胰岛素抵抗是2型糖尿病的主要特征之一。在对新型胰岛素增敏剂的研究中，我们采用细胞基础性研究系统作为筛选方式，此系统可部分性模拟胰岛素对细胞的生理学和代谢性影响。通过对我们专有的小分子化合物信息库的筛选，我们发现证实了一种全新的非噻唑烷二酮类化合物，P1736-05。转活分析发现P1736-05不能活化人类的PPAR（γ/a）受体。P1736-50可促进胰岛素抵抗的脂肪细胞（EC50-400nM）摄取葡萄糖，但是此效应可被PI3K抑制剂，Wortmannin，预处理后所消除。共聚焦显微镜观察发现P1736-05可诱导GLUT4的浆膜易位。P1736-05此种体外的胰岛素增敏特性提示其可作为降糖试剂治疗胰岛素抵抗和糖尿病动物模型，如db/db和ob/ob鼠。给予db/db鼠P1736-05或罗格列酮（5mg/kg，bid）口服治疗15天可使动物血糖分别降低41%和63%。甘油三酯水平分别降低32%（P1736-05）和40%（罗格列酮）。P1736-05对体重或肝脏酶系无影响，但是罗格列酮可增加体重13%（p<0.05），并使ALT水平升高2倍。db/db鼠模型研究发现P1736-05（150mg/kg，qd）较二甲双胍（150mg/kg）更能有效地降低血糖（35% vs 25%）和甘油三酯水平（38% vs 31%）。P1736-05的降糖和胰岛素增敏作用亦在ob/ob鼠模型研究中得到证实。给予ob/ob鼠P1736-05（5mg/kg，bid）治疗10天；分离比目鱼肌并检测其葡萄糖摄取能力。P1736-05治疗后ob/ob鼠的血糖下降35%，而且其分离的比目鱼肌中胰岛素介导的葡萄糖摄取增加了67%，提示可改善外周组织的胰岛素敏感性。给予Wistar大鼠P1736-05连续追加剂量治疗28天后，即使应用60倍有效剂量大鼠的血容量亦无明显改变，而罗格列酮应用8倍有效剂量后大鼠血容量明显增高。
鉴于其胰岛素增敏效应和极佳的安全性，P1736-05将成为一种可供选择的理想的2型糖尿病治疗药物。
(中日友好医院侯志强译 李宏亮校)
英文原文：
Discovery of a Novel Orally Active Antidiabetic Compound that Improves Peripheral Insulin Sensitivity in Mice
Authors:
A. ROSALIND MARITA, Mumbai, India
Results:
Insulin resistance is a cardinal feature of type 2 diabetes. In the search for new insulin sensitizers, we have used cell-based systems, that partly mimic insulin action on cell physiology and metabolism, as screening models. Screening of our proprietary small molecule library led to the identification of a novel non-thiazolidinedione compound, P1736-05. P1736-05 did not activate human PPAR (γ/α) receptors in the transactivation assay. P1736-05 potentiated glucose uptake in the insulin resistant adipocytes (EC50 - 400nM). This effect was abolished by pretreatment with Wortmannin, a known PI3-kinase inhibitor. Also P1736-05 induced translocation of GLUT4 transporter to the plasma membrane, when visualized by confocal microscopy. The invitro insulin sensitizing characteristics of P1736-05 suggested that it could act as a glucose lowering agent in animal models of insulin resistance and diabetes such as db/db and ob/ob mice. Treatment of db/db mice with P1736-05 or rosiglitazone (5mg/kg, twice daily orally) for 15 days reduced plasma glucose levels by 41% and 63%, respectively. Triglyceride levels were reduced by 32% (P1736-05) and 40% (rosiglitazone). P1736-05 did not affect body weight or liver enzymes whereas rosiglitazone increased body weight by 13% (p<0.05) and ALT levels by two-fold. In db/db mice, P1736-05 (150mg/kg, once daily) was found to be more efficacious than metformin (150mg/kg) in lowering glucose (35% vs 25%) and triglyceride levels (38% vs 31%). P1736-05 was also evaluated for its glucose lowering and insulin sensitizing activity in ob/ob mice. Groups of ob/ob mice were administered 5mg/kg of P1736-05 twice daily for 10 days; soleus muscles were isolated and glucose uptake was determined. P1736-05 elicited 35% decrease in plasma glucose levels. Further, soleus muscles from P1736-05 treated animals demonstrated a 67% increase in insulin-induced glucose uptake, indicating peripheral insulin sensitization. Repeated dosing of Wistar rats with P1736-05 for 28 days, revealed no changes in plasma volume, even at 60 times the efficacious dose while rosiglitazone at 8 times the efficacious dose, induced significant increase. In view of its insulin sensitizing property and superior safety profile, P1736-05 presents an attractive alternative therapeutic option for type 2 diabetes.
来源：国际糖尿病
http://www.idiabetes.com.cn/
