Macrophage migration inhibitory factor is a therapeutic target in treatment of non‐insulin‐dependent diabetes mellitus

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in the pathogenesis of a variety of autoimmune inflammatory diseases. Here, we investigated the role of MIF in the pathogenesis of non‐insulin‐dependent diabetes mellitus (NIDDM) using MIF−/− mice and a mouse model of streptozotocin (STZ)‐induced NIDDM. Following single injection of STZ, MIF +/+ BALB/c mice showed a significant increase in blood glucose levels, developed polyuria, and succumbed to disease. In contrast, no such increase in blood glucose was observed in MIF −/− BALB/c mice treated with STZ. These mice produced significantly less inflammatory cytokines and resistin as compared with MIF +/+ mice and failed to develop clinical disease. Finally, oral administration of a smallmolecule MIF antagonist, CPSI‐1306, to outbred ICR mice following induction of NIDDM significantly lowered blood glucose levels in the majority of animals, which was also associated with a significant reduction in the levels of the proinflammatory cytokines IL‐6 and TNF‐α in the sera. Taken together, these results demonstrate that MIF is involved in the pathogenesis of NIDDM and is a therapeutic target to treat this disease.—Sanchez‐Zamora, Y., Terrazas, L. I., Vilches‐Flores, A, Leal, E., Jua´rez, I., Whitacre, C, Kithcart, A., Pruitt, J., Sielecki, T., Satoskar, A. R, Rodriguez‐Sosa, M. Macrophage migration inhibitory factor is a therapeutic target in treatment of non‐insulin‐dependent diabetes mellitus. FASEB J. 24, 2583–2590 (2010). www.fasebj.org