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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 - Thorax (2013)

Bottom Line: S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux.Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK.

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 5×10(5) colony-forming units (CFU)/cm(2) 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 1×10(7) 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.

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Related in: MedlinePlus

Metformin (MF) reverses the effect of Staphylococcus aureus infection on paracellular glucose flux across airway epithelium. H441 monolayers with and without 1 mM metformin pretreatment, were infected with S aureus. (A) Paracellular glucose flux measured by adding radiolabelled l-glucose to the basolateral surface and monitoring its appearance at the apical surface, n=8. (B) Transepithelial l-glucose flux across ex vivo murine tracheas from S aureus-infected mice pretreated with phosphate-buffered saline (PBS) or metformin, n=3. *p<0.05, ****p<0.0001.
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THORAXJNL2012203178F8: Metformin (MF) reverses the effect of Staphylococcus aureus infection on paracellular glucose flux across airway epithelium. H441 monolayers with and without 1 mM metformin pretreatment, were infected with S aureus. (A) Paracellular glucose flux measured by adding radiolabelled l-glucose to the basolateral surface and monitoring its appearance at the apical surface, n=8. (B) Transepithelial l-glucose flux across ex vivo murine tracheas from S aureus-infected mice pretreated with phosphate-buffered saline (PBS) or metformin, n=3. *p<0.05, ****p<0.0001.

Mentions: The decrease in RT evoked by apical S aureus gave rise to an increase in the rate of basolateral-to-apical paracellular L-glucose flux, from 7.3±0.5 to 49.3±4.6 nmoles/min/cm2 (10 mM basolateral glucose; p<0.0001; n=8; figure 8A). Metformin significantly impaired the rise in L-glucose flux (p<0.0001; n=8; figure 8A). Similarly, metformin treatment significantly reduced the L-glucose flux across infected ex vivo mouse tracheas by 40±5% (p<0.05; n=3; figure 8B).


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 - Thorax (2013)

Metformin (MF) reverses the effect of Staphylococcus aureus infection on paracellular glucose flux across airway epithelium. H441 monolayers with and without 1 mM metformin pretreatment, were infected with S aureus. (A) Paracellular glucose flux measured by adding radiolabelled l-glucose to the basolateral surface and monitoring its appearance at the apical surface, n=8. (B) Transepithelial l-glucose flux across ex vivo murine tracheas from S aureus-infected mice pretreated with phosphate-buffered saline (PBS) or metformin, n=3. *p<0.05, ****p<0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756442&req=5

THORAXJNL2012203178F8: Metformin (MF) reverses the effect of Staphylococcus aureus infection on paracellular glucose flux across airway epithelium. H441 monolayers with and without 1 mM metformin pretreatment, were infected with S aureus. (A) Paracellular glucose flux measured by adding radiolabelled l-glucose to the basolateral surface and monitoring its appearance at the apical surface, n=8. (B) Transepithelial l-glucose flux across ex vivo murine tracheas from S aureus-infected mice pretreated with phosphate-buffered saline (PBS) or metformin, n=3. *p<0.05, ****p<0.0001.
Mentions: The decrease in RT evoked by apical S aureus gave rise to an increase in the rate of basolateral-to-apical paracellular L-glucose flux, from 7.3±0.5 to 49.3±4.6 nmoles/min/cm2 (10 mM basolateral glucose; p<0.0001; n=8; figure 8A). Metformin significantly impaired the rise in L-glucose flux (p<0.0001; n=8; figure 8A). Similarly, metformin treatment significantly reduced the L-glucose flux across infected ex vivo mouse tracheas by 40±5% (p<0.05; n=3; figure 8B).

Bottom Line: S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux.Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas.Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Sciences, Centre for Cell Physiology and Pharmacology, St George's, University of London, London, UK.

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 5×10(5) colony-forming units (CFU)/cm(2) 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 1×10(7) 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.

Show MeSH
Related in: MedlinePlus