Somatostatin Explained

Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion.^{[1] [2]}

Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 amino acids (shown in infobox to right), the other consisting of 28 amino acids.^{[3] [4]}

Among the vertebrates, there exist six different somatostatin genes that have been named: SS1, SS2, SS3, SS4, SS5 and SS6.^[5] Zebrafish have all six.^[5] The six different genes, along with the five different somatostatin receptors, allow somatostatin to possess a large range of functions.^[6] Humans have only one somatostatin gene, SST.^{[7] [8] [9]}

Nomenclature

Synonyms of "somatostatin" include:

• growth hormone–inhibiting hormone (GHIH)
• growth hormone release–inhibiting hormone (GHRIH)
• somatotropin release–inhibiting factor (SRIF)
• somatotropin release–inhibiting hormone (SRIH)

Production

Digestive system

Somatostatin is secreted by delta cells at several locations in the digestive system, namely the pyloric antrum, the duodenum and the pancreatic islets.^[10]

Somatostatin released in the pyloric antrum travels via the portal venous system to the heart, then enters the systemic circulation to reach the locations where it will exert its inhibitory effects. In addition, somatostatin release from delta cells can act in a paracrine manner.^[10]

In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion.^[10] Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin and histamine which effectively slows down the digestive process.

Brain

Somatostatin is produced by neuroendocrine neurons of the ventromedial nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamohypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone.

Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, populations of somatostatin neurons occur in the arcuate nucleus,^[11] the hippocampus,^[12] and the brainstem nucleus of the solitary tract.

Functions

Somatostatin is classified as an inhibitory hormone, and is induced by low pH. Its actions are spread to different parts of the body. Somatostatin release is inhibited by the vagus nerve.^[13]

Anterior pituitary

In the anterior pituitary gland, the effects of somatostatin are:

• Inhibiting the release of growth hormone (GH)^[14] (thus opposing the effects of growth hormone–releasing hormone (GHRH))
• Inhibiting the release of thyroid-stimulating hormone (TSH)^[15]
• Inhibiting adenylyl cyclase in parietal cells
• Inhibiting the release of prolactin (PRL)

Gastrointestinal system

• Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones
• Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine^[14]
• Suppresses the release of pancreatic hormones
  • Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release.^{[16] [17]}
  • Inhibits the release of glucagon^{[16] [2]}
• Suppresses the exocrine secretory action of the pancreas

Synthetic substitutes

Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone, and has a much longer half-life (about 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome and acromegaly.^{[18] [19]} It is also finding increased use in polycystic diseases of the liver and kidney.

Lanreotide (Somatuline, Ipsen Pharmaceuticals) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration on August 30, 2007.

Pasireotide, sold under the brand name Signifor, is an orphan drug approved in the United States and the European Union for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy. It was developed by Novartis. Pasireotide is somatostatin analog with a 40-fold increased affinity to somatostatin receptor 5 compared to other somatostatin analogs.

Evolutionary history

Six somatostatin genes have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes:SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the Sarcopterygii and Actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3.^[5]

