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Posts Tagged ‘Gastroenterology’


Gastrointestinal Endocrinology

Writer and Curator: Larry H Bernstein, MD, FCAP

The Gut Microbial Endocrine Organ: Bacterially Derived Signals Driving Cardiometabolic DiseasesMark Brown and Stanley L. Hazen

Annual Review of Medicine Jan 2015; 66: 343-359
http://dx.doi.org:/10.1146/annurev-med-060513-093205

The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention.

Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

Antonella Amato, Sara Baldassano, Rosa Liotta1, Rosa Serio and Flavia Mulè
J Endocrinol April 1, 2014 221 29-37
http://dx.doi.org:/10.1530/JOE-13-0525

Glucagon-like peptide 1 (GLP1) is a naturally occurring peptide secreted by intestinal L-cells. Though its primary function is to serve as an incretin, GLP1 reduces gastrointestinal motility. However, only a handful of animal studies have specifically evaluated the influence of GLP1 on colonic motility. Consequently, the aims of this study were to investigate the effects induced by exogenous GLP1, to analyze the mechanism of action, and to verify the presence of GLP1 receptors (GLP1Rs) in human colon circular muscular strips. Organ bath technique, RT-PCR, western blotting, and immunofluorescence were used. In human colon, exogenous GLP1 reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions without affecting the frequency and the resting basal tone. This inhibitory effect was significantly reduced by exendin (9–39), a GLP1R antagonist, which per se significantly increased the spontaneous mechanical activity. Moreover, it was abolished by tetrodotoxin, a neural blocker, or Nω-nitro-L-arginine – a blocker of neuronal nitric oxide synthase (nNOS). The biomolecular analysis revealed a genic and protein expression of the GLP1R in the human colon. The double-labeling experiments with anti-neurofilament or anti-nNOS showed, for the first time, that immunoreactivity for the GLP1R was expressed in nitrergic neurons of the myenteric plexus. In conclusion, the results of this study suggest that GLP1R is expressed in the human colon and, once activated by exogenous GLP1, mediates an inhibitory effect on large intestine motility through NO neural release.

The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects

N A Rhee, S H Østoft, J J Holst, C F Deacon, T Vilsbøll and F K Knop
Eur J Endocrinol September 1, 2014 171 353-36
http://dx.doi.org:/10.1530/EJE-14-0314

Objective Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects. Design A randomised, controlled and open-labelled study. Methods Ten healthy subjects (six women; age, 40±5 years (mean±S.E.M.); BMI, 24±3 kg/m2; fasting plasma glucose, 5.1±0.2 mmol/l and HbA1c, 34±1 mmol/mol (5.3±0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A1+B1) and without (A2+B2) preceding administration of the DPP4 inhibitor sitagliptin. Results Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1±0.1 vs 4.9±0.1 mmol/l, P=0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151±35 vs 137±26 mmol/l×min, P=0.7) or peak plasma glucose during OGTT (8.5±0.4 vs 8.1±0.3 mmol/l, P=0.3) was observed. Neither incretin effect (40±9% (without DPP4 inhibitor) vs 40±7% (with DPP4 inhibitor), P=1.0), glucagon responses (1395±165 vs 1223±195 pmol/l×min, P=0.41), GIGD (52±4 vs 56±5%, P=0.40) nor gastric emptying (Tmax for plasma paracetamol: 86±9 vs 80±12 min, P=0.60) changed following DPP4 inhibition. Conclusions These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.

Morphology and Tissue Distribution of Four Kinds of Endocrine Cells in the Digestive Tract of the Chinese Yellow Quail (Coturnix japonica)

He, M., Liang, X., Wang, K., (…), Li, X., Liu, L.
Analytical and Quantitative Cytology and Histology 2014; 36 (4), pp. 199-205

Objective: To describe the tissue distribution, density, and the morphological characteristics of 4 kinds of endocrine cells in the digestive tract of the Chinese yellow quail (Coturnix japonica). Study design: The streptavidin-biotin-peroxidase complex immunohistochemical method was used to identify the distribution of somatostatin (SS), serotonin (5-HT), gastrin and neuropeptide Y (NPY) in digestive tracts including proventriculus, duodenum, jejunum, ileum, and rectum. SPSS 19.0 software was used to perform biological statistical analysis. Results: The results showed that the SS and 5-HT secreting cells were mainly distributed in the proventriculus (19.2±6.9 and 16.1±3.4 cfu/mm2) and duodenum (2.9±2.0 and 1.9±0.6 cfu/mm2). Gastrin and NPY were not detected in each section of the digestive tract. Moreover, there was no significant difference in the quantitative distribution and morphological characteristics of SS and 5-HT secreting cells in the digestive tract between male and female quails. Conclusion: The distribution and morphological characteristics of endocrine cells were closely related to the physiological functions of different parts in the digestive tract. The preferential location of endocrine cells provides additional information for future studies on the physiological roles of gastrointestinal peptides in the gastrointestinal tract of the Chinese yellow quail

GEP-NETS update: Functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs)

Wouter W de Herder
Eur J Endocrinol May 1, 2014 170 R173-R183
http://dx.doi.org:/10.1530/EJE-14-0077

For patients with neuroendocrine tumours (NETs) of the gastrointestinal tract and pancreas (GEP) (GEP-NETs), excellent care should ideally be provided by a multidisciplinary team of skilled health care professionals. In these patients, a combination of nuclear medicine imaging and conventional radiological imaging techniques is usually mandatory for primary tumour visualisation, tumour staging and evaluation of treatment. In specific cases, as in patients with occult insulinomas, sampling procedures can provide a clue as to where to localise the insulin-hypersecreting pancreatic NETs. Recent developments in these fields have led to an increase in the detection rate of primary GEP-NETs and their metastatic deposits. Radiopharmaceuticals targeted at specific tumour cell properties and processes can be used to provide sensitive and specific whole-body imaging. Functional imaging also allows for patient selection for receptor-based therapies and prediction of the efficacy of such therapies. Positron emission tomography/computed tomography (CT) and single-photon emission CT/CT are used to map functional images with anatomical localisations. As a result, tumour imaging and tumour follow-up strategies can be optimised for every individual GEP-NET patient. In some cases, functional imaging might give indications with regard to future tumour behaviour and prognosis.

An immunohistochemical study on the distribution of endocrine cells in the digestive tract of gray goose (Anser anser)

Jun YANG1, Lei ZHANG,, Xin LI, , Leii ZHANG, , Xiangjiang LIU, , Kemei PENG

Turk. J. Vet. Anim. Sci. 2012; 36(4): 373-379
http://dx.doi.org:/10.3906/vet-1101-654

The objective of this study was to investigate the morphology and the distribution of 5-hydroxytryptamine (5-HT), somatostatin (SS), gastrin (Gas), glucagon (Glu), and substance P immunoreactive (IR) cells in the digestive tract of gray goose by the immunohistochemical streptavidin-peroxidase method.

