Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide.
Glucagon-like peptide 1 (7-37)/(7-36) amide (GLP-1) is derived from the intestinal proglucagon processing. It is considered an important insulin-releasing gut hormone. This study uses exendin (9-39) amide as a GLP-1 receptor antagonist to evaluate the contribution of GLP-1 to the incretin effect. Anesthetized rats were challenged by an intraduodenal glucose infusion to evaluate maximally occurring GLP-1 and gastric inhibitory polypeptide (GIP) plasma levels. Maximal immunoreactive (IR) GLP-1 plasma levels amounted to 10 pmol/l (IR-GIP 11 pmol/l). Exendin (9-39) amide abolished the insulin-stimulatory effect of 60 pmol of GLP-1 or of the GLP-1 agonist exendin-4 (0.5 nmol) injected as bolus, respectively. An intravenous bolus injection of 5.94 nmol of exendin (9-39) amide 3 min before enteral glucose infusion grossly reduced the total insulin secretory response (by 60%) and significantly increased circulating blood glucose levels (P < 0.05). In contrast, the GLP-1 antagonist left the insulin response after an intravenous glucose or glucose plus GIP (60 pmol) load unaltered. Our data support the concept that GLP-1 is an important incretin factor. Exendin (9-39) amide is a useful GLP-1 antagonist for in vivo studies.
Kolligs
F
F
Department of Internal Medicine, Philipps University of Marburg, Germany.
Fehmann
H C
HC
Göke
R
R
Göke
B
B
D000818:Animals; D004347:Drug Interactions; D000077270:Exenatide; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000494:pharmacology / Q000502:physiology; D005934:Glucagon / Q000097:blood / Q000494:pharmacology / Q000502:physiology; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D011498:Protein Precursors / Q000097:blood / Q000494:pharmacology / Q000502:physiology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D014688:Venoms
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; C055453:glucagon-like peptide 1 (7-36)amide; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D005947:Glucose