二甲双胍50年课件.pptVIP

* 二甲双胍抗高血糖机制小结 二甲双胍通过一系列依赖和不依赖胰岛素的作用机制拮抗高血糖。包括改善细胞膜生理；通过受体后酪氨酸激酶级联改善来自胰岛素受体的信号转移；促进穿膜葡萄糖转运子的募集和/或活化；通过血糖管理相关的细胞内机制，如对线粒体和AMPK活化的影响；最终，降低循环中葡萄糖和游离脂肪酸水平，分别缓解糖毒性和脂毒性而改善胰岛素敏感性。 Summary of antihyperglycaemic mechanisms of metformin (2) Metformin counters hyperglycaemia through a range of insulin dependent and insulin independent mechanisms. These include improvements in membrane physiology, improved translocation of the signal from the insulin receptor through the post-receptor tyrosine kinase cascade and improved recruitment and/or activation of transmembrane glucose transporters. Intracellular mechanisms related to glucose management also contribute, such as effects on mitochondria and activation of AMPK. Finally, reduced circulating levels of glucose and free fatty acids will tend to improve insulin sensitivity through relief of glucotoxicity and lipotoxicity, respectively. Yang J, Holman GD. Long-term metformin treatment stimulates cardiomyocyte glucose transport through an AMP-activated protein kinase-dependent reduction in GLUT4 endocytosis. Endocrinology 2006;147:2728-36. Kumar N, Dey CS. Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells. Br J Pharmacol 2002;137:329-36. Grigorescu F, Laurent A, Chavanieu A, Capony JP. Cellular mechanism of metformin action. Diabete Metab 1991;17:146-9. Wiernsperger NF. Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab 1999;25:110-27. * * 二甲双胍胃肠道副作用的剂量关系 确定耐受性问题是否会抵消较大剂量二甲双胍的降糖效益很重要。Garber和他的同事进行了一项随机双盲平行剂量反应研究，在早前幻灯片中已有讨论，数据显示这个担心并不成立。无论胃肠道副反应发生率，还是因此而中断治疗的比率，在二甲双胍剂量超过 1000 mg时，都没有明确的剂量反应关系。 Dose-relationship of gastrointestinal side-effects of metformin It is important to establish whether tolerability issues may offset the glycaemic benefits available from higher dosages of metformin. Data from the double-blind, randomised, parallel-group dose-response study by Garber and coll