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Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose

Garnett, JP; Baker, EH; Naik, S; Lindsay, JA; Knight, GM; Gill, S; Tregoning, JS; Baines, DL (2013) Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose. THORAX, 68 (9). 835 - 845 (11). ISSN 0040-6376 https://doi.org/10.1136/thoraxjnl-2012-203178
SGUL Authors: Baines, Deborah Baker, Emma Harriet Lindsay, Jodi Anne Garnett, James Peter

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Abstract

Background Diabetes is a risk factor for respiratory infection, and hyperglycaemia is associated with increased glucose in airway surface liquid and risk of Staphylococcus aureus infection. Objectives To investigate whether elevation of basolateral/blood glucose concentration promotes airway Staphylococcus aureus growth and whether pretreatment with the antidiabetic drug metformin affects this relationship. Methods Human airway epithelial cells grown at air–liquid interface (±18 h pre-treatment, 30 μM–1 mM metformin) were inoculated with 5×105 colony-forming units (CFU)/cm2 S aureus 8325-4 or JE2 or Pseudomonas aeruginosa PA01 on the apical surface and incubated for 7 h. Wild-type C57BL/6 or db/db (leptin receptor-deficient) mice, 6–10 weeks old, were treated with intraperitoneal phosphate-buffered saline or 40 mg/kg metformin for 2 days before intranasal inoculation with 1×107 CFU S aureus. Mice were culled 24 h after infection and bronchoalveolar lavage fluid collected. Results Apical S aureus growth increased with basolateral glucose concentration in an in vitro airway epithelia–bacteria co-culture model. S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux. Metformin inhibited the glucose-induced growth of S aureus, increased RT and decreased glucose flux. Diabetic (db/db) mice infected with S aureus exhibited a higher bacterial load in their airways than control mice after 2 days and metformin treatment reversed this effect. Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas. Conclusions Hyperglycaemia promotes respiratory S aureus infection, and metformin modifies glucose flux across the airway epithelium to limit hyperglycaemia-induced bacterial growth. Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.

Item Type: Article
Additional Information: PubMed ID: 23709760
Keywords: Airway Epithelium, Bacterial Infection, COPD Exacerbations, Respiratory Infection, Science & Technology, Life Sciences & Biomedicine, Respiratory System, Airway Epithelium, Bacterial Infection, COPD Exacerbations, Respiratory Infection, ACTIVATED PROTEIN-KINASE, CYSTIC-FIBROSIS, EPITHELIAL-CELLS, TIGHT JUNCTIONS, TRANSPORT, INFLAMMATION, SECRETIONS, PNEUMONIA, RISK, HOMEOSTASIS
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: THORAX
ISSN: 0040-6376
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Dates:
DateEvent
1 September 2013Published
Web of Science ID: WOS:000323167500009
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URI: https://openaccess.sgul.ac.uk/id/eprint/102759
Publisher's version: https://doi.org/10.1136/thoraxjnl-2012-203178

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