Review article

P. CERANOWICZ, Z. WARZECHA, A. DEMBINSKI

PEPTIDYL HORMONES OF ENDOCRINE CELLS ORIGIN IN THE GUT
- THEIR DISCOVERY AND PHYSIOLOGICAL RELEVANCE

Department of Physiology, Jagiellonian University Medical College, Cracow, Poland
In 1902 William Bayliss and Ernest Starling discovered secretin and it was the beginning of general endocrinology as well as, endocrinology of gastrointestinal tract. Ernest Starling was also a first person who introduced a term hormone for the substances which serves to transfer the information between cells of organism. Subsequent years delivered discovery of successive hormones of the digestive tract. Gastrin was discovered in 1905; whereas cholecystokinin in 1928. Ghrelin and obestatin are last hormones determined in the gastrointestinal tract and they were found in 1999 and 2006, respectively. Both above hormones are originating from the common prohormone. In 60s of past century, the biochemical structure of the gastrointestinal tract hormones was determined for the first time. Substantial progress in endocrinology of the digestive tract took place when radioimmunoassay was employed to measure of hormones concentration. Subsequently, radiolabeled hormones were used to localize hormonal receptors. Next breakthrough in the gastrointestinal tract endocrinology happened after introduction to experimental methods the cloning of complementary DNA. This method has allowed, among the others, to establish the full structure of receptors as well as, a genes coding hormones and their receptors. Discovery of genes structure allowed subsequently introducing these genes into foreign cells, what gives a chance to obtain significant amount of recombined hormones possessing species specificity. This review is presenting a history of the gastrointestinal tract endocrinology, as well as a relevance of gastrointestinal tract hormones in the regulation of body physiological activity.
Key words:
gastrointestinal tract, hormone, endocrine cell, cholecystokinin, secretin, ghrelin, hormone, receptor

INTRODUCTION

The publication of article by Bayliss and Starling in 1902 is generally regarded as the birth date of general endocrinology and endocrinology of gastrointestinal tract (1). They discovered that infusion of hydrochloric acid into a denervated loop of the small intestine caused secretion of pancreatic juice in dogs. These findings led them to a conclusion that a chemical substance released by the acidified intestine and transported by the bloodstream to the pancreas triggered stimulation of pancreatic secretion. They also showed that an acid extract of the intestinal mucosa given intravenously stimulated pancreatic secretion. Those findings confirmed that the exocrine pancreas was stimulated by a chemical factor produced in the intestinal mucosa and released by luminal acid (1). They called this substance secretin. The term “hormone” was first introduced by Starling in 1905 to describe a chemical substance that transmits information between cells (2).

In the next years, other hormones that had biological effects in the gastrointestinal tract were extracted from different parts of the gut (Fig. 1). The discovery of gastrin, a hormone that controls gastric acid secretion, by Edkins in 1905 was a significant achievement in that earliest period of gastrointestinal endocrinology (3). Initially, a concept of endogenous chemical factor that stimulates gastric acid secretion did not receive recognition from the scientific community. Further studies suggested that histamine might be gastrin (4). However, later study of Komarov demonstrated that histamine-free extract of pyloric mucosa could induce gastric acid secretion (5) Moreover, Komarov established that this substance was distinct from histamine and had a protein nature (6, 7).

Cholecystokinin was described for the first time in 1928 as a stimulant of gallbladder contraction present in intestinal extracts (8). In 1943, Harper and Raper showed that extracts of intestine were capable of stimulating pancreatic enzyme secretion, and that this property was distinct from the capacity of secretin to stimulate the exocrine pancreatic function (9). They called this factor a pancreozymin. For many years cholecystokinin and pancreozymin were considered as two separate hormones. It changed in 1966, when Jorpes and Mutt (10) tried to isolate cholecystokinin and pancreozymin and noted that both activities were mediated by a same hormone. They called it cholecystokinin-pancreozymin and for a while that term was in use. Actually this hormone is commonly known as cholecystokinin (CCK).

Figure 1
Fig. 1. The discovery of gastrointestinal hormones.

The development of novel analytic methods that helped to isolate active substances from tissue extracts and determine their chemical composition and molecular structure was another key achievement in gastrointestinal endocrinology. In 1964, Gregory et al. for the first time described amino acid constitution of gastrin (11), while Anderson et al. performed synthesis of this hormone (12). In the next years, chemical structures of other gastrointestinal hormones were determined. Department of Biochemistry at Karolinska Institute in Stockholm was the place of initial chemical characterization of many hormones, including secretin (13), cholecystokinin (CCK) (14), vasoactive intestinal polypeptide (VIP) (15), gastric inhibitory polypeptide actually known as glucose-dependent insulinotropic polypeptide (GIP) (16), motilin (17), and gastrin-releasing peptide (GRP) (18).

The development of radioimmunoassay technique to measure minute quantities of hormones in body fluids represents a milestone in the history of endocrinology. This method was primary introduced by Rosalyn Yalow and Solomon Berson in 1959 for determination of plasma insulin in human subjects (19) and after that was used for measurement of gastrointestinal hormones (20). Later, anti-hormone antibodies and radiolabeled hormones used in radioimmunoassay were also applied in other scientific technique. Antibodies against gastrointestinal hormones were used to locate hormone-secreting cells by immunohistochemistry (21); whereas radiolabeled hormones were used to identify relevant hormone receptors. Moreover, the study of affinity of receptors to radiolabeled hormones made it possible to classify hormone receptors into distinct subtypes (22). The development of synthetic receptor ligands, agonists and antagonists (23) enabled researchers to define the role of gastrointestinal hormones in controlling the function of the digestive system.

The introduction of genetic engineering techniques, in particular cloning of the complementary DNA (cDNA), was the next breakthrough in research on gastrointestinal endocrinology. The use of partial amino acid sequence of a receptor protein to design an oligonucleotide probe for hybridization purposes made it possible to determine a structure of a complete receptor molecule (24). Chimeric receptors that combine specific regions of two or more receptors can be useful in identifying which domain is important for a given function.

Genes encoding gastrointestinal hormones and their receptors were also identified (25). Thus, genetic information for hormones could be introduced into different cells in order to grow stable cell lines that express specific genes and produce unlimited quantities of species-specific recombinant hormones (26).

Genetically modified (transgenic) organisms that might exhibit enhanced, decreased or suppressed expression of receptors and hormones, were also created to define the role of these factors in different body functions. This method was used in studies on hormones and hormone receptors. Moreover, in situ hybridization technique for identifying genetic information that encodes hormones and hormone receptors was applied to localize cells and tissues expressing these hormones and receptors (27).

Usually, in a typical sequence of events, the first step in the discovery of gastrointestinal hormones was an extraction of hormone and determination of its biological functions. Then, receptors for this hormone were identified and molecular structures of the hormone, and relevant hormone receptors were investigated. Finally, synthetic agonists and antagonists for these receptors were created.

In the case of ghrelin, sequence of events in the discovery of this hormone was reversed. Initially, peptidyl and non-peptidyl molecules stimulating the release of growth hormone from the anterior pituitary gland were synthesized (28). These substances were named growth hormone secreatgogues (GHSs). GHSs were demonstrated to induce secretion of growth hormone through binding to growth hormone secretagogue receptor (GHS-R) in the pituitary gland that is distinct from that for growth hormone-releasing hormone (GHRH). The next step in the discovery of ghrelin was cloning GHS-R in 1996 (29). In 1999 Kojima et al. identified an endogenous peptide that binds to GHS-R. For its growth hormone-releasing activity, this peptide was called ghrelin (in Proto-Indo-European language “ghre” means “growth”, “relin” means “release”) (30). Ghrelin was originally isolated from the gastric mucosa, where it is produced by X/A-like neuroendocrine cells (31). The stomach is also the main source of endogenous ghrelin (30).

ENTEROENDOCRINE CELLS AND THEIR ROLE IN THE CONTROL OF GASTROINTESTINAL FUNCTIONS

The function of the gastrointestinal system is regulated by gastrointestinal neurons, hormones produced by enteroendocrine cells, and cytokines synthesized in somatic cells. The enteric nervous system consists of some hundred millions neurons divided into extrinsic and intrinsic neurons. Extrinsic neuron’s cell body is located outside the gut; whereas intrinsic neuron’s cell body is located inside the gut within two plexuses, called the myenteric plexus or Auerbach’s plexus and the submucosal plexus called also Meissner’s plexus. The extrinsic innervation of the gastrointestinal tract is a part of the parasympathetic and sympathetic nervous systems. The most of peptidergic neurons located in the gut belongs to intrinsic neurons of enteric nervous system.

In 1968, Pearse introduced a concept of APUD (Amine Precursor Uptake and Decarboxylation) cell system (32). He described morphological and functional characteristics of enteroendocrine cells and found that these cells share certain morphological and functional characteristics with peptidergic neurons. He concluded his finding that it might suggest common genesis of both group of these cells. However, more recent studies have not confirmed that peptidergic neurons and enteroendocrine cells have common origin. Peptidergic neurons derive from the neural crest, so they are of neuro-ectodermal origin; whereas enteroendocrine cells are derive from pluripotent endodermal stem/progenitor cells, just like cells of gastrointestinal mucosa (33).

The enteroendocrine cells within the gut do not form separate endocrine glands. They are scattered between the exocrine and mucosal cells of the gastrointestinal tract and are able to produce hormone precursors (prohormones). Prohormones undergo post-translational enzymatic processing to be converted into active hormones. The hormones are stored inside the endocrine cells in the form of secretory granules for immediate release by a mechanism know as exocytosis. The enteroendocrine cells may be divided into two groups: open-type cells and closed-type cells. The open-type endocrine cells have apical cytoplasmic processes that reach the intestinal lumen and receive chemical information from intestinal contents. The closed-type endocrine cells do not contact with the intestinal lumen and may response only to nervous or hormonal signals.

Gastrointestinal hormones are released and exert their effects by multiple pathways using paracrine, autocrine, neurocrine, as well as endocrine routes. Peptidyl hormones produced by the enteroendocrine cells of the gut can be classified by similarity in structure and function into several main categories or hormone families as follows:

  1. gastrin
  2. secretin
  3. pancreatic polypeptide
  4. somatostatin
  5. neurotensin
  6. ghrelin-motilin

GASTRIN FAMILY OF GASTROINTESTINAL HORMONES

The gastrin family of gastrointestinal hormones includes two hormones with similar structures and partial synergistic effects: gastrin and cholecystokinin.

Gastrin

Gastrin is produced and released by G cells in the stomach. G cells are open-type endocrine cells. Their apical processes project into the gastric lumen and thus the luminal content influences their excretory activity. G cells are found mainly in the pyloric mucosa of the stomach. G cells in the stomach produce about 90% of gastrin, and the remaining 10% is produced in the duodenum. Gastrin is present in three biologically active molecular forms: 34-amino acid peptide called the “big gastrin” (G-34), 17-amino acid peptide called the “little gastrin” (G-17) and 14-amino acid peptide called the “mini gastrin” (G-14) (34-36). The enzymatic processing of preprogastrin produces all of the above mentioned physiologically active forms of gastrin. The fourteen C-terminal amino acids are identical in all three forms (G-14, G-17 and G-34). The sixth amino acid from the C-terminal is tyrosine, which may or may not be sulfated without affecting the biologic action or potency of the peptide (37). The sequence of five C-terminal amino acids are identical to those in cholecystokinin (CCK).

