Metabolomics/Hormones/Somatostatin

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= Introduction =

Somatostatin (SS) was first discovered in hypothalamic extracts. It is defined as a polypeptide hormone that inhibited secretion of other hormones, especially growth hormone, glucagons, insulin, thyrotropin, gastrin, and etc, depending on physiologic situation. Besides hypothalamus, it is found to be secreted by many other tissues such as pancreas, intestinal tract, and regions of the central nervous system outside the hypothalamus. Regardless where it is found, the synthesis and structure appears to be identical. Also, no matter where it is found, the action of it is always inhibitory.

Link to the website:

= Structure and Synthesis =

Somatostatin is synthesized as a 116 amino acid preprohormone that is subsequently cleaved to two forms. The two forms are SS-14 and SS-28 amino acid coupounds. They reflect their amino acid length. Both forms of somatostatin are produced by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Two cysteine residules in SS-14 allow the peptide to form an internal disulfide bond.

Fig. 1: Shows the formation of SS-14 and SS-28

The production amount of the two forms, SS-14 and SS-28, depends upon the tissue they are being secreted in. SS-14 is the predominates in the hypothalamus and endocrine pancreas. SS-28 is more abundant in the GI tract. The two forms also can have the different biological potencies. 

Receptors and Mechanism of Action
Somatostatin acts by both endocrine and paracrine pathways to affect its target cells. There are all together five stomatostatin receptors that are recognized and characterized. All of them five belong to G protein-coupled receptor superfamily. Each of the receptors activates different signaling mechanisms within cells. However, all inhibit adenylyl cyclase. It is found that four of the five receptors do not differentiate SS-14 from SS-28.



Effects on the Pituitary Gland
Fig. 2: Pituitary GH and hepatic IGF-1 secretion in the hypothalamic-pituitary feedback system.

Growth hormones is produced in the pituitary and it is stimulated by hypothalamic growth hormone releasing hormone (GHRH). The growth hormone secretion is controlled by the interaction of somatostatin and growth hormone. The figure above shows the feedback system how the inhibition takes place. 

Effects on the Pancreas
Fig. 3: Shows the pancreatic islet and what is secreted in it. 

The diagram shows cells within pancreatic islets secrete insulin, glucagon and somatostatin. Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.



Effects on the Gastrointestinal Tract
Somatostatin is secreted by scattered cells in the GI epithelium. Somatostatin shows the inhibition of many GI hormones such as gastrin, cholecystokinin, secretin, and so on. It also suppresses the secretion of gastric and pepsin which lowers the rate of gastric emptying and reduces smooth muscle contractions and blood flow within the intestine. Overall, these effects tend to decrease the rate of nutrient absorption.

Effects on the Nervous System
Somatostatin is also produced in the nervous system. It has neuromodulatory activity within the central nervous system. It has a variety of complex effects on neural transmission. For example, injection of somatostatin into the brain of rodents leads to such things as increased arousal and decreased sleep, and impairment of some motor responses.



Pharmacologic Uses
Somatostatin and its synthetic analogs are used clinically due to its ability to inhibit certain hormones secretion. It is used to treat a variety of neoplasms such as giantism and acromegaly.



Somatostatin Analogs for Diagnosis and Staging of Tumors
http://www.med.harvard.edu/JPNM/TF93_94/Mar8/WriteUpMar8.html

This article is a case presentation of a 49 year old female who was diagnosed with non-Hodgkin’s lymphoma stage IIIA in 1983. After successful chemotherapy, the cancer went into remission. However, in 1990 a recurrence was detected using a gallium-67 scintigraphy which suggested that the tumor was an indolent tumor. Since most human tumors originating from somatostatin target tissue have conserved their somatostatin receptors, a somatostatin analog, octreotide, was given to the patient and traced inside her body. This analog has all of the same pharmaceutical properties as somatostatin, except that it stays in the body much longer. Using in vitro audiography with 25-I-Tyr-3-Octreotide, the somatostatin receptor’s status was evaluated in the tumor cells. It showed that the high grade lymphomas expressed a very high density of receptors. The low to intermediate grade lymphomas also expressed a moderate density of receptors.

This relates to the course because it shows that the hormone somatostatin is still present on tumor cells. It has some functionality in the regulation of the tumor because the tumor cells exhibit different densities of somatostatin receptors at different stages of the cancer.

Somatostatin
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/somatostatin.html

This article gives a summary of somatostatin and its regulation and effects on different organs or glands in the body. Somatostatin has two polypeptide forms, a 14 amino acid chain (SS-14) and a 28 amino acid chain (SS-28). These are both generated by the cleavage of prosomatostatin. The effects of somatostatin can be summarized in that it inhibits the secretion of many other hormones. Specifically, somatostatin affects the pituitary gland in that it causes inhibition of secretion of growth hormone which is vital to cells in growth and metabolism. In the pancreas, somatostatin inhibits the secretion of insulin and glucagon which play an important role in glucose regulation in the body.

