Pancreatic polypeptide: a unique model for vagal control of endocrine systems

doi:10.1016/0165-1838(83)90134-0

Journal of the Autonomic Nervous System

Volume 9, Issue 1, October 1983, Pages 99-111

Journal of the Auton...

https://doi.org/10.1016/0165-1838(83)90134-0 Get rights and content

Abstract

Pancreatic polypeptide (PP) is a hormone synthesized only in the duodenal pancreas where the PP cell is the dominating endocrine cell type. The secretion of PP is regulated by food-intake and by plasma glucose—in both cases through vagal cholinergic mechanisms. In vitro cholinergic stimulation is 4–10 times as potent as any other stimulatory mechanism, e.g. beta-adrenergic stimulation. Although other agents such as gastrointestinal hormones and neuropeptides are potent stimulators of PP secretion in vivo, their action is totally eliminated by blockade of the muscarinic receptor and in several cases also abolished by vagotomy. Furthermore, these peptides have no or only a weak effect in vitro. The stimulation of PP secretion by hypoglycemia and inhibition by hyperglycemia is mediated also through an efferent vagal mechanism. Under extreme hypoglycemia the stimulation of PP release becomes partially atropine resistant, although still totally dependent on the vagus; conceivably the release of other transmitters, like e.g. VIP, is activated under these circumstances. In the basal state, PP secretion is under oscillating cholinergic tone. Thus, the secretion of PP is unique in the way that the cholinergic, vagal stimulation is not only the most powerful stimulatory mechanism, but also the key through which other mechanisms act. PP secretion can be used, e.g. as a sensitive indicator of autonomic disorders in patients with diabetes.

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Cited by (64)