Plasma G-17 concentration rises during the digestive phase, and it is believed to be the main physiological form of the hormone that is released in response to a meal (38).

During the interdigestive phase, G-34 is the principal form found in the circulation. Circulatory half-life of gastrin varies with molecular size. It is approximately 7 minutes for G-17 and about 30 minutes for G-34. Gastrin is metabolized by tissues throughout the body. The larger forms, G-17 and G-34, are not affected while passing through the liver, but the liver removes the smaller forms (39).

Gastrin secretion is regulated by luminal, hormonal and neural stimuli. Cholinergic vagal fibers contact with peptidergic nerve fibers containing gastrin-releasing peptide (GRP). For this reason, stimulation of vagal nerves leads to GRP release and gastrin secretion by antral G cells. Vagal fibers innervate also, via the enteric nervous system, the antral D cells, which secrete somatostatin. The interneuron in this case is cholinergic and its effect on D cell secretion is inhibitory. Somatostain suppresses gastrin release form G cells. Thus, inhibition of somatostatin secretion results in increased gastrin secretion. The secretion of somatostatin and the secretion of gastrin are closely related to pH of the gastric content. The secretion of somatostatin by D cells is directly stimulated by increased concentration of H+ leading to inhibition of gastrin and gastric acid secretion. Gastrin release is partially inhibited at an antral luminal pH of 3.5 and completely inhibited at a luminal pH of 2.0. Gastrin release is also inhibited by secretin (40).

Ingestion of a meal is the strongest stimulant of the secretion of gastrin. Small peptides, aromatic amino acids (e.g., phenylalanine and tryptophan) act directly on the G cell to stimulate gastrin release (41). Elevated calcium in serum or in gastric lumen, alcoholic beverages, and coffee (including caffeine-free coffee) are also effective stimuli for gastrin secretion (42). Distention of the gastric walls causes reflexive gastrin release. These reflexes operate through long, vago-vagal and short, enteric nervous system pathways.

A primary physiological effect of gastrin is the stimulation of gastric acid secretion by the parietal cells of the gastric glands in the gastric mucosa. Gastrin stimulates HCl secretion mainly via binding to the cholecystokinin-2 (CCK2) receptors on enterochromaffin-like cells (ECL), and to a lesser extent, by direct action on CCK2 receptors present on parietal cells (24, 43). ELC cells release histamine in response to gastrin. Histamine, in turn, stimulates HCl secretion by binding to the H2 receptor on nearby parietal cells (40).

The second physiological action of gastrin is its trophic effect on gastric and colonic mucosa. Gastrin stimulates mucosal proliferation. In its absence, these tissues will go atrophy unless exogenous gastrin is administered (44, 45). Hypergastrinemia, such as that associated with gastrin-producing pancreatic tumors (gastrinoma) lead to gastric hyperplasia and gastric acid hypersecretion. Gastrin is also a weak stimulant of pepsinogen secretion (46).

Gastrin induces mucin and bicarbonate secretion by the mucus-producing cells in the stomach to protect gastric mucosa against detrimental effects of low pH. Gastroprotective activity of gastrin can also be observed as regards other harmful factors such as high ethanol concentration, stress or bile salts. This effect, at least in part, depends on activation of sensory C-fibers, release of nitric oxide (NO) and increase in mucosal blood flow (47, 48).

Gastrin inhibits gastric emptying, stimulates both gastric and intestinal motility, constricts the pyloric sphincter and lower esophageal sphincter (49), and high concentrations of gastrin contract the gallbladder (50).

In addition, gastrin stimulates insulin and glucagon secretion, induces secretion of pancreatic enzymes and gallbladder emptying, and acts as a weak trophic factor for the pancreas.

Cholecystokinin (CCK)

CCK is synthesized principally in the open-type I cells of the duodenum and (to a lesser extent) proximal 2/3 of the jejunum (51, 52). Some amount of CCK was found in the neurons of the enteric nervous system (53, 54), and high amount of this hormone has been found in the central nervous system (CNS) (55). CCK exists in multiple molecular forms, including molecules containing 8, 22, 33, 39 and 58 amino acids (14, 56). Larger precursor forms (CCK-83) have also been identified (57). CCK-8 and CCK-33 are thought to play a key role in gastrointestinal physiology.

CCK is structurally similar to gastrin, with the 5 amino acids (Phe-Asp-Met-Trp-Gly) at the carboxyl terminus identical to both hormones. All forms of CCK share the same octapeptide C-terminal amino acid sequence (Phe-Asp-Met-Trp-Gly-Met-Tyr-Asp). The tyrosine residue in the seventh position from the C-terminus must be sulfated to exhibit the CCK pattern of biological activity. Desulfation of the C-7 tyrosine results in a gastrin activity pattern (58). The minimum fragment for CCK activity is the C-terminal octapeptide (CCK-8).

CCK-8 has a circulatory half-life of only about 1 minute (59). The liver is the major site responsible for clearing CCK-8 from the circulation, and the molecule is almost completely cleared from the liver in a single pass through the portal circulation (60, 61). The larger forms of CCK are actively eliminated by the kidneys and capillary bed.

The principal stimuli for CCK release from the duodenal and jejunal I cells are digestion products of fat and protein in lumen of the intestine. Fatty acids with carbon chain lengths of eight or longer or their monoglycerides are the most potent stimulus for CCK release. Peptides and aromatic (particularly tryptophan and phenylalanine) or aliphatic (particularly valine and methionine) amino acids, are also strong stimulants (62). CCK secretion is also induced by other intraluminal factors such as CCK-releasing peptide (CCK-RP) that is released from enterocytes or monitoring peptide that is released by pancreatic acinar cells. Both peptides stimulate CCK release by I cells of the duodenal and jejunal mucosa (63).

CCK has numerous physiological actions. It is a strong stimulus for pancreatic enzyme secretion. It also potentiates secretin-induced bicarbonate production in the pancreas. CCK stimulates pancreatic enzyme secretion by acinar cells mainly via activation of CCK1 receptors on vagal afferent terminals. Activation of CCK-receptors triggers vagal efferents from motor nuclei in the brainstem leading to an increase in acetylcholine release and stimulation of enzyme secretion from the pancreatic acinar cells (64). CCK has a trophic action on the pancreas, leading to increase in pancreatic DNA synthesis, pancreatic content of DNA, RNA and protein, and pancreatic weight (65, 66). Secretin potentates this trophic effect (65).

CCK is a potent stimulus for bile expulsion from the gallbladder by causing the smooth muscle of the gallbladder to contract and the sphincter of Oddi to relax. CCK induces gallbladder contraction both directly and indirectly through activation of vagal afferent neurons (67).

CCK also has been shown to delay gastric emptying and inhibit food intake. CCK is the first gastrointestinal hormone found to elicit satiety (68) and this effect has been observed in animals (68) and humans (69). Animal studies have shown that intraperitoneal infusion of CCK at the onset of meal reduces amount of food ingested during one meal, but increases daily meal number. Average body weight drops on the first day of CCK infusion, but over the following 5 days returns to level observed in control animals (70).

CCK is responsible for short-term regulation of food intake. In healthy lean volunteers postprandial plasma CCK concentration reaches maximum at the first 15 min (71). Human studies have also shown that fasting and postprandial plasma CCK concentration in obese women is markedly lower than that observed in lean women (72).

CCK stimulates insulin secretion from β-cells in the pancreas (73) and exhibits trophic effect in the small bowel mucosa (74).

SECRETIN FAMILY OF GASTROINTESTINAL HORMONES

The family members display structural similarities with secretin molecule. This group comprises numerous peptide hormones that are produced by endocrine cells in the gastrointestinal tract or are released to the circulation from the endings of peptidergic neurons. Some of them are also hormones that have systemic effects. Apart from secretin, this family includes vasoactive intestinal polypeptide (VIP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP) and hormones with systemic effects such as glucagon, calcitonin and parathyroid hormone. Secretin family members that are produced by the endocrine cells in the gastrointestinal tract include secretin, GIP and GLP-1 (75), and for this reasons only those three hormones are described in details below.

Secretin

Secretin is produced by S-cells that are most abundant in the duodenum. Some S-cells are also present in the jejunal and ileal mucosa (76). S-cells are open-type cells. Secretin is a 27-amino-acid peptide. Its half-life is of about 3–4 minutes. The kidney is the major site of secretin removal from the circulation.

The most potent stimulus for secretin release is acidification of the duodenum. Duodenal acidification is the consequence of emptying of the stomach. Secretin release begins when duodenal pH falls below 4.0. Secretin release is directly related to the load of titratable acid (H+) delivered to the duodenum. Fatty acids, particularly the oleic acid, as well as bile salts and ethanol are weak stimulants for secretin release. The vagus nerve and secretin-releasing peptide are also involved in the mechanism of secretin release (77).

The primary action of secretin is the stimulation of the secretion of bicarbonate from the pancreatic and biliary ducts, and duodenal glands. Secretin increases CCK-induced pancreatic enzyme secretion, inhibits gastric acid secretion, stimulates pepsin secretion, inhibits gastric motility and gastric emptying. Secretin has also been shown to lower the esophageal sphincter tone and stimulate insulin release from pancreatic b-cells (78).

Glucose-dependent insulinotropic polypeptide (GIP)

GIP was originally named gastric inhibitory peptide, until it became clear that inhibition of acid secretion is not a physiological action of this hormone. Therefore, this peptide is currently called glucose-dependent insulinotropic polypeptide. GIP is secreted by the K-cells in the duodenal and jejunal mucosa (79). GIP is a linear 42-amino-acid peptide. The complete molecule is required for full biological activity. It has a long circulatory half-life of about 20 minutes. The kidney is believed to be the major site for removing GIP from the circulation (80). The primary stimulus for GIP release is food, especially glucose, as well as long-chain fatty acids and their monoglycerides in the lumen of the small intestine. Certain amino acids (arginine, histidine, isoleucine, leucine, lysine and threonine) are effective in releasing GIP (81). Neither acidification nor neutralization of the upper small intestine are involved in GIP release. Its release may be inhibited by high levels of insulin or glucagon, but the physiological significance of that is not clear.

Initially, GIP has been shown to suppress gastrin release and acid secretion, and to inhibit gastric and intestinal motility. However, it was subsequently shown that the effects on gastric acid secretion are seen only at very high concentrations of GIP, outside the physiological range. It is now generally accepted that the major physiological action of GIP is the incretin activity leading to stimulation of insulin release in response to food ingestion (82, 83). Postprandial plasma level of GIP depends on type of food ingredients. In healthy humans, plasma GIP concentration is greater after ingestion of carbohydrates than after ingestion of proteins or carbohydrates plus proteins (84).

In addition to stimulating insulin secretion, GIP enhances insulin gene transcription, promotes β-cell proliferation and reduces β-cell apoptosis (85).

In contrast to GLP-1, GIP administration in healthy subjects increases food intake and decreases energy expenditure (83). In adipose tissue, GIP stimulates the insulin-dependent glucose uptake, fatty acids synthesis and lipogenesis, as well as reduces glucagon-stimulated lipolysis (85, 86).

Although GIP is potent insulinotropic hormone in healthy humans GIP-evoked insulin secretion is markedly diminished in patients with type 2 diabetes (87). Moreover, unlike GLP-1, GIP does not inhibit, but stimulates glucagon secretion in humans (88). For this reason GIP seems to be useless as a potential remedy in the treatment of diabetes (89).

