Metformin Treatment Rescues Alterations of Insulin‐Sensitive Glucose Transporters in the Lung of Type 2 Diabetic Mice During H1N1 Influenza Infection

Abstract

Type 2 diabetes is characterized by hyperglycemia due to lack of insulin action which, in combination with obesity, is an independent risk factor for the development of respiratory infections. However, the regulation of glucose transport in the lung (a major organ to utilize glucose) has received little attention. Therefore, we hypothesized that metformin would rescue diabetes‐induced alterations of glucose transport in the lung during influenza infection. To test this hypothesis, we induced an insulin‐resistant diabetic mouse model by feeding a high‐fat diet for 16 weeks (n=10/group). A subset of mice was treated with metformin for 8 weeks. At the end of the study, a subset of mice was intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU). Bronchoalveolar lavage (BAL) fluid was analyzed spectrophotometrically for glucose concentration. Protein content of basal and insulin‐sensitive glucose transporters (GLUTs) was quantified by Western blotting whole lung homogenates. Cell‐surface GLUT protein content was quantified using the state‐of‐the‐art biotinylated photolabeling technique in the lung. After feeding a high‐fat diet, mice became obese, mildly hyperglycemic, hyperinsulinemic, and insulin resistant. Similar to non‐infected mice, total protein content of GLUT4 decreased in the lung of the diabetic infected group compared to controls, while GLUT12 protein expression increased (p<0.05). Infected diabetic mice also demonstrated significantly reduced cell‐surface GLUT4 protein expression. These alterations in pulmonary GLUT protein expression were rescued by metformin treatment. These findings were confirmed with immunohistochemistry. Interestingly, cell‐surface GLUT4 significantly increased in infected control mice versus non‐infected control counterparts (p<0.05). Both control and diabetic infected mice possessed significantly increased glucose in the BAL fluid, which was also rescued with metformin treatment (p<0.05). Influenza infection also induced neutrophilia in the BAL fluid of both control and diabetic mice, which was reduced with metformin treatment (p<0.05). These novel findings suggest that 1) regulation of glucose transport is altered in the lung during obesity and hyperglycemia, potentially increasing the risk for pulmonary infection, and 2) metformin treatment rescues glucose transporter alterations in the lung of type 2 diabetic mice with HI1N1 influenza infection. In conclusion, metformin, or other blood glucose‐lowering pharmacological interventions, may be of substantial importance in both the rescue of pulmonary glucose homeostasis and the potential prevention of respiratory infection in type 2 diabetic patients.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.