Pancreatic polypeptide revisited: Potential therapeutic effects in obesity-diabetes
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Citation Excerpt :
Such an effect that can be partially recapitulated by sham-feeding [85], but is abolished by vagotomy [83,86], highlighting a critical role of vagal transmission for PP hormone release. Indeed, this cholinergic pathway is considered to be the primary regulator of PP secretion [84]. The second phase is linked to the GIT and triggered by various enteric stimulus, including protein [104], lipid [1] and carbohydrates [62].
Pancreatic polypeptide (PP), a member of the neuropeptide Y (NPY) family of peptides, is a hormone secreted from the endocrine pancreas with established actions on appetite regulation. Thus, through activation of hypothalamic neuropeptide Y4 (NPY4R or Y4) receptors PP induces satiety in animals and humans, suggesting potential anti-obesity actions. In addition, despite being actively secreted from pancreatic islets and evidence of local Y4 receptor expression, PP mediated effects on the endocrine pancreas have not been fully elucidated. To date, it appears that PP possesses an acute insulinostatic effect, similar to the impact of other peptides from the NPY family. However, it is interesting that prolonged activation of pancreatic Y1 receptors leads to established benefits on beta-cell turnover, preservation of beta-cell identity and improved insulin secretory responsiveness. This may hint towards possible similar anti-diabetic actions of sustained Y4 receptor modulation, since the Y1 and Y4 receptors trigger comparable cell signalling pathways. In terms of exploiting the prospective therapeutic promise of PP, this is severely restricted by a short circulating half-life as is the case for many regulatory peptide hormones. It follows that long-acting, enzyme resistant, forms of PP will be required to determine viability of the Y4 receptor as an anti-obesity and -diabetes drug target. The current review aims to refocus interest on the biology of PP and highlight opportunities for therapeutic development.
Therapeutic peptidomimetics in metabolic diseases
2022, Peptide and Peptidomimetic Therapeutics: From Bench to Bedside
Understanding glucose homeostasis is critical to the study of both health and disease. In this chapter, we follow carbohydrates as they start their journey from a planned meal to food on the plate, through consumption and secretion. We focus on glucose transport from the gastrointestinal tract to the blood and from the blood and into cells, glucose storage and release, and glucose secretion. Special attention is given to diabetes, of which the prevalence has risen dramatically in countries of all income levels during recent years. We also describe current approaches to pharmaceutical management of diabetes, highlighting the roles of peptidomimetic molecules in the field.
The role of pancreatic polypeptide in the regulation of energy homeostasis
2015, Molecular and Cellular Endocrinology
Citation Excerpt :
The information from the NTS is relayed to various regions of the brain, including the PVN in the hypothalamus as well as other nuclei in the brainstem. It has been long established that PP release is dependent on function of the vagus nerve (Schwartz, 1983), and that following vagotomy, PP no longer exerts its anorectic effects (Asakawa et al., 2003). PP responses to meal ingestion, as well as its actions on energy homeostasis, are collectively dependent on several pathways that are under the control of vagal cholinergic reflex circuits involving changes in expression of hypothalamic feeding-regulatory peptides and activity of the vago-vagal and vago-sympathetic reflex axis.
Imbalances in normal regulation of food intake can cause obesity and related disorders. Inadequate therapies for such disorders necessitate better understanding of mechanisms that regulate energy homeostasis. Pancreatic polypeptide (PP), a robust anorexigenic hormone, effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, leading to vagal stimulation that mediates complex actions via the neuropeptide Y4 receptor in arcuate nucleus of the hypothalamus, subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. Novel studies indicate affinity of PP for the relatively underexplored neuropeptide y6 receptor, mediating actions via the suprachiasmatic nucleus and pathways involving vasoactive intestinal polypeptide and insulin like growth factor 1. This review highlights detailed mechanisms by which PP mediates its actions on energy balance through various areas in the brain.
Gut Hormones and Obesity: Physiology and Therapies
2013, Vitamins and Hormones
Citation Excerpt :
The vagus is also an effector of central control of energy homeostasis. The vagus nerve stimulates release of satiety signals in response to a meal, including PYY(3–36), PP, and GLP-1 (McTigue & Rogers, 1995; Roberge & Brubaker, 1993; Rocca & Brubaker, 1999; Schwartz, 1983). It is also responsible for the cephalic phase of glucagon secretion, a phenomenon lost in pancreas transplant patients due to denervation of the pancreas (Secchi et al., 1995).
Over the past 30 years, it has been established that hormones produced by the gut, pancreas, and adipose tissue are key players in the control of body weight. These hormones act through a complex neuroendocrine system, including the hypothalamus, to regulate metabolism and energy homeostasis. In obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Alterations in gut hormone secretion following gastric bypass surgery are likely to underlie the dramatic and persistent loss of weight following this procedure, as well as the observed amelioration in type 2 diabetes mellitus. Medications based on the gut hormone GLP-1 are currently in clinical use to treat type 2 diabetes mellitus and have been shown to produce weight loss. Further therapies for obesity based on other gut hormones are currently in development.
Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis
2012, Neuropeptides
The gut–brain axis refers to the bidirectional communication between the gut and the brain. Four information carriers (vagal and spinal afferent neurons, immune mediators such as cytokines, gut hormones and gut microbiota-derived signalling molecules) transmit information from the gut to the brain, while autonomic neurons and neuroendocrine factors carry outputs from the brain to the gut. The members of the neuropeptide Y (NPY) family of biologically active peptides, NPY, peptide YY (PYY) and pancreatic polypeptide (PP), are expressed by cell systems at distinct levels of the gut–brain axis. PYY and PP are exclusively expressed by endocrine cells of the digestive system, whereas NPY is found at all levels of the gut–brain and brain–gut axis. The major systems expressing NPY comprise enteric neurons, primary afferent neurons, several neuronal pathways throughout the brain and sympathetic neurons. In the digestive tract, NPY and PYY inhibit gastrointestinal motility and electrolyte secretion and in this way modify the input to the brain. PYY is also influenced by the intestinal microbiota, and NPY exerts, via stimulation of Y1 receptors, a proinflammatory action. Furthermore, the NPY system protects against distinct behavioural disturbances caused by peripheral immune challenge, ameliorating the acute sickness response and preventing long-term depression. At the level of the afferent system, NPY inhibits nociceptive input from the periphery to the spinal cord and brainstem. In the brain, NPY and its receptors (Y1, Y2, Y4, Y5) play important roles in regulating food intake, energy homeostasis, anxiety, mood and stress resilience. In addition, PP and PYY signal to the brain to attenuate food intake, anxiety and depression-related behaviour. These findings underscore the important role of the NPY-Y receptor system at several levels of the gut–brain axis in which NPY, PYY and PP operate both as neural and endocrine messengers.
Improvement in β-cell function after diet-induced weight loss is associated with decrease in pancreatic polypeptide in subjects with type 2 diabetes
2012, Journal of Diabetes and its Complications
Citation Excerpt :
In healthy humans stimulation of PYY and PP is dependent on fat digestion (Feinle-Bisset, Patterson, Ghatei, Bloom, Horowitz, 2005). Pancreatic polypeptide (PP) is produced under vagal control by F-cells of the endocrine pancreatic islets, and to a lesser extent in the exocrine pancreas, colon and rectum in response to a meal (Schwartz, 1983) and regulates pancreatic and gastric secretion (Hazelwood, 1993; Schwartz et al., 1976). Peripheral administration reduces food intake in humans (Batterham et al., 2003).
The aim of our study was to evaluate the effect of a lifestyle intervention program on β-cell function and to explore the role of gastrointestinal peptides in subjects with T2D.
Subjects with T2D (n = 74) received 24 weeks of intervention: 12 weeks of slimming diet (− 500 kcal/day) and the subsequent 12 weeks of diet were combined with aerobic exercise. All subjects were examined at weeks 0, 12 and 24. β-cell function was assessed during standard meal tests. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and β-cell function was quantified with a mathematical model. Plasma concentrations of gastrointestinal peptides were measured in a fasting state and during hyperinsulinemia induced by hyperinsulinemic isoglycemic clamp.
Mean weight loss was 5.03 ± 4.38 kg (p < 0.001) in weeks 0–12. Weight did not change significantly in weeks 12–24. Both insulin secretion at the reference level and glucose sensitivity increased in weeks 0–12 (by 33% ± 54% and by 26% ± 53%, respectively, p < 0.001) and remained unchanged in weeks 12–24. Both fasting and hyperinsulinemic plasma concentrations of pancreatic polypeptide (PP) decreased in weeks 0–12 (p < 0.05 for both) and did not change significantly in weeks 12–24. Changes in insulin secretion at the reference level correlated negatively with plasma concentrations of PP during hyperinsulinemia (r = − 0.36; p < 0.001). Changes in glucose sensitivity correlated negatively with changes in plasma concentrations of PP, both in fasting and during hyperinsulinemia (r = − 0.2; p = 0.01 for both). The correlations remained significant after adjustment for changes in body-mass-index.
After diet-induced weight loss, β-cell function improved in T2D subjects and remained unchanged after the addition of exercise. We demonstrate for the first time that these changes are associated with a decrease in PP secretion.