The samples were taken from 10 healthy  adult gray geese. Th e results showed that 5 kinds of IR cells were mainly distributed between the mucous epithelium and intestinal gland. The number of 5-HT-IR cells was highest in the rectum and duodenum, but none were observed  in the pylorus. SS-IR cells appeared in great numbers in the pylorus, duodenum, and cecum; however, they were not found in esophagus. Gas-IR cells were mainly distributed in the glandular stomach and jejunum. Glu-IR cells appeared  in small numbers in the glandular stomach, duodenum, and jejunum, but were not detected in other tissues. Substance  P-IR cells were located in the jejunum, cecum, and rectum. Analysis of the present study showed that the distribution and morphological features of these 5 different endocrine cells were related to the feeding habits and metabolism in the digestive tract of the gray goose

Chapter 154 – Somatostatin

Mathias Guggera, Jean-Claude Meunierb

Handbook of Biologically Active Peptides 2006, Pages 1123–1130
http:/dx.doi.org:/10.1016/B978-012369442-3/50157-4

Somatostatin is abundant in the mucosa and in the enteric nervous system of the gastrointestinal tract and in the pancreas. In these tissues, it exerts a broad range of mainly inhibitory physiological actions in multiple targets, including endocrine glands, exocrine glands, smooth muscles, blood vessels, and immune cells, mediated by up to six somatostatin receptor subtypes. Several diseases of the gastrointestinal tract are characterized by disturbances in the somatostatin production or by overexpression of somatostatin receptors. In particular, somatostatin receptors have been found to be overexpressed in neuroendocrine gastroenteropancreatic tumors. These tumors can be diagnostically and therapeutically targeted with somatostatin analogs. In addition, various nonneoplastic diseases, including bleeding in the upper gastrointestinal tract, fistulas, and diarrhea can also be treated with somatostatin analogs.

Immunocytochemical study of the distribution of endocrine cells in the pancreas of the Brazilian sparrow species Zonotrichia Capensis Subtorquata (Swaison, 1837)

Nascimento, AA.*; Sales, A.; Cardoso, TRD.; Pinheiro, NL.; Mendes, RMM.
Braz. J. Biol. Nov. 2007; 67(4):  São Carlos

In the present study, we investigated types of pancreatic endocrine cells and its respective peptides in the Brazilian sparrow species using immunocytochemistry. The use of polyclonal specific antisera for somatostatin, glucagon, avian pancreatic polypeptide (APP), YY polypeptide (PYY) and insulin, revealed a diversified distribution in the pancreas. All these types of immunoreactive cells were observed in the pancreas with different amounts. Insulin- Immunoreactive cells to (B cells) were most numerous, preferably occupying the central place in the pancreatic islets. Somatostatin, PPA, PYY and glucagon immunoreactive cells occurred in a lower frequency in the periphery of pancreatic islets.

Immunolocalisation of the serotonin in the fundus ventriculi and duodenum of the Asia minor ground squirrel: (Spermophilus xanthoprymnus)

Timurkaan, S., Özkan, E., Ilgün, R., Gür, F.M
Veterinarski Arhiv 2009; 79 (1), pp. 69-76

Serotonin immunoreactive cells were located and distributed in the fundus and duodenum with variable frequencies. They were spherical or spindle-shaped and the highest frequency serotonin immunoreactive cells were detected in the whole fundic region. The regional distribution of the endocrine cells in the fundus and duodenum of the citellus resembled other mammalian species.

An Immunohistochemical Study of Gastrointestinal Endocrine Cells in the BALB/c Mouse

Ku, S.K., Lee, H.S., Lee, J.H.
J Vet Med Series C: Anatomia Histologia Embryologia 2004; 33 (1), pp. 42-48

The distributions and frequencies of some endocrine cells in the eight portions of the gastrointestinal tract (GIT) of BALB/c mouse were studied. Endocrine cells were stained using immunohistochemical method with seven types of anti-sera against bovine chromogranin (BCG), serotonin, gastrin, cholecystokinin (CCK)-8, somatostatin, glucagon and human pancreatic polypeptide (HPP), and the regional distributions and their relative frequencies were observed in the eight portions of the GIT of BALB/c mice. All seven types of immunoreactive (IR) cells were identified. Most of the IR cells in the intestinal portion were generally spherical or spindle in shape (open type cell) while round-shaped cells (closed type cell) were found in the intestinal gland and stomach regions occasionally. Their relative frequencies varied according to each portion of the GIT. BCG-IR cells were observed throughout the whole GIT except for the rectum and they were most predominant in the pylorus. Serotonin-IR cells were detected throughout the whole GIT and they showed the highest frequency in the fundus. Gastrin- and CCK-IR cells were restricted to the pylorus and duodenum with a majority in the pylorus and rare or a few frequencies in the duodenum. Compared with other mammals, somatostatin-IR cells were restricted to the fundus and pylorus with a few frequencies, respectively. In addition, glucagon- and HPP-IR cells were restricted to the fundus and duodenum, respectively, with relative low frequencies. Some species-dependent unique distributions and frequencies of endocrine cells were observed in the GIT of BALB/c mouse compared with other rodents.

Immunohistochemical study of the distribution of serotonin in the gastrointestinal tract of the porcupines (Hystrix cristata)

Timurkaan, S., Karan, M., Aydin, A.
Revue de Medecine Veterinaire 2005; 156 (11), pp. 533-536

Serotonin immunoreactive cells were located in the gastric glands and in the intestinal epithelium with variable frequencies. They were spherical or spindle-shaped. Serotonin immuno-reactive cells were detected in almost all regions of the gastrointestinal tract and they showed highest frequency in the stomach and colon.

Effects of carbachol on gastrin and somatostatin release in rat antral tissue culture

Wolfe, M.M., Jain, D.K., Reel, G.M., McGuigan, J.E.
Gastroenterology 1984; 87 (1), pp. 86-93

Recent studies have demonstrated that somatostatin-containing cells are in close anatomic proximity to gastrin-producing cells in antral mucosa, suggesting a potential local regulatory role for somatostatin. The purpose of this study was to examine further the relationships between gastrin and somatostatin and the effects of the cholinergic agonist carbachol on content and release of gastrin and somatostatin using rat antral mucosa in tissue culture. Antral mucosa was cultured at 37 °C in KrebsHenseleit buffer, pH 7.4, gassed with 95% O2-5% CO2. After 1 h, the culture medium was decanted and the tissue was boiled to extract mucosal gastrin and somatostatin. Inclusion of carbachol 2.5 × 10-6 M in the culture medium decreased medium somatostatin from 1.91 ± 0.28 (SEM) ng/mg tissue protein to 0.62 ± 0.12 ng/mg (p < 0.01), extracted mucosal somatostatin from 2.60 ± 0.30 to 1.52 ± 0.16 ng/mg (p < 0.001), and percentage of somatostatin released from 42% ± 2.6% to 27% ± 2.2% (p < 0.01). Carbachol also increased culture media gastrin from 14 ± 2.5 to 27 ± 3.0 ng/mg protein (p < 0.01). Tissue content and release of gastrin and somatostatin were also examined during culture of rat antral mucosa in culture media containing antibodies to somatostatin in the presence and in the absence of carbachol. Incubation with somatostatin antisera, both with and without carbachol, markedly increased culture media concentrations of somatostatin, all of which was effectively bound by antibodies present in the media. Antibody binding of somatostatin was accompanied by significant increases in culture media gastrin concentrations, both in the presence and in the absence of carbachol. Results of these studies support the hypothesis that antral somatostatin exerts a local regulatory effect on gastrin release and that cholinergic stimulation of gastrin release is mediated, at least in part, through inhibition of somatostatin synthesis and release.

