Screening of clinical medicines for effects on gene expressions and protein productions of adipocytokines by using a newly-isolated preadipocyte line

我们从03H/He小鼠皮下新分离的前体脂肪细胞系AP-18细胞表达多种脂肪细胞特异性基因和脂肪细胞相关基因，并在胰岛素作用下自发分化为成熟脂肪细胞。利用AP-18细胞体外实验，观察了不同临床用药对糖尿病患者脂联素和GLUT4基因表达及脂联素蛋白产生的影响。格列齐特和格列本脲(磺脲类)、吡格列酮(噻唑烷二酮)和地拉普利(ACE抑制剂)增加脂联素和GLUT4的基因表达以及脂联素蛋白的生成，而二甲双胍(双胍)、替莫卡普利和卡托普利(ACE抑制剂)、坎地沙坦(ARB)、多沙唑辛(α-I受体阻滞剂)、美托洛尔和选择素(β-1受体阻滞剂)和甲基半胱氨酸(半胱氨酸衍生物)没有这种作用。由于已发现磺脲类药物刺激脂肪细胞产生脂联素，因此我们测定了血清中脂肪细胞运动的浓度，包括脂联素、肿瘤坏死因子-α、白介素I-β和甲基半胱氨酸观察格列齐特和格列苯肼对14 16例患者IL-6和瘦素的体内效应。尽管样本量较小，但格列齐特组患者的血清脂联素浓度有高于格列本佳组的趋势，而血清TN F-α浓度则相反。使用AP-I8细胞的研究表明，磺脲类药物增加了脂联素和GLUT-4的基因表达，并增加了脂联素蛋白的产生。

We have shown that the AP-18 cell, an preadipocyte line newly isolated from subcutaneous tissue of the 03H/He mouse, expresses various adipocyte-specific and adipocyte?related genes, and spontaneously differentiates to mature adipocyte during culture with insulin.Using AP-1 8 cells in vitro, we observed effects of various clinical medicines used for diabetic patients on gene expressions of adiponectin and GLUT4, and on production of adiponectin protein. Gliclazide and glibenclamide (sulfonylureas), pioglitazone (thiazolidinedione), and delapril (ACE inhibitor) increased gene expressions of adiponectin and GLUT4, and adiponectin protein production, whereas metformin (biguanide), temocapril and captopril (ACE inhibitors), candesartane (ARB), doxazosine (alpha-i blocker), metprolol and selectol (beta-1 blockers), and methylcysteine (cysteinderivative) had no such effects.Because it has been indicated that sulfonylurea stimulates adipocytes to produce adiponectin, we measured serum concentration of adipocytekines including adiponectin, TNF-alpha, IL-i-beta, IL-6 and leptin in patients (n = 14 ? 16) treated with gliclazide or glibenclimide to observe in vivo effects of these medicines. There was a tendency that serum adiponecitn concentration was higher in patients treated with gliclazide than those with glibenclimide, and serum TN F-alpha concentration was vice versa, although sample size was small.The study using AP-i8 cells indicates that sulfonylurea increases gene expressions of adiponectin and GLUT-4, and production of adiponecitn protein.