Insulin Rescues Diabetes-Induced Pulmonary Complications

Hyperglycemia is an independent risk factor for the development of respiratory diseases, including influenza infections. Although the lung is a major organ to utilize glucose, the regulation of glucose transport in the healthy and diabetic lung has received little attention. We hypothesized that hyperglycemia would predispose diabetic mice to alterations in pulmonary glucose transport and pulmonary complications during Influenza A infection. 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 to restore euglycemia. After 8 weeks, an additional subset of mice was intranasally infected with influenza A H1N1 (A/PR/8/34; 250 PFU). Viral titer was determined from bronchoalveolar lavage (BAL) fluid by plaque assay. Glucose concentration in BAL fluid was measured spectrophotometrically. Glucose transporter (GLUT) protein content was quantified in whole lung homogenates by Western blotting. Both infected and uninfected diabetic mice had higher glucose concentrations in BAL fluid than their control or insulin-treated counterparts (p<0.05). There was a trend towards a decrease in protein content of GLUT4 (the major insulin-sensitive isoform) and GLUT1 (a basal isoform) in the diabetic lung (p<0.1). Total protein content of GLUT12 (a novel isoform) was increased in the diabetic lung (p<0.05). Diabetic mice possessed a significantly higher percentage of lymphocytes in their BAL fluid (p<0.05). GLUT protein content and lymphocyte alterations were rescued when mice were treated with insulin. Influenza-infected diabetic mice also had a higher percentage of lymphocytes (p<0.05), and a trend toward an increase in viral load in BAL fluid vs. infected control mice. These novel findings suggest that 1) the regulation of glucose transport is altered in the lung during hyperglycemia, and 2) diabetic mice are predisposed to pulmonary inflammation and viral replication during influenza infection. Disclosure A. Campolo: None. Z. Maria: None. M. Hinsdale: None. L. Liu: None. V. Lacombe: None.