INS and diabetes mellitus: These impairments not only directly decrease PI/INS production, they may also lead to abnormal intracellular accumulation of INS precursors (including PPI and/or PI) that may affect coexpressed WT bystander PPI and/or PI and may induce ER stress and cell toxicity, all of which can contribute to the development and progression of diabetes (1, 10, 16).