Dapagliflozin‐lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice

Abstract

Background and PurposeHyperglycaemia increases glucose concentrations in airway surface liquid and increases the risk of pulmonary Pseudomonas aeruginosa infection. We determined whether reduction of blood and airway glucose concentrations by the anti‐diabetic drug dapagliflozin could reduce P. aeruginosa growth/survival in the lungs of diabetic mice.Experimental ApproachThe effect of dapagliflozin on blood and airway glucose concentration, the inflammatory response and infection were investigated in C57BL/6J (wild type, WT) or leptin receptor‐deficient (db/db) mice, treated orally with dapagliflozin prior to intranasal dosing with LPS or inoculation with P. aeruginosa. Pulmonary glucose transport and fluid absorption were investigated in Wistar rats using the perfused fluid‐filled lung technique.Key ResultsFasting blood, airway glucose and lactate concentrations were elevated in the db/db mouse lung. LPS challenge increased inflammatory cells in bronchoalveolar lavage fluid from WT and db/db mice with and without dapagliflozin treatment. P. aeruginosa colony‐forming units (CFU) were increased in db/db lungs. Pretreatment with dapagliflozin reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in db/db mice towards those seen in WT. Dapagliflozin had no adverse effects on the inflammatory response in the mouse or pulmonary glucose transport or fluid absorption in the rat lung.Conclusion and ImplicationsPharmacological lowering of blood glucose with dapagliflozin effectively reduced P. aeruginosa infection in the lungs of diabetic mice and had no adverse pulmonary effects in the rat. Dapagliflozin has potential to reduce the use, or augment the effect, of antimicrobials in the prevention or treatment of pulmonary infection.

Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease

“…4 In animal models the antihyperglycemic agents metformin and dapagliflozin reduced airway glucose concentrations and inhibited growth of S aureus or P aeruginosa . 8 , 10 , 11 However, a recent trial of metformin in hospitalized patients with COPD found no effect on inflammatory mediators or clinical outcomes. 29 In this study metformin was commenced after hospital admission, with the full dose reached after only 4 days.…”

“…Staphylococcus aureus and Pseudomonas aeruginosa use glucose as a growth substrate, and their growth is promoted by high ASL glucose concentrations. 6 , 7 , 8 , 9 There is a link between increased airway glucose concentrations and bacterial colonization in animal models, 8 , 10 , 11 but the relationship between airway glucose concentrations and infection in vivo in human subjects is less well studied. One study has linked glucose in bronchial aspirates to infection with methicillin-resistant S aureus 12 ; however, sputum glucose concentrations were not related to exacerbation frequency in patients with cystic fibrosis.…”

Susceptibility for Some Infectious Diseases in Patients With Diabetes: The Key Role of Glycemia

“…On the other hand, some studies have shown that pretreatment with dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, reduced blood and bronchoalveolar lavage glucose concentrations and P. aeruginosa CFU in leptin receptor-deficient (db/db) mice, as compared to those seen in wild type (WT) mice ( 239 ).…”

Covid-19 and Diabetes: A Complex Bidirectional Relationship

“…An additional class of anti-diabetic medications associated with lowering inflammation are the glifozins, or SGLT2 (sodium-glucose cotransporter-2/SLC5A2) inhibitors, which attenuate reabsorption of glucose in the kidney to lower blood sugar. So far, this reported anti-inflammatory effect focuses on the kidney, cardiovascular system and pancreas, rather than lungs ( 96 , 97 ), though it has been shown to indirectly reduce pulmonary infection in diabetic mice ( 98 ). Although SGLT2 inhibitors are associated with dehydration and anorexia and therefore may pose a risk for critically ill patients, a new study focusing on hospitalized adult patients with Covid-19 commenced in April 2020, with the aim of understanding the substantial cardio- and nephroprotective effects of SLGT2 inhibitors in reducing disease progression, complications, and all-cause mortality ( 99 ).…”