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The gut hormones GLP-1 and GIP are the major incretins responsible for insulin secretion by the pancreas in response to food ingestion. But insulin response is rapid in response to meals and a neural contribution is likely. The cephalic phase of insulin secretion which occurs in the pre-absorptive stage, Am J Physiol.1982 Apr;242(4):E280-5.    is thought to be mediated by the vagus through cholinergic fibres. While acetyl choline is the major neurotransmitter, other neurotransmitters have also been described to be released from the post ganglionic nerve cells in the pancreatic ganglia, namely VIP and PACAP ( Pancreatic Adenylate Cyclase Activating Polypeptide), both of which stimulate insulin in a glucose dependent manner. Regul Pept. 1998 Jun 30;74(2-3):167-75.

PACAP is a neuropeptide belonging  to the secretin-glucagon-VIP family of peptides, and thought to play a role in the neural regulation of insulin  and glucagon secretion. Regul Pept. 1998 Jun 30;74(2-3):167-75.   PACAP was originally isolated from the hypothalamus Biochem Biophys Res Commun. 1989 Oct 16;164(1):567-74.  , but  seems to be ubiquitously distributed in the central nervous system and peripheral neurones  supplying various organs including the adrenals, GIT, blood vessels, and the respiratory tract. Neuroscience. 1993 Dec;57(3):725-32.The highest density of PACAP in the human brain is in the dorsal vagal complex, the median eminence-pituitary stalk and the peri and paraventricular hypothalamic nuclei.   Brain Res. 1995 Nov 13;699(1):116-20.   PACAP has been described in the pancreatic neurones where it is colocalized with VIP in the pancreatic ganglia governing the action of parasympathetic, cholinergic nerves, Am J Physiol. 1997 Aug;273(2 Pt 1):G436-46   but not in the pancreatic endocrine cells. Regul Pept. 1998 Jun 30;74(2-3):167-75  suggesting that it may function purely as a neurotransmitter in this organ. Despite this, solitary non-reproduced evidence is present in literature for its presence in islet cells as well,   J Physiol.1997 Dec 1;505 ( Pt 2):319-28.  and hence further clarification with immunocytochemistry is awaited.      The fact that PACAP  is co-localised with CGRP and substance P, and the fact that its concentration is markedly reduced by the sensory neurotoxin capsaicin Ann N Y Acad Sci. 1998 Dec 11;865:542-6.  could suggest a sensory role for this neurotransmitter.  It has multiple functions other than being a neurotransmitter in the hypothalamus. It acts as a hormone, vasodilator, neurotrophin and neuromodulator.


PACAP receptors and degradation

Two forms of the peptide have been described, namely PACAP-38 and   PACAP-27.    Jpn J Physiol. 1998 Oct;48(5):301-31.   PACAP 38 seems to be the predominant form in most tissues. PACAP is highly conserved between species, with PACAP 27 having 68% homology with VIP. A PACAP related peptide has also been described although its function remains unknown. DNA Cell Biol. 1992 Jan-Feb;11(1):21-30.   PACAP-38 is tightly bound to ceruloplasmin in circulation making estimations of PACAP levels difficult presently but the total levels of PACAP is very likely low at <10 pmol/L with rapid degradation and clearance from circulation with a circulating half life of <1 minute. J Clin Endocrinol Metab. 1997 Sep;82(9):3093-8.   PACAP is degraded by DPP-IV enzyme which also inactivates GLP-1, GLP-2, oxyntomodulin, and Neuropeptide Y. Peptides. 2006 Jan 5;   Three receptors have been identified for PACAP, namely PAC1-R,  VPAC1-R, and VPAC2-R.  Pharmacol Rev. 1998 Jun;50(2):265-70.   PAC1 and VPAC2 seem to be the main receptors in the pancreas. 