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Pancreatic polypeptide: a unique model for vagal control of endocrine systems

Abstract

Lancet

Gastroenterology

Rec. Progr. Horm. Res.

Lancet

Metabolism

Regulat. peptides

Gastroenterology

J. biol. Chem.

Gastroenterology

Life Sci.

Regulat. Peptides

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Regulat. Peptide

Life Sci.

Distribution and release of human pancreatic-polypeptide

Gut

Pancreatic-polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas

Diabetologia

Pharmacokinetics of pancreatic polypeptide in man

Gut

The importance of cholinergic tone in the release of pancreatic polypeptide by gut hormones in man

Life Sci.

Inhibition of secretion stimulated pancreatic secretion by pancreatic-polypeptide

Gut.

Effect of age on fasting plasma levels of pancreatic hormones in man

J. clin. Endocrinol. Metab.

The location of VIP in the pancreas of man and rat

Diabetologia

Pancreatic endocrine responses to stimulation of the peripheral ends of the vagus nerves in conscious calves

J. Physiol, (Lond.)

Human pancreatic-polypeptide (HPP) and bovine pancreatic-polypeptide (BPP)

Influence of the autonomic nervous system on the release of vasoactive intestinal polypeptide from the porcine gastrointestinal tract

J. Physiol. (Lond.)

Effect of atropine on vagal release of gastrin and pancreatic polypeptide

J. clin. Invest.

The ability of pancreatic polypeptide (APP and BPP) to return to normal the hyperglycemia, hyperinsulinemia and weight gain of New Zealand obese mice

Horm. Res.

Regional distribution and concentration of pancreatic-polypeptide in the human and canine pancreas

Diabetes

Evidence for extra vagal cholinergic dependence of pancreatic-polypeptide response to beef ingestion in man

Clin. Res.

Plasma human pancreatic polypeptide responses to administered secretin: effect of surgical vagotomy, cholinergic blockade and chronic pancreatitis

J. Clin. Endocrinol. Metab.

Somatostatin inhibits the release of acetylcholine induced electrically in the myenteric plexus

Endocrinology

Hormone-stimulated release of pancreatic polypeptide before and after vagotomy in dogs

Amer. J. Physiol.

Stimulatory effect of 2-deoxy-d-glucose on pancreatic polypeptide and glucagon secretion in man: evidence for cholinergic mediation

Diabetologia

The influence of calcium on the basal and acetylcholine stimulated secretion of pancreatic polypeptide

Endocrinology

Effect of 2-deoxy-d-glucose, glucose and insulin on efferent activity in gastric vagus nerve

Experientia

Peptidergic neurones

Nature (Lond.)

The relation between catecholamines, glucagon and pancreatic polypeptide during hypoglycemia in man

Acta Endocrinol.

Effects of pancreatic polypeptide on the secretion of enzymes and electrolytes by in vitro preparations of rat and cat pancreas

Yonsei Med. J.

Impaired response of pancreatic polypeptide to hypoglycemia: an early of autonomic neuropathy in diabetics

Brit. Med. J.

Pancreatic-polypeptide a postulated hormone: identification of its cellular storage site by light and electron microscopic immunocytochemistry

Diabetologia