Mutated lncRNA increase the risk of type 2 diabetes by promoting β cell dysfunction and insulin resistance

Islet beta 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 beta cell specific Mut-Reg1cp knock-in have more severe beta 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 stimulated insulin secretion test reveal that Mut-Reg1cp disrupts the stabilization of insulin mRNA by inhibiting the phosphorylation of PTBP1 in beta cells. Furthermore, islet derived exosomes transfer Mut-Reg1cp into peripheral tissue, which then promote insulin resistance by inhibiting AdipoR1 translation and adiponectin signaling. Our findings identify a novel mutation in lncRNA involved in the pathogenesis of T2D, and reveal a new mechanism for the development of T2D.

Automated summary

This study identifies a rs3819316 C > T mutation in lncRNA Reg1cp as a risk factor for Type 2 diabetes (T2D). Analysis of a Chinese population reveals that individuals with Mut-Reg1cp have a higher likelihood of developing T2D and exhibit impaired insulin secretion and increased insulin resistance. Further investigations demonstrate that Mut-Reg1cp disrupts insulin mRNA stability by inhibiting PTBP1 phosphorylation in islet beta cells, leading to the development of insulin resistance.