Juan Zhang, Rong Zhang, Chanwei Liu, Xiaoxu Ge, Ying Wang, Fusong Jiang, Langen Zhuang, Tiantian Li, Qihan Zhu, Yanyan Jiang, Yating Chen, Ming Lu, Yanzhong Wang, Meisheng Jiang, Yanjun Liu, Limei Liu
Diabetologia 2024 AugMutations 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 Isl1E283D mouse model to investigate the disease-causing mechanism of diabetes mellitus. The ISL1E283D mutation (c. 849A>T) was identified by whole exome sequencing on an early-onset type 2 diabetes family and then the Isl1E283D 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 Isl1E283D was evaluated by cell-based luciferase reporter assay and electrophoretic mobility shift assay, and the expression levels of Ins2 driven by Isl1 wild-type (Isl1WT) and Isl1E283D mutation in rat INS-1 cells were determined by RT-PCR and western blotting. Impaired GSIS and elevated glucose level were observed in Isl1E283D 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 Isl1E283D 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 Isl1WT led to an upregulation of Ins2 expression. Isl1E283D 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 Isl1E283D 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.
Juan Zhang, Rong Zhang, Chanwei Liu, Xiaoxu Ge, Ying Wang, Fusong Jiang, Langen Zhuang, Tiantian Li, Qihan Zhu, Yanyan Jiang, Yating Chen, Ming Lu, Yanzhong Wang, Meisheng Jiang, Yanjun Liu, Limei Liu. Missense mutation of ISL1 (E283D) is associated with the development of type 2 diabetes. Diabetologia. 2024 Aug;67(8):1698-1713
PMID: 38819467
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