Metabolic effects of sub-chronic ablation of the incretin receptors by daily administration of (Pro3)GIP and exendin(9-39)amide in obese diabetic (ob/ob) mice.
Effects of chemical ablation of the GIP and GLP-1 receptors on metabolic aspects of obesity-diabetes were investigated using the stable receptor antagonists (Pro3)GIP and exendin(9-39)amide. Ob/ob mice received a daily i.p. injection of saline vehicle, (Pro3)GIP, exendin(9-39)amide or a combination of both peptides over a 14-day period. Non-fasting plasma glucose levels were significantly (p<0.05) lower in (Pro3)GIP-treated mice compared to control mice after just 9 days of treatment. (Pro3)GIP-treated mice also displayed significantly lower plasma glucose concentrations in response to feeding and intraperitoneal administration of either glucose or insulin (p<0.05 to p<0.001). The (Pro3)GIP-treated group also exhibited significantly (p<0.05) reduced pancreatic insulin content. Acute administration of exendin(9-39)amide immediately prior to re-feeding completely annulled the beneficial effects of sub-chronic (Pro3)GIP treatment, but non-fasting concentrations of active GLP-1 were unchanged. Combined sub-chronic administration of (Pro3GIP) with exendin(9-39)amide revealed no beneficial effects. Similarly, daily administration of exendin(9-39)amide alone had no significant effects on any of the metabolic parameters measured. These studies highlight an important role for GIP in obesity-related forms of diabetes, suggesting the possible involvement of GLP-1 in the beneficial actions of GIP receptor antagonism.
Parker
Jeremy C
JC
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
Irwin
Nigel
N
Lavery
Kerry S
KS
Green
Brian D
BD
O'Harte
Finbarr P M
FP
Gault
Victor A
VA
Flatt
Peter R
PR
D000818:Animals; D001786:Blood Glucose / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage*; D000067757:Glucagon-Like Peptide-1 Receptor; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011964:Receptors, Gastrointestinal Hormone / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor