Sympathetic effects and mediation
Sympathetic nerves inhibit insulin and stimulate glucagon secretion. Their activation may help mediate stress-induced changes in islet hormone secretion including the glucagon counterregulatory response to hypoglycemia.These effects may be mediated by the combination of the classical neurotransmitter noradrenaline and the sympathetic neuropeptides (galanin and NPY). All three neurotransmitters can inhibit insulin and stimulate glucagon secretion, thus mimicking the effects of sympathetic activation on islet hormone secretion. In addition, galanin and NPY meet several other of the criteria needed to be classified as a physiologic neurotransmitter (see  and Tables 9.1 and 9.3).
Islet sensory neuropeptides
Islets are innervated by sensory, as well as autonomic, nerves. Some sensory nerves, usually the pain fibers, contain the neuropeptides calcitonin gene-related peptide (CGRP) and substance P [1,44,45], which allows their localization by immunocytochemistry. These sensory islet nerves innervate mainly the peripheral portions of islets. They travel with the sympathetic nerves from the pancreas, reaching the spinal cord By way of the splanchnic nerves.The neurotoxin capsaicin causes deafferentation of small unmyelinated C-fibers and a substantial reduction of the number of islet CGRP nerves and a more moderate reduction of the number of islet substance P nerves . Such chronic sensory denervation studies have shown that insulin secretion and glucose elimination are both increased in mice  and in Zucker diabetic fatty rats , suggesting that these sensory nerves tonically inhibit insulin secretion.
Calcitonin gene-related polypeptide (CGRP)
CGRP was originally described in a medullary thyroid carcinoma cell line, where it was found to be encoded in the same gene as calcitonin [45,48]. This gene, which is called the calcitonin complex gene A (CALCA) encodes for two different mRNAs, one that is translated to preprocalcitonin and the other translated to the 128-amino acid prepro CGRP, which is further processed to α-CGRP. Later, another gene was described, named calcitonin complex gene B (CALCB), which encodes for β-CGRP. The α and β CGRPs are both 37-amino acid peptides and have a high degree of homology with each other and with islet amyloid polypeptide (IAPP) and adrenomedullin . CGRP is localized both to the central and peripheral nervous systems. In the latter, it is largely found in sensory nerves. In the pancreas, CGRP nerves are scattered throughout the parenchyma, with particular density along small blood vessels and within islets where neurotransmitter release sites are in close apposition to the endocrine cells , suggesting an islet action. Exogenous administration of CGRP inhibits insulin secretion and in isolated islets, this inhibition is accompanied by reduction of the formation of cAMP which is prevented by pertussis toxin and therefore most likely mediated by an inhibitory Gi-protein .
CGRP, as well as IAPP, calcitonin, and adrenomedullin, can act through either the calcitonin receptor-like receptor (CRLR) or the calcitonin receptor (CTR). The affinity of these receptors for the different ligands is regulated: three different receptor activity-modifying proteins (RAMPs) govern the specificity of the receptors for the different ligands: RAMP1-transported CRLR is a CGRP receptor, whereas RAMP2- or RAMP3-transported CRLR is an adrenomedullin receptor. IAPP binding is more related to RAMP-transported CTR . Of particular interest for islet physiology is the demonstration that CRLR and the RAMPs are expressed in β cells , suggesting that the regulation of RAMP1 expression and function governs the islet influence of CGRP. In conclusion, CGRP fulfills some, but not all, criteria for a sensory inhibitory islet neurotransmitter.
Substance P was discovered in 1931 and is today known to be within the tachykinin family of peptides . It consists of 11 amino acids and is ubiquitously distributed in sensory neurons with its main function involved in pain perception . Immunohistochemistry of mouse and pig pancreas has demonstrated that substance P is expressed in islet sensory nerves [44,51]. It may therefore, together with CGRP, be involved in the regulation of islet function. This hypothesis is supported by the effect of acute capsaicin administration, which releases substance P from the pancreas . The effects of substance P on insulin secretion remain, however, controversial. On one hand, substance P inhibits insulin secretion in mice and rats [52–54], whereas substance P stimulates insulin secretion in the pig pancreas . There is more agreement regarding glucagon secretion: substance P stimulates glucagon secretion in both rats and pigs [51,52,55]. The main and preferred receptor for substance P is the neurokinin 1 receptor (NK1 receptor), which is a G protein-coupled receptor . This receptor is abundantly expressed on α cells, but it has not been convincingly demonstrated to be expressed on β cells . Therefore, although substance P is expressed in islet sensory nerves, controversy persists regarding its physiologic significance for islet hormone secretion.