Insulin Treatment Rescues Alterations in the Lung following H1N1 Influenza Virus Infection in Diabetic Mice

Abstract

Hyperglycemia has recently been identified as a major risk factor for the development and worsening severity of viral respiratory infections. However, the regulation of glucose homeostasis in the diabetic lung and during influenza infection is currently under‐investigated. We hypothesized that hyperglycemia would predispose diabetic mice to alterations in pulmonary glucose homeostasis following influenza A infection, which would be rescued by in vivo insulin treatment. To test this hypothesis, we used a streptozotocin‐induced type 1 diabetic mouse model (n=8–12/group). A subset of diabetic mice was treated with insulin via a subcutaneous insulin pump. After 8 weeks, mice were intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU) and sacrificed 3 days post infection. Glucose concentration in BAL fluid was measured spectrophotometrically. Glucose transporter (GLUT) protein location was determined via immunohistochemistry, and GLUT protein content was quantified by Western blotting. As expected, diabetic (non‐infected and influenza‐infected) mice displayed hyperglycemia while insulin‐treated diabetic mice remained euglycemic. In addition, H&E‐stained lungs revealed that infection with H1N1 induced hemorrhage, inflammatory cell infiltration, and vasculitis in the lungs of both diabetic and control mice. Interestingly, infected diabetic mice displayed significant upregulation of non‐insulin‐sensitive GLUT protein (−1, −12) versus their control counterparts, with a concurrent significant downregulation of the insulin‐sensitive GLUT4 protein (p<0.05). In contrast, non‐infected diabetic mice demonstrated a significant downregulation of GLUT1 protein in the lung (p<0.001). These alterations in GLUT protein expression in the lung were rescued when diabetic mice were treated with insulin for 8 weeks. Both infected and non‐infected diabetic mice had a higher concentration of glucose in BAL fluid than their control counterparts, which was rescued following in vivo insulin treatment (p<0.05). Interestingly, infected mice of both the control and diabetic groups had a significantly higher glucose concentrations than their non‐infected counterparts (p=0.0032 and p=0.0299, respectively), while both non‐infected and infected insulin‐treated mice possessed similar BAL glucose concentrations. BAL glucose concentration was significantly correlated with blood glucose in both non‐infected and infected groups (p=0.045 and p=0.07, respectively). In addition, in vivo insulin treatment partially rescued the neutrophilic response in BALF of infected diabetic mice (p<0.05). These novel findings suggest that 1) the regulation of glucose transport is altered in the lungs of diabetic mice, potentially worsening response to H1N1 influenza infection, and 2) in vivo insulin treatment rescues the significant pathological alterations found in the diabetic lung following influenza infection.Support or Funding InformationThis study was funded by the Oklahoma Center for Respiratory and Infectious Disease (OCRID – CoBRE, NIH 1P20 GM103648), the Harold Hamm Diabetes Center, and Oklahoma State University Center for Veterinary Health Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.