McKillop Aine M, Moran Brian M, Abdel-Wahab Yasser H A, Gormley Noella M, Flatt Peter R
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Diabetologia. 2016 Dec;59(12):2674-2685. doi: 10.1007/s00125-016-4108-z. Epub 2016 Sep 27.
AIMS/HYPOTHESIS: Abnormal cannabidiol (Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice.
Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0.1 μmol/kg) or saline vehicle (0.9% wt/vol. NaCl) over 28 days. Body weight, food intake, fluid intake, plasma glucose, insulin, glucose tolerance, insulin release, lipid profile and pancreatic morphology were examined. Mechanism of action of agonists was assessed in acute studies using incretin-receptor-knockout mice.
Abn-CBD and AS-1269574 decreased plasma glucose (20-26%, p < 0.05) and increased circulating insulin (47-48%, p < 0.05) by 10-28 days, compared with saline-treated diabetic controls. Food intake and polydipsia were reduced by both agonists (21-23%, p < 0.05 and 33-35%, p < 0.01, respectively). After 28 days of treatment, plasma glucagon concentrations were reduced (p < 0.01) and glucose tolerance was enhanced by 19-44% by Abn-CBD (p < 0.05 or p < 0.001) and AS-1269574 (p < 0.05 to p < 0.001). Plasma insulin responses were improved (p < 0.01) and insulin resistance was decreased (p < 0.05 or p < 0.01) in both Abn-CBD- and AS-1269574-treated groups. Triacylglycerols were decreased by 19% with Abn-CBD (p < 0.05) and 32% with AS-1269574 (p < 0.01) while total cholesterol was reduced by 17% (p < 0.01) and 15% (p < 0.05), respectively. Both agonists enhanced beta cell proliferation (p < 0.001) although islet area was unchanged. Acute studies in Gipr- and Glp1r-knockout mice revealed an important role for the glucagon-like peptide 1 (GLP-1) receptor in the actions of both agonists, with the glucose-lowering effects of Abn-CBD also partly mediated through the glucose-dependent insulinotropic peptide (GIP) receptor.
CONCLUSIONS/INTERPRETATION: These data highlight the potential for fatty acid G-protein-coupled receptor-based therapies as novel insulinotropic and glucose-lowering agents acting partly through the activation of incretin receptors.
目的/假设：异常大麻二酚（Abn-CBD）和AS-1269574分别是GPR55和GPR119的强效选择性激动剂。本研究评估了这些小分子激动剂对抗小鼠实验性糖尿病的作用和能力。
通过连续5天每天腹腔注射40 mg/（kg体重）链脲佐菌素，在NIH瑞士小鼠中诱导糖尿病。糖尿病小鼠在28天内每天口服Abn-CBD或AS-1269574（0.1 μmol/kg）或生理盐水载体（0.9%重量/体积的NaCl）。检测体重、食物摄入量、液体摄入量、血浆葡萄糖、胰岛素、葡萄糖耐量、胰岛素释放、血脂谱和胰腺形态。使用肠促胰岛素受体敲除小鼠在急性研究中评估激动剂的作用机制。
与生理盐水处理的糖尿病对照组相比，Abn-CBD和AS-1269574在10 - 28天时可降低血浆葡萄糖（20 - 26%，p < 0.05）并增加循环胰岛素（47 - 48%，p < 0.05）。两种激动剂均降低了食物摄入量和多饮（分别为21 - 23%，p < 0.05和33 - 35%，p < 0.01）。治疗28天后，血浆胰高血糖素浓度降低（p < 0.01），Abn-CBD（p < 0.05或p < 0.001）和AS-1269574（p < 0.05至p < 0.001）使葡萄糖耐量提高了19 - 44%。在Abn-CBD和AS-1269574治疗组中，血浆胰岛素反应均得到改善（p < 0.01），胰岛素抵抗降低（p < 0.05或p < 0.01）。Abn-CBD使三酰甘油降低了19%（p < 0.05），AS-1269574使其降低了32%（p < 0.01），而总胆固醇分别降低了17%（p < 0.01）和15%（p < 0.05）。两种激动剂均增强了β细胞增殖（p < 0.001），尽管胰岛面积未改变。对Gipr和Glp1r敲除小鼠的急性研究表明，胰高血糖素样肽1（GLP-1）受体在两种激动剂的作用中起重要作用，Abn-CBD的降糖作用也部分通过葡萄糖依赖性促胰岛素多肽（GIP）受体介导。
结论/解读：这些数据突出了基于脂肪酸G蛋白偶联受体的疗法作为新型促胰岛素分泌和降糖药物的潜力，其部分作用是通过激活肠促胰岛素受体实现的。
