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降低IGF1R减弱衰老,并改善胰腺β细胞的功能
Kanako Iwasaki1,2, Benjamin Lalani1, Jiho Kahng1
1Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, United States.
Frontiers in endocrinology
|July 13, 2023
概括
在胰腺β细胞中降低胰岛素样生长因子1受体 (IGF1R) 信号,改善葡萄糖调节,抑制细胞衰老,为2型糖尿病 (T2D) 和衰老提供潜在的治疗点.
科学领域:
- 内分泌学和新陈代谢学
- 细胞衰老和衰老的过程
- 糖尿病研究 糖尿病研究
背景情况:
- 增强的β细胞衰老有助于胰岛素抵抗,细胞功能障碍和转录性身份丧失,导致2型糖尿病 (T2D).
- 衰老特征之间的相互作用,包括衰老和通过β细胞的胰岛素/IGF1通路改变的营养感知,仍然不完全理解.
- 在β细胞中增加IGF1R表达是衰老的标志物,但它在与年龄相关的功能障碍和衰老中的直接作用需要阐明.
研究的目的:
- 研究IGF1R在β细胞功能和衰老中的直接作用.
- 确定IGF1/IGF1R信号减少对与年龄相关的β细胞功能障碍和T2D病原体的影响.
主要方法:
- 使用了两种IGF1/IGF1R信号减少的小鼠模型:Ames矮鼠 (缺乏生长激素) 和可诱导β细胞特异性IGF1R淘汰 (βIgf1rKD) 的小鼠.
- 评估了β细胞功能,衰老标志物 (p21Cip1),葡萄糖平衡和胰岛素分泌.
- 在βIgf1rKD小鼠的小岛上进行RNA-Seq,以分析信号通路和基因表达的变化.
主要成果:
- 贝塔细胞 (在两种模型中) 的IGF1R信号减少与抑制的衰老标志物和改善的葡萄糖清除和胰岛素分泌有关.
- βIgf1rKD小鼠表现出衰老降调通路的恢复 (硫化物氧化,自,mTOR信号传递) 和增加关键β细胞身份基因的表达 (例如,Mafa,Nkx6.1).
- 删除IGF1R降低了与衰老相关的基因,并改善了β细胞功能,即使是在高脂肪饮食条件下.
结论:
- IGF1R信号传递在衰老诱导的β细胞功能障碍和T2D中起着因果作用.
- 降低IGF1R信号与胰腺β细胞中抑制的细胞衰老有关.
- 向IGF1R信号是一种潜在的治疗策略,可以恢复β细胞的功能和身份,减轻T2D的进展.
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