International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #44: Neuropeptides and Islet Hormone Secretion Part 3 of 5

Islet sympathetic nerves

Islets are densely innervated by sympathetic nerves, as demonstrated by fluorescence microscopy, electron microscopy, and immunocytochemistry [1]. The islet sympathetic nerves are postganglionic nerve fibers with most nerve cell bodies located in the celiac ganglion and some in the paravertebral sympathetic ganglia (Figure 9.1(a)). Electrical activation of the sympathetic nerves inhibits insulin secretion and stimulates glucagon secretion [31]. The effects of sympathetic nerve activation on insulin and glucagon secretion are partially mediated by the classical neurotransmitter noradrenaline through activation of α-adrenoreceptors, which in turn results in inhibition of adenyl cyclase, with reduced formation of cAMP. However, hyperpolarization with closure of the voltage-sensitive calcium channels and a direct exocytotic action may also be involved.

In addition to noradrenaline, neuropeptides also contribute to sympathetically induced inhibition of insulin secretion. The evidence for this is twofold. First, combined α2- and β-adrenoreceptor blockade by yohimbine and propranolol does not prevent the effect of sympathetic activation to inhibit basal insulin secretion. Second, exogenous noradrenaline does not mimic the effect of sympathetic activation to inhibit basal insulin secretion [31]. Two sympathetic neuropeptides, galanin and neuropeptide Y, may mediate these nonadrenergic effects because they (a) are localized to both the islet sympathetic nerve terminals and their neuronal cell bodies in the celiac ganglion, (b) are released from the pancreas in response to electrical activation of the sympathetic nerves, and (c) each inhibit insulin secretion as demonstrated both in vivo and in vitro [1].

Galanin

Galanin was isolated from the porcine gastrointestinal tract in 1983 and named because of its glycine C-terminus and alanine N-terminus [32]. In most species it is 29 amino acids in length and amidated in its C-terminus. However, the human form is 30 amino acids long and is not C-terminally amidated.

Galanin is a widely distributed neuropeptide both in the central and peripheral nervous systems. In islets, dense galanin innervation was first demonstrated in dogs, and later in other species, including humans [30,32]. However, species differences exist; for example, islet galanin innervation is more abundant in dogs and cats than in common laboratory animals like rats and mice [32]. In dogs, islet nerves that contain galanin also contain tyrosine hydroxylase as do their neuronal cell bodies in the celiac ganglion [30]. Thus, islet galanin nerves appear to be sympathetic.This hypothesis is supported by the substantial, although not total, loss of pancreatic galanin nerves that develops after chemical sympathectomy with 6-hydroxydopamine.

Further evidence comes from the dog, whose pancreatic galanin is released after sympathetic nerve activation, and from the mouse, whose pancreatic galanin content is reduced by exercise stress [30]. Therefore, although galanin may occasionally also be found in certain other nerves, most data suggest that islet galanin is a sympathetic neuropeptide.

Galanin has been demonstrated to potently inhibit basal and stimulated insulin secretion both in vivo, as demonstrated in dogs, rats, and mice, and in vitro, as shown in isolated rodent and human islets and in perfused rat pancreas. Galanin also stimulates glucagon secretion [32]. The actions of galanin have been shown to be transmitted by signals induced by activation of three different galanin receptor subtypes, called GalR1, GalR2, and GalR3, respectively. All three are G-protein-coupled receptors encoded by different genes [32]. The GalR1 form is expressed in insulin-producing cells and therefore most likely the mediator of the inhibitory effect of galanin on insulin secretion [33].

The mechanism underlying this inhibitory action involves opening of ATP-sensitive potassium channels and inhibition of the cellular uptake of calcium by closure of voltage-sensitive calcium channels through hyperpolarization, although also inhibition of the formation of cAMP through involvement of a pertussis toxin-sensitive G-protein, and through actions on proteins which are of critical importance for the exocytosis of secretory granules have been suggested [32–35].

Functional studies have demonstrated that galanin is released from the dog pancreas during sympathetic nerve activation in a quantity that is sufficient to mimic the inhibition of insulin secretion induced by sympathetic nerve stimulation [30]. These data therefore suggest that galanin helps mediate sympathetically induced inhibition of insulin secretion. A similar conclusion comes from a study in mice in which two minutes of swimming causes a 50% inhibition of glucose-stimulated insulin secretion [36]. When galanin was immunoneutralized in these mice by pretreatment with a high-titer galanin antiserum, swimming no longer inhibited glucose-stimulated insulin secretion, suggesting that galanin mediated this exercise-induced inhibition of insulin secretion.

Further support comes from galanin knockout mice where the inhibitory effect of sympathetic nerve activation of insulin secretion is impaired [37]. Although a galanin receptor antagonist, galantide, exists [38], studies using this approach to prove a role for galanin in sympathetically mediated inhibition of insulin secretion remain to be performed.

Neuropeptide Y (NPY)

NPY was isolated from the porcine brain in 1982 and shown to be of a 36-amino acid residue with tyrosine at both N- and C-termini. It has structural homology with peptide YY (PYY) and pancreatic polypeptide (PP) and is widely distributed in the central and peripheral tissues. In most tissues the peptide is localized to perivascular adrenergic nerve fibers. In the pancreas, NPY-containing nerve terminals have been demonstrated around vessels, in the exocrine portion of the gland, as well as in islets in dogs, pigs, and mice [1,39,40]. NPY is co-localized with tyrosine hydroxylase in most islet nerves, suggesting that it is mainly a sympathetic neuropeptide. This hypothesis is supported by the localization of NPY to nerve cell bodies of the celiac ganglion, which also stain for tyrosine hydroxylase [1,40]. However, some islet nerves that do not contain tyrosine hydroxylase also express NPY, suggesting an additional nonsympathetic function for islet NPY [40]. NPY is released from the pancreas during nerve activation and most studies suggests that NPY inhibits glucose-stimulated insulin secretion, that is, it exerts sympathetic-like effect, both in vivo and in vitro [1,39–41].

Several NPY receptors exist, all of which are G-protein coupled with seven transmembrane domains. In insulin producing cells, it is the Y1 receptor subtype (Y1R) that mediates islet actions of NPY [41]. The mechanism underlying NPY’s inhibition of glucose-stimulated insulin secretion involves inhibition of adenylate cyclase which reduces the formation of cAMP [41]. However, NPY also seems to inhibit insulin secretion through a mechanism distal to the formation of cAMP, because insulin secretion stimulated by a cAMP analogue can also be inhibited by NPY [1]. Although the physiologic importance of NPY for islet function remains to be established, there is some evidence that endogenous islet NPY tonically restrains insulin secretion. Thus, immunoneutralization of NPY in isolated islets leads to increased insulin secretion [42], and mice with genetic deletion of NPY have increased insulin secretion [43].

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