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

Liraglutide significantly improved endothelium-dependent relaxation in mesenteric resistance arteries of db/db mice.

• Male db/db mice and non-diabetic controls were treated with liraglutide at 300 μg/kg/day intraperitoneally or saline for two weeks.
• Vascular function was assessed in mesenteric resistance arteries using wire myography.
• Endothelium-dependent relaxation was impaired in diabetic db/db mice compared to non-diabetic controls, and liraglutide treatment restored this function.

Liraglutide restored high glucose-induced impairment of eNOS phosphorylation and nitric oxide production in HUVECs.

• Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose conditions with or without liraglutide.
• Endothelial NO signaling was evaluated by eNOS phosphorylation at Ser1177 and nitrite production.
• High glucose impaired eNOS phosphorylation and NO production, and liraglutide treatment reversed these effects.

Diabetes in db/db mice was associated with marked gut dysbiosis characterized by reduced alpha diversity and depletion of SCFA-producing taxa.

• Gut microbiota composition was analyzed by 16S rRNA gene sequencing.
• Diabetic db/db mice showed reduced alpha diversity compared to non-diabetic controls.
• SCFA-producing bacterial taxa were depleted in the diabetic gut microbiota.

Liraglutide treatment substantially restored microbial diversity and enriched beneficial genera including Lachnospiraceae and Lactobacillus in db/db mice.

• 16S rRNA gene sequencing was used to characterize gut microbiota composition after two weeks of liraglutide treatment.
• Liraglutide-treated db/db mice showed restoration of alpha diversity relative to saline-treated diabetic mice.
• Beneficial genera enriched by liraglutide included Lachnospiraceae and Lactobacillus, which are known SCFA-producing taxa.

Low-dose butyrate modestly enhanced nitric oxide production in endothelial cells.

• HUVECs were exposed to high glucose conditions with or without the short chain fatty acid butyrate.
• Butyrate treatment resulted in a modest enhancement of NO production in endothelial cells.
• This finding is consistent with the hypothesis that SCFA-mediated signaling may contribute to liraglutide's vascular effects.