Insulin receptor isoform B is required for efficient proinsulin processing in pancreatic β cells

Mingchao Jiang; Ning Wang; Yuqin Zhang; Jinjin Zhang; Youwei Li; Xiu Yan; Honghao Zhang; Chengbin Li; Youfei Guan; Bin Liang; Weiping Zhang; Yingjie Wu

doi:10.1016/j.isci.2024.110017

Insulin receptor isoform B is required for efficient proinsulin processing in pancreatic β cells

iScience. 2024 May 17;27(7):110017. doi: 10.1016/j.isci.2024.110017. eCollection 2024 Jul 19.

Authors

Mingchao Jiang¹, Ning Wang¹, Yuqin Zhang¹, Jinjin Zhang², Youwei Li^{1

3}, Xiu Yan¹, Honghao Zhang¹, Chengbin Li⁴, Youfei Guan⁵, Bin Liang⁴, Weiping Zhang⁶, Yingjie Wu^{1

2}

Affiliations

¹ 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.
² 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.
³ Haidu College, Qingdao Agricultural University, Laiyang, Shandong 265200, China.
⁴ Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China.
⁵ Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
⁶ Department of Pathophysiology, Naval Medical University, Shanghai 200433, China.

Abstract

The insulin receptor (INSR, IR) has two isoforms, IRA and IRB, through alternative splicing. However, their distinct functions in vivo 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 in vivo and highlights the important roles of IRB in insulin processing and protecting β cells from lipotoxicity in obesity.

Keywords: Cell biology; Molecular biology; Physiology; Transcriptomics.