4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes

Abstract

Abstract Background: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases by anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. Methods: The mouse model of streptozotocin (STZ) induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were further examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. Results: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. Meanwhile, the islet insulitis and beta cell function were significantly restored by OI intervention. Indeed, OI did not change the count of macrophages but significantly downregulated the proportion of M1 macrophages. In addition, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. We also found higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. Conclusions: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.