INS and type 2 diabetes mellitus: These results reveal for the first time that misfolded proinsulin can interact with ProIR in the ER, impairing intracellular processing of ProIR and leading to defective insulin signaling that may contribute to β-cell failure in both MIDY and T2D.—Liu, S., Li, X., Yang, J., Zhu, R., Fan, Z., Xu, X., Feng, W., Cui, J., Sun, J., Liu, M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in β cells.