据药理学教研室与药剂学教研室共同学术会议安排，11月1日早8：00由马雪博士为大家做学术报告，主要讲解二甲双胍降血糖作用机理的新发现，英文名称为Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-αin mice. 热烈欢迎感兴趣的同学和老师参加并讨论。
Aims/hypothesis Metformin is widely used for the treatment of type 2 diabetes. Although it reduces hepatic glucose production, clinical studies show that metformin may reduce plasma dipeptidyl peptidase-4 activity and increasecirculating levels of glucagon-like peptide 1 (GLP-1). We examined whether metformin exerts glucoregulatory actions via modulation of the incretin axis.
Methods Metformin action was assessed in Glp1r−/−, Gipr−/−, Glp1r:Gipr−/−, Pparα (also known as Ppara)−/− and hyperglycaemic obese wild-type mice with or without the GLP-1 receptor (GLP1R) antagonist exendin(9-39). Experimental endpoints included glucose tolerance, plasma insulin levels, gastric emptying and food intake. Incretin receptor expression was assessed in isolated islets from metformintreated wild-type and Pparα−/− mice, and in INS-1 832/3 beta cells with or without peroxisome proliferator-activated receptor (PPAR)-α or AMP-activated protein kinase (AMPK) antagonists.
Results In wild-type mice, metformin acutely increased plasma levels of GLP-1, but not those of gastric inhibitory polypeptide or peptide YY; it also improved oral glucose tolerance and reduced gastric emptying. Metformin significantly improved oral glucose tolerance despite loss of incretin action in Glp1r−/−, Gipr−/− and Glp1r−/−:Gipr−/− mice, and in wild-type mice fed a high-fat diet and treated with exendin(9-39). Levels of mRNA transcripts for Glp1r, Gipr and Pparα were significantly increased in islets from metformin-treated mice. Metformin directly increased Glp1r expression in INS-1 beta cells via a PPAR-α- dependent, AMPK-independent mechanism. Metformin failed to induce incretin receptor gene expression in islets from Pparα−/− mice.
Conclusions/interpretation As metformin modulates multiple components of the incretin axis, and enhances expression of the Glp1r and related insulinotropic islet receptors through a mechanism requiring PPAR-α, metformin may be mechanistically well suited for combination with incretin-based therapies.