Endogenous somatostatin-28 modulates postprandial insulin secretion. Immunoneutralization studies in baboons

J W Ensinck, R E Vogel, E C Laschansky, D J Koerker, et al.
J Clin Invest. 1997; 100(9):2295–2302.
http://dx.doi.org:/10.1172/JCI119767

Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic D cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic B cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14. We attempted to demonstrate a hormonal effect of these peptides by measuring their concentrations before and after infusing a somatostatin-specific monoclonal antibody (mAb) into baboons and comparing glucose, insulin, and glucagon-like peptide-1 levels before and for 4 h after intragastric nutrients during a control study and on 2 d after mAb administration (days 1 and 2). Basal growth hormone (GH) and glucagon levels and parameters of insulin and glucose kinetics were also measured. During immunoneutralization, we found that (a) postprandial insulin levels were elevated on days 1 and 2; (b) GH levels rose immediately and were sustained for 28 h, while glucagon fell; (c) basal insulin levels were unchanged on day 1 but were increased two to threefold on day 2, coincident with decreased insulin sensitivity; and (d) plasma glucose concentrations were similar to control values. We attribute the eventual rise in fasting levels of insulin to its enhanced secretion in compensation for the heightened insulin resistance from increased GH action. Based on the elevated postmeal insulin levels after mAb administration, we conclude that S-28 participates in the enteroinsular axis as a decretin to regulate postprandial insulin secretion.

The Therapeutic Value of Somatostatin and Its Analogues

Sadaf Farooqi, John S. Bevan, Michael C. Shepperd, John A. H. Wass
Pituitary June 1999; 2(1), pp 79-88
http:/dx.doi.org:/10.1023/A:1009978106476

In this review we discuss the physiological effects of somatostatin, which are mediated by specific receptor subtypes on different tissues. These observations have suggested new therapeutic possibilities for the use of the synthetic somatostatin analogues in the treatment of acromegaly as well as a number of other endocrine and non-endocrine disorders.

Somatostatin and Somatostatin Receptors

Ujendra Kumar, Michael Grant
Cellular Peptide Hormone Synthesis and Secretory Pathways
(Results and Problems in Cell Differentiation) 2010; 50: pp 97-120
http://dx.doi.org:/10.1007/400_2009_29

The biological effects of somatostatin (SST) were first encountered unexpectedly in the late 1960s in two unrelated studies, one by Krulich et al. (1968) who reported on a growth hormone (GH)-releasing inhibitory substance from hypothalamic extracts, and the other, by Hellman and Lernmark (1969), on the presence of a potent insulin inhibitory factor from the extracts of pigeon pancreatic islets. However, the inhibitory substance was not officially identified until 1973 by Guillemin’s group (Brazeau et al. 1973). In both synthetic and naturally occurring forms, this tetradecapeptide, originally coined as somatotropin release-inhibitory factor (SRIF, SST-14) was shown by Brazeau et al. to be the substance controlling hypothalamic GH release. This single achievement not only pioneered SST research but was also duly recognized, as Guillemin shared the 1977 Nobel Prize in Medicine. The following years bequeathed an exponential increase in SST-related studies. It soon became clear that SST-synthesis was not restricted to the hypothalamus. Its production is widely distributed throughout the central nervous system (CNS), peripheral neurons, the gastrointestinal tract, and the pancreatic islets of Langerhans (Luft et al. 1974; Arimura et al. 1975; Dubois 1975; Hokfelt et al. 1975; Orci et al. 1975; Pelletier et al. 1975; Polak et al. 1975; Patel and Reichlin 1978). In fact, SST-like immunoreactivity can be found throughout various tissues of vertebrates and invertebrates, including the plant kingdom (Patel 1992; Tostivint et al. 2004). Given its broad anatomical distribution, it is no wonder that SST produces a wide spectrum of biological effects. Generally regarded as an inhibitory factor, SST can function either locally on neighboring cells or distantly through the circulation, to regulate such physiological processes as glandular secretion, neurotransmission, smooth muscle contractility, nutrient absorption, and cell division (Reichlin 1983a, b; Patel 1992, 1999; Patel et al. 2001; Barnett 2003).

Receptor-Mediated Tumor Targeting with Radiopeptides. Part 1. General Concepts and Methods: Applications to Somatostatin Receptor-Expressing Tumors

Alex N. Eberle, Gabriele Mild, and Sylvie Froidevaux
Journal of Receptors and Signal Transduction  2004; 24(4) , Pages 319-455
http://dx.doi.org:/10.1081/RRS-200040939

Radiolabeled peptides have become important tools in nuclear oncology, both as diagnostics and more recently also as therapeutics. They represent a distinct sector of the molecular targeting approach, which in many areas of therapy will implement the old “magic bullet” concept by specifically directing the therapeutic agent to the site of action. In this three-part review, we present a comprehensive overview of the literature on receptor-mediated tumor targeting with the different radiopeptides currently studied. Part I summarizes the general concepts and methods of targeting, the selection of radioisotopes, chelators, and the criteria of peptide ligand development. Then, the >400 studies on the application to somatostatin/somatostatin-release inhibiting factor receptor-mediated tumor localization and treatment will be reviewed, demonstrating that peptide radiopharmaceuticals have gained an important position in clinical medicine.

The somatostatin neuroendocrine system: physiology and clinical relevance in gastrointestinal and pancreatic disorders

Malcolm J. Low
Best Practice & Res Clin Endocr & Metab, 2004; 18(4), pp. 607–622
http://dx.doi.org:/10.1016/j.beem.2004.08.005

The physiologic functions of hypothalamic somatostatin in the regulation of pituitary hormone secretion and the clinical use of somatostatin analogs for the treatment of pituitary adenomas have been reviewed. Similarly, the distribution, normal function and potential pathogenic roles of somatostatin in the central nervous system have been reported in detail. This review will focus exclusively on the physiologic actions of somatostatin and its receptors in the gastrointestinal tract, pancreas and immune system. Diagnostic and therapeutic roles of somatostatin analogs in a diverse catalog of neoplastic, inflammatory and autoimmune conditions affecting peripheral systems are outlined, with an emphasis on both well-established indications and current areas of exploration.

