Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes due to pleiotropic effects, such as the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-life owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics lead to 10 days of glycaemic control in three different mouse models of diabetes, as well as the reduction of glycosylated haemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.

刺激胰高血糖素样肽 1 (GLP1) 受体是治疗 2 型糖尿病的一种有用的治疗策略，因为它具有多效性，例如调节胰岛激素和诱导饱腹感。然而，GLP1 受体的天然配体由于酶失活和快速清除而半衰期较短。在这里，我们表明，单次注射与热敏弹性蛋白样多肽重组融合的 GLP1 后形成的皮下储库可导致零级释放动力学，并且在小鼠中循环时间长达 10 天，在猴子中循环时间长达 17 天。优化的药代动力学可在三种不同的糖尿病小鼠模型中实现 10 天的血糖控制，并在连续 8 周内每周治疗一次的 ob/ob 小鼠中降低糖基化血红蛋白水平和体重增加。我们的结果表明，优化的 GLP1 制剂可以通过消除峰谷药代动力学并提高整体安全性和耐受性来增强治疗效果。我们建立的设计原则应该广泛适用于改善其他肽和蛋白质疗法的药理学性能。