Genetic protection from type 1 diabetes resulting from accelerated insulin mRNA decay

Abstract

Insulin gene (INS) variation and beta-cell stress are associated with the risk of development of type 1 diabetes (T1D) and autoimmunity against insulin. The unfolded protein response alleviating endoplasmic reticulum (ER) stress involves activation of inositol-requiring enzyme 1α (IRE1α) that impedes translation by mRNA decay. We discover that the IRE1α digestion motif is present in insulin mRNA carrying SNP rs3842752 (G>A). This SNP in the 3' untranslated region of INS associates with protection from T1D (INS^P). ER stress in beta cells with INS^P led to accelerated insulin mRNA decay compared with the susceptible INS variant (INS^S). Human islets with INS^P showed improved vitality and function and reversed diabetes more rapidly when transplanted into diabetic mice than islets carrying INS^S only. Surrogate beta cells with INS^P expressed less ER stress and INS-DRiP neoantigen. This explanation for genetic protection from T1D may act instead of or in concert with the previously proposed mechanism attributed to INS promoter polymorphism.

Keywords: ER stress; beta cell function; defective ribosomal product; genetic risk; immune tolerance; immunogenicity; insulin gene; neoantigen; type 1 diabetes; unfolded protein response.