摘要二甲双胍主要通过降低肝糖异生和促进外周葡萄糖利用而发挥降糖效应。抑制肝糖异生在二甲双胍的降糖作用中尤为重要,其分子机制复杂多样,与药物浓度等因素有关。药理浓度的二甲双胍可直接抑制mGDP,使得胞液中还原型烟酰胺腺嘌呤二核苷酸( NADH)积聚,导致丙酮酸/乳酸比值降低,从而抑制糖异生,此种作用既不依赖于AMP也不依赖于一磷酸腺苷激活的蛋白激酶( AMPK)。药理浓度的二甲双胍还能促进AMPK的亚单位组装而直接激活AMPK,发挥抑制糖异生的作用,此种作用不依赖于AMP但依赖于AMPK。超药理浓度的二甲双胍则抑制线粒体复合体Ⅰ,引起ATP/AMP比值降低,激活AMPK,抑制糖异生。 ATP/AMP比值的降低还能通过能荷机制直接抑制糖异生,并能通过拮抗胰升糖素-cAMP-蛋白激酶A( PKA)系统而抑制糖异生。超药理浓度的二甲双胍尚能抑制AMP脱氨酶,绕开呼吸链直接升高AMP,激活AMPK,抑制糖异生；亦能通过蛋白激酶Cζ( PKCζ)-肝激酶B1( LKB1)-AMPK磷酸化级联而抑制糖异生。此外,二甲双胍在吸收入血前还能通过激活肠黏膜 AMPK 促进胰升糖素样肽1(GLP-1)分泌,GLP-1作用于肠迷走神经传入神经元,通过脑孤束核的迷走神经传出神经元,抑制肝糖异生(肠-脑-肝轴途径)。

abstracts[Summary] 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) .