Journal
CELL DEATH & DISEASE
Volume 13, Issue 10, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-022-05348-w
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [92149306, 82120108009, 81930022, 82170903]
- National Postdoctoral Program for Innovative Talents of China Postdoctoral Science Foundation [BX20200390]
- China Postdoctoral Science Foundation [2021M703642]
- Youth Science Foundation of Xiangya Hospital [2020Q01]
Ask authors/readers for more resources
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.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available