title: Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets.
abstract: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by endocrine K-cells in response to nutrient absorption. This study has utilised numerous well-characterised dipeptidyl peptidase IV-resistant GIP analogues to evaluate the glucagonotropic actions of GIP in Wistar rats and isolated rat islets. Intraperitoneal administration of GIP analogues (25 nmol/kg body weight) in combination with glucose had no effect on circulating glucagon concentrations compared to controls in Wistar rats. However, plasma glucose concentrations were significantly (p<0.05 to p<0.001) lowered by the GIP-receptor agonists, N-AcGIP, GIP(Lys37)PAL and N-AcGIP(Lys37)PAL. The GIP antagonist, (Pro3)GIP, caused a significant (p<0.05) reduction in glucagon levels following concurrent administration with saline in Wistar rats. In isolated rat islets native GIP induced a significant (p<0.01) enhancement of glucagon release at basal glucose concentrations, which was completely annulled by (Pro3)GIP. Furthermore, glucagon release in the presence of GLP-1, GIP(Lys37)PAL, N-AcGIP(Lys37)PAL and (Pro3)GIP was significantly (p<0.05 to p<0.001) decreased compared to native GIP in isolated rat islets. These data indicate a modest effect of GIP on glucagon secretion from isolated rat islets, which was not observed in vivo. However, the GIP agonists N-AcGIP, GIP(Lys37)PAL and N-AcGIP(Lys37)PAL had no effect on glucagon release demonstrating an improved therapeutic potential for the treatment of type 2 diabetes.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: Roslyn S
authors.initials: RS
authors.lastname: Cassidy
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon