Pharmacological stimulation of serotonin 5-HT1B receptors enhances increases in plasma active glucagon-like peptide-1 levels induced by dipeptidyl peptidase-4 inhibition independently of feeding in mice

Aim: Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L cells in response to nutrient ingestion. Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the active form of GLP-1 to an inactive form in the bloodstream. The present study aimed to investigate the role of serotonin (5-HT)1B receptors in the regulation of plasma active GLP-1 levels and glucose tolerance under DPP-4 inhibition. Methods: C57BL6J mice treated with or without alogliptin, a highly selective DPP-4 inhibitor, for 4 days were intraperitoneally injected with either saline, the 5-HT1B/2C receptor agonist meta-chlorophenylpiperazine (mCPP) at 2.5. mg/kg and 5. mg/kg or the selective 5-HT1B receptor agonist CP94253 at 2.5. mg/kg and 5. mg/kg, and food-deprived after treatment. An hour later, plasma active GLP-1 levels were determined. Also, a glucose tolerance test was done by injecting d-glucose (2. g/kg) following the injection of saline or CP94253 (5. mg/kg) in mice treated with alogliptin. Results: Intraperitoneal injection of mCPP (2.5 and 5. mg/kg) or CP94253 (2.5 and 5. mg/kg) in mice treated with alogliptin for 4 days significantly increased plasma active GLP-1 levels compared with saline controls in mice that were food-deprived after the injections. While intraperitoneal injection of either mCPP or CP94253 alone had no significant effect on plasma active GLP-1 levels, the injection of CP94253 improved glucose tolerance in mice treated with alogliptin compared with saline. Conclusion: These findings suggest that pharmacological stimulation of 5-HT1B receptors enhances the increases in plasma active GLP-1 induced by DPP-4 inhibition independently of feeding and also improves glucose tolerance in mice.