PAC1 receptor–deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance
Françoise Jamen, Kristin Persson, Gyslaine Bertrand, Nieves Rodriguez-Henche, Raymond Puech, Joël Bockaert, Bo Ahrén, Philippe Brabet
Françoise Jamen, Kristin Persson, Gyslaine Bertrand, Nieves Rodriguez-Henche, Raymond Puech, Joël Bockaert, Bo Ahrén, Philippe Brabet
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Article

PAC1 receptor–deficient mice display impaired insulinotropic response to glucose and reduced glucose tolerance

Abstract

Pituitary adenylate cyclase–activating polypeptide (PACAP) is a ubiquitous neuropeptide of the vasoactive intestinal peptide (VIP) family that potentiates glucose-stimulated insulin secretion. Pancreatic β 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.

Authors

Françoise Jamen, Kristin Persson, Gyslaine Bertrand, Nieves Rodriguez-Henche, Raymond Puech, Joël Bockaert, Bo Ahrén, Philippe Brabet

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Genetic inactivation of the PAC1 gene. (a) Genomic organization of the m...
Genetic inactivation of the PAC1 gene. (a) Genomic organization of the mouse PAC1 receptor gene. Exons are represented by boxes, with open boxes for untranslated sequences and filled boxes for translated sequences. The numbers beneath indicate exon numbering. (b) Genomic structure of wild-type and targeted PAC1 alleles and the targeting vector. Primers (p7, p8, and pNeo) used for PCR analysis, 5′ probe used for Southern blot analysis, and expected NcoI restricted fragment sizes of the wild-type and mutated alleles are indicated. (c) Southern blot analysis of the NcoI-digested DNA from tail biopsies of wild-type (PAC1+/+) mice, PAC1+/– mice, and PAC1–/– mice. (d) PCR analysis of DNA from tail biopsies of wild-type mice, PAC1+/– mice, and PAC1–/– mice. wt, wild-type; mut, mutant.