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 th e intestinal proglucagon processing. It is considered an important ins ulin-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 intraduodena l glucose infusion to evaluate maximally occurring GLP-1 and gastric i nhibitory polypeptide (GIP) plasma levels. Maximal immunoreactive (IR) GLP-1 plasma levels amounted to 10 pmol/l (IR-GZP 11 pmol/l). Exendin (9-39) amide abolished the insulin-stimulatory effect of 60 pmol of G LP-1 or of the GLP-1 agonist exendin-4 (0.5 nmol) injected as bolus, r espectively. An intravenous bolus injection of 5.94 nmol of exendin (9 -39) amide 3 min before enteral glucose infusion grossly reduced the t otal insulin secretory response (by 60%) and significantly increased c irculating blood glucose levels (P < 0.05). In contrast, the GLP-1 ant agonist left the insulin response after an intravenous glucose or gluc ose plus GIP (60 pmol) load unaltered. Our data support the concept th at GLP-1 is an important incretin factor. Exendin (9-39) amide is a us eful GLP-1 antagonist for in vivo studies.