PACAP Actions

PACAP-38 is the major form in the pancreas with distribution in the nerve fibres of the exocrine and endocrine pancreas as well as pancreatic ganglia. PACAP seems to be a parasympathetic neurotransmitter as evidenced by its increased release on vagal electrical stimulation, and reduction by vagotomy.  Am J Physiol.1997 Aug;273(2 Pt 1):G436-46   It also has a sensory neurotransmitter role as described above. Both PACAP27 and PACAP38 dose-dependently and equipotently stimulates insulin secretion in isolated mouse and rat islets.  Regul Pept. 1998 Jun 30;74(2-3):167-75.  
Over-expression of PACAP in transgenic mouse pancreatic {beta}-Cells has been shown to enhance insulin secretion with amelioration of Streptozotocin-induced Diabetes.  Diabetes. 2003 May;52(5):1155-62.  Another approach with PAC1-R knock out mice show a 50% reduction in PACAP induced insulin secretion.  Despite PAC1-R knock out, the mice showed normal development and normal glucose and insulin levels although PACAP-mediated insulin stimulation in the presence of glucose was halved. J Clin Invest. 2000 May;105(9):1307-15.   This potentially questions the physiological role of PACAP in normal insulin secretion and glucose homeostasis, although preservation of some action of PACAP could be due to presence of VPAC1-R and VPAC2-R receptors in these PAC1-R knock outs. It is crucial that since PACAP is a neurotransmitter in pancreatic nerves, in vitro studies with PACAP administration are interpreted based on innervation J Biol Chem. 1994 Jan 14;269(2):1290-3.   or denervation of the islets,   Regul Pept. 1998 Jun 30;74(2-3):167-75,   Biochem Biophys Res Commun. 1999 Mar 24;256(3):664-7.   as this could greatly vary the responses obtained. In rodents and other animals, PACAP, (PACAP38  and PACAP27) and VIP demonstrates similar potency in stimulation of insulin release from the pancreas.  Am J Physiol. 1998 May;274(5 Pt 1):E834-42.
PACAP and Insulinotropism

PACAP increases cAMP levels in insulin producing beta cells. Endocrinology. 1996 Jul;137(7):2791-8.  Protein Kinase A inhibitors (H89) inhibits PACAP-mediated insulin secretion.  Pharmacol Rev. 2000 Jun;52(2):269-324.  But the PKC-IP3 pathway seems to be less relevant as demonstrated by studies using down-regulation of PKC,  J Biol Chem. 1996 Jan 19;271(3):1660-8    although a differential contribution of the various pathways to early vs late response of insulin is possible.  PACAP has vasodilatory functions in the pancreas as elsewhere  Regul Pept. 1996 Jul 5;63(2-3):123-8   but the  contribution of this effect to islet hormone secretion is not clear.

In humans, synthetic human PACAP27 administered intravenously as an infusion at the rate of 3 pmol/kg/min increased basal levels of insulin, C peptide, and glucagon without significantly influencing basal glucose. J Clin Endocrinol Metab. 1997 Sep;82(9):3093-8. In the same study, co-infusion of glucose with synthetic human PACAP 27, resulted in significantly higher stimulation of insulin secretion compared to saline and glucose, without alteration of hepatic extraction. PACAP infusion increased serum insulin levels in overnight-fasted healthy humans with improved insulin and C-peptide responses to an intravenous glucose challenge.  The dosing of PACAP was restricted by flushing due to its vasodilatory properties,  J Cardiovasc Pharmacol. 1992 Jul;20(1):83-7. with associated blood pressure reductions of up to 10 mmHg.  Over and above hormonal regulation, PACAP seems to have effects on the transcription of insulin genes, glucose transporter genes and hexokinase genes which could have potential beneficial long term implications. Endocrinology. 1999 Dec;140(12):5530-7.  In addition to insulin secretion stimulation, PACAP stimulates glucagon secretion from the pancreas in invitro rat studies  Cell Tissue Res. 1992 Aug;269(2):275-9.   as well as in humans, J Clin Endocrinol Metab. 1997 Sep;82(9):3093-8,   -an effect that is glucose dependent, demonstrated by reduction in glucagon secretion stimulation on glucose infusion.  It is thought that PACAP may  regulate the glucagon response to hypoglycaemia which is parasympathetic mediated, Diabetes.1998 Jul;47(7):995-1005.  supported by the fact that PAC1-R knock out mice show impaired glucose recovery after insulin induced hypoglycaemia.   Diabetes.2001 Sep;50(9):1959-69.   Whether the actions on islet hormones is mediated directly through receptors in the pancreatic nerves or centrally via hypothalamus (autonomic control) remains to be clarified.

