'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies.
'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies.
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代谢综合征中针对 PPARgamma 的“取得正确平衡”：人类遗传学研究的新见解。
DOI：
10.1155/2007/83593
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Gurnell, Mark
中科院分区：
文献类型：
--
作者：
Gurnell, Mark
在肥胖和2型糖尿病这对孪生流行病威胁甚至吞噬资源最充足的西方医疗保健系统的时候，核受体过氧化物酶体增殖物激活受体γ（PPARγ）已经成为治疗人类代谢疾病的真正治疗靶点。新型胰岛素增敏性抗糖尿病噻唑烷二酮（TZD，例如，罗格列酮、吡格列酮）是高亲和力的PPARγ配体，其有益作用超出了改善血脂控制，包括改善血脂异常、降低血压和有利地调节巨噬细胞脂质处理和炎症反应。然而，临床使用抑制TZD的主要缺点是体重增加，反映了脂肪生成和液体潴留的增强，这两者在已经超重且易于患心血管疾病的人群中都是不希望的。因此，“搜索正在进行”，以鉴定下一代PPARγ调节剂，其将通过靶向代谢综合征的特定方面（葡萄糖耐受不良/糖尿病、血脂异常和高血压）而促进最大临床益处，同时避免PPARγ活化的不良副作用（例如，体重增加）。本文概述了在携带PPARγ遗传变异的人类受试者中进行的重要临床和实验室观察结果，这些观察结果支持这种治疗策略。
At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARγ ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the “search is on” to identify the next generation of PPARγ modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARγ activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARγ that support such a therapeutic strategy.
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