Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes

doi:10.1007/s00125-024-06186-5

科研成果详情

题名	Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes
作者	Zhang, Juan 1,2; Zhang, Rong 1; Liu, Chanwei 1; Ge, Xiaoxu 3; Wang, Ying 4; Jiang, Fusong 1; Zhuang, Langen 5; Li, Tiantian 1; Zhu, Qihan6; Jiang, Yanyan 1; Chen, Yating 1; Lu, Ming 7; Wang, Yanzhong 8; Jiang, Meisheng 9; Liu, Yanjun 10; Liu, Limei 1
发表日期	2024-05-31
发表期刊	DIABETOLOGIA 影响因子和分区
语种	英语
原始文献类型	Article ; Early Access
关键词	Insulin secretion ISL1 Isl1(E283D) mutation KI mouse model Mechanism Type 2 diabetes mellitus
其他关键词	LIM/HOMEODOMAIN GENE ISLET-1 ; CELL GLUCOSE-TRANSPORTER ; PANCREATIC BETA-CELLS ; GLUT2 GENE ; INSULIN ; TRANSCRIPTION ; EXPRESSION ; HOMEODOMAIN ; CHINESE ; LIVER
摘要	Aims/hypothesis Mutations in Isl1, encoding the insulin enhancer-binding protein islet-1 (ISL1), may contribute to attenuated insulin secretion in type 2 diabetes mellitus. We made an Isl1(E283D) mouse model to investigate the disease-causing mechanism of diabetes mellitus. Methods The ISL1(E283D) mutation (c. 849A>T) was identified by whole exome sequencing on an early-onset type 2 diabetes family and then the Isl1(E283D) knockin (KI) mouse model was created and an IPGTT and IPITT were conducted. Glucose-stimulated insulin secretion (GSIS), expression of Ins2 and other ISL1 target genes and interacting proteins were evaluated in isolated pancreas islets. Transcriptional activity of Isl1(E283D) was evaluated by cell-based luciferase reporter assay and electrophoretic mobility shift assay, and the expression levels of Ins2 driven by Isl1 wild-type (Isl1(WT)) and Isl1(E283D) mutation in rat INS-1 cells were determined by RT-PCR and western blotting. Results Impaired GSIS and elevated glucose level were observed in Isl1(E283D) KI mice while expression of Ins2 and other ISL1 target genes Mafa, Pdx1, Slc2a2 and the interacting protein NeuroD1 were downregulated in isolated islets. Transcriptional activity of the Isl1(E283D) mutation for Ins2 was reduced by 59.3%, and resulted in a marked downregulation of Ins2 expression when it was overexpressed in INS-1 cells, while overexpression of Isl1(WT) led to an upregulation of Ins2 expression. Conclusions/interpretation Isl1(E283D) mutation reduces insulin expression and secretion by regulating insulin and other target genes, as well as its interacting proteins such as NeuroD1, leading to the development of glucose intolerance in the KI mice, which recapitulated the human diabetic phenotype. This study identified and highlighted the Isl1(E283D) mutation as a novel causative factor for type 2 diabetes, and suggested that targeting transcription factor ISL1 could offer an innovative avenue for the precise treatment of human type 2 diabetes.
资助项目	National Natural Science Foundation of China
出版者	SPRINGER
ISSN	0012-186X
EISSN	1432-0428
卷号	67 期号:8 页码:1698-1713
DOI	10.1007/s00125-024-06186-5
页数	16
WOS类目	Endocrinology & Metabolism
WOS研究方向	Endocrinology & Metabolism
WOS记录号	WOS:001236509900001
收录类别	SCIE ; SCOPUS ; PUBMED
URL	查看原文
PubMed ID	38819467
SCOPUSEID	2-s2.0-85194731471
通讯作者地址	[Liu, Limei]Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Shanghai Key Clin Ctr Metab Dis,Sch Med, Dept Endocrinol & Metab,Shanghai Peoples Hosp 6, Shanghai, Peoples R China. ; [Liu, Yanjun]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Pediat, Shanghai, Peoples R China.
Scopus学科分类	Internal Medicine;Endocrinology, Diabetes and Metabolism
TOP期刊	TOP期刊
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/214590
专题	附属第一医院_内分泌科
通讯作者	Liu, Yanjun; Liu, Limei
作者单位	1.Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Shanghai Key Clin Ctr Metab Dis,Sch Med, Dept Endocrinol & Metab,Shanghai Peoples Hosp 6, Shanghai, Peoples R China; 2.Huanghuai Univ, Sch Med, Zhumadian, Henan, Peoples R China; 3.Shanghai Jiao Tong Univ, Tongren Hosp, Dept Endocrinol, Sch Med, Shanghai, Peoples R China; 4.Harbor UCLA Med Ctr, Angeles Biomed Res Inst, Dept Pediat, Torrance, CA USA; 5.Bengbu Med Coll, Dept Endocrinol, Affiliated Hosp 1, Bengbu, Peoples R China; 6.Wenzhou Med Univ, Dept Endocrinol, Affiliated Hosp 1, Wenzhou, Peoples R China; 7.Shanghai Univ Tradit Chinese Med, Dept Endocrinol & Metab, Putuo Hosp Attached, Shanghai, Peoples R China; 8.Kings Coll London, Sch Populat Hlth & Environm Sci, London, England; 9.Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA; 10.Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Pediat, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Juan,Zhang, Rong,Liu, Chanwei,et al. Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes[J]. DIABETOLOGIA,2024,67(8):1698-1713.
APA	Zhang, Juan., Zhang, Rong., Liu, Chanwei., Ge, Xiaoxu., Wang, Ying., ... & Liu, Limei. (2024). Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes. DIABETOLOGIA, 67(8), 1698-1713.
MLA	Zhang, Juan,et al."Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes".DIABETOLOGIA 67.8(2024):1698-1713.