Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions
Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions
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DOI：
10.1007/s00125-007-0646-8
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发表时间：
2007-06-01
期刊：
影响因子：
8.2
通讯作者：
Wong-Kai-In, P.
中科院分区：
文献类型：
--
作者：
Fyfe, M. C. T.;White, J. R.;Wong-Kai-In, P.
目的/假说我们评价了葡萄糖激活剂(GKA)的胰岛素调节和降血糖作用，特别是通过对(2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide(一种新的有效的GKA)的大鼠糖尿病模型的急性和亚慢性研究。材料和方法研究了PsN-GK1对以下方面的作用：(1)对人肝葡萄糖激酶的作用；结果在5 mmol/L葡萄糖浓度下，PsN-GK1激活的葡萄糖激酶是正常对照组的4.3倍，胰岛素分泌增加26倍，EC50为267nmol/L；2-dG肝细胞摄取增加3倍，EC50为1mU/L；在较高的葡萄糖浓度下，其EC(50)S和倍数效应均较低。在C57BL/6小鼠中，PSN-GK1在1 mg/kg和10 mg/kg的剂量下经口给药可显著降低血糖，但在较高剂量时可显著升高胰岛素。在高胰岛素10-mmo1/L葡萄糖钳夹中，PSN-GK1使2-DG掺入肝糖原的量增加了6倍，直接证明了肝脏的作用。PSN-GK1改善了db/db小鼠和Zucker糖尿病肥胖大鼠的血糖谱，在这两种糖尿病动物模型中，GKA的有效性以前没有被描述过，而不会导致低血糖。在ob/ob小鼠中，它呈剂量依赖性地减少OGTT的漂移。结论PSN-GK1通过影响胰岛素释放和肝脏糖代谢而具有明显的降血糖作用。它是文献中描述的最有效的GKA之一，在糖尿病动物模型中很活跃，到目前为止还没有GKA显示出疗效的报道。正在进行的人体试验正在研究这种新的治疗方法的潜力。
Aims/hypothesis We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA.Materials and methods The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-D-[H-3]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice.Results At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC50] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC50 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC50 1 mu mol/l); at higher glucose concentrations, EC(50)s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight.Conclusions/interpretation PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.