TY - JOUR
T1 - Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets
AU - Cassidy, Roslyn S.
AU - Irwin, Nigel
AU - Flatt, Peter
PY - 2008/2
Y1 - 2008/2
N2 - 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(Lys(37)) PAL and N-AcGIP(Lys(37))PAL. The GIP antagonist, (Pro(3))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 (Pro(3))GIP. Furthermore, glucagon release in the presence of GLP-1, GIP(Lys(37))PAL, N-AcGIP(Lys(37)) PAL and (Pro(3))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(Lys(37))PAL and N-AcGIP(Lys(37))PAL had no effect on glucagon release demonstrating an improved therapeutic potential for the treatment of type 2 diabetes.
AB - 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(Lys(37)) PAL and N-AcGIP(Lys(37))PAL. The GIP antagonist, (Pro(3))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 (Pro(3))GIP. Furthermore, glucagon release in the presence of GLP-1, GIP(Lys(37))PAL, N-AcGIP(Lys(37)) PAL and (Pro(3))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(Lys(37))PAL and N-AcGIP(Lys(37))PAL had no effect on glucagon release demonstrating an improved therapeutic potential for the treatment of type 2 diabetes.
U2 - 10.1515/BC.2008.019
DO - 10.1515/BC.2008.019
M3 - Article
SN - 1437-4315
VL - 389
SP - 189
EP - 193
JO - Biological Chemistry
JF - Biological Chemistry
IS - 2
ER -
