Borthwick E B, Houston M P, Coughtrie M W, Burchell A
Department of Obstetrics & Gynecology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
Horm Metab Res. 2001 Dec;33(12):721-6. doi: 10.1055/s-2001-19136.
Excessive glucose production by the liver contributes significantly to diabetic hyperglycemia. The enzyme system glucose-6-phosphatase plays a key role in regulating hepatic glucose production and therefore its inhibition is a potential therapeutic target for the correction of hyperglycemia. It has previously been shown that sulfated steroids, such as estrone sulfate and dehydroepiandrosterone sulfate, inhibit the glucose-6-phosphatase system in vitro, principally through inhibition of endoplasmic reticulum glucose-6-phosphate transport. We report here that in the obese/diabetic ob/ob mouse model, orally administered estrone sulfate reduces the abnormally elevated hepatic glucose-6-phosphatase enzyme activity and enzyme protein levels that are characteristic in the ob/ob mouse, and that this reduction is associated with normalization of blood glucose levels. Other sulfated and non-sulfated steroids also reduced, to a lesser extent, glucose-6-phosphatase enzyme activity - with the exception of dehydroepiandrosterone sulfate, which had no apparent effect on this system in ob/ob mice. Estrone sulfate is therefore an effective antihyperglycemic agent in ob/ob mice, and the glucose-6-phosphatase system can be successfully targeted for the therapeutic management of hyperglycemia in this animal model of non-insulin-dependent diabetes mellitus.
肝脏过度生成葡萄糖在很大程度上导致了糖尿病患者的高血糖症。葡萄糖-6-磷酸酶酶系统在调节肝脏葡萄糖生成中起关键作用，因此抑制该酶是纠正高血糖症的一个潜在治疗靶点。此前已有研究表明，硫酸化类固醇，如硫酸雌酮和硫酸脱氢表雄酮，在体外可抑制葡萄糖-6-磷酸酶系统，主要是通过抑制内质网葡萄糖-6-磷酸转运来实现。我们在此报告，在肥胖/糖尿病ob/ob小鼠模型中，口服硫酸雌酮可降低ob/ob小鼠特有的异常升高的肝脏葡萄糖-6-磷酸酶活性和酶蛋白水平，且这种降低与血糖水平的正常化相关。其他硫酸化和非硫酸化类固醇也在较小程度上降低了葡萄糖-6-磷酸酶活性——硫酸脱氢表雄酮除外，它对ob/ob小鼠的该系统没有明显影响。因此，硫酸雌酮是ob/ob小鼠有效的抗高血糖药物，在这种非胰岛素依赖型糖尿病动物模型中，葡萄糖-6-磷酸酶系统可成功作为治疗高血糖症的靶点。
