Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat.
Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid peptide produced by K cells of the mammalian proximal small intestine and is a potent stimulant of insulin release in the presence of hyperglycemia. However, its relative physiological importance as a postprandial insulinotropic agent is unknown. Using LGIPR2 cells stably transfected with rat GIP receptor cDNA, GIP (1-42) stimulation of cyclic adenosine monophosphate (cAMP) production was inhibited in a concentration-dependent manner by GIP (7-30)-NH2. Competition binding assays using stably transfected L293 cells demonstrated an IC50 for GIP receptor binding of 7 nmol/liter for GIP (1-42) and 200 nmol/liter for GIP (7-30)-NH2, whereas glucagonlike peptide-1 (GLP-1) binding to its receptor on ++betaTC3 cells was minimally displaced by GIP (7-30)-NH2. In fasted anesthetized rats, GIP (1-42) stimulated insulin release in a concentration-dependent manner, an effect abolished by the concomitant intraperitoneal administration of GIP (7-30)-NH2 (100 nmol/ kg). In contrast, glucose-, GLP-1-, and arginine-stimulated insulin release were not affected by GIP (7-30)-NH2. In separate experiments, GIP (7-30)-NH2 (100 nmol/kg) reduced postprandial insulin release in conscious rats by 72%. It is concluded that GIP (7-30)-NH2 is a GIP-specific receptor antagonist and that GIP plays a dominant role in mediating postprandial insulin release.
Tseng
C C
CC
Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Kieffer
T J
TJ
Jarboe
L A
LA
Usdin
T B
TB
Wolfe
M M
MM
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005215:Fasting; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D014162:Transfection
D007328:Insulin; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D011994:Recombinant Proteins; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP