近日，四川大学教授邓成及其课题组提出了组成型活性胰高血糖素受体驱动鸟类高血糖。2025年3月3日出版的《自然》杂志发表了这项成果。

研究组发现，禽类胰高血糖素受体（GCGR）在肝脏中的高表达与组成型活性Gs信号传导有关，这取决于不同结构域的相互作用。体内实验聚焦于调节肝细胞中组成活性GCGR的表达，通过激活下游信号通路，在鱼类、爬行动物、鸟类和哺乳动物中导致相应的高血糖、快速的肝脂利用和高代谢率。

此外，研究人员在鸡的近端基因区域发现了一个点突变，导致GCGR mRNA减少和体重增加。在小鼠中过度表达一种具有适度构成活性的天然人类GCGR突变（hsGCGR^H339R），表明这种变体的高水平表达增强了高血糖，同时降低了体重。胰高血糖素受体的高表达和组成活性的结合可能促进了鸟类祖先的飞行进化。

研究人员表示，作为人体能量的主要来源，血糖的维持对整体健康和代谢稳态是必不可少的。它主要受胰高血糖素受体家族调控，该家族在脊椎动物中高度保守。与其他脊椎动物相比，鸟类的血糖水平相对较高，但其调节机制一个多世纪以来一直不为人知。

附：英文原文

Title: Constitutively active glucagon receptor drives high blood glucose in birds

Author: Zhang, Chang, Xiang, Xiangying, Liu, Jian, Huang, Yongjie, Xue, Jingwen, Sun, Qian, Leng, Song, Liu, Shaobo, He, Xuefei, Hu, Peng, Zhan, Xiangjiang, Qiu, Qiang, Yang, Shilong, Brosius, Jrgen, Deng, Cheng

Issue&Volume: 2025-03-03

Abstract: As the body’s primary source of energy, the maintenance of blood glucose is indispensable for overall health and metabolic homeostasis. It is predominantly regulated by the glucagon receptor family which is highly conserved in vertebrates1–4. Compared to other vertebrates, avian blood glucose levels are relatively high5,6, yet its regulatory mechanisms have remained obscure for more than a century. We show that high hepatic expression of the avian glucagon receptor (GCGR) in association with constitutively active Gs signaling was dependent upon the interaction of different domains. In vivo experiments focusing on the regulation of constitutively active GCGR expression in hepatic cells led to correspondingly high blood glucose, rapid hepatic lipid utilization and high metabolic rates via downstream signaling pathway activation in fish, reptiles, birds, and mammals. Furthermore, we identified a point mutation in chicken at the proximal gene region that resulted in GCGR mRNA reduction and weight increase. Overexpressing a natural human GCGR mutation (hsGCGR^H339R) with modest constitutive activity in mice, demonstrated that high level expression of this variant augmented high blood glucose, while reducing body weight. The combination of high expression and constitutive activity of the glucagon receptor may have contributed to the evolution of flight in the ancestors of birds.

DOI: 10.1038/s41586-025-08811-8

Source: https://www.nature.com/articles/s41586-025-08811-8