Somatostatin is produced in enteroendocrine D cells and intrinsic neurons of the stomach, intestines and pancreas. Its physiologic actions are mediated primarily by somatostatin receptors type 2 and 5, and include the inhibition of secretion of most endocrine and exocrine factors. Diseases directly attributable to somatostatin excess or deficiency are rare, although there is a complex pathogenic relationship between persistent Helicobacter pylori infection and reduced somatostatin in chronic gastritis. Abundant somatostatin receptors on many neoplastic and inflammatory cells are the basis for sensitive in vivo imaging with radiolabeled somatostatin analogs and provide a therapeutic target. Current indications for somatostatin therapy include hormone-expressing neuroendocrine tumors, intractable diarrhea and variceal bleeding secondary to portal hypertension. Exciting advances are being made in the development of high-affinity nonpeptide analogs with receptor-subtype selectivity and increased bioavailability. Somatostatin analogs coupled to high-energy radionuclides show promise as novel cytotoxic agents for certain metastatic tumors.

Evolution of the somatostatin gene family Both forms of mammalian somatostatin are derived post-translationally from a common pro-hormone by the action of specific pro-protein convertases (PCs). Genetic studies indicate a primary role for PC2 in the generation of SST147, which is the predominant form of somatostatin produced in the brain and most other tissues. SST28 is found in its highest concentrations in the gastrointestinal tract, especially the mucosal epithelial cells of the intestines.
A revised evolutionary concept of the somatostatin gene family is that a primordial gene underwent duplication during or before the advent of chordates and that the two resulting genes subsequently underwent differing rates of mutation to produce the distinct prepro-somatostatin and prepro-cortistatin genes in mammals. A second gene duplication event likely occurred in teleosts to generate PSS1 and PSS-II from the ancestral somatostatin gene.
It is possible that additional related genes have not yet been identified. Recent studies utilizing unique polyclonal antisera and a strain of somatostatin-deficient mouse have demonstrated the existence of a novel gastrointestinal peptide with homology to the amino acid sequence of SST28(1–13) that has been named thrittene.
Somatostatin gene organization and regulation The mammalian PPS1 (or SMST) gene has a relatively simple organization consisting of two coding exons separated by one intron. A single promoter directs transcription of the PPS1 gene in all tissues, and there are no known alternative mRNA splicing events. The molecular mechanisms underlying the developmental and hormonal regulation of somatostatin gene transcription have been most extensively studied in pancreatic islets and islet-derived cell lines. The proximal enhancer elements in the somatostatin gene promoter that bind complexes of homeodomain-containing transcription factors (PAX6, PBX, PREP1) to upregulate transcription in pancreatic islets may actually represent gene silencer elements in neurons (promoter elements TSEII and UE-A). Conversely, another related cis-element in the somatostatin gene (promoter element TSEI) apparently binds a homeodomain transcription factor PDX1 (also called STF1/ IDX1/IPF1) that is common to developing brain, pancreas and foregut, and regulates gene expression in both the CNS and gut.
Enteroendocrine cells of the gut mucosa differentiate from pluripotential stem cells in the crypts, share molecular phenotypes and retain close paracrine interactions among the daughter cells. Similarly, pancreatic islet cells share common precursors. Recent studies have demonstrated that bone marrow contains a stem cell population capable of producing islet-like cell clusters in vitro that contain somatostatin-positive cells together with the other cell types found in normally differentiated islets.
Somatostatin Receptors  There are five somatostatin receptor subtypes (SSTR1–5) encoded by separate genes located on different chromosomes. Alternative mRNA splicing generates SSTR2α and SSTR2β from heteronuclear RNA after transcription from the single SSTR2 gene. SSTRs are members of the rhodopsin-like G protein-coupled receptor superfamily and are most closely related structurally to the opioid receptors. The unique amino acid signature of SSTRs is contained in a seven-element fingerprint of peptide sequences located in conserved regions of the N and C termini, extra- and intra-cellular loops, and transmembrane domains. SSTRs are expressed in discrete or partially overlapping distributions in multiple target organs and differ in their coupling to second messenger signaling molecules, and therefore in their range and mechanism of intracellular actions. The subtypes also differ in their binding affinity to specific somatostatin-like ligands. Some of these differences have important implications for the use of somatostatin analogs in diagnostic imaging and in pharmacotherapy.
All SSTR subtypes are coupled to pertussis toxin-sensitive G proteins and bind SST14 and SST28 with high affinity in the low nanomolar range, although SST28 has a modestly higher affinity for SSTR5. All the subtypes are expressed in brain and pituitary to varying degrees with different distributions, but SSTR2 and SSTR5 are clearly the most abundant in peripheral tissues. These two subtypes are also the most physiologically important in pancreatic islets. SSTR5 is responsible for the inhibition of insulin secretion from b-cells, and SSTR2 is essential for the inhibition of glucagon from a-cells. SSTR1 is expressed at low levels in gastrointestinal structures. The binding of somatostatin to its receptors leads to the activation of one or more inhibitory G proteins (Gi/o), which in turn decrease adenylyl cyclase activity and the concentration of intracellular cAMP. Other G protein-mediated actions common to all The somatostatin neuroendocrine system 609 SSTRs are activation of a vanadate-sensitive phosphotyrosine phosphatase (PTP) and modulation of mitogen-activated protein kinases (MAPKs).
Inhibition of endocrine and exocrine secretion Somatostatin has diverse biologic activities in the gastrointestinal system. It is secreted from D cells into the extracellular space to act as a paracrine factor on nearby endocrine cells and as an autocrine factor to inhibit its own secretion. Most of the circulating hormonal somatostatin originates from the stomach and intestines. Basal plasma levels are in the range of 30–100 pg/ml and increase postprandially by as much as 100% over baseline for a duration up to 2 hours. The release of somatostatin from enteric D cells is regulated by a combination of nutritional, humoral, neural and paracrine signals.

The modulatory role of somatostatin in gastric acid secretion by parietal cells illustrates the typical complexity of hormonal, paracrine and neural integration within the gastrointestinal tract.
Somatostatin secreted from gastric D cells modulates the gastrin-enterochromaffin-like cell—parietal cell axis. Gastrin, secreted from G cells, stimulates the release of histamine from enterochromaffin-like cells (ECL), which is in turn a major secretagog of hydrochloric acid (HCl) from gastric parietal (P) cells. Somatostatin (SST14) inhibits secretion from each of these cell types, although the predominant actions are on the G and ECL cells. Food intake mediates gastric acid secretion by activating both vagal nerves and intrinsic gastric neurons. D cells are stimulated by the autocrine release of amylin, the paracrine release of bombesin and atrial natiuretic peptide (ANP), the enteric neuron release of pituitary adenylate cyclase-activating peptide (PACAP) and cholecystokinin (CCK), and the T lymphocyte release of interleukin-4 (IL-4).D cells are inhibited by histamine acting on H3 receptors in a negative paracrine feedback loop from ECL cells and by other factors, including gamma-aminobutyric acid (GABA) and opioid peptides. The pathways illustrated are not all-inclusive but represent many of the key regulatory steps.

Practice points

† long-acting somatostatin analogs are primary therapeutic tools for the symptomatic treatment of the excessive hormone and monoamine secretion from carcinoids and other neuroendocrine tumors

† somatostatin and long-acting somatostatin analogs are effective first-line
medical treatment for upper gastrointestinal bleeding from esophageal varices associated with hepatic cirrhosis and portal hypertension but are not indicatedfor the treatment of bleeding from gastric varices or duodenal ulcers

† radiolabeled somatostatin analogs provide a sensitive imaging technique for a wide range of neoplastic and inflammatory disorders, including neuroendocrine tumors, meningiomas and sarcoidosis because of their high level expression of somatostatin receptors.

The role(s) of somatostatin, structurally related peptides and somatostatin receptors in the gastrointestinal tract: a review

J Van Op den bosch, D Adriaensen, L Van Nassauw, Jean-Pierre Timmermans
Regulatory Peptides 156 (2009) 1–8
http://dx.doi.org:/10.1016/j.regpep.2009.04.003

Extensive functional and morphological research has demonstrated the pivotal role of somatostatin (SOM) in the regulation of a wide variety of gastrointestinal activities. In addition to its profound inhibitory effects on gastrointestinal motility and exocrine and endocrine secretion processes along the entire gastrointestinal tract, SOM modulates several organ-specific activities. In contrast to these well-known SOM-dependent effects, knowledge on the SOM receptors (SSTR) involved in these effects is much less conclusive. Experimental data on the identities of the SSTRs, although species- and tissue-dependent, point towards the involvement of multiple receptor subtypes in the vast majority of gastrointestinal SOM-mediated effects. Recent evidence demonstrating the role of SOM in intestinal pathologies has extended the interest of gastrointestinal research in this peptide even further. More specifically, SOM is supposed to suppress intestinal inflammatory responses by interfering with the extensive bidirectional communication between mucosal mast cells and neurons. This way, SOM not only acts as a powerful inhibitor of the inflammatory cascade at the site of inflammation, but exerts a profound anti-nociceptive effect through the modulation of extrinsic afferent nerve fibers. The combination of these physiological and pathological activities opens up new opportunities to explore the potential of stable SOM analogues in the treatment of GI inflammatory pathologies.

Schematic overview of the distribution of the SSTRs 1–5

Schematic overview of the distribution of the SSTRs 1–5

Schematic overview of the distribution of the SSTRs 1–5 in the murine small intestine under control conditions (left panel) and during intestinal schistosomiasis (right panel). In non-inflamed conditions, SSTR1, SSTR2A and SSTR4 are expressed in non-neuronal (glial cells, enterocytes…) and neuronal cells, both from intrinsic and extrinsic origin. SSTR3 and SSTR5 are undetectable. In response to intestinal schistosomiasis, profound sprouting of nerve fibres expressing SSTR1, SSTR3 and SSTR4 is observed, in addition to the expression of SSTR1 and SSTR3 in mucosal mast cells (MMC).

Somatostatin and Its Receptor Family

Yogesh C. Patel
Frontiers in Neuroendocrinology 1999; 20, 157–198 Article ID frne.1999.0183

Somatostatin (SST), a regulatory peptide, is produced by neuroendocrine, inflammatory, and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors, and cytokines. The peptide is released in large amounts from storage pools of secretory cells, or in small amounts from activated immune and inflammatory cells, and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells that are widely distributed in the brain and periphery. These actions are mediated by a family of seven  transmembrane (TM) domain G-protein-coupled receptors that comprise five distinct subtypes (termed SSTR1–5) that are endoded by separate genes segregated on different chromosomes. The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. Short synthetic octapeptide and hexapeptide analogs bind well to only three of the subtypes, 2, 3, and 5. Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified. The ligand binding domain for SST ligands is made up of residues in TMs III–VII with a potential contribution by the second extracellular loop. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell. The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dependent mechanisms.

Somatostatin receptors

Lars Neisig Møller, Carsten Enggaard Stidsen, Bolette Hartmann, Jens Juul Holst
Biochimica et Biophysica Acta 1616 (2003) 1 – 84
http://dx.doi.org:/10.1016/S0005-2736(03)00235-9

In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing the characteristic seven-transmembrane-segment (STMS) topography. Years of intensive research have resulted in cloning of five receptor subtypes (sst1-sst5), one of which is represented by two splice variants (sst2A and sst2B). The individual subtypes, functionally coupled to the effectors of signal transduction, are differentially expressed throughout the mammalian organism, with corresponding differences in physiological impact. It is evident that receptor function, from a physiological point of view, cannot simply be reduced to the accumulated operations of individual receptors. Far from being isolated functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst2 and sst5 receptors) in characteristic proportions. In other words, levels of individual receptor subtypes are highly cell-specific and vary with the co-expression of different-ligand receptors. However, the question is how to quantify the relative contributions of individual receptor subtypes to the integration of transduced signals, ultimately the result of collective receptor activity. The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype-selective analogues. Several have become available.

Somatostatin And Its Analogues In The Therapy Of Gastrointestinal Disease

Wynick, J. M. Polak And S. R. Bloom
Pharmac. Ther. 1989; 41, pp. 353-370

During the course of efforts to determine the distribution of growth hormone-releasing factor (GHRF) in rat hypothalamus a substance that inhibited growth hormone release was unexpectedly detected by Krulich et aL (1968). Their findings led them to hypothesize that the secretion of growth hormone from the pituitary was regulated by two different interacting neurohumoral factors–one stimulatory, the other inhibitory–each under the control of the nervous system. At about the same time Hellman and Lernmark (1969) found a factor in extracts of pigeon pancreatic islet-cells that inhibited insulin release in vivo from cultured pancreatic islet-cells. These two observations, seemingly unrelated, were ultimately to converge with the chemical identification of somatostatin, as an inhibitory peptide found in both the hypothalamus and pancreas.

