Rosiglitazone, PPARγ, and type 2 diabetes.
Rosiglitazone, PPARγ, and type 2 diabetes.
复制标题
DOI：
10.1056/nejmcibr1012075
复制
发表时间：
2010-12-30
期刊：
影响因子：
--
通讯作者：
McGraw TE
中科院分区：
文献类型：
--
作者：
Kahn BB;McGraw TE
肥胖、糖耐量受损和2型糖尿病的患病率正在以惊人的速度上升。如果目前的趋势继续下去，到2050年，美国33%的成年人可能患有糖尿病，这一预测强调了对新的，有效的和安全的预防和治疗策略的需求。最近，Choi等人2报道了可能能够开发靶向过氧化物酶体增殖物激活受体γ（PPARγ）的更安全的抗糖尿病药物的发现，过氧化物酶体增殖物激活受体γ是一种核受体和转录因子，调节数百个基因的表达并在脂肪细胞分化中起重要作用。是主要作为有效的胰岛素增敏剂的少数几类药物之一，从而降低血浆胰岛素水平，并且理论上降低与高胰岛素血症相关的并发症。噻唑烷二酮类药物的疗效被认为是由于PPARγ的转录活性改变所致，尽管不同PPARγ配体的降糖作用与受PPARγ调节的基因表达变化不一致。3噻唑烷二酮类药物的副作用包括体重增加、液体潴留、充血性心力衰竭和骨质疏松4（图1）。由于这种副作用越来越明显，这些药物的使用已成为有争议的。今年早些时候，美国食品和药物管理局严格限制使用最常用的噻唑烷二酮类药物之一罗格列酮，因为它会增加心血管并发症的发生率。
The prevalence of obesity, impaired glucose tolerance, and type 2 diabetes mellitus is escalating at an alarming rate. If current trends continue, 33% of adults in the United States may have diabetes by the year 2050, 1 a prediction that underscores the need for new, effective, and safe strategies for prevention and treatment. Recently, Choi et al. 2 reported findings that may enable the development of safer antidiabetic agents that target peroxisome-proliferator–activated receptor γ (PPARγ), a nuclear receptor and transcription factor that regulates the expression of hundreds of genes and has a fundamental role in adipocyte differentiation.Synthetic activators of PPARγ, called thiazoli-dinediones, are one of the few classes of drugs that act primarily as effective insulin sensitizers, thereby reducing plasma insulin levels and, theoretically, the complications associated with hyperinsulinemia. The efficacy of thiazolidinediones was thought to result from altered transcriptional activity of PPARγ, although the glucose-lowering effects of different PPARγ ligands do not correspond with changes in the expression of genes regulated by PPARγ. 3 Side effects of thiazolidinediones include weight gain, fluid retention, congestive heart failure, and bone fractures4 (Fig. 1). Since such side effects have become more evident, the use of these drugs has become controversial. Earlier this year, the Food and Drug Administration severely restricted the use of one of the most commonly prescribed thiazolidinediones, rosiglitazone, because of an associated increase in the rates of complications from cardiovascular causes.