Glucagon-like peptide-1 (GLP-1)

GLP-1, formerly called enteroglucagon, is produced by intestinal endocrine L-cells, open-type cells that are most abundant in the distal ileum and colon. L-cells are also present in the duodenum (90). Apart from GLP-1, L-cells release also GLP-2 and peptide YY. GLP-1 is a product of 158-amino-acid preproglucagon. GLP-1 is produced as an inactive 37-amino- acid peptide, GLP-1 (1-37). The active form of GLP-1 is produced by post-translational cleavage of six amino acids from the N-terminal end. The biologically active circulating forms of GLP-1 are: 31-amino acid GLP-1 (7-37) and 30-amino acid GLP-1 (7-36) amide. Both of them have similar biological activities (91). GLP-1 is released in response to food, especially glucose, fatty acids, proteins and bile salts in the bowel (90). Like GIP, GLP-1 is an incretin hormone. GLP-1 stimulates secretion of endogenous insulin and inhibits glucagon release (83, 91). Administration of GLP-1 leads to decrease in blood glucose levels both in healthy individuals and in patients with type 2 diabetes (92). The insulinotropic (93) and glucagonostatic (94) effects of GLP-1 are glucose-dependent. Reduction in glucagon release and stimulation of insulin secretion by GLP-1 occur at hyper- or euglycemia, but not at hypoglycemia (94). This mechanism protects against the GLP-1-induced excessive reduction in plasma glucose concentration.

GLP-1 controls energy and water intake. Animal studies have shown that central administration of GLP-1 causes decrease in food and water intake (95, 96). Similar effects have been observed in human beings. Intravenous administration of GLP-1 has been shown to promote satiety and suppress energy intake in healthy, diabetic and obese humans (97-99).

Other important effects of GLP-1 in the gut include the inhibition of pancreatic and gastric exocrine secretion, the reduction of gastric empting, and suppression of hepatic glucose production (100). In the cardiovascular system, GLP-1 exhibits cardiotropic and cardioprotective effects. Administration of this peptide increases heart rate and blood pressure, improves ventricular function in experimental models of cardiovascular dysfunction, and reduces cardiomyocyte apoptosis (100).

Animal and human experimental studies mentioned above have indicated that GLP-1 may be useful in the therapy of type 2 diabetes and obesity. However, GLP-1 has a very short circulating half life of 5–6 min (101) due to the action of proteases, mainly dipeptidyl peptidase IV (DPP-4). DPP-4 cleaves N-terminal dipeptides with a proline or alanine residue, an area which is safe with respect to degradation by nonspecific proteases. GIP and GLP-1 contain alanin at position 2 and both those hormones are substrates for DPP-4 (84). Short half life of native GLP-1 limits its practical application. The therapeutic use of native GLP-1 would require multiple subcutaneous injection or continuous intravenous or subcutaneous infusion. This problem has been solved by use of chemically modified degradation-resistant agonists of GLP-1 receptor and by use of DDP-4 inhibitors. The most often used GLP-1 receptor agonists, exenatide and liraglutide, given together with oral antihyperglycemic agents have been shown to be effective in the treatment of type 2 diabetes (83, 102). Administration of those GLP-1 receptor agonists reduces fasting and postprandial blood glucose level without developing hypoglycemia, decreases concentration of HbA1c and lowers body weight in diabetic patients (83, 102). DDP-4 inhibitors called also incretin effect amplifiers or incretin enhancers have been also approved in the treatment of type 2 diabetes mellitus. Their administration reduces degradation of endogenous GLP-1 and GIP, and allows to maintain a blood level of those hormones in range showing therapeutic effect. Likely GLP-1 receptor agonists, DDP-4 inhibitors stimulate insulin secretion, inhibit glucagon secretion and reduce postprandial blood glucose level. Their differences from GLP-1 receptor agonists include: oral bioavailability, less side effect, no direct CNS effects and no influence on body mass (83, 102).

A new idea of type 2 diabetes treatment with GLP-1 is gene therapy. Animal studies have shown that GLP-1 gene therapy protects mice from streptozotocin-induced diabetes through preservation of the β-cell mass (103). Gene therapy allows also ectopic expression of degradation-resistant agonists of GLP-1 receptor. Double-strand adeno-associated virus-mediated exendin-4 expression in salivary glands enhances insulin secretion in vivo and significantly controls the onset of hyperglycemia in rat model of diabetes mellitus (104).

PANCREATIC POLYPEPTIDE FAMILY

The pancreatic polypeptide family of peptides, also called the PP-fold family of peptides, includes pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY). The amidated C-terminal residue is common to all members of the pancreatic polypeptide family of peptides and all of them act upon the same family of receptors. The members of the NPY family act upon the same family of receptors. Therefore, it is recommended that the receptors for PP, PYY and NPY are classified as NPY receptors. Five distinct NPY receptors have been cloned (Y1, Y2, Y4, Y5 and Y6). All Y receptors subtypes are expressed in either the small or large bowel. Y1, Y2, Y5 and Y6 receptors show a much higher affinity for NPY and PYY than PP; whereas Y4 receptors show high affinity for PP and lower affinity for NPY, and PYY (105).

PP and PYY are stored and secreted from specialized enteroendocrine cells, whereas NPY is a neurotransmitter found in the central and peripheral nervous systems and for this reason NPY is not described below.

Pancreatic polypeptide

Pancreatic polypeptide (PP) is a linear peptide composed of 36 amino acids. It is produced and secreted by PP cells located peripherally in pancreatic islet (106). Some of PP cells are scattered throughout the exocrine pancreas. PP has a half-life of about 7 minutes (107), and the kidney is the major site of its removal from the circulation. The physiological stimuli and release mechanism are not clearly identified. PP is released in response to food ingestion. Large amounts of PP are also released by vagal stimulation and acetylcholine during a cephalic phase of digestion period. Presence of protein digestion products (particularly phenylalanine and tryptophan) in the lumen of the gut is very impotent releaser of PP; fat and carbohydrate are less effective. Also CCK, gastrin, GRP, neuromedin B and C and secretin can induce PP secretion (108).

The primary physiological role proposed for PP is modulating pancreatic and gastric secretion, as well as inhibition of gastric emptying (109). In physiological doses it inhibits both basal and hormone-stimulated pancreatic exocrine secretion, having about equipotent effects on enzyme and bicarbonate release. PP has an insulin-sensitizing effect in the liver, deficiency of PP reduces the insulin-evoked decrease in hepatic glucose production (110).

Peripheral administration of PP suppresses food intake and gastric emptying. On the other hand, central administration of PP increases food intake and gastric emptying (109).

PP affects mucosal growth in the stomach. Animal studies have shown that peripheral or central administration of PP inhibits the food- and pentagastrin-stimulated growth of gastric mucosa (111).

Some pancreatic endocrine tumors are associated with increased levels of PP, and PP appears to be a marker for these tumors (112).

Peptide YY (PYY)

PYY is also known as peptide tyrosine tyrosine. Like PP, PYY consists of 36 amino acids. PYY is secreted by L-cells in the ileum and colon in response to food intake. Fats and other products of food digestion, such as carbohydrates are primary stimulants for PYY release. It is also supposed that neural mechanisms, including GRP, are involved in PYY secretion. PYY has a half-life of about 8–12 minutes in the circulation, depending on animal species (113).

PYY inhibits both gastric and intestinal motility and suppresses gastric and pancreatic exocrine secretion (113, 114). Reduced intestinal motility may increase efficiency of food digestion and nutrient absorption (115).

SOMATOSTATIN FAMILY OF GASTROINTESTINAL HORMONES

The somatostatin family of gastrointestinal hormones consists of only one hormone, somatostatin. Somatostatin is essential not only for gastrointestinal function, but also for the whole body. Somatostatin exists in two main molecular forms: one composed of 14 amino acids (SS14) and the second one composed of 28 amino acids (SS28) (116). Both SS14 and SS28 derived from their common precursor a 116-amino-acid presomatostatin peptide (117), and both have identical fourteen C-terminal amino acid residues. Both forms have intrachain disulfide bonds that maintain their cyclic structure (116, 117). Somatostatin is produced and released by neurons in the central and peripheral nervous systems, as well as by D cells in the gastrointestinal mucosa and pancreatic islets. D cells may be both open-type and closed-type cells, depending on their location. SS14 has a short circulatory half-life of about 1 minute, whereas for SS28, a half-life is approximately 3 minutes. Somatostatin is mainly degraded in the liver, but capillary bed also plays a role in elimination of this hormone (118).

Somatostatin release is stimulated by dietary components of a meal, especially fat and proteins (119). Low pH of the stomach content increases somatostatin expression and release from pyloric D cells (120). Somatostatin release is also induced by numerous hormones and neuropeptides that inhibit hydrochloric acid secretion in the stomach, including glucagon, secretin, GLP-1, CCK, GRP, and VIP (121). CGRP released from the endings of the sensory nerves is also a stimulator of somatostatin secretion in the gastric wall. This effect is supposed to be involved in the defense mechanisms of gastric mucosa that protect stomach against damage evoked by noxious agents (122). Gastrin upregulates somatostatin synthesis and release. This suggests that somatostatin plays a role in the prevention of hypergastrinemia throughout negative feedback mechanisms (123).

A primary physiological effect of somatostatin in the gut is suppression all activities of gastrointestinal tract (124). Somatostatin inhibits exocrine activity of the stomach and pancreas, as well as reduces bile and saliva secretion (125). Somatostatin may evoke direct inhibitory effect on target cells via interaction with specific membrane G protein-coupled somatostatin receptors or indirect inhibitory effect by supression of release of gastrointestinal hormones. Somatostatin mediates a paracrine inhibition of gastrin secretion in response to pyloric acidification. It also suppresses release of CCK, secretin, PP, GIP, motilin, glucagon and insulin (124, 125).

Moreover, somatostatin inhibits gastrointestinal motility, decreases visceral blood flow, as well as cell growth and cell renewal in the gastrointestinal tract (124, 125).

Somatostatin and its analogs are useful in therapy and diagnosis of several clinical conditions. Therapeutic application of long-acting stable analogs of somatostatin, octreotide and lanreotide, has been approved for the treatment of acromegaly and gigantism, pituitary tumors secreting thyroid stimulating hormone, carcinoid syndrome and diarrhea in patients with tumors secreting vasoactive intestinal polypeptide (126). Somatostatin analogs play a prominent role in the symptomatic control of patients with gastroenteropancreatic-neuroendocrine tumors leading to reduction in hypersecretion and tumoral growth in the majority of cases. (126). Somatostatin analogs labeled with indium-111 are useful in noninvasively scintigraphic imaging of neuroendocrine and other tumors expressing somatostatin receptors. Analogs of somatostatin labeled with carbon-11 or gallium-68 enable imaging with positron emission tomography (PET) (127, 128). Somatostatin analogs labeled with yttrium-90 or lutetium-177 can be used in peptide receptor radionuclide therapy (PRRT) for treatment of patients with metastasized or inoperable neuroendocrine tumors (127, 129).

NEUROTENSIN FAMILY OF GASTROINTESTINAL HORMONES

The neurotensin 170-amino-acid precursor polypeptide undergoes complex posttranslational processing in tissue specific manner. Neurotensin family consists of neurotensin, neuromedin N and large 125-138-amino-acids peptides with neurotensin or neuromedin sequence at their C-terminus (130).

