Therapeutic potential of vasoactive intestinal peptide and its receptor VPAC2 in type 2 diabetes

Abstract

Owing to the increasing prevalence of type 2 diabetes, the development of novel hypoglycemic drugs has become a research hotspot, with the ultimate goal of developing therapeutic drugs that stimulate glucose-induced insulin secretion without inducing hypoglycemia. Vasoactive intestinal peptide (VIP), a 28-amino-acid peptide, can stimulate glucose-dependent insulin secretion, particularly by binding to VPAC2 receptors. VIP also promotes islet β-cell proliferation through the forkhead box M1 pathway, but the specific molecular mechanism remains to be studied. The clinical application of VIP is limited because of its short half-life and wide distribution in the human body. Based on the binding properties of VIP and VPAC2 receptors, VPAC2-selective agonists have been developed to serve as novel hypoglycemic drugs. This review summarizes the physiological significance of VIP in glucose homeostasis and the potential therapeutic value of VPAC2-selective agonists in type 2 diabetes.

Gene deletion of the PACAP/VIP receptor, VPAC2R, alters glycemic responses during metabolic and psychogenic stress in adult female mice

“…To determine if the metabolic profiles in Vipr2 VPAC2R contributes to physiological responses to metabolic and psychogenic challenges in several ways. Our results support previous studies emphasizing that VPAC2R agonists may be leveraged as attractive drug candidates for the treatment of diabetes 21,23,28,30,82 and stress-related psychopathologies. [83][84][85] 4.1 | Strengths and limitations to the study…”

“…It is unlikely that impaired hypoglycemia during insulin challenge was a direct result of loss of VPAC2R function, since activation of VPAC2 receptors does not inhibit hepatic glycogenolysis and secretion of the glycogenolytic hormone glucagon 28 . In fact, because of their inability in this process, in conjunction with their insulinotropic action, VPAC2 receptors are studied for their potential as a novel target for the treatment of T2D 28,30 . More likely is the possibility that, in the absence of VPAC2R in our mutant mice, PACAP‐ or VIP‐mediated activation of the preserved and unchallenged VPAC1 and/or PAC1 receptors, respectively, can promote glucose output via direct hepatic glycogenolytic effects and/or indirectly by stimulating pancreatic secretion of glucagon to counter insulin action 26,27,75 .…”

“…[26][27][28][29] These counterregulatory responses produced by PACAP and VIP include direct hepatic effects but also indirect effects via secretion of the glycogenolytic hormones, glucagon and epinephrine. 26,27,30 In combination, previous research reports demonstrate that VIP and PACAP and their receptors have complex actions on glucose metabolism. Importantly, VIP derivatives that selectively bind to VPAC2R are promising hypoglycemic drugs that act to promote glucose-stimulated insulin secretion and enhance glucose disposal.…”

“…28 In fact, because of their inability in this process, in conjunction with their insulinotropic action, VPAC2 receptors are studied for their potential as a novel target for the treatment of T2D. 28,30 More likely is the possibility that, in the absence of VPAC2R in our mutant mice, PACAP-or VIP-mediated activation of the preserved and unchallenged VPAC1 and/or PAC1 receptors, respectively, can promote glucose output via direct hepatic glycogenolytic effects and/or indirectly by stimulating pancreatic secretion of glucagon to counter insulin action. 26,27,75 Indeed, deletion of the PAC1R gene produces impaired but viable insulin-induced hypoglycemia and impaired secretion of glucagon.…”

“…Indeed, PACAP and VIP application can trigger hepatic glycogenolysis and gluconeogenesis via VPAC receptors 26–29 . These counterregulatory responses produced by PACAP and VIP include direct hepatic effects but also indirect effects via secretion of the glycogenolytic hormones, glucagon and epinephrine 26,27,30 . In combination, previous research reports demonstrate that VIP and PACAP and their receptors have complex actions on glucose metabolism.…”