The respiratory tract is covered by a thin layer of fluid that lines the luminal surface of the epithelium (airway surface liquid, ASL), which is important for lung defence against infection. Glucose concentrations are normally 12.5x lower in humans (~0.4 mM) and 3-20x lower in other species, in ASL than in plasma [1, 2]. In an in vitro model of human airway epithelial cells grown at air-liquid-interface, apical glucose concentration was 1.1 ±0.4, 5.4±1.1 and 10.3±3.4 mM, lower than corresponding basolateral concentrations of 10, 20 and 40 mM (P≤0.01, n=4). Using in vitro airway epithelial models, we found under normal conditions, that glucose predominantly diffuses from blood/interstitial fluid across the respiratory epithelium into ASL via paracellular pathways, and that this is limited by the permeability of the epithelium. In the airway, apical and basolateral facilitative GLUT-mediated transport restricts glucose accumulation in ASL. Glucose transporters identified in the airway include GLUT1, 2 and 10. Inhibition of apical or basolateral GLUTs with phloretin (1mM) significantly increased apical glucose accumulation (P≤0.05, n=5). In H441 cells, paracellular flux (3.3 nmol/min/cm-2) was less than the combined effects of apical and basolateral glucose uptake (4.0 nmol/min/cm-2; n=3). There is currently little evidence for Na+-glucose co-transport in vivo in the airway or in airway cells, although this transporter has an important role in the distal lung. Glucose taken up into the cell is rapidly metabolised. This is critical to maintain low intracellular glucose concentrations which provide a driving force for glucose uptake via GLUT transporters. It also limits the transcellular transport of glucose and predicts that ASL glucose concentrations equilibrate with intracellular glucose concentration. In H441 airway cells, lactate, a product of glucose metabolism was secreted into ASL [3]. Paracellular diffusion of glucose across the epithelium and ASL glucose concentrations are increased by raising the basolateral to apical glucose concentration gradient. Pre-treatment with pro-inflammatory agents reduced transepithelial ionic resistance (Rt) and increased transepithelial glucose flux into ASL. Interestingly, whilst pro-inflammatory agents also increased the abundance of GLUT transporters, paracellular glucose flux (9.7 nmol/min/cm-2) exceeded bilateral glucose uptake (4.8 nmol/min/cm-2; n=3) and led to accumulation of glucose in ASL [2]. ASL glucose concentrations are elevated in humans with Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD). ASL glucose concentrations are also increased by hyperglycaemia. Diabetes mellitus is a common comorbidity with COPD and CF. The combination of lung inflammation and hyperglycaemia produced a further increase in ASL glucose concentration [1]. Elevated ASL glucose concentrations are associated with an increased risk of respiratory infection, particularly with meticillin-resistant S. aureus (MRSA)[4]. Diabetes is a predisposing factor for nasal colonisation with S. aureus and acquisition of multiple antibiotic resistant Ps. aeruginosa in humans with CF. Both S. aureus and Ps. aeruginosa utilise glucose as a growth substrate. In vitro, elevation of ASL glucose concentration promoted the apical growth of S. aureus and Ps. aeruginosa on normal and CF airway epithelial cells. In a mouse model of S. aureus airway infection, more bacteria were present in the airways of hyperglycaemic db/db mice than in wild type post infection (P≤0.01, n=9). Pre-treatment with metformin (1 mM 18 hrs, H441 cells; 40mg/kg 2 days intraperitoneal, mouse) suppressed the growth of these pathogens in vitro and prevented glucose accumulation in ASL. Metformin also suppressed the growth of S. aureus in vivo. Metformin significantly increased transepithelial resistance (P≤0.001, n=15), reduced glucose flux (P≤0.01, n=6) and maintained glucose transport independently of any effects on blood glucose concentration [5]. Thus, we propose that airway epithelial glucose transport, metabolism and transepithelial flux pathways are important for lung defence against infection. Furthermore, manipulation of these pathways could provide therapeutic targets for the prevention of respiratory infection.