Neurotensin

Neurotensin is a 13-amino-acid peptide that was primary isolated from bovine hypothalamus (131), and has subsequently been also found in the digestive tract (132). Neurotensin can be found in neurons of the central nervous system (133). It is also produced and released by open-type endocrine N cells in the gastrointestinal tract. N cells are predominantly expressed in the ileum. These cells, are also present in small number in the jejunal, duodenal and colonic mucosa (132). Neurotensin has been also identified in the neurons of the enteric nervous system (134).

Neurotensin is mainly released by intestinal fatty acids. The release of neurotensin is mediated by both hormonal and neurohormonal mechanisms. GRP analogues stimulate neurotensine secretion in vivo. Release of neurotensin has also been studied using isolated ileal segments. These studies demonstrated that neurotensin is also released by bombezine, GRP, carbachol and substance P (135). A half-life of neurotensin is about 4 minutes.

Neurotensin has a number of biological effects, including inhibition of gastric acid secretion and emptying, and decrease in lower esophageal sphincter tone (136). Moreover, neurotensin promotes pancreatic and intestinal exocrine secretion, and converts interdigestive pattern of small intestinal motility to a digestive pattern (137). Neurotensin increases colonic motility (138) and visceral blood flow (137).

GHRELIN-MOTILIN FAMILY OF GASTROINTESTINAL HORMONES

The ghrelin family of gastrointestinal hormones consists of three hormones: motilin, ghrelin and obestatin (139, 140).

Motilin

Motilin is a 22-amino-acid peptide (17) that is found primarily in the duodenum and in smaller amounts in the more distal portions of the small bowel. Motilin is secreted by M cells of the small intestine (141). Motilin is produced from a 115-amino-acid prepromotilin (142). Its circulating half-life is about 4 minutes, and the kidney plays the most important role in its elimination (143).

Plasma motilin level is low during the digestive phase of gastrointestinal activity in dogs and pigs, and its concentration increases, and varies cyclically during the interdigestive phase. Motilin peak concentration coincides with the initiation of the phase III of migrating motor complex (MMC) in the stomach (144). Food ingestion stops cyclic fluctuations of motilin levels. In humans, circulating motilin levels change during the interdigestive period with peak in the phase III of this period (145). However, in contrast with dogs, motilin may be also released in humans immediately after intestinal acidification, and food digestion, especially fat consumption (146).

Initiation of phase III of the MMC is considered as a physiological effect of motilin (145). In addition, motilin may stimulate exocrine secretory activity of the pancreas and stomach, induce constriction of the lower esophageal sphincter and gallbladder, and increase small intestinal motility (147) during phase III of the MMC. Moreover, motilin promotes gastric emptying and insulin secretion (148).

Ghrelin

Ghrelin is a 28-amino-acid peptide and ghrelin is a natural ligand for hormone secretagogue receptors (GHS-R). There are two types of the growth hormone secretagogue receptors: GHS-R1a and GHS-R1b. Ghrelin is a ligand for both receptors, but only GHS-R1a is biologically active (149). GHS-R1a is a G-protein coupled receptor. Signal transduction pathway activated by ghrelin through GHS-R1a results in activation of phospholipase C and production of intracellular inositol triphosphate (IP3), that act on IP3 receptors to release Ca2+ from the endoplasmic reticulum (150).

Ghrelin is derived from 117-amino-acid preproghrelin which also generates another peptide called obestatin. Ghrelin circulates in two different forms - an active acyl ghrelin and inactive desacyl ghrelin (30, 31). The human ghrelin gene is located on chromosome 3, at locus 3p25–26. The half-life of acyl ghrelin is only about 11 minutes; whereas the half-life of desacyl ghrelin is 29 minutes (151).

Ghrelin is predominantly secreted in the stomach. However, it was also found in other body organs such as intestine, pancreas, kidneys, pituitary gland and hypothalamus (30, 152). Ghrelin may exhibit some paracrine effects by acting on GHS-R1a receptors, but most of its effects are thought to be related to endocrine activity. GHS-R1a receptors occur predominantly in the pituitary gland and hypothalamus. However, they may also be found in other organs (152). Ghrelin has a strong stimulatory, dose-dependent effect on the growth hormone secretion in the anterior pituitary gland (30). It also potentiates GHRH effect on the growth hormone release. Apart from a potent growth hormone-releasing effect, ghrelin induces adrenocorticotropic hormone (ACTH), cortisol and prolactin secretion (139, 153). Recent studies have also shown that ghrelin plays an important role in the regulation of female reproduction (154).

Ghrelin affects energy balance of the body. This peptide increases food intake and fat accumulation in adult humans and animals (155, 156). Appetite-inducing effects of ghrelin are due to its action on hypothalamic neurons that release orexin and neuropeptide Y (NPY). Fasting plasma ghrelin level is inversely correlated with body mass index (BMI) (157). Therefore, plasma ghrelin level is low in patients with obesity and high in those with anorexia (157). Food has significant effect on circulating ghrelin levels which are high during periods of fasting and low after eating. Ghrelin is believed to influence not only a short-term but also a long-term regulation of food intake (157) (Fig. 2).

Figure 2
Fig. 2. Effects of ghrelin in gastrointestinal tract.

The effect of ghrelin on exocrine secretory activity of the stomach is not clear. Some studies in anesthetized rats demonstrated that intravenous (158) and intraventricular (159) administration of ghrelin induced gastric acid secretion in the stomach. However, studies in rats with chronic gastric fistulas and in pylorus-ligated rats suggested that ghrelin did not affect exocrine secretory activity of the stomach (160). Stimulation of gastric motility is one of well-established actions of ghrelin in the stomach (158). On the other hand, activity of the stomach seems to affect release of ghrelin. There are studies suggesting inhibitory effect of gastrin on ghrelin release from ghrelin-positive cells in gastric mucosa (161).

Studies concerning the effect of ghrelin on pancreatic function demonstrated that ghrelin inhibits exocrine secretory activity of the pancreas (162). However, effect of ghrelin on endocrine pancreatic function was controversial. Some initial studies indicated that ghrelin stimulated insulin secretion (163, 164); whereas other reports showed inhibitory effect on insulin release (165, 166). Actually, it is generally accepted that ghrelin, acting directly on islet β cells, inhibits glucose-dependent insulin secretion (167, 168). In vitro studies have shown that pharmacological or genetic blockade of islet-derived ghrelin markedly enhances insulin release evoked by glucose (167). Also in vivo animal studies have given evidences that ablation of ghrelin, GHS-R or ghrelin O-acyltransferase (GOAT), an enzyme that causes the acylation of the third serine residue of ghrelin, increases insulin release and prevent impaired glucose tolerance (167, 168).

Influence of ghrelin on the maturation and growth of digestive tract organs is age-dependent. In young suckling rats, administration of ghrelin reduces gastric and pancreatic growth; whereas in young peripubertal rats, administration of ghrelin stimulates growth of gastrointestinal mucosa and the pancreas, and increases pancreatic content of amylase (169-171).

Experimental studies have demonstrated that exogenous ghrelin exhibits protective effect in the heart (172), kidney (173) and brain (174) against ischemic injury, reduces the severity of sepsis-induced lung injury and mortality (175). Ghrelin shows gastroprotective effect in numerous experimental models of gastric mucosal damage (176, 177). Moreover, this peptide inhibits the development of acute pancreatitis (178, 179) and exhibits the healing-promoting effect in the course of this disease (180, 181). Therapeutic effect of ghrelin has been also shown in experimental models of gastric (182-184) and duodenal ulcers (182, 185), oral ulcers (196), and inflammatory bowel disease (187).

Human studies have shown that ghrelin could be useful in the treatment of diseases associated with negative energy balance. Administration of exogenous ghrelin and its analogs improves appetite and food intake in patients with cancer, chronic wasting disease and kidney disease and treated with dialysis (188). Antagonists of ghrelin as anorexigenic agents could be valuable in the treatment of obesity and type 2 diabetes (189).

Obestatin

Obestatin, like ghrelin, was originally identified in the rat stomach and the stomach is main source of endogenous obestatin. Obestatin was discovered by Zhang et al. in 2005 (190). Their research suggested that this novel peptide inhibited food intake and therefore they named it obestatin from the Latin word “obedere,” meaning to devour, and “statin”, denoting suppression. Zhang et al. proposed that obestatin exerts its biological effect by binding to the G protein-coupled receptor 39 (GPR39) (190). However, more recent findings showed that GPR39 is not the obestatin receptor and the receptor for this hormone remains unknown (191). Studies by Granata et al. suggest that obestatin signaling pathways, at least in the pancreas, involve the glucagon-like peptide-1 receptor (GLP-1R) (192).

Obestatin is a 23-amino-acid peptide derived from a 117-amino-acid preproghrelin by posttranslational processing (190). Preproghrelin is a common precursor for ghrelin, desacyl ghrelin and obestatin. Moreover, Seim et al. have demonstrated that the sense and antisense alternative transcripts of ghrelin gene may function as non-coding regulatory RNA, or code for novel protein isoforms. They have found putative obestatin and C-ghrelin specific transcripts. These data suggest that these ghrelin gene-derived peptides may also be produced independently of preproghrelin (193).

The effect of obestatin on food intake is controversial. Anorexigenic effect of obestatin was first described by Zhang et al. (190). However, this effect has not been confirmed in most of subsequent studies (188, 194). Recent data suggest that obestatin inhibits thirst (195), suppresses vasopressin secretion (196) and stimulates pancreatic exocrine secretion (197). This peptide exhibits also some effects in the central nervous system. Obestatin inhibits anxiety, improves memory (198), exhibit the sleep-promoting effect leading to increase in a deep of NREM phase of sleep (199).

Animal studies have also shown that obestatin might exhibit protective and therapeutic effects in the gastrointestinal tract. Obestatin increases cell proliferation, as well as vitality of isolated human pancreatic islets and β-cells (192). Pretreatment with obestatin inhibits the development of cerulein-induced acute pancreatitis (200). Administration of obestatin exhibits anti-inflammatory effect in dextran sodium sulfate-induced colitis in rats. Therapeutic effect of obestatin in acute colitis is associated with reduction in lipid peroxidation (187). Furthermore, current studies have demonstrated that exogenous obestatin promotes the healing of experimental gastric ulcers (201) (Fig. 3).

Figure 3
Fig. 3. Effects of obestatin in gastrointestinal tract.

OTHER IMPORTANT HORMONAL PEPTIDES PRODUCED BY CELLS IN THE GUT

Apelin

Apelin, an endogenous ligand of the orphan G-coupled receptor APJ, has been extracted from bovine stomach in 1998 by Tatemoto et al. (202). Apelin is a product of posttranslational processing of preproapelin consisting of 77 aminoacid residues and the apelin sequence was encoded in the C-terminal regions (202). After translocation of preproapelin into the endoplasmic reticulum and clevage of signal peptid, preapelin consisting of 55 amino acids is a source for several molecular active froms of apelin, including molecules containing 12, 13, 17 and 36 amino acids. Apelin-13 may also undergo a pyroglutamylation at the level of its N-terminal glutamine residue (203). Apelin and apelin receptor (actual name of AJP receptor) are widely expressed in various organs such as the brain, heart, lung, kidney, liver, adipouse tissue, mammary glands, placenta and endothelium (202, 204, 205).

