Unravelling the mechanism by which vildagliptin and linagliptin inhibit pyroptosis in lung injury through the NLRP3 inflammatory pathway in type 1 diabetic rats.

Abstract

Diabetes mellitus (DM) represents a multifactorial condition linked to hyperglycemia, which, can lead to damage across multiple organs, including the lungs. Nod-like receptor protein-3 (NLRP3)- mediated pyroptosis could contribute to the onset of DM consequences. Several approaches have been established aimed to minimizing the complications associated with DM. Among these, linagliptin and vildagliptin, di-peptidyl peptidase-4 (DPP-4) inhibitors, are known to exert not only antihyperglycemic effects but also additional beneficial biological activities. The current study investigated the impact of linagliptin and vildagliptin on pulmonary function, oxidative stress, and NLRP3-induced pyroptosis in rats. Thirty-two male Sprague Dawley rats were given a 7-day acclimatization period. A single intraperitoneal injection of freshly produced STZ (60 mg/kg) was utilized to develop DM type-1 in rats. Following STZ treatment, all rats were given a 5% glucose solution overnight. Blood glucose levels were monitored in overnight fasted rats 72 h later, with a threshold of 250 mg/dL or higher confirming the onset of DM. The diabetic rats were randomly allocated to treated daily with either vildagliptin (5 mg/kg/p.o.) or linagliptin (5 mg/kg/p.o.) for 30 days. Additionally, the typical control group received merely the vehicle. The findings revealed that vildagliptin improves pulmonary dysfunctions associated with DM by restoring glucose homeostasis, insulin, redox marker levels, and inflammatory indices. Additionally, the NLRP3-pyroptosis-mediated IL-1β was suppressed. Vildagliptin has been shown to mitigate the detrimental effects of diabetes mellitus (DM) on the lungs, as evidenced by a reduction in pathological lung alterations and a decrease in Caspase 3 expression, which is indicative of immunohistochemical changes. In conclusion, pyroptosis triggered by the NLRP3 inflammasome possibly exacerbate diabetic pulmonary injury in rats. Vildagliptin is superior to linagliptin in ameliorating diabetes-induced lung injury primarily via targeting the NLRP3 inflammasome pathway.