Glitazones: clinical effects and molecular mechanisms
Glitazones: clinical effects and molecular mechanisms
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DOI：
10.1080/ann.34.3.217.224
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发表时间：
2002-01
影响因子：
4.4
通讯作者：
M. Stumvoll;H. Häring
中科院分区：
文献类型：
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作者：
M. Stumvoll;H. Häring
噻唑烷二酮类药物罗格列酮和吡格列酮成为许多国家 2 型糖尿病的新型治疗方法。作为单一疗法，空腹血糖和糖化血红蛋白 (HbA1c) 平均可分别改善约 40 mg/dl 和近 1%。与其他药物结合使用时，其功效是相加的。噻唑烷二酮不仅可以降低 2 型糖尿病的胰岛素抵抗，还可以降低与胰岛素抵抗相关的非糖尿病病症（例如肥胖）。作用机制涉及与过氧化物酶体增殖物激活受体 (PPAR) n 的结合，这是一种转录因子，可调节特定基因的表达，尤其是在脂肪细胞中，但也在其他组织中。噻唑烷二酮类很可能主要作用于 PPAR n 主要表达的脂肪组织。噻唑烷二酮类已被证明可以干扰源自脂肪组织的胰岛素抵抗介质（例如游离脂肪酸、脂肪细胞因子，如肿瘤坏死因子 f、抵抗素、脂联素）的表达和释放，从而导致胰岛素敏感性（即在肌肉和肝脏中）的净改善。然而，不能排除骨骼肌中的直接分子效应。干扰转录可能会带来潜在的副作用风险，但目前尚无法明确评估。例如，脂肪形成分化的体外刺激可能是体重增加的临床观察的基础。从理论上讲，从长远来看，这可能会适得其反。然而，目前还没有足够的人类证据，特别是没有长期数据来做出结论性的说法。另一方面，用曲格列酮观察到的肝毒性似乎不是 PPAR n 介导的，而是继发于有毒代谢物的。由于药物代谢的差异，罗格列酮或吡格列酮相对不太可能出现此问题。无法解释但并非不重要的是液体潴留的倾向。总之，噻唑烷二酮类药物提供了治疗胰岛素抵抗的新概念，理论上也可用于预防 2 型糖尿病。长期数据对于这些物质的最终风险效益评估是必不可少的。
With the thiazolidinediones rosiglitazone and pioglitazone a novel treatment modality for type 2 diabetes has become available in many countries. As monotherapy, fasting blood glucose and glycosylated hemoglobin (HbA1c), on average, can be improved by approximately 40 mg/dl and almost 1%, respectively. In combination with other agents their efficacy is additive. Thiazolidinediones reduce insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity. The mechanism of action involves binding to the peroxisome proliferator-activated receptor (PPAR) n, a transcription factor that regulates the expression of specific genes especially in fat cells but also in other tissues. It is likely that thiazolidinediones primarily act in adipose tissue where PPAR n is predominantly expressed. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g. free fatty acids, adipocytokines such as tumor necrosis factor f, resistin, adiponectin) in a way that results in net improvement of insulin sensitivity (i.e. in muscle and liver). Nevertheless, a direct molecular effect in skeletal muscle cannot be excluded. Interference with transcription entails a potential for side-effect risk, that cannot definitively be assessed yet. For example, the in-vitro stimulation of adipogenic differentiation may underlie the clinical observation of weight gain. Theoretically, this may turn out to be counterproductive in the long run. However, there is not sufficient evidence from humans at the moment, especially no long-term data, to allow a conclusive statement. The hepatotoxicity observed with troglitazone, on the other hand, does not seem to be PPAR n -mediated but secondary to toxic metabolites. Based on differences in drug metabolism this problem is relatively unlikely to occur with rosiglitazone or pioglitazone. Unexplained but not unimportant is the propensity for fluid retention. In summary, with the thiazolidinediones a novel concept for the treatment of insulin resistance is available that in theory could also be used for prevention of type 2 diabetes. Long-term data are indispensable for a final risk-benefit assessment of these substances.