See also

• FK962
• Hypothalamic–pituitary–somatic axis
• Laetrile
• Octreotide

Further reading

• Florio T, Schettini G . [Somatostatin and its receptors. Role in the control of cell proliferation] . Minerva Endocrinologica . 26 . 3 . 91–102 . September 2001 . 11753230 .
• Yamada Y, Reisine T, Law SF, Ihara Y, Kubota A, Kagimoto S, Seino M, Seino Y, Bell GI, Seino S . Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase . Molecular Endocrinology . 6 . 12 . 2136–42 . December 1992 . 10.1210/mend.6.12.1337145 . 1337145 . 28499704 . free .
• Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino S . Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney . Proceedings of the National Academy of Sciences of the United States of America . 89 . 1 . 251–5 . January 1992 . 1346068 . 48214 . 10.1073/pnas.89.1.251 . 1992PNAS...89..251Y . free .
• Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R . Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone . Science . 179 . 4068 . 77–9 . January 1973 . 4682131 . 10.1126/science.179.4068.77 . 1973Sci...179...77B . 10997771 .
• Shen LP, Pictet RL, Rutter WJ . Human somatostatin I: sequence of the cDNA . Proceedings of the National Academy of Sciences of the United States of America . 79 . 15 . 4575–9 . August 1982 . 6126875 . 346717 . 10.1073/pnas.79.15.4575 . 1982PNAS...79.4575S . free .
• Shen LP, Rutter WJ . Sequence of the human somatostatin I gene . Science . 224 . 4645 . 168–71 . April 1984 . 6142531 . 10.1126/science.6142531 . 1984Sci...224..168S .
• Montminy MR, Goodman RH, Horovitch SJ, Habener JF . Primary structure of the gene encoding rat preprosomatostatin . Proceedings of the National Academy of Sciences of the United States of America . 81 . 11 . 3337–40 . June 1984 . 6145156 . 345502 . 10.1073/pnas.81.11.3337 . 1984PNAS...81.3337M . free .
• Zabel BU, Naylor SL, Sakaguchi AY, Bell GI, Shows TB . High-resolution chromosomal localization of human genes for amylase, proopiomelanocortin, somatostatin, and a DNA fragment (D3S1) by in situ hybridization . Proceedings of the National Academy of Sciences of the United States of America . 80 . 22 . 6932–6 . November 1983 . 6196780 . 390100 . 10.1073/pnas.80.22.6932 . 1983PNAS...80.6932Z . free .
• Panetta R, Greenwood MT, Warszynska A, Demchyshyn LL, Day R, Niznik HB, Srikant CB, Patel YC . Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28 . Molecular Pharmacology . 45 . 3 . 417–27 . March 1994 . 7908405 .
• Demchyshyn LL, Srikant CB, Sunahara RK, Kent G, Seeman P, Van Tol HH, Panetta R, Patel YC, Niznik HB . Cloning and expression of a human somatostatin-14-selective receptor variant (somatostatin receptor 4) located on chromosome 20 . Molecular Pharmacology . 43 . 6 . 894–901 . June 1993 . 8100352 .
• Kaupmann K, Bruns C, Hoyer D, Seuwen K, Lübbert H . Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain . FEBS Letters . 331 . 1–2 . 53–9 . September 1993 . 8405411 . 10.1016/0014-5793(93)80296-7 . 22557713 . free .
• Aguila MC, Rodriguez AM, Aguila-Mansilla HN, Lee WT . Somatostatin antisense oligodeoxynucleotide-mediated stimulation of lymphocyte proliferation in culture . Endocrinology . 137 . 5 . 1585–90 . May 1996 . 8612489 . 10.1210/endo.137.5.8612489 . free .
• Sharma K, Patel YC, Srikant CB . Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3 . Molecular Endocrinology . 10 . 12 . 1688–96 . December 1996 . 10.1210/mend.10.12.8961277 . 8961277 . free .
• Dournaud P, Boudin H, Schonbrunn A, Tannenbaum GS, Beaudet A . Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin . The Journal of Neuroscience . 18 . 3 . 1056–71 . February 1998 . 9437026 . 6792775 . 10.1523/JNEUROSCI.18-03-01056.1998.
• Barnea A, Roberts J, Ho RH . Evidence for a synergistic effect of the HIV-1 envelope protein gp120 and brain-derived neurotrophic factor (BDNF) leading to enhanced expression of somatostatin neurons in aggregate cultures derived from the human fetal cortex . Brain Research . 815 . 2 . 349–57 . January 1999 . 9878821 . 10.1016/S0006-8993(98)01098-1 . 21793593 .
• Ferone D, van Hagen PM, van Koetsveld PM, Zuijderwijk J, Mooy DM, Lichtenauer-Kaligis EG, Colao A, Bogers AJ, Lombardi G, Lamberts SW, Hofland LJ . In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells . Endocrinology . 140 . 1 . 373–80 . January 1999 . 9886848 . 10.1210/endo.140.1.6398 . free . 1765/8996 . free .
• Brakch N, Lazar N, Panchal M, Allemandou F, Boileau G, Cohen P, Rholam M . The somatostatin-28(1-12)-NPAMAP sequence: an essential helical-promoting motif governing prosomatostatin processing at mono- and dibasic sites . Biochemistry . 41 . 5 . 1630–9 . February 2002 . 11814357 . 10.1021/bi011928m .
• Oomen SP, van Hennik PB, Antonissen C, Lichtenauer-Kaligis EG, Hofland LJ, Lamberts SW, Löwenberg B, Touw IP . Somatostatin is a selective chemoattractant for primitive (CD34(+)) hematopoietic progenitor cells . Experimental Hematology . 30 . 2 . 116–25 . February 2002 . 11823046 . 10.1016/S0301-472X(01)00772-X . free .
• Simonetti M, Di BC . Structural motifs in the maturation process of peptide hormones. The somatostatin precursor. I. A CD conformational study . Journal of Peptide Science . 8 . 2 . 66–79 . February 2002 . 11860030 . 10.1002/psc.370 . 20438890 .

