Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
Mol Med. 2023 Mar 14;29(1):31. doi: 10.1186/s10020-023-00626-5.
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 via 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.
The mouse models 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 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.
OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1β production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment.
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.
胰腺β细胞功能障碍和活化巨噬细胞浸润是 1 型糖尿病发病机制的早期特征。一种三羧酸循环代谢物，可强烈激活巨噬细胞中的核因子红细胞 2 相关因子 2（Nrf2），它通过抗炎和抗氧化特性在一系列炎症相关疾病中发挥重要作用。然而，它在 1 型糖尿病中的作用尚不清楚。我们使用了可穿透细胞的衣康酸衍生物 4-辛基衣康酸（OI），来探讨其在 1 型糖尿病小鼠模型中的预防和治疗作用，以及巨噬细胞表型重编程的潜在机制。
使用链脲佐菌素（STZ）诱导的 1 型糖尿病和自发性自身免疫性糖尿病小鼠模型来评估 OI 的预防和治疗作用，通过测量血糖、胰岛素水平、促炎和抗炎细胞因子的分泌、组织病理学检查、流式细胞术和胰岛蛋白质组学来进行评估。通过分离 STZ 诱导的糖尿病小鼠的腹腔巨噬细胞，并在体外将 OI 预处理的炎症巨噬细胞与 MIN6 细胞共培养，来检测 OI 的保护作用及其机制。此外，还评估了 OI 治疗后 1 型糖尿病患者外周血单个核细胞（PBMC）的炎症状态。
OI 改善了 STZ 诱导的糖尿病小鼠和非肥胖型糖尿病（NOD）小鼠的血糖恶化、增加了系统胰岛素水平并改善了葡萄糖代谢。OI 干预显著恢复了胰岛炎和β细胞功能。OI 并没有改变巨噬细胞的数量，但显著下调了 M1 巨噬细胞的比例。此外，OI 显著抑制了 MAPK 在巨噬细胞中的激活，从而减轻了巨噬细胞的炎症反应，最终改善了体外的β细胞功能障碍。此外，我们在 1 型糖尿病患者的 PBMC 中检测到 LPS 刺激后更高的 IL-1β 产生，OI 治疗可减轻这种产生。
这些结果首次提供了证据，表明 OI 可以预防血糖恶化、过度炎症和β细胞功能障碍的进展，主要通过限制 1 型糖尿病小鼠模型中巨噬细胞 M1 极化来实现。
