Metformin reduces airway glucose permeability and hyperglycaemia-inducedStaphylococcus aureusload independently of effects on blood glucose

Abstract

BackgroundDiabetes is a risk factor for respiratory infection, and hyperglycaemia is associated with increased glucose in airway surface liquid and risk of Staphylococcus aureus infection.ObjectivesTo investigate whether elevation of basolateral/blood glucose concentration promotes airway Staphylococcus aureus growth and whether pretreatment with the antidiabetic drug metformin affects this relationship.MethodsHuman 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.ResultsApical 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.ConclusionsHyperglycaemia 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.

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

“…In doing so, this work has revealed an elusive link between the stress-sensing components and the cell polarity pathways (see legend, Figure 10), and improved our understanding of molecular mechanisms of how epithelial monolayers are protected despite being constantly bombarded by energetic stressors by fortifying cell-cell junctions against stress-induced collapse. Because GIV serves as a junctional scaffold in both epithelial (Sasaki et al, 2015) and endothelial cells (Ichimiya et al, 2015), it is possible that the stress-triggered mechanisms outlined here also account for the protective role of AMPK on cell junctions observed consistently in a variety of tissue and cell types, in both epithelial (Garnett et al, 2013; Patkee et al, 2016; Seo-Mayer et al, 2011; Spruss et al, 2012) and endothelial (Castanares-Zapatero et al, 2013; Liu et al, 2014; Takata et al, 2013) cells, in the face of diverse chemical, bacterial and metabolic stressors. Given the overlapping substrate specificity of AMPK and its related kinases [reviewed in (Shackelford and Shaw, 2009)], it seems likely that AMPK-related family members such as the MARKs, may phosphorylate S245 on GIV under other conditions or in specific tissues.…”

“…Together, these discoveries established the first links between energetic stress, cell polarity and oncogenesis. Since then, multiple studies have reported the protective role of AMPK in maintaining cell-cell junctions across a variety of cell types in diverse tissue types [lung (Garnett et al, 2013), heart (Castanares-Zapatero et al, 2013), the blood-brain barrier (Liu et al, 2014; Takata et al, 2013), kidney (Seo-Mayer et al, 2011), intestine (Spruss et al, 2012)] while mounting a pathologic response to a variety of stressors, from bacterial invasion (Patkee et al, 2016) to ischemia (Seo-Mayer et al, 2011). …”

A novel fluorescent sensor protein for detecting changes in airway surface liquid glucose concentration

“…in diabetes mellitus) and, more potently, when both are present. Similar changes can also be detected in the ASL of in vitro models of airway epithelium in response to basolateral hyperglycaemia and pro-inflammatory stimuli [5–7]. The increase in ASL glucose concentrations makes the airways more susceptible to infection from pathogens such as methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa .…”

Metformin and other glucose-lowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a Danish nationwide population-based cohort study

“…8 Limited epidemiological data are available comparing the association of different GLDs with risk of infections. 6 9 In a Swedish study based on 51 675 patients with type 2 diabetes treated Strengths and limitations of this study ▪ Large nationwide population-based study based on prospectively collected data from hospitals and general practices.…”