Growth hormone-release inhibitory activity was re-discovered in 1972 by Brazeau et al. (1973). A concentrated effort to isolate and sequence the active principal was successful and it proved to be a cyclic peptide, to which the term ‘somatostatin’ (somatotrophin release inhibitory factor) was applied.               Subsequent work (Reichlin, 1982a,b, 1983a,b; Iverson, 1983; Guillemin, 1978a,b) has considerably expanded the initially simple concept of somatostatin as a 14 amino-acid containing peptide (tetradecapeptide), bridged by a sulphur-sulphur bond whose main function was the regulation of growth-hormone secretion (Bonfils, 1985). Somatostatin related peptides are now known to constitute a family that includes the original identified peptide (designated somatostatin 14), an N-terminal extended somatostatin (somatostatin 28), several species specific variants and larger prohormone forms.
The name somatostatin may now be considered to be inappropriate because this compound is distributed widely in cells that have nothing to do with growth-hormone regulation or release. Tissues where somatostatin may be found include the nervous system, the gut and endocrine glands.
Somatostatin is present in every vertebrate class and even in primitive invertebrates (Vale et al., 1976; Falkmer et al., 1978; Jackson, 1978). This would suggest that this molecule and its controlling gene or genes evolved before the appearance on earth of differentiated cell-cell and nerve-cell communication (Roth et al., 1982). The evolutionary paths of mammals and fish are thought to have diverged at least 400 million years ago. The fact that the phenotype of somatostatin 14 is so well conserved (as to a lesser degree is that of somatostatin 28) suggests that throughout evolutionary history the specific configuration of somatostatin 14 has endowed a selective advantage on the animal kingdom, and its absence is not compatible with life.
Though widely distributed in cells throughout the body of vertebrates somatostatin does not in Guillemin’s words (1978a), “inhibit secretion of everything and anything” (since, for example it has no effect on the release of LH and FSH). Despite this it has certainly earned itself the nickname ‘endocrine cyanide’ (Bloom and Polak, 1987). The peptide is found in most but not all organs and displays specific and selective functions depending on its location. Within the nervous system somatostatinergic neurons are found in the cortex, limbic system, anterior pituitary, brain stem and spinal cord.
The various biological effects of somatostatin seem to be mediated through its specific high affinity receptors found in the brain, pituitary, adrenal, pancreas and gastrointestinal tract. Not only normal target tissue, but also tumors from the same endocrine tissues i.e. human pituitary adenomas, human and hamster pancreatic insulinomas, glucagonomas and VIPomas all bear somatostatin receptors (Reubi et al., 1981, 1982a, 1984a, 1985a, 1987a,b). Interestingly, tumors from tissues which are not established targets for somatostatin also seem to bear somatostatin receptors (Goodman et al., 1982; Reubi et al., 1986). Reubi et al. (1987b) demonstrated that many endocrine tumors including meningiomas, breast, pancreatic and pituitary tumors all have somatostatin receptors however, they demonstrated no receptors in prostatic carcinomas, ovarian carcinomas, endometrial carcinomas, primary liver cell carcinomas, pheochromocytomas, aldosterone secreting tumors, medullary carcinoma of the thyroid and a number of pulmonary carcinoids. Somatostatin receptors were also found in benign or malignant tumors originating from tissues not primarily known as somatostatin target organs, the biological function of such receptors is therefore unknown though it may be that they mediate the anti-proliferative effect of somatostatin and may therefore potentially be of therapeutic interest (Blankenstein et al., 1983, 1984).

Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumoursModlin,

M. Pavel[1], M. Kidd & B. I. Gustafsson
Aliment Pharmacol Ther 2009; 31, 169–188
http://dx.doi.org:/10.1111/j.1365-2036.2009.04174.x

Background

The discovery of somatostatin (SST) and the synthesis of a variety of analogues constituted a major therapeutic advance in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours (GEP-NETs). They currently provide the most efficient treatment to achieve symptomatic relief and have recently been demonstrated to inhibit tumour growth.

Aim To review 35 years of experience regarding the clinical application and

efficacy of SST analogues. Methods The PubMed database (1972–2009) was searched using somatostatin as a search term with combinations of terms including ‘treatment’; ‘neuroendocrine’; ‘carcinoid’; ‘tumor’; ‘octreotide’; ‘lanreotide’ and ‘pasireotide’. Results In a review of 15 studies including 481 patients, the slow-release formulations Sandostatin LAR and Somatuline SR⁄ Autogel achieved symptomatic relief in 74.2% (61.9–92.8%) and 67.5% (40.0–100%), biochemical response in 51.4% (31.5–100%) and 39.0% (17.9–58%), and tumor response in 69.8% (47.0–87.5%) and 64.4% (48.0–87.0%) respectively. New SST analogues like SOM230 (pasireotide) that exhibit pan SST receptor activity and analogues with high affinity to specific somatostatin receptor (sstr) subtypes show promise. Conclusion As more precise understanding of NET cell biology evolves and molecular biological tools advance, more accurate identification of individual tumours sstr profile will probably facilitate a more precise delineation of SST analogue treatment.

Novel Autonomic Neurotransmitters And Intestinal Function

S. Taylor and R. A. R. Bywater
Pharmac. Ther. 1989; 40, pp. 401 to 438

In this review we will discuss some of the difficulties encountered in ascribing a neurotransmitter function to the more recently discovered peptides and other substances within the intestine. We will also provide a brief (and of necessity incomplete) account of some of the properties of intestinal putative neurotransmitters, and their possible roles in the functions of the small and large intestine.
The Enteric Nervous System The diverse intestinal functions associated with transit, digestion and absorption rely upon an intact enteric nervous system. The enteric nervous system essentially consists of those neurons whose cell bodies lie within the walls of the gastrointestinal tract. In the small and large intestine the cell bodies lie within the myenteric and submucous plexuses; their processes ramify throughout the majority of the intestinal wall and in many areas give rise to additional plexuses (Furness and Costa, 1987; Gabella, 1987). Functionally, these neurons can be divided into sensory neurons, interneurons and motor neurons. Some enteric neurons receive projections from extrinsic neurons and/or send projections centrally; we will not consider these projections further here.
The early observations of the co-existence of peptides in the enteric nervous system (Schultzberg et al., 1980) have now been extended and these studies demonstrate that the co-existence of two or more peptides is the rule rather than the exception (H6kfelt et al., 1987). The mix of peptides within neurons does not appear to be random; rather, there appears to be a systematic grouping of peptides in neurons with particular projections. This has led to the concept of “chemical coding” of enteric neurons. According to this concept, particular combinations of peptides are associated with particular neural pathways and perhaps with particular functions. For example, in the guinea pig small intestine, two chemically coded groups of submucous neurons have projections of different lengths running to the mucosa. Cell bodies with longer projections show immunoreactivity for dynorphin (DYN) and VIP. The other group shows immunoreactivity for choline acetyltransferase (CHAT), cholecystokinin, (CCK), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and somatostatin (SOM) (Costa et al., 1986a; Furness et al., 1987a). More recently it has been demonstrated that both groups of neurons show immunoreactivity for galanin (GAL) (Furness et al., 1987a,b). As for the neurotransmitter roles in the gut, the key question then becomes; “How does the presence of specific combinations of chemical substances (including peptides) relate to neuronal function?” It has been known for several years that “classical” transmitter substances can coexist in combination with various peptides (H6kfelt et al., 1980; Gilbert and Emson, 1983).
The above commentary upon the possible co-existence of several putative transmitter substances highlights the complex neurochemistry of the enteric nervous system. A corresponding degree of complexity appears to exist for the neuronal circuitry that ultimately directs the differing, but highly organized, patterns of motility and the secretory/absorptive functions of the intestinal tract. In vitro electrophysiological studies of the myenteric and submucous plexuses have indicated that several different types of neurons are present, each with their own biophysical characteristics. Furthermore, neurotransmission through, and probably between, the plexuses involves synaptic potentials which have time courses ranging from several milliseconds up to several minutes, depending upon the characteristics (stimulus strength, frequency and train length, etc.) and location of the applied electrical stimulus (see Wood, 1987, for references). Intracellular recordings from smooth muscle cells have also shown that excitatory and inhibitory junction potentials (EJPs and IJPS) of varying time courses can be evoked at various locations along the intestine during transmural electrical stimulation in response to selective stimulus regimens (see, for instance, Bywater and Taylor, 1986).
A number of authors have proposed criteria which should be fulfilled in order that transmitter status can be bestowed upon a particular substance (see Furness and Costa, 1982, for references). These criteria were developed with reference to the classical transmitter substances such as ACh, using the paradigm of a single transmitter per neuron. Regardless of the coexistence of several putative transmitters, status can only be granted to those substances that are found to be released from that nerve terminal. In the enteric nervous system a particular putative transmitter may be contained in several different functional pathways. However, in general, the methods used for eliciting release of putative transmitter substances (e.g. transmural electrical stimulation) are not specific for particular projections. Thus, for any substance, the association of demonstrated release with a given transmitter role is not facile.

