Gene Deletion of the PACAP/VIP Receptor, VPAC2R, Alters Glycemic Responses During Metabolic and Psychogenic Stress in Adult Female Mice

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. These opposing actions need further characterization, as does the role of VIP receptor 2 (VPAC2R) in the regulation of glucose metabolism. In this study, we examined the participation of VPAC2R on basal glycemia, fasted glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/-) female mice. The mean basal glycemia was significantly greater in Vipr2-/- in the fed state and after an 8h overnight fast as compared to wildtype (WT) mice. Insulin tolerance testing following a 5h fast (morning fast, 0.38 U/kg) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg), Vipr2-/- females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal in Vipr2-/-, but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate the action of upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels in Vipr2-/- mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling in Vipr2-/-: upregulated medullary tyrosine hydroxylase (Th) and downregulated hypothalamic Vip. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.