In the gastrointestinal tract, apelin is mainly expressed in gastric mucosa, and to a lesse degree in the villi of the duodenum, jejunum and ileum (206). In the stomach appelin is produced in both exocrine and endocrine cells (206, 207). Apelin receptor has been found in gastric fundic glands and intestinal mucosa (208), as well as in pancreatic β-cells (209).

Apelin affects numerous function of the body, including regulation of cardiovascular system and fluid homeostasis. This peptide modulates vascular tone, where apelin released from endothelial cells would act on apelin receptors on the endothelium to cause vasodilation or on underlying smooth muscle cells to cause vasoconstriction (205). In the heart, studies in vivo and in vitro have shown that apelin exhibits positive inotropic effect in animals and humans (210-212).

The regulatory actions of apelin on thirst and drinking behavior have been reported; however, the nature of these responses is not clear. In mice or rats, intracerebroventricular or intravenous administration of apelin counteracts vasopressin anti-diuretic effect leading to increase in diuresis and decrease in urine osmolality (213, 214). Dehydration increases apelin and apelin receptor expression and decreases vasopresin expression in rat magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei (215, 216). In humans, osmotic stimuli have been show to exert opposing effects on plasma apelin and vasopressin levels. Water-loading condition increases plasma apelin concentration and decreases plasma level of vasopressin; whereas, increased plasma osmolality increases plasma vasopressin and decreases plasma apelin concentration (217).

In the stomach, Ohno et al. have shown that apelin stimulates gastric acid secretion though an increase in histamine release (218). Studies in vitro performed by Wang et al. have indicated that apelin stimulates gastric cell proliferation (206). Moreover administration of apelin reverses the ischemia-induced inhibition of colonic and gastric epithelial cell proliferation (219) and reduces apoptosis, and DNA damage in gastrointestinal tract (209).

Apelin has been also shown to stimulate cholecystokinin release (218). Intravenous administration of apelin inhibits pancreatic exocrine secretion in anaesthetized rats in dose-dependent manner; whereas apelin given intraduodenally stimulated pancreatic secretion in those rats (220).

Apelin affects also endocrine activity of the pancreas. Studies in vivo and in vitro in mice have shown that apelin inhibits the glucose-stimulated secretion of insulin (221). The inhibitory effect of apelin on insulin secretion is mediated by activation of of PI3-kinase-phosphodiesterase 3B (222). On the other hand, apelin promotes GLUT4 translocation from the cytoplasm to the plasma membrane, stimulates glucose and reduces insulin resistance in 3T3-L1 adipocytes (223). Actually, it is suggested that apelin participates in the regulation of glucose homeostasis (224) and this peptide is necessary for the maintenance of insulin sensitivity (225).

Leptin

Leptin is a 16 kDa protein encoded by the obese (ob) gene (226). The name of “leptin” is derived from the Greek word “leptos,” which means “thin”. This protein is predominantly produced and secreted by adipocytes and plasma leptin level corresponds to the amount of fat tissue (227). The primary physiological role of leptin is linked to the control of food intake and body weight. Leptin reaches the hypothalamus via a blood to induce satiety by suppression of neuropeptide Y release (228).

Apart from a regulation of food intake and energy expenditure, leptin participates in the regulation of inflammatory processes. Inflammation and pro-inflammatory cytokines increase plasma level of leptin (229-231). Serum concentration of leptin is significantly higher in patients with exacerbation of ulcerative colitis or infectious diarrhea than in patients with remission of ulcerative colitis or recovered from infectious diarrhea (232).

Apart from adipose tissue and the hypothalamus, the presence of leptin and its receptors was detected in the others organs, including the stomach, liver and pancreas (233-236). The stomach is the second, besides adipose tissue, source of circulation leptin. Feeding, cholecystokinin and gastrin greatly increase plasma leptin concentration and this effect is associated with a decrease in leptin content in the gastric epithelium (233-234).

Experimental studies have shown that administration of exogenous leptin or the cholecystokinin-, gastrin- or meal-induced release of endogenous leptin protects gastric mucosa against damage evoked by noxious agents (236, 237) and promotes the healing of chronic gastric ulcer (238).

Protective and therapeutic effect of leptin has been also shown in the pancreas. Administration of leptin inhibits the development of acute experimental pancreatitis (236, 239) and accelerates recovery in this disease (240).

Apart anti-inflammatory and regenerative effect, leptin play a crucial role in oncogenesis mediating interactions between malignant cell and tumor microenvironment (241). Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells. Critical role of leptin in tumorigenesis is based on its oncogenic, mitogenic, pro-inflammatory, and pro-angiogenic action (242). Leptin is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness (241). Leptin stimulates ovarian cancer cell growth and inhibits apoptosis (243). The same growth promoting and anti-apoptotic effect of leptin was also found in esophageal adenocarcinoma (244). Apart from progression of esophageal adenocarcinoma, leptin may be also involved in the development of this disease. Expression of leptin receptor protein is significantly higher in patients with Barrett’s esophagus compared to normal or obese controls (245). On the other hand, it is well known that Barrett’s esophagus is associated with a 40 to 100-fold increase in risk of developing esophageal adenocarcinoma (246, 247).

In conclusion, data concerning hormonal activity in the gut allow understanding mechanisms involved in regulation of gastrointestinal exocrine and endocrine secretion, motility, blood perfusion and cell renewal in physiological and pathological condition. It is most likely that new finding concerning endocrinology of the gastrointestinal tract will bring input to discovery of new effective therapeutic methods. These possibilities are especially promised in the area of glucose homeostasis and energy balance.

Conflict of interests: None declared.

