Liraglutide alters gut microbiota and improves endothelium-dependent relaxation in db/db mice

Abstract

Endothelial dysfunction is a hallmark of type 2 diabetes mellitus (T2DM) and a major contributor to cardiovascular complications. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemic control and cardiovascular outcomes, the mechanisms linking GLP-1RA therapy, gut microbiome modulation, and endothelial function remain incompletely understood. In this study, we investigated whether the GLP-1RA liraglutide improves endothelial dysfunction in T2DM through microbiome-associated mechanisms that support vascular homeostasis. Male db/db mice and non-diabetic controls were treated with liraglutide (300 μg/kg/day, intraperitoneally) or saline for two weeks. Vascular function was assessed in mesenteric resistance arteries using wire myography. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose with or without liraglutide or the short chain fatty acid (SCFA), butyrate. Endothelial nitric oxide (NO) signaling was evaluated by eNOS (at Ser1177) phosphorylation and nitrite production. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Liraglutide significantly improved endothelium-dependent relaxation in db/db mice and restored high glucose-induced impairment of eNOS phosphorylation and NO production in HUVECs. In vivo , diabetes was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa. Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera, including Lachnospiraceae and Lactobacillus . Consistently, low-dose butyrate modestly enhanced NO production in endothelial cells. These findings support the concept of a GLP-1RA–microbiome–vascular axis, in which liraglutide-associated remodeling of the gut microbiota may contribute to improved endothelial NO signaling and vascular function in diabetes. © 2026 The Authors.