl Med. 2017. 1:26-41)