REFERENCES

  1. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902; 28: 325-353.
  2. Starling EH. The Croonian Lectures on the chemical correlation of the function of the body. Lecture 1. Lancet 1905; 2: 339-341.
  3. Edkins JS. On the chemical mechanism of gastric secretion. Proc R Soc Lond B Biol Sci 1905; 76: 376.
  4. Popielski L. β-Imidazolylathylamin und die Organextrakte. I. β-Imidazolylathylamin als Machtiger Erreger der Magendrusen. Pfugers Arch Ges Physiol 1919; 178: 214-259.
  5. Komarov SA. Gastrin. Proc Soc Exp Biol Med 1938; 38: 514-516.
  6. Komarov SA. Studies on gastrin. I. Methods of isolation of specyfic gastric secretagogue from the pyloric mucous membrane and its chemical properties. Rev Can Biol 1942; 1: 191-205.
  7. Komarov SA. Studies on gastrin. II. Physiological properties of specyfic gastric secretagogue of the pyloric mucous membrane. Rev Can Biol 1942; 2: 377-401.
  8. Ivy AC, Oldberg EA. A hormone mechanism for gallblader contraction and evacuation. Am J Physiol 1928; 76: 599-613.
  9. Harper AA, Raper HS. Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. J Physiol 1943; 102: 115-125.
  10. Jorpes E, Mutt V. Cholecystokinin and pancreozymin, one sigle hormone? Acta Physiol Scand 1966; 66: 196-202.
  11. Gregory H, Hardy PM, Jones DS, Kenner GW, Sheppard RC. The antral hormone gastrin. Structure of gastrin. Nature 1964; 204: 931-933.
  12. Anderson JC, Barton MA, Gregory RA, et al. Synthesis of gastrin. Nature 1964; 204: 933-934.
  13. Jorpes JE, Mutt V, Magnusson S, Steele BB. Amino acid composition and N-terminal amino acid sequence of porcine secretin. Biochem Biophys Res Commun 1962; 9: 275-279.
  14. Mutt V, Jorpes JE. Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage with thrombin and with trypsin. Eur J Biochem 1968; 6: 156-162.
  15. Mutt V, Said SI. Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination. Eur J Biochem 1974; 42: 581-589.
  16. Jornvall H, Carlquist M, Kwauk S et al. Amino acid sequence and heterogeneity of gastric inhibitory polypeptide (GIP). FEBS Lett 1981; 123: 205-210.
  17. Brown JC, Mutt V, Dryburgh JR. The further purification of motilin, a gastric motor activity stimulating polypeptide from the mucosa of the small intestine of hogs. Can J Physiol Pharmacol 1971; 49: 399-405.
  18. McDonald TJ, Jornvall H, Tatemoto K, Mutt V. Identification and characterization of variant forms of the gastrin-releasing peptide (GRP). FEBS Lett 1983; 156: 349-356.
  19. Yalow RS, Berson SA. Assay of plasma insulin in human subjects by immunological methods. Nature 1959; 184: 1648-1649.
  20. Stremple JF, Meade RC. Production of antibodies to synthetic human gastrin I and radioimmunoassay of gastrin in the serum of patients with the Zollinger-Ellison syndrome. Surgery 1968; 64:165-174.
  21. Solcia E, Capella C, Vezzadini CP, Barbara L, Bussolati G. Immunohistochemical and ultrastructural detection of the secretin cell in the pig intestinal mucosa. Experientia 1972; 28: 549-550.
  22. Wennogle LP, Steel DJ, Petrack B. Characterization of central cholecystokinin receptors using a radioiodinated octapeptide probe. Life Sci 1985; 36: 1485-1492.
  23. Maton PN, Jensen RT, Gardner JD. Cholecystokinin antagonists. Horm Metab Res 1986; 18: 2-9.
  24. Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci USA 1992; 89: 3605-3609.
  25. Deschenes RJ, Haun RS, Funckes CL, Dixon JE. A gene encoding rat cholecystokinin. Isolation, nucleotide sequence, and promoter activity. J Biol Chem 1985; 260: 1280-1286.
  26. Wang W, Yum L, Beinfeld M. Expression of rat pro cholecystokinin (CCK) in bacteria and in insect cells infected with recombinant baculovirus. Peptides 1997; 18: 1295-1299.
  27. Gall JG, Purdue ML. Formation and detection of RNA-DNA hybrid molecules in cytological preparations. Proc Natl Acad Sci USA 1969; 63: 378-383.
  28. Cheng K, Chan WW, Butler B, et al. Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secreatgogue. Endocrinology 1993; 132: 2729-2731.
  29. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977.
  30. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone releasing acylated peptide from stomach. Nature 1999; 402: 656-660.
  31. Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000; 141: 4255-4261.
  32. Pearse AG. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proc R Soc Lond B Biol Sci 1968; 170: 71-80.
  33. Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 1974; 141: 537-561.
  34. Yalow RS, Berson SA. Size and charge distinctions between endogenous human plasma gastrin in peripheral blood and heptadecapeptide gastrins. Gastroenterology 1970; 58: 609-615.
  35. Gregory RA, Tracy HJ. Big gastrin. Mt Sinai J Med 1973; 40: 359-364.
  36. Gregory RA, Tracy HJ, Harris JI, et al. Minigastrin; corrected structure and synthesis. Hoppe Seylers Z Physiol Chem 1979; 360: 73-80.
  37. Gregory RA, Tracy HJ. The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 1964; 5: 103-114.
  38. Dockray GJ, Taylor IL. Heptadecapeptide gastrin: measurement in blood by specific radioimmunoassay. Gastroenterology 1976; 71: 971-977.
  39. Walsh JH, Debas HT, Grossman MI. Pure human big gastrin. Immunochemical properties, disappearance half time, and acid-stimulating action in dogs. J Clin Invest 1974; 54: 477-485.
  40. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995; 75: 155-189.
  41. Feldman M, Walsh JH, Wong HC, Richardson CT. Role of gastrin heptadecapeptide in the acid secretory response to amino acids in man. J Clin Invest 1978; 61: 308-313.
  42. Levant JA, Walsh JH, Isenberg JI. Stimulation of gastric secretion and gastrin release by single oral doses of calcium carbonate in man. N Engl J Med 1973; 289: 55-558.
  43. Dembinski A, Drozdowicz D, Gregory H, Konturek SJ, Warzecha Z. Inhibition of acid formation by epidermal growth factor in the isolated rabbit gastric glands. J Physiol 1986; 378: 347-357.
  44. Johnson LR. The trophic action of gastrointestinal hormones. Gastroenterology 1976; 70: 278-288.
  45. Dembinski A, Warzecha Z, Konturek SJ, Schally AV. Effect of somatostatin on the growth of gastrointestinal mucosa and pancreas in rats. Role of endogenous gastrin. Gut 1987; 28 (Suppl.): 227-232.
  46. Blandizzi C, Lazzeri G, Colucci R, et al. CCK1 and CCK2 receptors regulate gastric pepsinogen secretion. Eur J Pharmacol 1999; 373: 71-84.
  47. Stroff T, Lambrecht N, Peskar BM. Nitric oxide as mediator of the gastroprotection by cholecystokinin-8 and pentagastrin. Eur J Pharmacol 1994; 260: R1-R2.
  48. Konturek SJ, Brzozowski T, Pytko-Polonczyk J, Drozdowicz D. Role of endogenous gastrin in gastroprotection. Scand J Gastroenterol 1995; 30: 620-630.
  49. Sturdevant RA. Is gastrin the major regulator of lower esophageal sphincter pressure? Gastroenterology 1974; 67: 551-553.
  50. Valenzuela JE, Walsh JH, Isenberg JI. Effect of gastrin on pancreatic enzyme secretion and gallbladder emptying in man. Gastroenterology 1976; 71: 409-411.
  51. Konturek SJ, Tasler J, Obtułowicz W. Localization of cholecystokinin release in intestine of the dog. Am J Physiol 1972; 222: 16-20.
  52. Konturek SJ, Tasler J, Bilski J, de Jong AJ, Jansen JB, Lamers CB. Physiological role and localization of cholecystokinin release in dogs. Am J Physiol 1986; 250: G391-G397.
  53. Larsson LI. Innervation of the pancreas by substance P, enkephalin, vasoactive intestinal polypeptide and gastrin/CCK immunoractive nerves. J Histochem Cytochem 1979; 27: 1283-1284.
  54. Cantor P, Rehfeld JF. The molecular nature of cholecystokinin in the feline pancreas and related nervous structures. Regul Pept 1984; 8: 199-208.
  55. Beinfeld MC, Meyer DK, Eskay RL, Jensen RT, Brownstein MJ. The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay. Brain Res 1981; 212: 51-57.
  56. Eng J, Du BH, Pan YC, Chang M, Hulmes JD, Yalow RS. Purification and sequencing of a rat intestinal 22 amino acid C-terminal CCK fragment. Peptides 1984; 5: 1203-1206.
  57. Eberlein GA, Eysselein VE, Davis MT, et al. Patterns of prohormone processing. Order revealed by a new procholecystokinin-derived peptide. J Biol Chem 1992; 267: 1517-1521.
  58. Bonetto V, Jornvall H, Andersson M, Renlund S, Mutt V, Sillard R. Isolation and characterization of sulphated and nonsulphated forms of cholecystokinin-58 and their action on gallbladder contraction. Eur J Biochem 1999; 264: 336-340.
  59. Hoffmann P, Eberlein GA, Reeve JR, et al. Comparison of clearance and metabolism of infused cholecystokinins 8 and 58 in dogs. Gastroenterology 1993; 105: 1732-1736.
  60. Doyle JW, Wolfe MM, McGuigan JE. Hepatic clearance of gastrin and cholecystokinin peptides. Gastroenterology 1984; 87: 60-68.
  61. Sakamoto T, Fujimura M, Townsend CM, Greeley GH, Thompson JC. Interaction of neurotensin, secretin and cholecystokinin on pancreatic exocrine secretion in conscious dogs. Surg Gynecol Obstet 1988; 166: 11-16.
  62. Liddle RA, Goldfine ID, Williams JA. Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 1984; 87: 542-549.
  63. Liddle RA. Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 1995; 269: G319-G327.
  64. Singer MV, Niebergall-Roth E. Secretion from acinar cells of the exocrine pancreas: role of enteropancreatic reflexes and cholecystokinin. Cell Biol Int 2009; 33: 1-9.
  65. Petersen H, Solomon T, Grossman MI. Effect of chronic pentagastrin, cholecystokinin, and secretin on pancreas of rats. Am J Physiol 1978; 234: E286-E293.
  66. Dembinski A, Warzecha Z, Konturek SJ, Cai RZ, Schally AV. The effects of antagonists of receptors for gastrin, cholecystokinin and bombesin on growth of gastroduodenal mucosa and pancreas. J Physiol Pharmacol 1991; 42: 195-209.
  67. Shaffer EA. Review article: control of gall-bladder motor function. Aliment Pharmacol Ther 2000; 14 (Suppl. 2): 2-8.
  68. Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973; 84: 488-495.
  69. Pi-Sunyer X, Kissileff HR, Thornton J, Smith GP. C-terminal octapeptide of cholecystokinin decreases food intake in obese men. Physiol Behav 1982; 29: 627-630.
  70. West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 1984; 246: R776-R787.
  71. Pilichiewicz AN, Little TJ, Brennan IM, et al. Effects of load, and duration, of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men. Am J Physiol Regul Integr Comp Physiol 2006; 290: R668-R677.
  72. Zwirska-Korczala K, Konturek SJ, Sodowski M, et al. Basal and postprandial plasma levels of PYY, ghrelin, cholecystokinin, gastrin and insulin in women with moderate and morbid obesity and metabolic syndrome. J Physiol Pharmacol 2007; 58 (Suppl. 1): 13-35.
  73. Rushakoff RJ, Goldfine ID, Carter JD, Liddle RA. Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans. J Clin Endocrinol Metab 1987; 65: 395-401.
  74. Weser E, Bell D, Tawil T. Effects of octapeptide-cholecystokinin, secretin, and glucagon on intestinal mucosal growth in parenterally nourished rats. Dig Dis Sci 1981; 26: 409-416.
  75. Cardoso JC, Clark MS, Viera FA, Bridge PD, Gilles A, Power DM. The secretin G-protein-coupled receptor family: teleost receptors. J Mol Endocrinol 2005; 34: 753-765.
  76. Kopin AS, Wheeler MB, Leiter AB. Secretin: structure of the precursor and tissue distribution of the mRNA. Proc Natl Acad Sci USA 1990; 87: 2299-2303.
  77. Li P, Lee KY, Chang TM, Chey WY. Mechanism of acid-induced release of secretin in rats. Presence of a secretin-releasing peptide. J Clin Invest 1990; 86: 1474-1479.
  78. Chey WY, Chang TM. Secretin, 100 years later. J Gastroenterol 2003; 38: 1025-1035.
  79. Buchan AM, Polak JM, Capella C, Solcia E, Pearse AG. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 1978; 56: 37-44.
  80. Sarson DL, Hayter RC, Bloom SR. The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide (GIP) in man. Eur J Clin Invest 1982; 12: 457-461.
  81. Cleator IG, Gourlay RH. Release of immunoreactive gastric inhibitory polypeptide (IR-GIP) by oral ingestion of food substances. Am J Surg 1975; 130: 128-135.
  82. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131-2157.
  83. Verspohl EJ. Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol Ther 2009; 124: 113-138.
  84. Karamanlis A, Chaikomin R, Doran S, et al. Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects. Am J Clin Nutr 2007; 86: 1364-1368.
  85. McIntosh CH, Widenmaier S, Kim SJ. Glucose-dependent insulinotropic polypeptide signaling in pancreatic b-cells and adipocytes. J Diabetes Investig 2012; 3: 96-106.
