Institute for Biochemical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Austrian Drug Screening Institute GmbH, Innsbruck, Austria.
Eur J Pharmacol. 2019 Dec 15;865:172782. doi: 10.1016/j.ejphar.2019.172782. Epub 2019 Nov 6.
Despite being a successful diabetes type 2 drug for more than a half-century in Europe, the mode of action of metformin is still debated. It is the purpose of this review to inform the reader about most recent findings for metformin with respect to its antidiabetic activity as well as proposed benefits beyond glucose control in humans. Clinical evidence now suggests that most of metformin benefits originate from its actions in the gut, involving hormone signaling by glucagon-like peptide 1 and peptide YY. Growth differentiation factor 15, also mainly produced in the gut, was first identified as a biomarker for metformin use but is now suggested to play a significant role in e.g. weight loss of prediabetics. The pharmacokinetics of the drug in humans as basis for pharmacodynamics, resulting in high tissue levels of the intestinal wall, including the colon, proven by biopsies, is presented. A critical survey of metformin actions on mitochondria, increasing the AMP/ATP ratio but also acting as a mild uncoupler, and of postulated new cellular targets (lysosomes) is included.
尽管二甲双胍在欧洲作为一种成功的 2 型糖尿病药物已有半个多世纪，但它的作用机制仍存在争议。本文旨在向读者介绍二甲双胍在抗糖尿病活性方面的最新发现，以及在人类中除了控制血糖之外的潜在益处。临床证据表明，二甲双胍的大部分益处源自其在肠道中的作用，涉及胰高血糖素样肽 1 和肽 YY 的激素信号传导。生长分化因子 15 最初也主要在肠道中被鉴定为二甲双胍使用的生物标志物，但现在被认为在例如糖尿病前期患者的体重减轻中发挥重要作用。本文还介绍了二甲双胍在人体中的药代动力学作为药效学的基础，导致肠道（包括结肠）等组织中药物水平升高，这一点已通过活检得到证实。本文还对二甲双胍对线粒体的作用进行了批判性综述，包括增加 AMP/ATP 比值，以及作为一种温和的解偶联剂，以及推测的新细胞靶点（溶酶体）进行了综述。
