Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets

Roslyn S. Cassidy, Nigel Irwin, Peter Flatt

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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(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.
LanguageEnglish
Pages189-193
JournalBiological Chemistry
Volume389
Issue number2
DOIs
Publication statusPublished - Feb 2008

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Gastric Inhibitory Polypeptide
Glucagon
Hyperglycemia
Wistar Rats
Glucose
Dipeptidyl Peptidase 4
Incretins
Glucagon-Like Peptide 1
Endocrine Cells
Type 2 Diabetes Mellitus

Cite this

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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(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.",
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AU - Cassidy, Roslyn S.

AU - Irwin, Nigel

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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.

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