  86. McIntosh CH, Widenmaier S, Kim SJ. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitam Horm 2009; 80: 409-471.
  87. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993; 91: 301-307.
  88. Meier JJ, Gallwitz B, Siepmann N, et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 2003; 46: 798-801.
  89. Mentis N, Vardarli I, Kothe LD, et al. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 2011; 60: 1270-1276.
  90. Tolhurst G, Reimann F, Gribble FM. Nutritional regulation of glucagon-like peptide-1 secretion. J Physiol 2009; 587: 27-32.
  91. Doyle ME, Egan JM. Glucagon-like peptide-1. Recent Prog Horm Res 2001; 56: 377-399.
  92. Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF. Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects. Diabetes Care 1992; 15: 270-276.
  93. Goke R, Wagner B, Fehmann HC, Goke B. Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7-36) amide on the rat pancreas. Res Exp Med (Berl) 1993; 193: 97-103.
  94. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239-1246.
  95. Turton MD, O'Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 69-72.
  96. Tang-Christensen M, Larsen PJ, Goke R, et al. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Physiol 1996; 271: R848-R856.
  97. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 515-520.
  98. Gutzwiller JP, Drewe J, Goke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999; 276: R1541-R1544.
  99. Naslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 1999; 23: 304-311.
  100. Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. J Clin Endocrinol Metab 2009; 94: 1843-1852.
  101. Orskov C, Wettergren A, Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes 1993; 42: 658-661.
  102. Tasyurek HM, Altunbas HA, Balci MK, Sanlioglu S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev 2014; 30: 354-371.
  103. Tonne JM, Sakuma T, Deeds MC, et al. Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy. Dis Model Mech 2013; 6: 1236-1245.
  104. Wang J, Wang F, Xu J, Ding S, Guo Y. Double-strand adeno-associated virus-mediated exendin-4 expression in salivary glands is efficient in a diabetic rat model. Diabetes Res Clin Pract 2014; 103: 466-473.
  105. Michel MC, Beck-Sickinger A, Cox H, et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 1998; 50: 143-150.
  106. Larsson LI, Sundler F, Hakanson R. Pancreatic polypeptide - a postulated new hormone: identification of its cellular storage site by light and electron microscopic immunocytochemistry. Diabetologia 1976; 12: 211-226.
  107. Adrian TE, Greenberg GR, Besterman HS, Bloom SR. Pharmacokinetics of pancreatic polypeptide in man. Gut 1978; 19: 907-909.
  108. Schwartz TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 1983; 85: 1411-1425.
  109. Katsuura G, Asakawa A, Inui A. Roles of pancreatic polypeptide in regulation of food intake. Peptides 2002; 23: 323-329.
  110. Seymour NE, Brunicardi FC, Chaiken RL, et al. Reversal of abnormal glucose production after pancreatic resection by pancreatic polypeptide administration in man. Surgery 1988; 104: 119-129.
  111. Dembinski A, Warzecha Z, Ceranowicz P, et al. Influence of central and peripheral administration of pancreatic polypeptide on gastric mucosa growth. J Physiol Pharmacol 2004; 55: 223-237.
  112. Mortenson M, Bold RJ. Symptomatic pancreatic polypeptide-secreting tumor of the distal pancreas (PPoma). Int J Gastrointest Cancer 2002; 32: 153-156.
  113. Pappas TN, Debas HT, Chang AM, Taylor IL. Peptide YY release by fatty acids is sufficient to inhibit gastric emptying in dogs. Gastroenterology 1986; 91: 1386-1389.
  114. Lin HC, Zhao XT, Wang L, Wong H. Fat-induced ileal brake in the dog depends on peptide YY. Gastroenterology 1996; 110: 1491-1495.
  115. Liu CD, Aloia T, Adrian TE, et al. Peptide YY: a potential proabsorptive hormone for the treatment of malabsorptive disorders. Am Surg 1996; 62: 232-236.
  116. Burgus R, Ling N, Butcher M, Guillemin R. Primary structure of somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone. Proc Natl Acad Sci USA 1973; 70: 684-688.
  117. Shen LP, Pictet RL, Rutter WJ. Human somatostatin I: sequence of the cDNA. Proc Natl Acad Sci USA 1982; 79: 4575-4579.
  118. Raper SE, Kothary PC, Kokudo N, DelValle J, Eckhauser FE. The liver plays an important role in the regulation of somatostatin-14 in the rat. Am J Surg 1991; 161: 184-189.
  119. Penman E, Wass JA, Medbak S, et al. Response of circulating immunoreactive somatostatin to nutritional stimuli in normal subjects. Gastroenterology 1981; 81: 692-699.
  120. Schusdziarra V, Harris V, Conlon JM, Arimura A, Unger R. Pancreatic and gastric somatostatin release in response to intragastric and intraduodenal nutrients and HCl in the dog. J Clin Invest 1978; 62: 509-518.
  121. Eissele R, Koop H, Arnold R. Effect of glucagon-like peptide-1 on gastric somatostatin and gastrin secretion in the rat. Scand J Gastroenterol 1990; 25: 449-454.
  122. Holzer P. Neural emergency system in the stomach. Gastroenterology 1998; 114: 823-839.
  123. Shulkes A, Read M. Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. Endocrinology 1991; 129: 2329-2334.
  124. Lamers CB. Clinical and pathophysiological aspects of somatostatin and the gastrointestinal tract. Acta Endocrinol Suppl (Copenh) 1987; 286: 19-25.
  125. Low MJ. Clinical endocrinology and metabolism. The somatostatin neuroendocrine system: physiology and clinical relevance in gastrointestinal and pancreatic disorders. Best Pract Res Clin Endocrinol Metab 2004; 18: 607-622.
  126. De Martino MC, Hofland LJ, Lamberts SW. Somatostatin and somatostatin receptors: from basic concepts to clinical applications. Prog Brain Res 2010; 182: 255-280.
  127. Weiner RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases. Appl Radiat Isot 2002; 57: 749-763.
  128. van Essen M, Sundin A, Krenning EP, Kwekkeboom DJ. Neuroendocrine tumours: the role of imaging for diagnosis and therapy. Nat Rev Endocrinol 2014; 10: 102-114.
  129. Bergsma H, van Vliet EI, Teunissen JJ, et al. Peptide receptor radionuclide therapy (PRRT) for GEP-NETs. Best Pract Res Clin Gastroenterol 2012; 26: 867-881.
  130. Kitabgi P. Prohormone convertases differentially process pro-neurotensin/neuromedin N in tissues and cell lines. J Mol Med 2006; 84: 628-634.
  131. Carraway R, Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 1973; 248: 6854-6861.
  132. Kitabgi P, Carraway R, Leeman SE. Isolation of a tridecapeptide from bovine intestinal tissue and its partial characterization as neurotensin. J Biol Chem 1976; 251: 7053-7058.
  133. Uhl GR, Goodman RR, Snyder SH. Neurotensin-containing cell bodies, fibers and nerve terminals in the brain stem of the rat: immunohistochemical mapping. Brain Res 1979; 167: 77-91.
  134. Barber DL, Buchan AM, Leeman SE, Soll AH. Canine enteric submucosal cultures: transmitter release from neurotensin-immunoreactive neurons. Neuroscience 1989; 32: 245-253.
  135. Gill SS, Lee YC, Ghatei MA, Ghiglione M, Uttenthal LO, Bloom SR. The use of a rat isolated ileal preparation to investigate the release of neurotensin. Clin Exp Pharmacol Physiol 1984; 11: 457-465.
  136. Andersson S, Chang D, Folkers K, Rosell S. Inhibition of gastric acid secretion in dogs by neurotensin. Life Sci 1976; 19: 367-370.
  137. Sendur R, Thor P, Biernat J, Koziol R, Pawlik WW. Mechanism of action of neurotensin on microcirculation, metabolism and motility of the small intestine. Folia Med Cracov 1997; 38: 3-15.
  138. Thor K, Rosell S. Neurotensin increases colonic motility. Gastroenterology 1986; 90: 27-31.
  139. Peeters TL. Ghrelin: a new player in the control of gastrointestinal functions. Gut 2005; 54: 1638-1649.
  140. Cheung CK, Wu JC. Role of ghrelin in the pathophysiology of gastrointestinal disease. Gut Liver 2013; 7: 505-512.
  141. Satoh M, Sakai T, Koyama H, Shiba Y, Itoh Z. Immunocytochemical localization of motilin-containing cells in the rabbit gastrointestinal tract. Peptides 1995; 16: 883-887.
  142. Seino Y, Tanaka K, Takeda J, et al. Sequence of an intestinal cDNA encoding human motilin precursor. FEBS Lett 1987; 223: 74-76.
  143. Shima K, Shin S, Tanaka A, et al. Heterogeneity of plasma motilin in patients with chronic renal failure. Horm Metab Res 1980; 12: 328-331.
  144. Poitras P, Lemoyne M, Tasse D, Trudel L, Yamada T, Taylor IL. Variations in plasma motilin, somatostatin, and pancreatic polypeptide concentrations and the interdigestive myoelectric complex in dog. Can J Physiol Pharmacol 1985; 63: 1495-500.
  145. Vantrappen G, Janssens J, Peeters TL, Bloom SR, Christofides ND, Hellemans J. Motilin and the interdigestive migrating motor complex in man. Dig Dis Sci 1979; 24: 497-500.
  146. Mitznegg P, Bloom SR, Christofides N, et al. Release of motilin in man. Scand J Gastroenterol Suppl 1976; 39: 53-56.
  147. Fox JE, Daniel EE, Jury J, Robotham H. The mechanism of motilin excitation of the canine small intestine. Life Sci 1984; 34: 1001-1006.
  148. Suzuki H, Kuwano H, Mochiki E, et al. Effect of motilin on endogenous release of insulin in conscious dogs in the fed state. Dig Dis Sci 2003; 48: 2263-2270.
  149. McKee KK, Palyha OC, Feighner SD, et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415-423.
  150. Hattori N. Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm IGF Res 2009; 19: 187-197.
  151. Akamizu T, Takaya K, Irako T, et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol 2004; 150: 447-455.
  152. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988-2991.
  153. Broglio F, Benso A, Castiglioni C, et al. The endocrine response to ghrelin as a function of gender in humans in young and elderly subjects. J Clin Endocrinol Metab 2003; 88: 1537-1542.
  154. Rak-Mardyla A. Ghrelin role in hypothalamus-pituitary-ovarian axis. J Physiol Pharmacol 2013; 64: 695-704.
  155. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992-5995.
  156. Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 2540-2547.
  157. Shiiya T, Nakazato M, Mizuta M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240-244.
  158. Masuda Y, Tanaka T, Inomata N, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 905-908.
  159. Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S. Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun 2001; 280: 904-907.
  160. Dornonville de la Cour C, Lindstrom E, Norlen P, Hakanson R. Ghrelin stimulates gastric emptying but is without effect on acid secretion and gastric endocrine cells. Regul Pept 2004; 120: 23-32.
  161. Rau TT, Sonst A, Rogler A, et al. Gastrin mediated down regulation of ghrelin and its pathophysiological role in atrophic gastritis. J Physiol Pharmacol 2013; 64: 719-725.
  162. Zhang W, Chen M, Chen X, Segura BJ, Mulholland MW. Inhibition of pancreatic protein secretion by ghrelin in the rat. J Physiol 2001; 537: 231-236.
  163. Lee HM, Wang G, Englander EW, Kojima M, Greeley GH. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 2002; 143: 185-190.
  164. Date Y, Nakazato M, Hashiguchi S, et al. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes 2002; 51: 124-129.
  165. Reimer MK, Pacini G, Ahren B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 2003; 144: 916-921.
  166. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secreatgogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001; 86: 5083-5083.
  167. Dezaki K. Ghrelin function in insulin release and glucose metabolism. Endocr Dev 2013; 25: 135-143.
  168. Yada T, Damdindorj B, Rita RS, et al. Ghrelin signalling in b-cells regulates insulin secretion and blood glucose. Diabetes Obes Metab 2014; 16 (Suppl. 1): 111-117.
  169. Dembinski A, Warzecha Z, Ceranowicz P, et al. Variable effect of ghrelin administration on pancreatic development in young rats. Role of insulin-like growth factor-1. J Physiol Pharmacol 2005; 56: 555-570.
  170. Warzecha Z, Dembinski A, Ceranowicz P, et al. Dual age-dependent effect of ghrelin administration on serum level of insulin-like growth factor-1 and gastric growth in young rats. Eur J Pharmacol 2006; 529: 145-150.
  171. Warzecha Z, Dembinski A, Ceranowicz P, et al. Influence of ghrelin on gastric and duodenal growth and expression of digestive enzymes in young mature rats. J Physiol Pharmacol 2006; 57: 425-437.
  172. Frascarelli S, Ghelerdoni S, Ronca-Testoni S, Zucchi R. Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. Basic Res Cardiol 2003; 98: 401-405.
