Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-β subunit (IRβ) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdown via AAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice caused exacerbated MI/R injury and impairment of insulin-mediated signaling. In cultured neonatal mouse cardiomyocytes, incubation of FetB significantly reduced tyrosine kinase activity of IR and insulin-induced glucose uptake, and increased hypoxia/reoxygenation-induced apoptosis. Furthermore, FoxO1 knockdown by siRNA suppressed FetB expressions in hepatocytes treated with palmitic acid. In conclusion, upregulated FetB in diabetic liver contributes to increased MI/R injury and cardiac dysfunction via directly interacting with IRβ and consequently impairing cardiac insulin signaling.

2 型糖尿病 (T2DM) 患者更容易发生急性心肌缺血/再灌注 (MI/R) 损伤。然而，该机制在很大程度上仍然难以捉摸。临床观察表明，血浆中高水平的肝细胞因子胎球蛋白-B（FetB）与糖尿病和冠状动脉疾病均显着相关。本研究旨在确定主要来源于肝脏的 FetB 是否会加剧 MI/R 诱导的损伤以及 T2DM 的潜在机制。给予小鼠高脂饮食和链脲佐菌素以诱导 T2DM 模型，并进行 30 分钟的心肌梗死，然后再灌注。糖尿病导致肝脏 FetB 表达增加和心肌损伤加重，MI/R 后细胞凋亡和心肌酶释放增加就证明了这一点。在 T2DM 心中，胰岛素诱导的胰岛素受体底物 1 在 Tyr608 位点和 Ser473 位点的 Akt 磷酸化以及葡萄糖转运蛋白 4 膜易位显着降低。通过免疫沉淀分析评估了 FetB 和胰岛素受体-β 亚基 (IRβ) 之间的相互作用。更重要的是，FetB 击倒通过AAV9 减轻了 T2DM 小鼠的 MI/R 损伤并改善了心脏胰岛素诱导的信号传导。相反，正常小鼠中 FetB 的上调会导致 MI/R 损伤加剧和胰岛素介导的信号传导受损。在培养的新生小鼠心肌细胞中，FetB 的孵育显着降低了 IR 的酪氨酸激酶活性和胰岛素诱导的葡萄糖摄取，并增加了缺氧/复氧诱导的细胞凋亡。此外，siRNA 对 FoxO1 的敲低抑制了用棕榈酸处理的肝细胞中的 FetB 表达。总之，糖尿病肝脏中上调的 FetB通过与 IRβ 直接相互作用并因此损害心脏胰岛素信号传导，导致 MI/R 损伤和心脏功能障碍增加。