Five hundred thirty-seven million people globally suffer from diabetes. Insulin-producing β cells are reduced in number in most people with diabetes, but most individuals still have some residual β cells. However, none of the many diabetes drugs in common use increases human β cell numbers. Recently, small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) have been shown to induce immunohistochemical markers of human β cell replication, and this is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R) on β cells. However, it remains to be demonstrated whether these immunohistochemical findings translate into an actual increase in human β cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1R agonists (GLP1RAs) affect human β cell survival. Here, using an optimized immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO + ) protocol in mouse kidneys bearing human islet grafts, we demonstrate that combination of a DYRK1A inhibitor with exendin-4 increases actual human β cell mass in vivo by a mean of four- to sevenfold in diabetic and nondiabetic mice over 3 months and reverses diabetes, without alteration in human α cell mass. The augmentation in human β cell mass occurred through mechanisms that included enhanced human β cell proliferation, function, and survival. The increase in human β cell survival was mediated, in part, by the islet prohormone VGF. Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor–GLP1RA combination for diabetes treatment.

中文翻译：

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Harmine 和 exendin-4 联合疗法可在小鼠异种移植系统中安全地扩大体内人 β 细胞量


全球有五亿三千七百万人患有糖尿病。大多数糖尿病患者体内产生胰岛素的 β 细胞数量减少，但大多数人仍有一些残留的 β 细胞。然而，许多常用的糖尿病药物都没有增加人类β细胞数量。最近，抑制双酪氨酸调节激酶​​ 1A (DYRK1A) 的小分子已被证明可以诱导人 β 细胞复制的免疫组织化学标记，并且刺激胰高血糖素样肽 1 (GLP1) 受体 (GLP1R) 的药物可以增强这种作用。 β细胞。然而，这些免疫组织化学发现是否转化为体内人β细胞数量的实际增加仍有待证明。目前尚不清楚 DYRK1A 抑制剂与 GLP1R 激动剂 (GLP1RA) 一起使用是否会影响人类 β 细胞的存活。在这里，使用优化的免疫标记三维成像对溶剂清除的器官（iDISCO + ）在带有人类胰岛移植物的小鼠肾脏中进行实验，我们证明 DYRK1A 抑制剂与 exendin-4 的组合可在 3 个月内将糖尿病和非糖尿病小鼠的体内实际人类 β 细胞质量平均增加四到七倍，并逆转糖尿病，不改变人类α细胞群。人类 β 细胞数量的增加是通过增强人类 β 细胞增殖、功能和存活等机制实现的。人类 β 细胞存活率的增加部分是由胰岛激素原 VGF 介导的。总之，这些发现证明了 DYRK1A 抑制剂 - GLP1RA 组合治疗糖尿病的治疗潜力和良好的临床前安全性。