Notes and References

1. "somatostatin". Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2016. Web. 04 mag. 2016 .
2. Book: Nelson DL, Cox M, Hoskins AA . Lehninger Principles of Biochemistry . 2021 . 978-1-319-22800-2 . Eighth . New York, NY . Macmillan Learning . 1243000176 . The binding of somatostatin to its receptor in the pancreas leads to activation of an inhibitory G protein, or G_i, structurally homologous to G_s, that inhibits adenylyl cyclase and lowers [cAMP]. In this way, somatostatin inhibits the secretion of several hormones, including glucagon.
3. Web site: Sect. 5, Ch. 4: Structure, Synthesis, and Secretion of Somatostatin . 2008-02-19 . Costoff A . Endocrinology: The Endocrine Pancreas . Medical College of Georgia . 16 . dead . https://web.archive.org/web/20080405060426/http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch4/s5ch4_16.htm . April 5, 2008 .
4. Web site: somatostatin preproprotein [Homo sapiens] ]. NCBI Reference Sequence . National Center for Biotechnology Information Support Center (NCBI) .
5. Liu Y, Lu D, Zhang Y, Li S, Liu X, Lin H . The evolution of somatostatin in vertebrates . Gene . 463 . 1–2 . 21–8 . September 2010 . 20472043 . 10.1016/j.gene.2010.04.016 .
6. Gahete MD, Cordoba-Chacón J, Duran-Prado M, Malagón MM, Martinez-Fuentes AJ, Gracia-Navarro F, Luque RM, Castaño JP . Somatostatin and its receptors from fish to mammals . Annals of the New York Academy of Sciences . 1200 . 43–52 . July 2010 . 1 . 20633132 . 10.1111/j.1749-6632.2010.05511.x . 2010NYASA1200...43G . 23346102 .
7. Web site: Entrez Gene: Somatostatin .
8. Shen LP, Pictet RL, Rutter WJ . Human somatostatin I: sequence of the cDNA . Proceedings of the National Academy of Sciences of the United States of America . 79 . 15 . 4575–9 . August 1982 . 6126875 . 346717 . 10.1073/pnas.79.15.4575 . 1982PNAS...79.4575S . free .
9. Shen LP, Rutter WJ . Sequence of the human somatostatin I gene . Science . 224 . 4645 . 168–71 . April 1984 . 6142531 . 10.1126/science.6142531 . 1984Sci...224..168S .
10. Book: Boron WF, Boulpaep EL . Medical Physiology . Elsevier . Philadelphia, PA . 2012 . 2nd . 9781437717532 .
11. Minami S, Kamegai J, Sugihara H, Suzuki N, Wakabayashi I . Growth hormone inhibits its own secretion by acting on the hypothalamus through its receptors on neuropeptide Y neurons in the arcuate nucleus and somatostatin neurons in the periventricular nucleus . Endocrine Journal . 45 . Suppl . S19-S26 . April 1998 . 9790225 . 10.1507/endocrj.45.Suppl_S19 . free .
12. Stefanelli T, Bertollini C, Lüscher C, Muller D, Mendez P . Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles . Neuron . 89 . 5 . 1074–1085 . March 2016 . 26875623 . 10.1016/j.neuron.2016.01.024 . free .
13. Holst JJ, Skak-Nielsen T, Orskov C, Seier-Poulsen S . Vagal control of the release of somatostatin, vasoactive intestinal polypeptide, gastrin-releasing peptide, and HCl from porcine non-antral stomach . Scandinavian Journal of Gastroenterology . 27 . 8 . 677–85 . August 1992 . 1359631 . 10.3109/00365529209000139 .
14. Web site: Somatostatin . 2008-02-19 . Bowen R . 2002-12-14 . Biomedical Hypertextbooks . Colorado State University .
15. First Aid for the USMLE Step 1, 2010. Page 286.
16. Web site: Sect. 5, Ch. 4: Structure, Synthesis, and Secretion of Somatostatin . 2008-02-19 . Costoff A . Endocrinology: The Endocrine Pancreas . Medical College of Georgia . 17 . https://web.archive.org/web/20080331235236/http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch4/s5ch4_17.htm . March 31, 2008 . dead .
17. van der Meulen T, Donaldson CJ, Cáceres E, Hunter AE, Cowing-Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL, Huising MO . Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion . Nature Medicine . 21 . 7 . 769–76 . July 2015 . 26076035 . 4496282 . 10.1038/nm.3872 .
18. Web site: Carcinoid Tumors and Syndrome . The Lecturio Medical Concept Library . 5 July 2021.
19. Web site: Acromegaly. NIDDK. 5 July 2021. April 2012. live. https://web.archive.org/web/20160827213949/https://www.niddk.nih.gov/health-information/health-topics/endocrine/acromegaly/Pages/fact-sheet.aspx. 27 August 2016.