Sulfonylurea agents exhibit peroxisome proliferator-activated receptor γ agonistic activity
Sulfonylurea agents exhibit peroxisome proliferator-activated receptor γ agonistic activity
复制标题
DOI：
10.1074/jbc.m412113200
复制
发表时间：
2005-06-24
影响因子：
4.8
通讯作者：
Shimomura, I
中科院分区：
文献类型：
--
作者：
Fukuen, S;Iwaki, M;Shimomura, I
磺脲类药物，包括格列美脲和格列本脲，是目前应用最广泛的口服降糖药物，主要通过与胰岛β细胞质膜上的SU受体结合来刺激胰岛素的分泌。噻唑烷二酮类药物，如吡格列酮和罗格列酮，是通过激活过氧化体增殖物激活受体γ(PPARγ)有效改善外周胰岛素抵抗的其他降糖药。在本研究中，我们在荧光素酶报告实验中发现，格列美脲特异性地诱导了PPARγ的转录活性。格列美脲可促进辅活化子DRIP205的募集和辅抑制子的解离，如核受体辅阻遏子和视黄醇和甲状腺激素受体沉默介体。此外，格列美脲以与罗格列酮竞争的方式直接与PPAR Delta结合，罗格列酮是PPAR Delta的已被证明的配体。此外，在3T3-L1脂肪细胞中，格列美脲刺激了含有PPARγ反应元件的基因启动子的转录活性，并改变了PPARγ靶基因的mRNA水平，包括aP2、瘦素和脂联素。最后，格列美脲诱导3T3-F442a细胞的脂肪分化，已知以PPAR伽马依赖的方式分化为脂肪细胞。格列美脲的大多数疗效也见于格列本脲。这些数据有力地表明，格列美脲和格列本脲都属于SU类药物，应该具有PPARγ激动剂活性，其活性是吡格列酮最大活性的16-25%。我们观察到格列美脲和格列本脲不仅作用于SU受体，还作用于PPARγ，这可能为开发新的抗糖尿病药物提供重要线索，这些药物既能增强胰岛β细胞的胰岛素分泌，又能增强外周胰岛素的敏感性。
Sulfonylurea (SU) agents, including glimepiride and glibenclamide, are the most widely used oral hypoglycemic drugs, which stimulate insulin secretion primarily by binding to the SU receptor on the plasma membrane of pancreatic beta-cells. Thiazolidinediones, such as pioglitazone and rosiglitazone, are other hypoglycemic agents that effectively improve peripheral insulin resistance through activation of peroxisome proliferator-activated receptor gamma( PPAR gamma). In the present study, we found that glimepiride specifically induced the transcriptional activity of PPAR gamma in luciferase reporter assays. Glimepiride enhanced the recruitment of coactivator DRIP205 and dissociation of corepressors such as nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors. In addition, glimepride directly bound to PPAR delta in a manner competitive to rosiglitazone, which is a proven ligand for PPAR delta. Furthermore, in 3T3-L1 adipocytes, glimepiride stimulated the transcriptional activity of the gene promoter containing PPAR gamma responsive element and altered mRNA levels of PPAR gamma target genes including aP2, leptin, and adiponectin. Finally, glimepiride induced adipose differentiation in 3T3- F442A cells, which was known to differentiate into adipocytes in a PPAR gamma-dependent manner. Most effects observed with glimepiride were also seen with glibenclamide. These data strongly suggest that glimepiride and glibenclamide, both of which belong to SU agents, should have PPAR gamma agonist activity, whose potencies were 16-25% of the maximum level achieved by pioglitazone. Our observation that glimepiride and glibenclamide could act not only on SU receptor but also on PPAR gamma may give an important clue to the development of novel antidiabetic drugs, which can enhance both insulin secretion from pancreatic beta-cells and peripheral insulin sensitivity.