在肥胖小鼠中,β细胞Jagged1足够,但对于岛屿 activity和胰岛素分泌缺陷来说不必要
Nina Suda1, Alberto Bartolomé1, Jiani Liang1
1Department of Medicine, Columbia University, New York, NY, USA.
Molecular metabolism
|February 4, 2024
概括
在肥胖小鼠和患有2型糖尿病的人群中,Jagged1蛋白的含量升高,导致胰岛素分泌受损. 阻断Jagged1可以改善胰岛素分泌,但β细胞不是这种Jagged1信号的来源.
科学领域:
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
- 代谢性疾病研究研究
背景情况:
- 在肥胖期间,胰腺β细胞中重新激活了痕信号,导致功能障碍.
- 跨膜连接体的可用性,特别是Jagged1,会影响邻近细胞中的Notch信号.
研究的目的:
- 研究β细胞Jagged1表达在肥胖小鼠不适应的Notch反应和胰岛素分泌缺陷中的作用.
- 为了确定Jagged1是否是2型糖尿病的治疗点.
主要方法:
- 在高脂肪饮食 (HFD) 和db/db肥胖小鼠模型中评估了Notch路径组件.
- 在患有或没有2型糖尿病 (T2D) 患者的人类小岛上进行单细胞RNA测序 (scRNA-Seq).
- 使用可诱导,β细胞特异的Jagged1功能增益和丧失的小鼠模型和用中和抗体进行体外GSIS测定.
主要成果:
- 在肥胖小鼠和代谢不灵活的人类β细胞中,Jagged1是唯一一个高调的Notch配体,其Notch活性增加.
- 中和Jagged1抗体在肥胖小鼠的小岛上增强了葡萄糖刺激胰岛素分泌 (GSIS).
- 虽然强制Jagged1表达会降低葡萄糖耐受性,但β细胞特异性的Jagged1功能丧失并不能防止HFD诱导的胰岛素分泌缺陷.
结论:
- 从肥胖小鼠和T2D患者的岛屿中增加的Jagged1,加上在Jagged1中和后改善的GSIS,表明Jagged1抑制的治疗潜力.
- 遗传功能丧失研究表明,β细胞不太可能是驱动这些效应的Jagged1信号的主要来源.
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