Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #43: Neuropeptides and Islet Hormone Secretion Part 2 of 5

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #43: Neuropeptides and Islet Hormone Secretion Part 2 of 5

Sep 27, 2016

Vasoactive intestinal polypeptide (VIP)

VIP was originally isolated from the porcine small intestine in the early 1970s and found to consist of 28 amino acid residues, with a C-terminal α-amidation showing structural similarities to other members of the glucagon superfamily of peptides [18]. VIP is formed by processing of 149-amino acid proVIP and is highly conserved as illustrated by human, porcine, and rat VIP increased glucose tolerance with a reduction of circulating glucose [22].


Two VIP binding receptors exist and because they also show affinity for pituitary adenylate cyclase-activating polypeptide (PACAP) they are called the VPAC1 and VPAC2 receptors (VPAC1R and VPAC2R) [23]. They are both G-protein-coupled receptors having seven transmembrane domains. In situ hybridization using probes for the messages of VPAC1R and VPAC2R has demonstrated that VPAC2R but not VPAC1R is expressed in rat and mouse islets as well as in insulin-producing clonal cells [24]. This suggests that it is VPAC2R that transmits the VIP signal to islet endocrine cells. Through activation of VPAC2R, VIP activates adenylate cyclase, which increases the formation of cyclic AMP (cAMP), as has been demonstrated in islet cells [25]. cAMP in turn activates PKA, which enhances exocytosis in both direct and indirect manners. VIP also stimulates glucagon secretion as demonstrated in several species [21]; however, the mechanism underlying the glucagonotropic action of VIP has not been established.

Pituitary adenylate cyclase-activating polypeptide (PACAP)

PACAP exists in two forms, 27 and 38 amino acids, both of which, like VIP, belong to the glucagon superfamily. VIP and PACAP show 68% identity. The C-terminal 11 amino acids of PACAP38 are cleaved to produce PACAP27, with the main form being PACAP38 [26]. PACAP is found mainly in nerves of the central nervous system, the lungs, and the gastrointestinal tract. It is also found in nerve terminals and their neuronal cell bodies in pancreatic ganglia, as demonstrated both in mice and rats [26]. The localization of PACAP to autonomic nerve terminals in humans has not yet been established. The islet PACAP nerves are thought to be mainly parasympathetic nerves, because PACAP is co-stored with VIP in some islet nerves, is released from the pancreas during electrical activation of the vagal nerves, and pancreatic PACAP content is reduced by vagotomy.

PACAP potently stimulates insulin secretion as demonstrated both in vivo and in vitro [21,26]. It also augments glucose-stimulated insulin secretion in healthy volunteers upon exogenous administration, showing that PACAP is an insulinotropic neuropeptide in humans [27]. PACAP stimulates insulin secretion in a glucose-dependent manner via activation of adenylate cyclase, increased formation of cAMP, and activation of PKA [26]. PACAP also increases the cytoplasmic concentration of calcium and sodium through opening of membranous calcium and sodium channels, and stimulates a distal effect on the exocytosis machinery. The potency of PACAP to stimulate insulin secretion, which exceeds that of VIP, is likely due to the diversity of intracellular signals it activates to stimulate islet β cells.

There is a close relation between PACAP and VIP, which is evident by the structural similarity of the peptides and by the affinity of both peptides for VPAC1R and VPAC2R. However, PACAP also stimulates a third subtype of receptors, which is specific for PACAP.This receptor, the PAC1 receptor (PAC1R), like the two VPAC receptors, is G-protein-coupled and has seven transmembrane domains [23]. Gene expression and in situ hybridization studies have shown that PAC1 receptors and VPAC2 receptors are expressed in islets [26]. To study the physiology of PACAP, PAC1R knockout mice have been made [28]. These mice are viable, develop normally and have normal baseline glucose and insulin levels as well as normal pancreatic insulin content. The insulin response to PACAP is reduced by 50% in PAC1R knockout mice, showing that a main mediator of the PACAP-induced insulin secretion is the PAC1 receptor. A most interesting phenotype in the PAC1R-deleted mice is that they exhibit an impaired insulin response to glucose, both in vivo and in vitro. This suggests that PAC1R contributes both to PACAP- and glucose-induced insulin secretion, that is, PACAP is of physiologic importance for glucose-stimulated insulin secretion. In regard to these PAC1R-deleted mice, it is important to remember that expression of VPAC1R and VPAC2R is still intact, which likely allows PACAP to still exert some stimulation of insulin release and may explain why PACAP-induced insulin secretion is not abolished, but reduced only by approximately 50% in the PAC1R-deficient mice. Therefore, studies on VPAC1R- and VPAC2R-deleted mice are important for a more complete understanding of the insulinotropic role of PACAP. PACAP knockout mice are unlikely to be useful in this regard since they exhibit high mortality and have a marked psychomotor phenotype although their islet function has not been studied [26].

Because of its localization to parasympathetic nerves in the pancreas and release from the pancreas after vagal nerve activation as well as its potent stimulation of insulin secretion, PACAP may be of physiologic relevance for neural regulation of islet function before and during meals. Results showing that the insulin response to oral glucose in mice is inhibited by a PACAP receptor antagonist and impaired in PAC1R-deleted mice support this hypothesis [26,28]. However, further studies are needed to determine its exact role.

PACAP has also been shown to stimulate glucagon secretion in several species, including  humans [21,26,27]. It therefore mimics both the stimulation of insulin and glucagon secretion induced by parasympathetic nerve activation. The glucagon response to insulin-induced hypoglycemia has also been shown to be impaired in mice with genetic deletion of PAC1 receptors [29], which may suggest that PACAP contributes to neurally induced glucagon counterregulation.

Parasympathetic effects and mediation

As reviewed earlier, activation of the parasympathetic nerves stimulates both insulin and glucagon secretion, and this may be of particular relevance for the cephalic and early meal phases of insulin secretion as well as for the glucagon response to hypoglycemia. These effects may be mediated by the classical neurotransmitter acetylcholine and by the neuropeptides confined to these nerves (GRP, VIP, and PACAP). These four neurotransmitters are all potent stimulators of insulin and also, with the exception of GRP, glucagon secretion, and therefore mimic effects of parasympathetic activation on islet hormone secretion. In classical neurobiology, several criteria need to be met before a candidate neurotransmitter, such as these neuropeptides, can be proven to be a physiologic neurotransmitter [30] (Table 9.1).


These criteria include that the potential neurotransmitter is localized to the nerves, is released by activation of the nerves, its effects mimic that of the nerves and that inhibition of its effect alters the responses to nerve activation. Some of these criteria have been met for GRP, VIP, and PACAP, and therefore some of them are strong candidates for physiologic neurotransmitters (see Table 9.2).


Currently, convincing evidence has been presented for VIP and PACAP and evidence also exists for GRP. However, further studies are still required to firmly establish the involvement of GRP, VIP, and PACAP in parasympathetic control of islet function.

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