胰岛素受体异型B是胰腺β细胞中有效的亲胰岛素处理所需的
Mingchao Jiang1, Ning Wang1, Yuqin Zhang1
1Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, Liaoning 116000, China.
iScience
|July 18, 2024
概括
胰岛素受体异型B (IRB) 通过改善胰岛素处理和预防脂毒性来保护胰腺β细胞. 在IRB淘汰赛小鼠中,由于受损的亲胰岛素处理导致肥胖相关的糖尿病恶化.
科学领域:
- 内分泌学 在内分泌学.
- 分子生物学分子生物学
- 代谢疾病 代谢疾病
背景情况:
- 胰岛素受体 (INSR,IR) 存在两种异型,IRA和IRB,通过替代拼接生成.
- 在体内,IRA和IRB的不同功能在很大程度上仍未被描述,特别是在胰腺β细胞中.
研究的目的:
- 为了研究胰腺β细胞中胰岛素受体异型B (IRB) 的特定体内作用.
- 阐明在肥胖期间调节胰岛素处理和β细胞健康的IRB功能背后的分子机制.
主要方法:
- 产生β细胞特异性IRB淘汰 (βIRBKO) 鼠标.
- 在饮食诱导的肥胖模型中评估代谢参数,包括高胰岛素血和高胰岛素血.
- 分析涉及蛋白质处理,翻译和信号的分子通路,包括SREBP1和ERK通路.
主要成果:
- 在饮食诱导的肥胖中,βIRBKO小鼠表现出恶化的高胰岛素血症和高胰岛素血症.
- 失去了IRB,影响了β细胞内的亲胰岛素处理.
- 通过稳定固醇调节元素结合蛋白1 (SREBP1) 的稳定,IRB 缺乏导致抑制的真核转化启动因子4G1 (eIF4G1).
- 在βIRBKO小鼠中,过度的自身蛋白亲胰岛素通过IRA激活了细胞外信号调节激酶 (ERK),在反循环中进一步稳定了核SREBP1.
结论:
- 这项研究阐明了体内胰岛素受体的异型特异性功能.
- 在胰腺β细胞内,IRB在适当的胰岛素处理中起着至关重要的作用.
- 在肥胖和代谢功能障碍的背景下,IRB对于保护β细胞免受脂毒性至关重要.
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