Frame Sheelagh, Zheleva Daniella
Cyclacel Ltd., James Lindsay Place, Dundee, DD1 5JJ, UK.
Expert Opin Ther Targets. 2006 Jun;10(3):429-44. doi: 10.1517/14728222.10.3.429.
The renewed interest in an enzyme first discovered over 25 years ago stems from the potential of inhibitors of this enzyme to treat conditions as diverse as diabetes, Alzheimer's disease, stroke and bipolar disorder, and even to enhance the repopulating capacity of transplanted haematopoietic stem cells. The emergence of the first few potent and specific glycogen synthase kinase-3 (GSK-3) inhibitors will end years of speculation on their potential and finally allow the impact of GSK-3 inhibitors to be evaluated clinically. The next few years are likely to be particularly exciting ones for fans of this old enzyme. This review focuses on the role of GSK-3 in the insulin signalling pathway and highlights the evidence implicating the enzyme in insulin resistance. Pharmacological in vitro and in vivo proof-of-concept studies are also discussed, which establish the therapeutic potential of GSK-3 inhibitors as agents for the treatment of Type 2 diabetes.
对一种25多年前首次发现的酶重新燃起的兴趣，源于该酶抑制剂在治疗多种病症方面的潜力，这些病症包括糖尿病、阿尔茨海默病、中风和双相情感障碍，甚至还能增强移植造血干细胞的再增殖能力。首批几种强效且特异性的糖原合酶激酶-3（GSK-3）抑制剂的出现，将终结多年来对其潜力的猜测，并最终使得对GSK-3抑制剂的影响能够进行临床评估。对于这种古老酶的爱好者来说，未来几年可能会格外令人兴奋。本综述聚焦于GSK-3在胰岛素信号通路中的作用，并强调了该酶与胰岛素抵抗相关的证据。还讨论了药理学体外和体内概念验证研究，这些研究确立了GSK-3抑制剂作为治疗2型糖尿病药物的治疗潜力。
