Institute of Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
Peptides. 2023 Jul;165:171003. doi: 10.1016/j.peptides.2023.171003. Epub 2023 Mar 29.
Within recent decades glucagon receptor (GcgR) agonism has drawn attention as a therapeutic tool for the treatment of type 2 diabetes and obesity. In both mice and humans, glucagon administration enhances energy expenditure and suppresses food intake suggesting a promising metabolic utility. Therefore synthetic optimization of glucagon-based pharmacology to further resolve the physiological and cellular underpinnings mediating these effects has advanced. Chemical modifications to the glucagon sequence have allowed for greater peptide solubility, stability, circulating half-life, and understanding of the structure-function potential behind partial and "super"-agonists. The knowledge gained from such modifications has provided a basis for the development of long-acting glucagon analogues, chimeric unimolecular dual- and tri-agonists, and novel strategies for nuclear hormone targeting into glucagon receptor-expressing tissues. In this review, we summarize the developments leading toward the current advanced state of glucagon-based pharmacology, while highlighting the associated biological and therapeutic effects in the context of diabetes and obesity.
在最近几十年中，胰高血糖素受体 (GcgR) 激动剂作为治疗 2 型糖尿病和肥胖症的治疗工具引起了关注。在小鼠和人类中，胰高血糖素的给药可增加能量消耗并抑制食物摄入，这表明其具有有前途的代谢用途。因此，对基于胰高血糖素的药理学进行了合成优化，以进一步阐明介导这些作用的生理和细胞基础。对胰高血糖素序列进行化学修饰可提高肽的溶解度、稳定性、循环半衰期，并深入了解部分激动剂和“超”激动剂背后的结构-功能潜力。这些修饰所获得的知识为长效胰高血糖素类似物、嵌合单分子双激动剂和三激动剂以及核激素靶向表达胰高血糖素受体的组织的新型策略的开发提供了基础。在本文中，我们总结了导致当前基于胰高血糖素的药理学发展的情况，同时强调了在糖尿病和肥胖症背景下相关的生物学和治疗作用。