New roles of the multidimensional adipokine: Chemerin

Syeda Sadia Fatima, Rehana Rehman, Mukhtiar Baig, Taseer Ahmed Khan
Peptides 62 (2014) 15–20
http://dx.doi.org/10.1016/j.peptides.2014.09.019

The discovery of several adipokines with diverse activities and their involvement in regulation of various pathophysiological functions of human body has challenged the researchers. In the family of adipokine, chemerin is a novel and unique addition. Ever since the first report on chemerin as a chemo-attractant protein, there are numerous studies showing a multitasking capacity of chemerin in the maintenance of homeostasis, for the activation of natural killer cells, macrophages and dendritic cells in both innate and adaptive immunity. Its diversity ranges from generalized inflammatory cascades to being explicitly involved in the manifestation of arthritis, psoriasis and peritonitis. Its association with certain cancerous tissue may render it as a potential tumor marker. In present review, we aim to consolidate recent data of investigations on chemerin in context to functional characteristics with a special reference to its role as a metabolic signal in inflammation and non-metabolic syndromes.

Neuropeptide Y is expressed in subpopulations of insulin- and non-insulin-producing islet cells in the rat after dexamethasone treatment: a combined immunocytochemical and in situ hybridisation study

Myrs6n a, *, B. Ahr6n b, F. Sundler
Regulatory Peptides 1995; 60, 19-31

Neuropeptide Y (NPY) is known to occur in adrenergic and non-adrenergic nerves in rat pancreatic islets. Analysis of islet extracts has revealed local NPY synthesis after glucocorticoid treatment. The cellular localization of NPY expression in rat islets following dexamethasone treatment (2 mg/kg daily, for 12 days), was investigated by a combination of immunocytochemistry (ICC) and in situ hybridization (ISH). NPY-immunoreactive nerve fibers were seen in pancreatic islets of both control and dexamethasone-treated rats. In the controls weak NPY immunoreactivity but no NPY mRNA was observed in occasional i:dets. After dexamethasone treatment, clusters of islet cells distributed both centrally and peripherally displayed intense NPY immunoreactivity and NPY mRNA labelling. Immunocytochemical double staining and ISH combined with ICC for NPY and islet hormones revealed that most NPY expressing cells were identical with insulin cells; a few cells were identical[ with somatostatin or pancreatic polypeptide (PP) cells. In contrast, glucagon cells seemed to be devoid of NPY immunoreactivity and NPY mRNA labelling. Thus, in the rat, glucocorticoids cause a marked upregulation of NPY expression in islet cells, preferentially the insulin cells. The expression of NPY might represent an islet adaptation mechanism to the reduced peripheral insulin sensitivity.

Neuropeptide Y is expressed in islet somatostatin cells of the hamster pancreas: a combined immunocytochemical and in situ hybridization study

Ulrika Myrsrn, Frank Sundler
Regulatory Peptides 1995; 57, 65-76

Neuropeptide Y (NPY) is known to occur in the autonomic nervous system, including the pancreatic islet innervation. We now present evidence that NPY is also expressed in endocrine islet cells in hamster pancreas. Thus, NPY-immunoreactivity and gene expression were detected in peripheral islet cells, using immunocytochemistry (ICC), in situ hybridization (ISH), and a combination of these techniques. Double immunostaining for NPY and somatostatin enabled localization of NPY to the vast majority of the somatostatin cells. However, a few somatostatin cells were devoid of NPY immunoreactivity and an occasional NPY-immunoreactive cell was devoid of somatostatin. ISH with an NPY mRNA specific probe, showed labelling of cells in the islet periphery. Furthermore, combined ISH for NPY mRNA and ICC for somatostatin showed autoradiographic labelling of somatostatin cells to a varying degree. Both somatostatin and NPY are inhibitors of insulin and/or glucagon secretion. Thus, in the islets these two peptides may be coreleased and cooperate in the, regulation of islet hormone secretion. The role for NPY emanating from islet cells is probably paracrine rather than endocrine.

Neuropeptide Y and Peptide YY Immunoreactivities in the Pancreas of Various Vertebrates

Wei-Guang Ding, Hiroshi Kimura, Masaki Fujimura And Mineko Fujimiya
Peptides,  1997; 18(10), pp. 1523–1529   PII S0196-9781(97)00237-4

NPY-like immunoreactivity was observed in nerve fibers and endocrine cells
in pancreas of all species examined except the eel, which showed no NPY innervation. The density of NPY-positive nerve fibers was higher in mammals than in the lower vertebrates. These nerve fibers were distributed throughout the parenchyma, and were particularly associated with the pancreatic duct
and vascular walls. In addition, the density of NPY-positive endocrine cells was found to be higher in lower vertebrates than mammals; in descending order; eel 5 turtle 5 chicken . bullfrog . mouse 5 rat 5 human . guinea pig 5 dog. These NPY-positive cells in the eel and certain mammals tended to be localized throughout the islet region, whereas in the turtle and chicken they were mainly scattered in the exocrine region. PYY-immunoreactivity was only present in the pancreatic endocrine cells of all species studied, and localized similarly to NPY. Thus these two peptides may play endocrine or paracrine roles in the regulation of islet hormone secretion in various vertebrate species.

