Radziuk Jerry, Bailey Clifford J, Wiernsperger Nicolas F, Yudkin John S
Department of Medicine, Ottawa Hospital and University of Ottawa, ON, Canada.
Curr Drug Targets Immune Endocr Metabol Disord. 2003 Jun;3(2):151-69. doi: 10.2174/1568008033340298.
Although a number of assessments disagree, the preponderance of the evidence indicates that the major therapeutic action of metformin in type 2 diabetes (DM2) is on the liver, and glucose production (EGP) in particular. At the level of this organ, the actions of metformin can be characterized as pleiotropic. The major questions addressed here are therefore: (i) the methodological aspects of the determination of glucose fluxes: when glucose production is not found to be elevated in type 2 diabetes, it is not surprising that little action of metformin on this flux is found. The issues of populations examined, experimental protocols, and quantitative methods of flux determination are important in answering this question. Early morning EGP is increased and constitutes a valid target for metformin. (ii) the multiple targets of metformin: metformin acts at a number of sites and interacts with metabolites and hormones. Some of these actions may be expressed at different doses. Although their net effect is therapeutic, not all are oriented towards lowering hyperglycemia, perhaps explaining the more modest effect of this drug than could be anticipated from individual actions. Sites of metformin action can therefore be considered as a compilation of valid therapeutic targets in DM2. Gluconeogenesis, glycogenolysis and glycogen synthesis can be altered by metformin, although in vivo, this also depends on the methodology. Component processes from substrate supply and liver uptake, through a number of glucogenic enzymes, as well as glycogen synthase and phosphorylase have all been shown to be affected. (iii) unifying concepts: reported actions of metformin on the mitochondrial respiratory chain, free fatty acid metabolism, AMP-activated protein kinase, and on membrane proteins directly may all explain subsets of actions that are seen, providing more integrated targets for consideration in the therapy of DM2.
尽管一些评估结果存在分歧，但大量证据表明二甲双胍在2型糖尿病（DM2）中的主要治疗作用是针对肝脏，尤其是葡萄糖生成（EGP）。在这个器官水平上，二甲双胍的作用具有多效性。因此，这里探讨的主要问题是：（i）葡萄糖通量测定的方法学方面：当在2型糖尿病中未发现葡萄糖生成升高时，发现二甲双胍对该通量几乎没有作用也就不足为奇了。所研究的人群、实验方案以及通量测定的定量方法等问题对于回答这个问题很重要。清晨EGP升高，是二甲双胍的一个有效靶点。（ii）二甲双胍的多个靶点：二甲双胍作用于多个位点，并与代谢物和激素相互作用。其中一些作用可能在不同剂量下表现出来。尽管它们的总体效果是治疗性的，但并非所有作用都旨在降低高血糖，这或许可以解释该药物的效果比单个作用预期的更为温和。因此，二甲双胍的作用位点可被视为DM2中有效的治疗靶点集合。二甲双胍可改变糖异生、糖原分解和糖原合成，尽管在体内这也取决于方法。从底物供应和肝脏摄取开始，经过多种糖异生酶以及糖原合酶和磷酸化酶的组成过程均已显示受到影响。（iii）统一概念：报道的二甲双胍对线粒体呼吸链、游离脂肪酸代谢、AMP激活的蛋白激酶以及直接对膜蛋白的作用，可能都解释了所观察到的部分作用，为DM2治疗提供了更多综合靶点以供考虑。
