Liraglutide Increases Gastric Fundus Tonus and Reduces Food Intake in Type 2 Diabetic Rats

Background/Objectives: Incretin-based therapies have demonstrated benefits in glycemic control and the prevention of long-term complications of diabetes. In addition to glucose-dependent insulin secretion stimulation, glucagon-like peptide-1 (GLP-1) also inhibits gastric acid secretion, delays gastric emptying, inhibits gut motility and induces satiety. We aimed to understand the modulation of gastric fundus motility by GLP-1 receptor agonists (GLP-1RA). Methods: We have studied the relaxation to sodium nitroprusside (SNP) and noradrenaline (NA) of gastric fundus isolated from Wistar rats and Goto-Kakizaki (GK) rats, an animal model of spontaneous non-obese type 2 diabetes, after Liraglutide treatment (200 μg/kg s.c., b.i.d., 14 days). Results: Decreased relaxation induced by SNP and NA (0.01–889 μM) was observed in treated groups, with no significant changes in SNP maximum relaxation or in nNOS/p-nNOS levels between treated and non-treated rats of both animal models. Accordingly, in rat gastric fundus pre-contracted with 5 µM of carbachol, GLP-1RA (0.05–111.1 nM) induced contractile responses that were GLP-1R-dependent and -independent. Exenatide showed more intrinsic activity, while Liraglutide showed more potency than GLP-1 in Wistar rats. Moreover, GLP-1 showed more intrinsic activity in diabetic rats compared to control ones. Conclusions: Liraglutide-induced increased gastric muscle tone may contribute to the significant decrease in caloric intake and body weight in all treated rats, causing a reduction in gastric accommodation during food intake. Thus, the increased gastric fundus tone induced by GLP-1RA may constitute a peripheral mechanism by which they can reduce food intake and induce satiety.