Molecular mechanisms of hypoglycemic effect of metformin

Abstract

Metformin mainly gives play to the hypoglycemic effect by reducing hepatic gluconeogenesis and activating glucose utilization of peripheral tissues. It is especially important that inhibiting hepatic gluconeogenesis in the hypoglycemic effect of metformin, of which molecular mechanisms are complicated and diverse, and are related to drug concentrations. Metformin, at pharmacologic concentrations, may directly inhibit mitochondria glycerophosphate dehydrogenase, resulting in reduced nicotinamide adenine dinucleotide(NADH)accumulation in cytosol and reducing pyruvate/lactate ratio, thus inhibiting gluconeogenesis. This effect is dependent on neither AMP nor adenosine monophosphate-activated protein kinase(AMPK). Metformin at pharmacologic concentrations may also promote subunit assembly of AMPK to activate AMPK directly, thereby inhibiting hepatic gluconeogenesis. This effect is independent on AMP while dependent on AMPK. Metformin, at supra-pharmacologic concentrations, may inhibit mitochondrial complex Ⅰ, thus decrease ATP/AMP ratio, thereby activating AMPK and inhibiting hepatic gluconeogenesis. The reduction of ATP/AMP ratio also inhibits gluconeogenesis directly by energy chargeing 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. Metformin at supra-pharmacologic concentrations also inhibits AMP deaminase, and bypasses mitochondrial respiratory chain to increase AMP level, which activates AMPK and inhibits gluconeogenesis. Metformin at supra-pharmacologic concentrations also inhibits hepatic gluconeogenesis by protein kinase Cζ(PKCζ)-liver kinase B1(LKB1)-AMPK phosphorylation cascade. In addition, before metformin enters the blood, it activates intestinal mucosa(probablly L-cells)AMPK to increase glucagon-like peptide 1(GLP-1)secretion. GLP-1 acts on afferent neuron of intestines vagus to inhibit hepatic gluconeogenesis by vagus efferent neuron of nucleus tractus solitarii(intestines-brain-liver axis route). (Chin J Endocrinol Metab, 2016, 32: 716-722) Key words: Metformin; Diabetes mellitus; Adenosine monophosphate; AMP-activated protein kinase; Mitochondria; Gluconeogenesis