Jiang Mingchao, Wang Ning, Zhang Yuqin, Zhang Jinjin, Li Youwei, Yan Xiu, Zhang Honghao, Li Chengbin, Guan Youfei, Liang Bin, Zhang Weiping, Wu Yingjie
Institute 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.
Shandong Provincial Hospital, School of Laboratory Animal & Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250021, China.
iScience. 2024 May 17;27(7):110017. doi: 10.1016/j.isci.2024.110017. eCollection 2024 Jul 19.
The insulin receptor (INSR, IR) has two isoforms, IRA and IRB, through alternative splicing. However, their distinct functions remain unclear. Here we generated β cell-specific IRB knockout (KO) mice (βIRBKO). The KO mice displayed worsened hyperinsulinemia and hyperproinsulinemia in diet-induced obesity due to impaired proinsulin processing in β cells. Mechanistically, loss of IRB suppresses eukaryotic translation initiation factor 4G1 (eIF4G1) by stabilizing the transcriptional receptor sterol-regulatory element binding protein 1 (SREBP1). Moreover, excessive autocrine proinsulin in βIRBKO mice enhances the activity of extracellular signal-regulated kinase (ERK) through the remaining IRA to further stabilize nuclear SREBP1, forming a feedback loop. Collectively, our study paves the way to dissecting the isoform-specific function of IR and highlights the important roles of IRB in insulin processing and protecting β cells from lipotoxicity in obesity.
胰岛素受体（INSR，IR）通过可变剪接产生两种异构体，IRA和IRB。然而，它们的独特功能仍不清楚。在此，我们构建了β细胞特异性IRB基因敲除（KO）小鼠（βIRBKO）。由于β细胞中胰岛素原加工受损，KO小鼠在饮食诱导的肥胖中表现出更严重的高胰岛素血症和高胰岛素原血症。机制上，IRB的缺失通过稳定转录受体固醇调节元件结合蛋白1（SREBP1）来抑制真核翻译起始因子4G1（eIF4G1）。此外，βIRBKO小鼠中过量的自分泌胰岛素原通过剩余的IRA增强细胞外信号调节激酶（ERK）的活性，以进一步稳定核SREBP1，形成一个反馈环。总的来说，我们的研究为剖析IR异构体特异性功能铺平了道路，并突出了IRB在胰岛素加工以及保护β细胞免受肥胖中脂毒性影响方面的重要作用。
