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11.1学术活动
2010-10-31 10:17   发布范围:公开

 

Diabetologia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。

二甲双胍被广泛应用于二型糖尿病的治疗,现已发现它主要降低肝糖元的产生,临床研究表明它可能还通过其他途径达到降糖目的。这个新途径是如何发现以及怎样起作用的呢?请到时听马博士分解。

 

 

 

文章摘要如下:

 

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.

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