Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining β cells and to reduce caloric intake. Unfortunately, they fail to increase human β cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human β cell proliferation, but rates are modest (~2%), and their specificity to β cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human β cell replication (5 to 6%) accompanied by an actual increase in numbers of human β cells. GLP1R agonist-DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to β cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human β cells and β cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist-DYRK1A inhibitor combination to enhance human β cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative β cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human β cell specificity.

中文翻译：

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GLP-1 受体激动剂与 DYRK1A 抑制剂协同作用，增强功能性人类 β 细胞再生。


胰高血糖素样肽 1 受体 (GLP1R) 激动剂和二肽基肽酶 4 抑制剂是广泛使用的糖尿病药物，因为它们能够刺激剩余 β 细胞分泌胰岛素并减少热量摄入。不幸的是，它们无法增加人类β细胞的增殖。双特异性酪氨酸调节激酶​​ 1A (DYRK1A) 的小分子抑制剂能够诱导成人 β 细胞增殖，但增殖率较低 (~2%)，且对 β 细胞的特异性有限。在这里，我们提供的证据表明，将 GLP1R 激动剂类的任何成员与 DYRK1A 抑制剂类的任何成员组合可诱导人 β 细胞复制协同增加（5% 至 6%），同时人 β 细胞数量实际增加。 GLP1R激动剂-DYRK1A抑制剂的协同作用需要联合抑制DYRK1A和增加cAMP，并且不会导致β细胞去分化。这些对增殖的有益作用在正常人类 β 细胞和源自 2 型糖尿病患者的 β 细胞中均可见。 GLP1R 激动剂-DYRK1A 抑制剂组合增强人 β 细胞增殖、人胰岛素分泌和血糖控制的能力在体内扩展到移植到血糖正常和链脲佐菌素糖尿病免疫缺陷小鼠体内的人胰岛的研究。在为期 1 周的小鼠研究中没有观察到不良事件。由于 GLP1R 激动剂的相对 β 细胞特异性，该组合提供了改进的（尽管不是完全的）人类 β 细胞特异性程度。