mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1
mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1
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DOI：
10.1038/s42255-022-00536-6
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发表时间：
2022-02
影响因子：
20.8
通讯作者：
Dandan Zhong;Zhikang Wan;Jie Cai;Lingling Quan;Rumeng Zhang;Tian Teng;Hang Gao;Chenyu Fan;Meng Wang;Dong Guo;Hongxing Zhang;Zhanjun Jia;Ying Sun
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作者：
Dandan Zhong;Zhikang Wan;Jie Cai;Lingling Quan;Rumeng Zhang;Tian Teng;Hang Gao;Chenyu Fan;Meng Wang;Dong Guo;Hongxing Zhang;Zhanjun Jia;Ying Sun
β细胞功能障碍是1型和2型糖尿病的标志。2型糖尿病与通过未知机制出现的衰老相关β细胞异常密切相关。在这里，我们显示了更好的β细胞的身份，减少β细胞衰老，增强葡萄糖刺激的胰岛素分泌和改善葡萄糖稳态的整体微粒体前列腺素E合成酶-2（mPGES-2）缺陷小鼠用高脂饮食挑战或与2型糖尿病遗传模型（db/db小鼠）。此外，使用具有β细胞特异性mPGES-2缺陷或过表达的小鼠验证了mPGES-2在β细胞中的功能。从机制上讲，mPGES-2缺失的保护作用是通过干扰PGE 2-EP 3-NR 4A 1信号传导轴拮抗β细胞衰老而诱导的。我们还发现了mPGES-2的抑制剂SZ 0232，其保护β细胞功能障碍和糖尿病，类似于mPGES-2缺失。我们得出结论，mPGES-2通过PGE 2-EP 3-NR 4A 1信号传导轴促进衰老相关的β细胞衰老和功能障碍。药物阻断mPGES-2可能对治疗衰老相关的β细胞功能障碍和糖尿病有效。
β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through unknown mechanisms. Here we show better β-cell identity, less β-cell senescence, enhanced glucose-stimulated insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/dbmice). Furthermore, the function of mPGES-2 in β-cells is validated using mice with β-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing β-cell senescence via interference of the PGE2–EP3–NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against β-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated β-cell senescence and dysfunction via the PGE2–EP3–NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated β-cell dysfunction and diabetes.