The MIF-CD74 interaction connects this cytokine to diabetes type 1. Patients with type 1 diabetes have significantly higher circulating MIF levels and higher levels of its receptor CD74 in monocytes (Drug Disc. Today, 2019, 24(2), 428-439). Importantly, the islets of MIF knock-out mice showed increased resistance to cytokine-induced death. This indicates that interference with the MIF-CD74 receptor interaction has potential to alleviate auto-immunity in type 1 diabetes. MIF is connected to the pathology of type 2 diabetes by its ability to modulate immune responses and insulin sensitivity in adipose tissue. Together with TNF, IL-6 and IL-1β, MIF is considered as one of the initiators of insulin resistance in adipocytes (J. Immunol., 179 (2007), pp. 5399-5406). Increased insulin resistance can be explained by interference of MIF with the phosphorylation of insulin receptor substrate-1 (IRS-1) as part of the insulin reponse pathway. Indirectly, MIF increases the production of adipokines and pro-inflammatory cytokines, which also reduces insulin sensitivity. In addition, MIF reportedly has chaperone activity, supporting correct insulin folding, which improves insulin bioactivity (Cytokine, 2014, 69(1), 39-46). Indeed, insulin derived from MIF knock-out mice is poorly functional, and the direct physical interaction between MIF and insulin was shown in an ELISA assay. These effects were not blocked by inhibition of MIF’s tautomerase activity, thereby indicating that the tautomerase active site region is likely not involved in MIF’s chaperone function. Taken together, MIF exerts disadvantageous functions in diabetes via interaction with the CD74 receptor, while it also appears to have advantageous functions via its insulin chaperone activity. Seemingly, both activities are mediated by distinct regions on the MIF protein surface.