These results underscore the essential role of O-GlcNAc modification in governing basic cell homeostatic functions by controlling protein–protein interactions, and further suggest that reducing ICln O-GlcNAcylation may represent a novel strategy in the prevention or treatment of diseases where an RVD derangement might be involved, including chronic complications of diabetes mellitus such as diabetic nephropathy. Here, CLNS1A is linked to diabetes mellitus.