PAC1 receptor-deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a ubiquitous neuropeptide of the vasoactive intestinal peptide (VIP) family that potentiates glucose-stimulated insulin secretion. Pancreatic beta cells express two PACAP receptor subtypes, a PACAP-preferring (PAC1) and a VIP-shared (VPAC2) receptor. We have applied a gene targeting approach to create a mouse lacking the PAC1 receptor (PAC1(-/-)). These mice were viable and normoglycemic, but exhibited a slight feeding hyperinsulinemia. In vitro, in the isolated perfused pancreas, the insulin secretory response to PACAP was reduced by 50% in PAC1(-/-) mice, whereas the response to VIP was unaffected. In vivo, the insulinotropic action of PACAP was also acutely reduced, and the peptide induced impairment of glucose tolerance after an intravenous glucose injection. This demonstrates that PAC1 receptor is involved in the insulinotropic action of the peptide. Moreover, PAC1(-/-) mice exhibited reduced glucose-stimulated insulin secretion in vitro and in vivo, showing that the PAC1 receptor is required to maintain normal insulin secretory responsiveness to glucose. The defective insulinotropic action of glucose was associated with marked glucose intolerance after both intravenous and gastric glucose administration. Thus, these results are consistent with a physiological role for the PAC1 receptor in glucose homeostasis, notably during food intake.
Jamen
F
F
Unité Propre de Recherche (UPR9023) Centre National de la Recherche Scientifique, Montpellier, France.
Persson
K
K
Bertrand
G
G
Rodriguez-Henche
N
N
Puech
R
R
Bockaert
J
J
Ahrén
B
B
Brabet
P
P
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D000242:Cyclic AMP / Q000032:analysis; D005260:Female; D005934:Glucagon / Q000097:blood; D018149:Glucose Intolerance / Q000209:etiology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood*; D051379:Mice; D008817:Mice, Mutant Strains; D009479:Neuropeptides / Q000494:pharmacology*; D010179:Pancreas / Q000378:metabolism; D010477:Perfusion; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000172:deficiency*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
C495402:Adcyap1 protein, mouse; C495504:Adcyap1r1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C495510:Vipr2 protein, mouse; D014660:Vasoactive Intestinal Peptide; D005934:Glucagon; D000242:Cyclic AMP