MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis
MEK/ERK Signaling in β-Cells Bifunctionally Regulates β-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis
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DOI：
10.2337/db20-1295
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发表时间：
2021-07-01
期刊：
影响因子：
7.7
通讯作者：
Ueki, Kohjiro
中科院分区：
文献类型：
--
作者：
Ikushima, Yoshiko Matsumoto;Awazawa, Motoharu;Ueki, Kohjiro
在糖尿病病理中，经常同时观察到β细胞群不足，不能满足周围胰岛素需求，以及单个β细胞在胰岛素生产中的功能缺陷，共同引起高血糖。我们发现，在db/db小鼠和一组2型糖尿病患者的胰岛中，ERK1/2的磷酸化水平显著降低。在通过缺失Mek1和Mek2而消除胰腺β细胞ERK信号的小鼠中，在高脂肪饮食喂养条件下，由于胰岛素产生不足，β细胞增殖降低，β细胞质量减少，葡萄糖耐受不良加剧，而在单个β细胞中，观察到胰岛素胞吐事件的数量减少，参与胰岛素胞吐的分子被较少磷酸化。这些数据揭示了β细胞中MEK/ERK信号在葡萄糖稳态中的双重功能作用，即调节β细胞质量和控制单个β细胞的胰岛素分泌，从而不仅为了解糖尿病病理生理提供了新的视角，而且为开发治疗糖尿病的新药提供了潜在的线索。
In diabetic pathology, insufficiency in beta-cell mass, unable to meet peripheral insulin demand, and functional defects of individual beta-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic beta-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet-feeding conditions due to insufficient insulin production with lower beta-cell proliferation and reduced beta-cell mass, while in individual beta-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in beta-cells for glucose homeostasis, i.e., in regulating beta-cell mass as well as in controlling insulin exocytosis in individual beta-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.