Therapeutic strategies targeting the incretin system are effective in treating type 2 diabetes. GLP-1 receptor agonists (GLP-1RA) reduce post-prandial glucose levels by stimulating insulin and inhibiting glucagon release, but also by reducing gastric motility. Although GLP-1RA reduce gastric motility initially, their ability to sustain this over the long-term is reduced and the mechanism(s) underlying this change is not known. GLP-1R are expressed in neurons of the nucleus of the solitary tract (NTS) which play a fundamental role in regulating metabolism and gastric motility. Here, we examined whether long-term use of GLP-1RA alters GLP-1R expression in the NTS that can influence gastric motility. C57BL6 mice were treated with either saline, lixisenatide, liraglutide or exenatide ER, for 2hrs, 1d, 1wk, 2wks, 4wks or 6wks before their effects on gastric motility and NTS GLP-1R mRNA expression were evaluated. All GLP-1RA effectively slowed gastric emptying in the early stages of treatment, but within 1-2wks, their efficacy waned. By 4-6wks, no significant reduction in gastric motility was observed with any of the agonists. Of note, we observed a decline in GLP-1R mRNA expression in the NTS at 1-2wks of treatment which corresponded to the initial decline in drug efficacy. At 4wks, however, GLP-1R mRNA levels returned to pretreatment levels and suppression of gastric motility was no longer observed. To test whether the decrease in NTS GLP-1R expression contributed to attenuating the suppressive effects on gastric motility, we knocked down GLP-1R expression in the NTS using an adeno-associated viral vector to express a shRNA against the GLP-1R. Reducing NTS GLP-1R expression prevented the suppressive effects of lixisenatide on gastric motility, suggesting in mice, a decrease in NTS GLP-1R expression may contribute to the initial decrease in GLP-1RA efficacy, whereas receptor desensitization may play a more dominant role in the latter stages.
P. Wang: None. R. Mamillapalli: None. W. Zhu: None. O. Chan: None.