Chow Elaine, Yang Aimin, Chung Colin H L, Chan Juliana C N
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China.
The Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong 999077, China.
Pharmaceuticals (Basel). 2022 Apr 2;15(4):442. doi: 10.3390/ph15040442.
In type 2 diabetes, ecological and lifecourse factors may interact with the host microbiota to influence expression of his/her genomes causing perturbation of interconnecting biological pathways with diverse clinical course. Metformin is a plant-based or plant-derived medicinal product used for the treatment of type 2 diabetes for over 60 years and is an essential drug listed by the World Health Organization. By reducing mitochondrial oxidative phosphorylation and adenosine triphosphate (ATP) production, metformin increased AMP (adenosine monophosphate)-activated protein kinase (AMPK) activity and altered cellular redox state with reduced glucagon activity, endogenous glucose production, lipogenesis, and protein synthesis. Metformin modulated immune response by directly reducing neutrophil to lymphocyte ratio and improving the phagocytic function of immune cells. By increasing the relative abundance of mucin-producing and short-chain-fatty-acid-producing gut microbes, metformin further improved the host inflammatory and metabolic milieu. Experimentally, metformin promoted apoptosis and reduced proliferation of cancer cells by reducing their oxygen consumption and modulating the microenvironment. Both clinical and mechanistic studies support the pluripotent effects of metformin on reducing cardiovascular-renal events, infection, cancer, cognitive dysfunction, and all-cause death in type 2 diabetes, making this low-cost medication a fundamental therapy for individualization of other glucose-lowering drugs in type 2 diabetes. Further research into the effects of metformin on cognitive function, infection and cancer, especially in people without diabetes, will provide new insights into the therapeutic value of metformin in our pursuit of prevention and treatment of ageing-related as well as acute and chronic diseases beyond diabetes.
在2型糖尿病中，生态和生命历程因素可能与宿主微生物群相互作用，影响其基因组的表达，导致相互关联的生物途径紊乱，临床病程多样。二甲双胍是一种植物源或植物衍生的药物产品，用于治疗2型糖尿病已有60多年历史，是世界卫生组织列出的基本药物。通过降低线粒体氧化磷酸化和三磷酸腺苷（ATP）生成，二甲双胍增加了单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）活性，并改变细胞氧化还原状态，同时降低胰高血糖素活性、内源性葡萄糖生成、脂肪生成和蛋白质合成。二甲双胍通过直接降低中性粒细胞与淋巴细胞的比例并改善免疫细胞的吞噬功能来调节免疫反应。通过增加产生粘蛋白和短链脂肪酸的肠道微生物的相对丰度，二甲双胍进一步改善了宿主的炎症和代谢环境。在实验中，二甲双胍通过减少癌细胞的耗氧量和调节微环境来促进其凋亡并减少增殖。临床和机制研究均支持二甲双胍在降低2型糖尿病患者心血管-肾脏事件、感染、癌症、认知功能障碍和全因死亡方面的多效性，使这种低成本药物成为2型糖尿病中其他降糖药物个体化治疗的基础疗法。对二甲双胍在认知功能、感染和癌症方面作用的进一步研究，尤其是在非糖尿病患者中的研究，将为二甲双胍在预防和治疗除糖尿病外的衰老相关以及急慢性疾病中的治疗价值提供新的见解。
