Neratinib protects pancreatic beta cells in diabetes
Neratinib protects pancreatic beta cells in diabetes
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DOI：
10.1038/s41467-019-12880-5
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发表时间：
2019-11-01
影响因子：
16.6
通讯作者：
Maedler, Kathrin
中科院分区：
文献类型：
--
作者：
Ardestani, Amin;Li, Sijia;Maedler, Kathrin
产生胰岛素的功能性β细胞的丧失是糖尿病的一个标志。哺乳动物不育 20 样激酶 1 (MST1) 是胰腺 β 细胞死亡和功能障碍的关键调节因子；它的缺乏可以恢复功能性β细胞和正常血糖。 MST1 抑制剂的鉴定代表了一种有前途的 β 细胞保护性糖尿病治疗方法。在这里，我们将 neratinib（一种 FDA 批准的针对 HER2/EGFR 双激酶的药物）确定为一种有效的 MST1 抑制剂，可改善人类胰岛和 INS-1E 细胞在多种糖尿病条件下的 β 细胞存活率。在一项临床前研究中，neratinib 可减轻 1 型（链脲佐菌素）和 2 型（肥胖 Leprdb/db）糖尿病小鼠模型中的高血糖并改善 β 细胞功能、存活率和 β 细胞质量。总之，neratinib 是一种以前未被认识的 MST1 抑制剂，代表了一种潜在的 β 细胞保护药物，并在人类胰岛体外和 1 型和 2 型糖尿病啮齿动物模型体内进行了概念验证。
The loss of functional insulin-producing beta-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic beta-cell death and dysfunction; its deficiency restores functional beta-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a beta-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves beta-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves beta-cell function, survival and beta-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential beta-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.