# The SGLT2 Inhibitor Empagliflozin Mitigates the Harmful Effects of Methylglyoxal Exposure on Ovalbumin-Induced Mouse Airway Inflammation

## TL;DR

This study shows that empagliflozin, a diabetes drug, reduces airway inflammation in mice exposed to methylglyoxal, a harmful byproduct linked to asthma.

## Contribution

The study reveals a novel anti-inflammatory mechanism of SGLT2 inhibitors through methylglyoxal detoxification in allergic airway disease.

## Key findings

- Empagliflozin reduced MGO levels and inflammation markers in MGO-exposed asthmatic mice.
- Treatment increased glyoxylase-1 activity and IL-10 levels, promoting MGO detoxification.
- MGO exposure worsened airway inflammation, which was mitigated by empagliflozin.

## Abstract

Asthma is a chronic inflammatory airway disease that can be aggravated by metabolic comorbidities such as type 2 diabetes mellitus (DM2) and obesity. Elevated levels of methylglyoxal (MGO), a reactive glycolysis byproduct, have been associated with exacerbation of allergic airway disease. SGLT2 inhibitors have been successfully employed in DM2 treatment. Here, we hypothesized that elimination of MGO might be a potential anti-inflammatory mechanism of SGLT2 inhibitors. This study aimed to evaluate the effects of empagliflozin on ovalbumin (OVA)-induced airway inflammation in mice chronically exposed to MGO. Male C57BL/6 mice sensitized with OVA were exposed to 0.5% MGO for 12 weeks and treated with empagliflozin (10 mg/kg, gavage, two weeks). MGO exposure significantly enhanced airway eosinophil infiltration, mucus production and collagen deposition, as well as levels of IL-4, IL-5, eotaxin and TNF-α. Empagliflozin treatment significantly reduced OVA-induced airway disease, which was accompanied by reductions in IgE, IL-4, IL-5, eotaxin, and TNF-α levels. Empagliflozin significantly reduced the MGO levels in serum, and immunohistochemical staining, and protein expression of MGO-hydroimidazolone (MG-H1), while increasing IL-10 levels and glyoxylase-1 (GLO 1) activity in lungs. In conclusion, empagliflozin efficiently removes MGO from circulation, while increasing the MGO detoxification by GLO 1, thereby mitigating the OVA-induced inflammation in MGO-exposed mice.