基于肝糖异生的降血糖药物研发进展

Research Progress in Anti-hyperglycemics Targeting Gluconeogenesis in Liver

空腹高血糖既是2型糖尿病的重要临床诊断指标,也是2型糖尿病的主要治疗目标之一。肝糖异生亢进是2型糖尿病患者空腹血糖升高的一个重要病理机制,纠正亢进的肝糖生成有利于控制糖尿病发病进程及并发症。肝糖异生的效率在很大程度上依赖于激素、神经和代谢中间产物对糖异生相关基因的转录调控。因此,开发特异性靶向肝糖异生的抑制剂是降血糖药物研发的一个重要方向。糖异生调节剂包括以下几种类型:受体拮抗剂/激动剂/治疗性抗体、磷酸酶激动剂/抑制剂、转录因子调节剂和糖异生限速酶抑制剂。肝糖异生调节机制研究的进一步深入,将有助于发现更特异的靶点和先导化合物,从而促进新型降血糖药物的开发。

Fasting hyperglycemia is not only a diagnostic marker but also a therapeutic target in type 2 diabetes. Over-activated hepatic gluconeogenesis is one of the most important pathological mechanisms of fasting hyperglycemia and its correction is helpful to control pathogenesis and development of diabetes and related complications. The efficiency of gluconeogenesis in liver is highly correlated with transcriptional regulation of related genes by hormones, nerves system and metabolic intermediates. Therefore, the development of inhibitors specifically targeting gluconeogenesis is an important option for the development of anti-hyperglycemics. Regulatory agents of gluconeogenesis fall into the categories of antagonist/agonist/antibody of receptor, activator/inhibitor of phosphatase kinase, regulator of transcriptional factor and inhibitor of rate-limiting enzymes in gluconeogenesis. Further researches on regulatory mechanisms of hepatic gluconeogenesis will lead to the discovery of more specific target and lead compounds and promote the development of novel anti-hyperglycemics.