Diamant Michaela, Heine Robert J
Department of Endocrinology, Diabetes Centre, VU University Medical Centre, Amsterdam, The Netherlands.
Drugs. 2003;63(13):1373-405. doi: 10.2165/00003495-200363130-00004.
Type 2 diabetes mellitus is characterised by insulin resistance as well as progressive pancreatic beta cell dysfunction. The cornerstone of current oral blood-glucose lowering therapy consists of metformin, which primarily lowers hepatic glucose production, and the sulphonylureas that act by stimulating pancreatic beta-cells to secrete insulin. Recently, a novel class of agents, the thiazolidinediones, has been introduced that favourably influence insulin sensitivity and possibly also pancreatic beta-cell function. The thiazolidinediones are synthetic ligands that bind to the nuclear peroxisome proliferator-activated receptor-gamma and exert their action by activating transcription of genes that, among others, regulate adipocyte differentiation and adipogenesis as well as glucose and lipid metabolism. To date, the precise mechanisms underlying the actions of thiazolidinediones are largely unknown. When given as monotherapy or in combination with sulphonylureas, metformin or insulin in patients with type 2 diabetes, the currently available thiazolidinediones (rosiglitazone and pioglitazone) ameliorate glycaemic control, by lowering fasting and postprandial blood glucose levels, and improve insulin sensitivity in placebo-controlled trials. They seem to have differential effects on dyslipidaemia in patients with type 2 diabetes; rosiglitazone increases total cholesterol as well as high-density lipoprotein (HDL) and low-density lipoprotein cholesterol levels and affects plasma triglyceride levels depending on the baseline values, whereas pioglitazone lowers triglycerides and increases HDL cholesterol levels. The adverse events of both agents that occur with greater frequency than in patients treated with placebo are fluid retention and oedema. As demonstrated, mainly in preclinical studies to date, rosiglitazone and pioglitazone possess beneficial effects on other cardiovascular risk factors associated with the insulin resistance syndrome. Thus, these agents were shown to decrease blood pressure, enhance myocardial function and fibrinolysis, as well as possess anti-inflammatory and other beneficial vascular effects. Long-term efficacy and surveillance of this promising class of drugs in patients, however, still need to be demonstrated in outcome trials.
2型糖尿病的特征是胰岛素抵抗以及进行性胰腺β细胞功能障碍。当前口服降糖治疗的基石包括主要降低肝脏葡萄糖生成的二甲双胍，以及通过刺激胰腺β细胞分泌胰岛素起作用的磺脲类药物。最近，一类新型药物噻唑烷二酮类被引入，它们能有利地影响胰岛素敏感性，也可能影响胰腺β细胞功能。噻唑烷二酮类是合成配体，可与核过氧化物酶体增殖物激活受体γ结合，并通过激活基因转录发挥作用，这些基因除其他外还调节脂肪细胞分化和脂肪生成以及葡萄糖和脂质代谢。迄今为止，噻唑烷二酮类药物作用的确切机制很大程度上尚不清楚。在2型糖尿病患者中，当作为单一疗法或与磺脲类药物、二甲双胍或胰岛素联合使用时，目前可用的噻唑烷二酮类药物（罗格列酮和吡格列酮）在安慰剂对照试验中可通过降低空腹和餐后血糖水平改善血糖控制，并提高胰岛素敏感性。它们对2型糖尿病患者的血脂异常似乎有不同的影响；罗格列酮会增加总胆固醇以及高密度脂蛋白（HDL）和低密度脂蛋白胆固醇水平，并根据基线值影响血浆甘油三酯水平，而吡格列酮可降低甘油三酯并提高HDL胆固醇水平。这两种药物比接受安慰剂治疗的患者更频繁出现的不良事件是液体潴留和水肿。如主要在迄今为止的临床前研究中所示，罗格列酮和吡格列酮对与胰岛素抵抗综合征相关的其他心血管危险因素具有有益作用。因此，这些药物被证明可降低血压、增强心肌功能和纤维蛋白溶解，以及具有抗炎和其他有益的血管作用。然而，这类有前景的药物在患者中的长期疗效和监测仍需在结局试验中得到证实。
