Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
Diabetologia. 2011 Feb;54(2):339-49. doi: 10.1007/s00125-010-1937-z. Epub 2010 Oct 23.
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 increase circulating levels of glucagon-like peptide 1 (GLP-1). We examined whether metformin exerts glucoregulatory actions via modulation of the incretin axis.
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 metformin-treated 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.
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.
目的/假设：二甲双胍被广泛用于治疗 2 型糖尿病。尽管它可以减少肝葡萄糖生成，但临床研究表明，二甲双胍可能会降低二肽基肽酶-4 的活性并增加胰高血糖素样肽 1（GLP-1）的循环水平。我们研究了二甲双胍是否通过调节肠促胰岛素轴发挥血糖调节作用。
我们在 Glp1r(-/-)、Gipr(-/-)、Glp1r:Gipr(-/-)、Pparα(也称为 Ppara)(-/-)和高血糖肥胖野生型小鼠中评估了二甲双胍的作用，这些小鼠接受或不接受 GLP-1 受体（GLP1R）拮抗剂 exendin(9-39)的治疗。实验终点包括葡萄糖耐量、血浆胰岛素水平、胃排空和食物摄入。我们评估了来自接受二甲双胍治疗的野生型和 Pparα(-/-)小鼠的胰岛中的肠促胰岛素受体表达，以及在存在过氧化物酶体增殖物激活受体（PPAR）-α或 AMP 激活蛋白激酶（AMPK）拮抗剂的 INS-1 832/3β细胞中的表达。
在野生型小鼠中，二甲双胍可急性增加 GLP-1 的血浆水平，但不增加胃抑制多肽或肽 YY 的水平；它还改善了口服葡萄糖耐量并减少了胃排空。尽管在 Glp1r(-/-)、Gipr(-/-)和 Glp1r(-/-)：Gipr(-/-)小鼠中丧失了肠促胰岛素作用，以及在接受高脂肪饮食和 exendin(9-39)治疗的野生型小鼠中，二甲双胍仍显著改善了口服葡萄糖耐量。来自接受二甲双胍治疗的小鼠的胰岛中，Glp1r、Gipr 和 Pparα 的 mRNA 转录物水平显著增加。二甲双胍通过依赖于 PPAR-α、不依赖于 AMPK 的机制直接增加 INS-1β细胞中的 Glp1r 表达。二甲双胍未能在 Pparα(-/-)小鼠的胰岛中诱导肠促胰岛素受体基因表达。
结论/解释：由于二甲双胍调节肠促胰岛素轴的多个组成部分，并通过需要 PPAR-α的机制增强 Glp1r 和相关胰岛素分泌胰岛受体的表达，因此二甲双胍可能在机制上非常适合与肠促胰岛素治疗相结合。
