INS and type 2 diabetes mellitus: To date, several mechanisms contributing to the depletion of insulin in β cells in T2D patients and in response to glucolipotoxicity have been reported, including impaired insulin gene transcription55,56 and mRNA stability57–59; Endoplasmic reticulum-associated degradation (ERAD) and other proteasomal degradation routes60; as well as proinsulin processing and sorting61,62 and basal hypersecretion63.