Pillai Ashwin A, Melo Lara, Frishman William H, Aronow Wilbert S
From the Department of Medicine, University of Connecticut, Farmington, CT.
Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY.
Cardiol Rev. 2024 Dec 11. doi: 10.1097/CRD.0000000000000832.
Metformin, a biguanide derived from Galega officinalis, was first synthesized by Werner and Bell in 1922. Metformin was approved for the treatment of diabetes by the US Food and Drug Administration in 1994. It has since become the most widely used oral antidiabetic agent. The exact mechanisms by which metformin exerts its clinical effects remain the subject of ongoing research. Metformin interacts with multiple molecular pathways, and the downstream effects of which affect weight, cardiovascular health, and longevity. Metformin reduces hunger by mitigating insulin resistance in the hypothalamic pro-opiomelanocortin neurons. It enhances satiety by stimulating the enteral release of glucagon-like peptide 1. It also induces favorable changes to enteric microbiota, enhancing metabolism. These effects cumulatively contribute to metformin-induced weight loss. Metformin use has shown associations with improved cardiovascular outcomes including reduced all-cause mortality, lower rates of myocardial infarctions, and improved heart failure outcomes. Many of these actions are mediated through the direct activation of adenosine monophosphate-activated kinase (AMPK), which, in turn, enhances cellular energy production and endothelial nitric oxide synthase-mediated vascular relaxation. It antagonizes proinflammatory cytokines, reducing cardiac fibrosis and remodeling. The metformin-AMPK pathway may also explain the potential utility of metformin in mitigating aging. Acting through AMPK, it inhibits the mammalian target of rapamycin, leading to increased autophagy and cell growth. The metformin-AMPK-sirtuin pathway may also contribute to longevity. In this review, we will discuss the use of metformin in weight loss, cardiovascular health, and longevity, highlighting the historic background, molecular mechanisms, and current evidence.
二甲双胍是一种从山羊豆中提取的双胍类药物，于1922年由维尔纳和贝尔首次合成。1994年，二甲双胍被美国食品药品监督管理局批准用于治疗糖尿病。此后，它已成为使用最广泛的口服抗糖尿病药物。二甲双胍发挥临床作用的确切机制仍是正在进行的研究课题。二甲双胍与多种分子途径相互作用，其下游效应会影响体重、心血管健康和寿命。二甲双胍通过减轻下丘脑阿片-促黑素细胞皮质素神经元中的胰岛素抵抗来减少饥饿感。它通过刺激肠道释放胰高血糖素样肽1来增强饱腹感。它还能诱导肠道微生物群发生有益变化，促进新陈代谢。这些作用共同导致了二甲双胍引起的体重减轻。使用二甲双胍已显示与改善心血管结局相关，包括降低全因死亡率、降低心肌梗死发生率和改善心力衰竭结局。这些作用中的许多是通过直接激活单磷酸腺苷激活蛋白激酶（AMPK）介导的，而AMPK反过来又能增强细胞能量产生和内皮型一氧化氮合酶介导的血管舒张。它拮抗促炎细胞因子，减少心脏纤维化和重塑。二甲双胍-AMPK途径也可能解释了二甲双胍在延缓衰老方面的潜在效用。它通过AMPK发挥作用，抑制雷帕霉素靶蛋白，导致自噬增加和细胞生长。二甲双胍-AMPK-沉默调节蛋白途径也可能有助于延长寿命。在这篇综述中，我们将讨论二甲双胍在减肥、心血管健康和长寿方面的应用，重点介绍其历史背景、分子机制和当前证据。
