Thursday , August 16 2018
Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #42: Neuropeptides and Islet Hormone Secretion Part 1 of 5

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #42: Neuropeptides and Islet Hormone Secretion Part 1 of 5

Sep 20, 2016


The traditional view is that islet hormone secretion is mainly regulated by circulating nutrients (glucose, amino acids, free fatty acids) as well as the gut incretin hormones (glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)). However, in certain circumstances regulation of insulin and glucagon secretion is also dependent on the autonomic nerves which innervate the islets [1]. These nerves belong to the parasympathetic, sympathetic, and sensory branches of the autonomic nervous system (Figure 9.1(a)). Their nerve terminals traverse in close apposition to the islet endocrine cells and contain in their vesicles both the classical neurotransmitters (acetylcholine and noradrenaline) and several neuropeptides, which are released from activated nerves (Figure 9.1(b)). The neurotransmitters then diffuse a short distance to the islet β- and α cells and activate specific receptors resulting in stimulation or inhibition of islet hormone secretion (Figure 9.1(c) illustrates the parasympathetic-islet complex).The islet nerves also innervate the islet blood vessels, and may therefore also affect islet function through changes in blood flow.


Islet parasympathetic nerves

The parasympathetic nerves innervating the islets originate in the pancreatic ganglia, whose activity is controlled by preganglionic nerves, originating in the dorsal motor nucleus of the brain [1]. In addition, the adjacent duodenum projects parasympathetic fibers to the pancreatic ganglia [2]. The preganglionic nerve fibers form classical nerve terminals and synapses within the ganglia where they release acetylcholine to activate nicotinic receptors on the postganglionic neurons. The nerves have small vesicles which contain acetylcholine and large dense core vesicles which contain neuropeptides. Both acetylcholine and neuropeptides are released from small varicosities in the nerves, from which they diffuse to the islet endocrine cells and activate specific receptors which cause stimulation of both insulin and glucagon secretion. A main physiologic importance of this regulation is the early phase of feeding, both during the cephalic phase of meal-induced insulin secretion, which is the release in anticipation of the meal, and during the first few minutes after food is ingested but before significant amounts of nutrients have reached the islets to stimulate insulin secretion directly [3]. Another physiologic importance of the parasympathetic islet nerves may be, together with the sympathetic nerves, the stimulation of glucagon secretion during hypoglycemia [4].

The classical mechanism invoked to explain stimulation of insulin and glucagon secretion during vagal nerve activation is the release of the neurotransmitter acetylcholine. The released acetylcholine diffuses to the endocrine cells and activates muscarinic receptors (mainly the M1 and M3 subtypes of the muscarinic receptor) which results in stimulation of insulin and glucagon secretion [5]. The intracellular second messenger system induced by muscarinic receptor activation involves phospholipase C (PLC) with increased formation of inositol-1,4,5-trisphosphate (IP3) and liberation of calcium from intracellular stores; this occurs in conjunction with formation of diacyl glycerol (DAG) and subsequent activation of protein kinase C (PKC) [6,7]. Another mechanism is phosphorylation-/arrestin-dependent coupling of the muscarinic M3 receptor to protein kinase D1 [8].

The critical importance of the cholinergic mediation of islet hormone secretion for glucose homeostasis is evident from studies using mice with either β-cell deletion of the M3 receptors or β-cell overexpression of M3 receptors [8]. The β-cell M3 knockout mice have defective insulin secretion and glucose intolerance, whereas β-cell M3 receptor overexpressing mice have increased insulin secretion and enhanced glucose tolerance. The mice with β-cell overexpression of M3 receptors are also resistant to diet-induced glucose intolerance and hyperglycemia [8].

Neuropeptides contained in islet parasympathetic nerve terminals may also contribute to vagally induced stimulation of insulin and glucagon secretion, since in the dog insulin secretion after vagal nerve activation is not abolished by atropine, which blocks the muscarinic receptors. However, it is abolished by hexamethonium, which blocks the nicotinic receptors needed to activate postganglionic nerves [9]. The neuropeptides localized to islet parasympathetic nerve terminals and therefore potential mediators of the islet noncholinergic effects are gastrin-releasing polypeptide, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating polypeptide [9].

Gastrin-releasing polypeptide (GRP)

GRP is the mammalian homologue of the amphibian peptide bombesin. It consists of a 27-amino acid residue, which is α-amidated in its C-terminal methionine.The peptide is highly conserved during evolution, having an identical N-terminal end to bombesin, and the human and porcine forms of the peptide differ in only two residues. GRP is widely distributed in mammalian tissues, with particular abundance in the lung, the central nervous system, and the gut. In the pancreas, GRP is localized to islet nerves [1] and nerve terminals in the pancreatic ganglia, and is released from the isolated pig pancreas during vagal nerve activation [10]. GRP stimulates insulin secretion as shown in experimental studies in mice, pigs, and dogs [10–12]. This stimulation is mediated by activation of both β-cell and ganglionic GRP receptors, as evident from findings in vivo that the ganglionic antagonist hexamethonium and the muscarinic antagonist atropine both partially inhibit GRP-stimulated insulin secretion [1,13]. A main mechanism underlying the direct β-cell stimulation of GRP is increased cytoplasmic calcium due to stimulation of both calcium uptake from extracellular space and release from intracellular stores [14]. However, PKC [15] and phospholipase D (PLD) may also contribute to GRP-induced insulin secretion [1]. Hence, activation of several different signaling mechanisms may together contribute to the insulinotropic action of GRP.

Bombesin-like peptides activate several subspecies of receptors, but it is the GRP receptor (GRPR) that is the receptor subtype responsible for GRP-stimulated insulin secretion [16]. To study the physiology of GRP and islet function, mice with genetic deletion of the GRPR have been developed. These mice exhibit impaired insulin secretion in response to autonomic nerve activation by neuroglycopenia induced by 2-deoxyglucose (2-DG) [16]. 2-DG is known to activate the autonomic nerves, thereby increasing insulin secretion in mice by an effect that is counteracted by ganglionic blockade by hexamethonium [1]. Insulin secretion in response to oral glucose is also impaired in GRPR-deleted mice, indicating involvement of GRP in neural stimulation of insulin secretion after meal ingestion [17].

In contrast to the well-documented stimulation of insulin secretion by GRP, its potential effect on glucagon secretion is not established. One study demonstrated stimulation of glucagon secretion by GRP in mice [11], but other studies in dogs showed no effect on glucagon secretion [12]. Overall, GRP’s role seems more related to the insulinotropic than the glucagonotropic action of the parasympathetic nerves.

Click here to view all Chapter 9 references.