Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice

J Mol Cell Cardiol. 2021 Feb:151:163-172. doi: 10.1016/j.yjmcc.2020.03.002. Epub 2020 Mar 5.


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.

Keywords: Fetuin-B; Hepatokine; Insulin signaling; Myocardial ischemia/reperfusion injury; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / metabolism
  • Fetuin-B / metabolism*
  • Forkhead Box Protein O1 / metabolism
  • Hepatocytes / metabolism
  • Insulin / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Protein Binding
  • Receptor, Insulin / metabolism
  • Signal Transduction*
  • Up-Regulation


  • Fetuin-B
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Insulin
  • Receptor, Insulin