Despite increasing insulin release, PACAP does not seem to reduce glucose levels. Glucagon release is also stimulated by PACAP, but this may not be the contributor to anti-insulin action,  as no  glucagon rise is seen with intravenous glucose infusions. It is possible that PACAP itself decreases insulin sensitivity although studies on glucose uptake in fat cells do not support this. Peptides. 1999;20(8):943-8.  It is possible that PACAP stimulates epinephrine secretion leading onto decreased insulin sensitivity, Am J Physiol. 1998 May;274(5 Pt 1):E834-42   with increased hepatic glucose output through glycogenolysis.  Adrenalectomised animals show improvement of glucose levels with PACAP infusion,    Ann N Y Acad Sci. 2000;921:251-8. further supporting the role of catecholamines (epinephrine) in decreasing insulin sensitivity on PACAP infusion. The insulinotropic actions of PACAP may have implications for diabetes treatment.
PACAP- Other Actions

PACAP increases release of GH and ACTH from the pituitary. Endocr Rev. 1996 Feb;17(1):4-29.    In the adrenals, apart from the indirect action through stimulation of ACTH, PACAP directly stimulates synthesis and release of epinephrine possibly mediated through PAC1-R receptors.  Jpn J Physiol. 1998 Oct;48(5):301-31.  PACAP seems to produce relaxation of the smooth muscles of the stomach and intestines in rats, Ann N Y Acad Sci. 1996 Dec 26;805:364-78.    with inhibition of gastric acid secretion. Regul Pept. 1992 Apr 9;38(3):199-206.     Hepatic glucose output may be increased through glycogenolysis in rodents.  Peptides. 1995;16(1):55-60.    In blood vessels of healthy humans, PACAP produces vasodilation    J Cardiovasc Pharmacol. 1992 Jul;20(1):83-7.  with greater durability of effect than VIP and CGRP.

PACAP- the future

 Despite knowledge regarding the potential actions of PACAP under varying experimental conditions, its physiological role in the different organs in humans remains to be fully clarified. A role for PACAP in the regulation of ADH response to dehydration has also been suggested since prolonged dehydration increases immunoreactivity for PACAP-27, PACAP-38, and the type I PACAP receptor in the supraoptic nucleus of rats. Endocrinology. 2006 Feb;147(2):791-803.  PACAP seems to have neuromodulatory and anti-inflammatory activity. The expression of PACAP receptors in immune cells and the demonstration of modulation of immune responses in PACAP receptor knock outs suggests the potential for PACAP (and VIP) in the treatment of inflammatory diseases as Crohn's disease, Rheumatoid arthritis and multiple sclerosis.  Curr Top Med Chem. 2006;6(2):151-63. Daily injections of PACAP improve glycaemia in diabetic rats, and rats with impaired glucose tolerance.  Ann N Y Acad Sci. 2000;921:259-63.   A linkage has also been identified between the chromosomes where the genes for PACAP and type 2 diabetes are located.   Diabetes. 2001 Mar;50(3):675-80.   PACAP may thus turn out to have implications in treatment of type 2 diabetes, although  a demonstration of improved glycaemia with PACAP still remains unrealised. Peptides. 2006 Jan 5;