Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a “corrinated” Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.

用于治疗 2 型糖尿病的胰高血糖素样肽 1 受体 (GLP-1R) 激动剂经常会引起恶心、呕吐，并且在某些患者中会引起不良的厌食症。值得注意的是，这些行为效应是由直接中枢 GLP-1R 激活引起的。在此，我们描述了一种具有改良脑外显率的 GLP-1R 激动剂缀合物的创建，该缀合物可增强 GLP-1R 介导的血糖控制而不引起呕吐。GLP-1R 激动剂 exendin-4 (Ex4) 与二氰基可宾酰胺 (Cbi)（含有维生素 B12 前体的咕啉环）共价连接，产生“相关”Ex4 构建体 (Cbi-Ex4)。在麝香鼩（Suncus murinus）（一种催吐哺乳动物）中收集的数据揭示了 Cbi-Ex4 相对于 Ex4 的有益作用，葡萄糖耐量测试中血糖反应的改善和催吐事件的大幅减少就证明了这一点。我们的研究结果强调了 Cbi-Ex4 的临床应用潜力，可帮助数百万寻求改善血糖控制的患者，且不会产生当前 GLP-1 疗法特有的常见副作用（例如呕吐）。