دورية أكاديمية
Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes.
| العنوان: | Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes. |
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| المؤلفون: | Zhang J; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; School of Medicine, Huanghuai University, Henan, China., Zhang R; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Liu C; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Ge X; Department of Endocrinology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang Y; Department of Pediatrics, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA., Jiang F; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhuang L; Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical College, Bengbu, China., Li T; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhu Q; Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China., Jiang Y; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Chen Y; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Lu M; Department of Endocrinology & Metabolism, Putuo Hospital Attached to Shanghai University of Traditional Chinese Medicine, Shanghai, China., Wang Y; School of Population Health and Environmental Science, King's College London, London, UK., Jiang M; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Liu Y; Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. dryanjunliu@hotmail.com., Liu L; Shanghai Diabetes Institute, Department of Endocrinology & Metabolism, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. lmliu@sjtu.edu.cn. |
| المصدر: | Diabetologia [Diabetologia] 2024 Aug; Vol. 67 (8), pp. 1698-1713. Date of Electronic Publication: 2024 May 31. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0006777 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0428 (Electronic) Linking ISSN: 0012186X NLM ISO Abbreviation: Diabetologia Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Berlin Springer Verlag |
| مواضيع طبية MeSH: | Diabetes Mellitus, Type 2*/genetics , Diabetes Mellitus, Type 2*/metabolism , LIM-Homeodomain Proteins*/genetics , LIM-Homeodomain Proteins*/metabolism , Transcription Factors*/genetics , Transcription Factors*/metabolism , Mutation, Missense*, Animals ; Mice ; Humans ; Male ; Insulin/metabolism ; Female ; Rats ; Insulin Secretion/genetics ; Islets of Langerhans/metabolism |
| مستخلص: | 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. (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
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| معلومات مُعتمدة: | 81270876 National Natural Science Foundation of China; 81471012 National Natural Science Foundation of China; 81770791 National Natural Science Foundation of China; 81970686 National Natural Science Foundation of China; 82070823 National Natural Science Foundation of China; YG2019ZDA08 Interdisciplinary Program of Shanghai Jiao Tong University |
| فهرسة مساهمة: | Keywords: Isl1 E283D mutation; ISL1; Insulin secretion; KI mouse model; Mechanism; Type 2 diabetes mellitus |
| المشرفين على المادة: | 0 (LIM-Homeodomain Proteins) 0 (insulin gene enhancer binding protein Isl-1) 0 (Transcription Factors) 0 (Insulin) |
| تواريخ الأحداث: | Date Created: 20240531 Date Completed: 20240823 Latest Revision: 20240823 |
| رمز التحديث: | 20240823 |
| DOI: | 10.1007/s00125-024-06186-5 |
| PMID: | 38819467 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1007/s00125-024-06186-5 |