Introduction: Metformin, a biguanide on the WHO’s list of essential medicines has a long history of 50 years or more in treating hyperglycemia, and its therapeutic saga continues beyond diabetes treatment. Glucoregulatory actions are central to the physiological effects of metformin; surprisingly, the precise mechanism with which metformin regulates glucose metabolism is not thoroughly understood yet. Method: The main aim of this review is to explore the recent implications of metformin in hepatic gluconeogenesis, AMPKs, and SHIP2 and subsequently to elucidate the metformin action across intestine and gut microbiota. We have searched PubMed, google scholar, Medline, eMedicine, National Library of Medicine (NLM), clinicaltrials.gov (registry), and ReleMed for the implications of metformin with its updated role in AMPKs, SHIP2, and hepatic gluoconeogenesis, and gut microbiota. In this review, we have described the efficacy of metformin as a drug repurposing strategy in modulating the role of AMPKs and lysosomal-AMPKs, and controversies associated with metformin. Result: Research suggests that biguanide exhibits hormetic effects depending on the concentrations used (micromolar to millimolar). The primary mechanism attributed to metformin action is the inhibition of mitochondrial complex I, and subsequent reduction of cellular energy state, as observed with increased AMP or ADP ratio, thereby metformin can also activate the cellular energy sensor AMPK to inhibit hepatic gluconeogenesis. However, new mechanistic models have been proposed lately to explain the pleiotropic actions of metformin; at low doses, metformin can activate lysosomal-AMPK via the AXIN-LKB1 pathway. Conversely, in an AMPK-independent mechanism, metformin-induced elevation of AMP suppresses adenylate cyclase and glucagon-activated cAMP production to inhibit hepatic glucose output by glucagon. Metformin inhibits mitochondrial glycerophosphate dehydrogenase; mGPDH, and increases the cytosolic NADH/NAD+, affecting the availability of lactate and glycerol for gluconeogenesis. Metformin can inhibit Src homology 2 domain-containing inositol 5-phosphatase 2; SHIP2 to increase the insulin sensitivity and glucose uptake by peripheral tissues. Conclusion: In addition, new exciting mechanisms suggest the role of metformin in promoting beneficial gut microbiome and gut health; metformin regulates duodenal AMPK activation, incretin hormone secretion, and bile acid homeostasis to improve intestinal glucose absorption and utilization.

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二甲双胍对 SHIP2、AMPK 和肠道微生物群的影响：药理学最新进展

简介：二甲双胍是世界卫生组织基本药物清单中的一种双胍类药物，在治疗高血糖方面已有 50 年或更长时间的悠久历史，其治疗传奇不仅限于糖尿病治疗。血糖调节作用是二甲双胍生理作用的核心；令人惊讶的是，二甲双胍调节葡萄糖代谢的精确机制尚未完全了解。方法：本综述的主要目的是探讨二甲双胍在肝糖异生、AMPK 和 SHIP2 中的最新影响，并随后阐明二甲双胍在肠道和肠道微生物群中的作用。我们搜索了 PubMed、谷歌学者、Medline、eMedicine、国家医学图书馆 (NLM)、clinicalTrials.gov（注册中心）和 ReleMed，了解二甲双胍在 AMPK、SHIP2、肝糖异生和肠道微生物群中的最新作用的影响。在这篇综述中，我们描述了二甲双胍作为药物再利用策略在调节 AMPK 和溶酶体-AMPK 作用方面的功效，以及与二甲双胍相关的争议。结果：研究表明，双胍表现出毒物兴奋效应，具体取决于使用的浓度（微摩尔至毫摩尔）。二甲双胍作用的主要机制是抑制线粒体复合物 I，并随后降低细胞能量状态，如 AMP 或 ADP 比率增加所观察到的，因此二甲双胍还可以激活细胞能量传感器 AMPK 以抑制肝脏糖异生。然而，最近提出了新的机制模型来解释二甲双胍的多效作用；低剂量时，二甲双胍可以通过 AXIN-LKB1 途径激活溶酶体-AMPK。相反，在 AMPK 独立机制中，二甲双胍诱导的 AMP 升高抑制腺苷酸环化酶和胰高血糖素激活的 cAMP 产生，从而抑制胰高血糖素的肝葡萄糖输出。二甲双胍抑制线粒体甘油磷酸脱氢酶；mGPDH，并增加胞质 NADH/NAD+，影响糖异生中乳酸和甘油的可用性。二甲双胍可以抑制含有Src同源2结构域的肌醇5-磷酸酶2；SHIP2 增加外周组织的胰岛素敏感性和葡萄糖摄取。结论：此外，新的令人兴奋的机制表明二甲双胍在促进有益的肠道微生物组和肠道健康方面的作用；二甲双胍调节十二指肠 AMPK 激活、肠促胰岛素激素分泌和胆汁酸稳态，以改善肠道葡萄糖吸收和利用。