  173. Takeda R, Nishimatsu H, Suzuki E, et al. Ghrelin improves renal function in mice with ischemic acute renal failure. J Am Soc Nephrol 2006; 17: 113-121.
  174. Liu Y, Wang PS, Xie D, Liu K, Chen L. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chin J Physiol 2006; 49: 244-250.
  175. Wu R, Dong W, Zhou M, et al. Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats. Am J Respir Crit Care Med 2007; 176: 805-813.
  176. Sibilia V, Rindi G, Pagani F, et al. Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology 2003; 144: 353-359.
  177. Warzecha Z, Dembinski A. Protective and therapeutic effects of ghrelin in the gut. Curr Med Chem 2012; 19: 118-125.
  178. Dembinski A, Warzecha Z, Ceranowicz P, et al. Ghrelin attenuates the development of acute pancreatitis in rat. J Physiol Pharmacol 2003; 54: 561-573.
  179. Dembinski A, Warzecha Z, Ceranowicz P, et al. Role of growth hormone and insulin-like growth factor-1 in the protective effect of ghrelin in ischemia/reperfusion-induced acute pancreatitis. Growth Horm IGF Res 2006; 16: 348-56.
  180. Warzecha Z, Ceranowicz P, Dembinski A, et al. Therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis in rats. J Physiol Pharmacol 2010; 61: 419-427.
  181. Ceranowicz D, Warzecha Z, Dembinski A, et al. Role of hormonal axis, growth hormone - IGF-1, in the therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis. J Physiol Pharmacol 2010; 61: 599-606.
  182. Ceranowicz P, Warzecha Z, Dembinski A, et al. Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats. J Physiol Pharmacol 2009; 60: 87-98.
  183. Warzecha Z, Ceranowicz P, Dembinski M, et al. Involvement of cyclooxygenase-1 and cyclooxygenase-2 activity in the therapeutic effect of ghrelin in the course of ethanol-induced gastric ulcers in rats. J Physiol Pharmacol 2014; 65: 95-106.
  184. Szlachcic A, Majka J, Strzalka M, et al. Experimental healing of preexisting gastric ulcers induced by hormones controlling food intake ghrelin, orexin-A and nesfatin-1 is impaired under diabetic conditions. A key to understanding the diabetic gastropathy? J Physiol Pharmacol 2013; 64: 625-637.
  185. Warzecha Z, Ceranowicz D, Dembinski A. Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats. Med Sci Monit 2012; 18: BR181-BR187.
  186. Warzecha Z, Kownacki P, Ceranowicz P, Dembinski M, Cieszkowski J, Dembinski A. Ghrelin accelerates the healing of oral ulcers in non-sialoadenectomized and sialoadenectomized rats. J Physiol Pharmacol 2013; 64: 657-668.
  187. Pamukcu O, Kumral ZN, Ercan F, Yegen BC, Ertem D. Anti-inflammatory effect of obestatin and ghrelin in dextran sulfate sodium-induced colitis in rats. J Pediatr Gastroenterol Nutr 2013; 57: 211-218.
  188. Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev 2009; 61: 430-481.
  189. Costantino L, Barlocco D. Ghrelin receptor modulators: a patent review (2011-2014). Expert Opin Ther Pat 2014; 24: 1007-1019.
  190. Zhang JV, Ren PG, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 2005; 310: 996-999.
  191. Holst B, Egerod KL, Schild E, et al. GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology 2007; 148: 13-20.
  192. Granata R, Settanni F, Gallo D, et al. Obestatin promotes survival of pancreatic beta-cells and human islets and induces expression of genes involved in the regulation of beta-cell mass and function. Diabetes 2008; 57: 967-979.
  193. Seim I, Collet C, Herington AC, Chopin LK. Revised genomic structure of the human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts. BMC Genomics 2007; 8: 298.
  194. Gourcerol G, Million M, Adelson DW, et al. Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents. Peptides 2006; 27: 2811-2819.
  195. Samson WK, White MM, Price C, Ferguson AV. Obestatin acts in brain to inhibit thirst. Am J Physiol Regul Integr Comp Physiol 2007; 292: R637-R643.
  196. Samson WK, Yosten GL, Chang JK, Ferguson AV, White MM. Obestatin inhibits vasopressin secretion: evidence for a physiological action in the control of fluid homeostasis. J Endocrinol 2008; 196: 559-564.
  197. Kapica M, Zabielska M, Puzio I, et al . Obestatin stimulates the secretion of pancreatic juice enzymes through a vagal pathway in anaesthetized rats - preliminary results. J Physiol Pharmacol 2007; 58 (Suppl. 3): 123-130.
  198. Carlini VP, Schioth HB, Debarioglio SR. Obestatin improves memory performance and causes anxiolytic effects in rats. Biochem Biophys Res Commun 2007; 352: 907-912.
  199. Szentirmai E, Krueger JM. Obestatin alters sleep in rats. Neurosci Lett 2006; 404: 222-226.
  200. Ceranowicz P, Warzecha Z, Dembinski A, et al. Pretreatment with obestatin inhibits the development of cerulein-induced pancreatitis. J Physiol Pharmacol 2009; 60: 95-101.
  201. Dembinski A, Warzecha Z, Ceranowicz P, et al. Administration of obestatin accelerates the healing of chronic gastric ulcers in rats. Med Sci Monit 2011; 17: BR196-BR200.
  202. Tatemoto K, Hosoya M, Habata Y, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471-476.
  203. Lee DK, Cheng R, Nguyen T, et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem 2000; 74: 34-41.
  204. Kawamata Y, Habata Y, Fukusumi S, et al. Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 2001; 1538: 162-171.
  205. Pitkin SL, Maguire JJ, Bonner TI, Davenport AP. International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev 2010; 62: 331-342.
  206. Wang G, Anini Y, Wei W, et al. Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion. Endocrinology 2004; 145: 1342-1348.
  207. Susaki E, Wang G, Cao G, Wang HQ, Englander EW, Greeley GH. Apelin cells in the rat stomach. Regul Pept 2005; 129: 37-41.
  208. Wang G, Kundu R, Han S, et al. Ontogeny of apelin and its receptor in the rodent gastrointestinal tract. Regul Pept 2009; 158: 32-39.
  209. Sorhede Winzell M, Magnusson C, Ahren B. The receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul Pept 2005; 131: 12-17.
  210. Berry MF, Pirolli TJ, Jayasankar V, et al. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation 2004; 110 (11 Suppl. 1): 187-193.
  211. Perjes A, Skoumal R, Tenhunen O, et al. Apelin increases cardiac contractility via protein kinase Ce- and extracellular signal-regulated kinase-dependent mechanisms. PLoS One 2014; 9: e93473.
  212. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 2009; 54: 598-604.
  213. De Mota N, Reaux-Le Goazigo A, El Messari S, et al. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci USA 2004; 101: 10464-10469.
  214. Hus-Citharel A, Bodineau L, Frugiere A, Joubert F, Bouby N, Llorens-Cortes C. Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology 2014; 155: 4483-4493.
  215. Reaux-Le Goazigo A, Morinville A, Burlet A, Llorens-Cortes C, Beaudet A. Dehydration-induced cross-regulation of apelin and vasopressin immunoreactivity levels in magnocellular hypothalamic neurons. Endocrinology 2004; 145: 4392-4400.
  216. O'Carroll AM, Lolait SJ. Regulation of rat APJ receptor messenger ribonucleic acid expression in magnocellular neurones of the paraventricular and supraopric nuclei by osmotic stimuli. J Neuroendocrinol 2003; 15: 661-666.
  217. Azizi M, Iturrioz X, Blanchard A, et al. Reciprocal regulation of plasma apelin and vasopressin by osmotic stimuli. J Am Soc Nephrol 2008; 19: 1015-1024.
  218. Ohno S, Yakabi K, Ro S, et al. Apelin-12 stimulates acid secretion through an increase of histamine release in rat stomachs. Regul Pept 2012; 174: 71-78.
  219. Han S, Wang G, Qi X, Lee HM, Englander EW, Greeley GH. A possible role for hypoxia-induced apelin expression in enteric cell proliferation. Am J Physiol Regul Integr Comp Physiol 2008; 294: R1832-R1839.
  220. Antushevich H, Pawlina B, Kapica M, et al. Influence of fundectomy and intraperitoneal or intragastric administration of apelin on apoptosis, mitosis, and DNA repair enzyme OGG1,2 expression in adult rats gastrointestinal tract and pancreas. J Physiol Pharmacol 2013; 64: 423-428.
  221. Kapica M, Jankowska A, Antushevich H, et al. The effect of exogenous apelin on the secretion of pancreatic juice in anaesthetized rats. J Physiol Pharmacol 2012; 63: 53-60.
  222. Guo L, Li Q, Wang W, et al. Apelin inhibits insulin secretion in pancreatic beta-cells by activation of PI3-kinase-phosphodiesterase 3B. Endocr Res 2009; 34: 142-154.
  223. Zhu S, Sun F, Li W, et al. Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3-L1 adipocytes. Mol Cell Biochem 2011; 353: 305-313.
  224. Duparc T, Colom A, Cani PD, et al. Central apelin controls glucose homeostasis via a nitric oxide-dependent pathway in mice. Antioxid Redox Signal 2011; 15: 1477-1496.
  225. Yue P, Jin H, Aillaud M, et al. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol Endocrinol Metab 2010; 298: E59-E67.
  226. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432.
  227. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-770.
  228. Kotz CM, Briggs JE, Pomonis JD, Grace MK, Levine AS, Billington CJ. Neural site of leptin influence on neuropeptide Y signaling ways altering feeding and uncoupling protein. Am J Physiol 1998; 275: R478-R484.
  229. Barbier M, Cherbut C, Aube AC, Blottiere HM, Galmiche S. Elevated plasma leptin concentration in early stages of experimental intestinal inflammation in rats. Gut 1998; 43: 783-790.
  230. Sarraf P, Frederich RC, Turner EM, et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 1997; 185: 171-175.
  231. Faggioni R, Fantuzzi G, Fuller J, Dinarello CA, Feingold KR, Grunfeld C. IL-1 beta mediates leptin induction during inflammation. Am J Physiol 1998; 274: R204-R208.
  232. Biesiada G, Czepiel J, Ptak-Belowska A, et al. Expression and release of leptin and proinflammatory cytokines in patients with ulcerative colitis and infectious diarrhea. J Physiol Pharmacol 2012; 63: 471-481.
  233. Bado A, Levasseur S, Attoub S, et al. The stomach is a source of leptin. Nature 1998; 394: 790-793.
  234. Sobhani I, Bado A, Vissuzaine C, et al. Leptin secretion and leptin receptor in human stomach. Gut 2000; 47: 178-183.
  235. Lin J, Barb CR, Matteri RL, et al. Long form leptin receptor mRNA expression in the brain, pituitary, and other tissues in the pig. Domest Anim Endocrinol 2000; 19: 53-61.
  236. Konturek PC, Konturek SJ, Brzozowski T, Jaworek J, Hahn E. Role of leptin in the stomach and the pancreas. J Physiol (Paris) 2001; 95: 345-354.
  237. Brzozowski T, Konturek PC, Konturek SJ, et al. Leptin in gastroprotection induced by cholecystokinin or by a meal. Role of vagal and sensory nerves and nitric oxide. Eur J Pharmacol 1999; 374: 263-276.
  238. Konturek PC, Brzozowski T, Sulekova Z, et al. Role of leptin in ulcer healing. Eur J Pharmacol 2001; 414: 87-97.
  239. Jaworek J, Bonior J, Leja-Szpak A, et al. Sensory nerves in central and peripherial control of pancreatic integrity by leptin and melatonin. J Physiol Pharmacol 2002; 53: 51-74.
  240. Warzecha Z, Dembinski A, Ceranowicz P, et al. Influence of leptin administration on the course of acute ischemic pancreatitis. J Physiol Pharmacol 2002; 53: 775-790.
  241. Ando S, Barone I, Giordano C, Bonofiglio D, Catalano S. The multifaceted mechanism of leptin signaling within tumor microenvironment in driving breast cancer growth and progression. Front Oncol 2014; 4: 340.
  242. Jiang N, Sun R, Sun Q. Leptin signaling molecular actions and drug target in hepatocellular carcinoma. Drug Des Devel Ther 2014; 8: 2295-2302.
  243. Chen C, Chang YC, Lan MS, Breslin M. Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways. Int J Oncol 2013; 42: 1113-1119.
  244. Ogunwobi O, Mutungi G, Beales IL. Leptin stimulates proliferation and inhibits apoptosis in Barrett's esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. Endocrinology 2006; 147: 4505-4516.
  245. Mokrowiecka A, Sokolowska M, Luczak E, et al. Adiponectin and leptin receptors expression in Barrett's esophagus and normal squamous epithelium in relation to central obesity status. J Physiol Pharmacol 2013; 64: 193-199.
  246. Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 2007; 17: 2-9.
  247. Napier KJ, Scheerer M, Misra S. Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol 2014; 6: 112-120.
R e c e i v e d : June 23, 2014
A c c e p t e d : December 10, 2014
Author’s address: Assoc. Prof. Piotr Ceranowicz, Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland. e-mail: mpcerano@cyf-kr.edu.pl