biostudies-literatureUnknown13(10)Guo WHIslet β cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet β cell specific Mut-Reg1cp knock-in have more severe β cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulateCell death & disease904https://www.ebi.ac.uk/biostudies/studies/S-EPMC9613878biostudies-literatureMutated lncRNA increase the risk of type 2 diabetes by promoting β cell dysfunction and insulin resistance.PMC9613878Yan DDYan JLiu YLYang MGuo WHGuo QZhang RLuo XHJin LfalseMutated lncRNA increase the risk of type 2 diabetes by promoting β cell dysfunction and insulin resistance.Islet β cell dysfunction and insulin resistance are the main pathogenesis of type 2 diabetes (T2D), but the mechanism remains unclear. Here we identify a rs3819316 C > T mutation in lncRNA Reg1cp mainly expressed in islets associated with an increased risk of T2D. Analyses in 16,113 Chinese adults reveal that Mut-Reg1cp individuals had higher incidence of T2D and presented impaired insulin secretion as well as increased insulin resistance. Mice with islet β cell specific Mut-Reg1cp knock-in have more severe β cell dysfunction and insulin resistance. Mass spectrometry assay of proteins after RNA pulldown demonstrate that Mut-Reg1cp directly binds to polypyrimidine tract binding protein 1 (PTBP1), further immunofluorescence staining, western blot analysis, qPCR analysis and glucose stimulate2022-01-01T00:00:00Z2022 Oct2026-06-01T02:15:58.505Z2025-02-19T01:29:05.712ZS-EPMC96138783630274910.1038/s41419-022-05348-w