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

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 (INSP). ER stress in beta cells with INSP led to accelerated insulin mRNA decay compared with the susceptible INS variant (INSS). Human islets with INSP showed improved vitality and function and reversed diabetes more rapidly when transplanted into diabetic mice than islets carrying INSS only. Surrogate beta cells with INSP 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.