Inhibitory effect of somatostatin on inflammation and nociception

Erika Pintér, Zsuzsanna Helyes, János Szolcsányi
Pharmacology & Therapeutics 112 (2006) 440–456

Somatostatin is released from capsaicin-sensitive, peptidergic sensory nerve endings in response to noxious heat and chemical stimuli such as vanilloids, protons or lipoxygenase products. It reaches distant parts of the body via the circulation and exerts systemic anti-inflammatory and analgesic effects. Somatostatin binds to G-protein coupled membrane receptors (sst1–sst5) and diminishes neurogenic inflammation by prejunctional action on sensory-efferent nerve terminals, as well as by postjunctional mechanisms on target cells. It decreases the release of pro-inflammatory neuropeptides from sensory nerve endings and also acts on receptors of vascular endothelial, inflammatory and immune cells. Analgesic effect is mediated by an inhibitory action on peripheral terminals of nociceptive neurons, since circulating somatostatin cannot exert central action.
Somatostatin itself is not suitable for drug development because of its broad spectrum and short elimination half-life, stable, receptor-selective agonists have been synthesized and investigated. The present overview is aimed at summarizing the physiological importance of somatostatin and sst receptors, pharmacological significance of synthetic agonists and their potential in the development of novel anti-inflammatory and analgesic drugs. These compounds might provide novel perspectives in the pharmacotherapy of acute and chronic painful inflammatory diseases, as well as neuropathic conditions.

the sources, target cells and effects of somatostatin (SST) involved in inflammatory and nociceptive processes

the sources, target cells and effects of somatostatin (SST) involved in inflammatory and nociceptive processes

This schematic drawing demonstrates the sources, target cells and effects of somatostatin (SST) involved in inflammatory and nociceptive processes

Characterization, detection and regulation of somatostatin receptors

The physiological actions of SST are initiated by its binding to membrane receptors. Five human somatostatin receptors (sst), have been cloned and characterized and referred to as sst1-5 receptors using the nomenclature suggested by Hoyer et al. (1995). Structurally, sst receptors are 7 transmembrane domain glycoproteins, comprised of 7 membrane spanning α helical domains connected by short loops, an N-terminal extracellular domain and a C-terminal intracellular domain. On the basis of binding studies using synthetic somatostatin analogs, sst receptors can be divided into 2 different subgroups: SRIF1 group comprising sst2, sst3 and sst5 are able to bind octapeptide analogs, whereas SRIF2 group comprising sst1 and sst4 have negligible affinity for these compounds. Within sst2 receptors, sst2A and sst2B are encoded on the same chromosome 17 and generated through alternative splicing of sst2 mRNA (Patel et al., 1993). None of the peptide analogs bind exclusively to only one of the sst subtypes, although new approaches might yield subtype-selective agonists and antagonists (Hofland et al., 1995; Hoyer et al., 1995; Patel et al., 1995; Reisine & Bell, 1995; Florio & Schettini, 1996; Patel, 1997; Meyerhof, 1998; Janecka et al., 2001). Somatostatin receptors are linked to multiple cellular effector systems via G-proteins. They mediate the inhibition of adenylate cyclase activity (Jakobs et al., 1983; Patel et al., 1995), reduce the conductance of voltage-dependent Ca2+ channels (Schally, 1988; Patel et al., 1995) and activate K+ channels (Mihara et al., 1987; Moore et al., 1988; Wang et al., 1989). Somatostatin receptors also mediate the stimulation of tyrosine phosphatase activity, induce a reduction of cell proliferation and inhibit a Na+/H+ exchanger (NHE1) (Barber et al., 1989; Buscail et al., 1994; Patel et al., 1995). Sst receptors represent a major class of inhibitory receptors which play an important role in modulating higher brain functions, secretory processes, cell proliferation and apoptosis.
Endogenous Somatostatin-28 Modulates Postprandial Insulin Secretion Immunoneutralization Studies in Baboons

John W. Ensinck, Robin E. Vogel, Ellen C. Laschansky, Donna J. Koerker, et al.
J Clin Invest 1997. 100: 2295–2302.).  http://dx.doi.org/10.1172/JCI119767

Somatostatin-28 (S-28), secreted into the circulation from enterocytes after food, and S-14, released mainly from gastric and pancreatic δ cells and enteric neurons, inhibit peripheral cellular functions. We hypothesized that S-28 is a humoral regulator of pancreatic β cell function during nutrient absorption. Consistent with this postulate, we observed in baboons a two to threefold increase in portal and peripheral levels of S-28 after meals, with minimal changes in S-14. We attempted to demonstrate a hormonal effect of these peptides by measuring their concentrations before and after infusing a somatostatin-specific monoclonal antibody (mAb) into baboons and comparing glucose, insulin, and glucagon-like peptide-1 levels before and for 4 h after intragastric nutrients during a control study and on 2 d after mAb administration (days 1 and 2). Basal growth hormone (GH) and glucagon levels and parameters of insulin and glucose kinetics were also measured. During immunoneutralization, we found that
(a) postprandial insulin levels were elevated on days 1 and 2;
(b) GH levels rose immediately and were sustained for 28 h, while glucagon fell; (c) basal insulin levels were unchanged on day 1 but were increased two to threefold on day 2, coincident with decreased insulin sensitivity; and
(d) plasma glucose concentrations were similar to control values.
We attribute the eventual rise in fasting levels of insulin to its enhanced secretion in compensation for the heightened insulin resistance from increased GH action. Based on the elevated postmeal insulin levels after mAb administration, we conclude that S-28 participates in the enteroinsular axis as a decretin to regulate postprandial insulin secretion.

Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS

L van Bloemendaal, J S ten Kulve, S E la Fleur, R G Ijzerman and M Diamant
Journal of Endocrinology 2014; 221, T1–T16
http://dx.doi.org:/10.1530/JOE-13-0414

The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behavior and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.

Critical role for peptide YY in protein-mediated satiation and body-weight regulation

Rachel L. Batterham, Helen Heffron, Saloni Kapoor, Joanna E. Chivers, et al.
Cell Metab 2006; 4, 223–233 http://dx.doi.org:/10.1016/j.cmet.2006.08.001

Dietary protein enhances satiety and promotes weight loss, but the mechanisms by which appetite is affected remain unclear. We investigated the role of gut hormones, key regulators of ingestive behavior, in mediating the satiating effects of different macronutrients. In normal-weight and obese human subjects, high-protein intake induced the greatest release of the anorectic hormone peptide YY (PYY) and the most pronounced satiety. Long-term augmentation of dietary protein in mice increased plasma PYY levels, decreased food intake, and reduced adiposity. To directly determine the role of PYY in mediating the satiating effects of protein, we generated PYY null mice, which were selectively resistant to the satiating and weight-reducing effects of protein and developed marked obesity that was reversed by exogenous PYY treatment. Our findings suggest that modulating the release of endogenous satiety factors, such as PYY, through alteration of specific diet constituents could provide a rational therapy for obesity.

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