Somatostatin affects the gastrointestinal tract (GI) by inhibiting the secretion of gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. Finally, injection of somatostatin into the nervous system of rodents can cause increased arousal, decreased sleep, and an impairment of some motor responses.

This article relates to the course because it talks about somatostatin’s role in the pancreas in which it affects insulin and glucagon. Insulin and glucagon regulate the body’s glucose levels. The regulation of these hormones were studied in-depth, but without much talk on somatostatin. This article shows that somatostatin has a regulation effect on these hormones.

Can somatostatin control acute bleeding from oesophageal varices in Schistosoma mansoni patients?
http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=539281&blobtype=pdf

This article deals with a proposed study on subjects infected with Schistosoma mansoni. People infected by the parasite suffer from fibrosis, hepatomegaly, splenomegaly, haematemesis, varices, portal hypertension, ascites formation and eventually can lead to death. Portal hypertension can lead to the formation of gastro-oesophageal varices. Due to their fragility, these gastro-oesophageal varices are prone to bleed and can lead to death. So far, treatments such as praziquantel are effective against the worm stages of the parasite but they are not effective against the bleeding. The neuropeptide, somatostatin, has been proposed to be able to reduce bleeding in Schistosoma mansoni infected subjects. A research study is to be put underway in which adolescent subjects, age range varying from 12–17 years, will be chosen who are infected with the parasite and will be split into two groups. One group will be given praziquantel and somatostatin, while the other will be given praziquantel and propanolol. The results of this have not been included in the article. However it is believed that the patients who are given somatostatin will stop bleeding immediately and delay rebleeding and mortality. Even though this article talks about medical uses of somatostatin, which was not covered in the course, it still has relations to the course. This article gives a medical use of somatostatin, a hormone, which is involved in regulation of growth and metabolism of cells. In many of the chapters studied, biochemistry has been linked with medicine.

A pilot study of a long acting somatostatin analogue for the treatment of refractory rheumatoid arthritis
http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1753815&blobtype=pdf

This article deals with a study for treatment of rheumatoid arthritis with long acting somatostatin. Chronic inflammation, which is caused by this arthritis, can lead to development of a pannus, which causes progressive destruction of the joints. In vitro studies of somatostatin have shown to inhibit the proliferation of human lymphocytes, the production of immunoglobulins by B lymphocytes, and neutrophilchemotaxis. Activated T lymphocytes, macrophages, B cells and the cytokines they produce are involved in the aggravated inflammatory tissue which develops into the pannus. From this past research, researches set out to test the effect of a somatostatin analogue on patients with rheumatoid arthritis. Ten patients (all of whom were women age 18-70) with longstanding rheumatoid arthritis who had no reaction to multiple disease modifying antirheumatic drugs (DMARDs) were chosen for this experiment. These patients were treated with monthly injections of 20 mg Sandostatin-Lar, which contains an analogue of somatostatin, for three months. The results showed that six patients responded achieving an ACR 20 response. This concluded that treatment of somatostatin on patients with active, refractory rheumatoid arthritis led to significant clinical improvements that were also safe. This article relates to the class because, like the Schistosomiosis paper, it relates biochemistry to medicine and how the hormone somatostatin can play a part in medicinal purposes.

=Oxidative Phosphorylation & Molecular Oxygen Regulation=

Somatostatin has been proven to be incapable of affecting changes of O2 consumption (ΔO2) that had been stimulated by mitochondrial fuels. It was once assumed that somatostatin is produced during alterations in respiratory control of oxidative phosphorylation. Findings indicated that the hormone directly inhibits oxidative phosphorylation at a step prior to the TCA cycle.

An 8-CPT stable membrane permeable cAMP analog has been proven to not inhibit ΔO2 by somatostatin, which removed the possibility of reduced levels of cytosolic cAMP being involved in this inhibition. However, the molecular target(s) for this inhibition remain unknown.

The inhibition of ΔO2 by the somatostatin receptor type- (sstr) selective analogs is in support of the effects of somatostatin developing exclusively through binding to sstr5. This sstr5 is responsible for mediating activation of the KATP channel, and inhibiting the secretion of insulin in mice, rats, and men.

O2 reduction can occur via the mitochondrial electron transport chain, or NAD(P)H oxidase activity and superoxide production. A range of NAD(P)H oxidase isoforms have been identified as being expressed within pancreatic islet tissue. The p47PHOX isoform has been discovered to be predominantly expressed in pancreatic beta-cells, at the plasma membrane. Somatostatin was discovered to inhibit ΔO2 without mechanisms involving NAD(P)H oxidase activity. Furthermore, the inhibition of the mitochondrial reduction of O2 by azides was proven to nullify the effect of somatostatin on ΔO2. This indicates that azides have no effect on the oxidase activity of NAD(P)H. Overall, the role of NAD(P)H oxidases in the effect of somatostatin on ΔO2 is still undetermined.

Link to article:

http://endo.endojournals.org/cgi/content/full/147/3/1527#SEC3

Glossary of terms:
Scintigraphy: A diagnostic technique in which a two-dimensional picture of a bodily radiation source is obtained by the use of radioisotopes.

Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions.

Mediastinal: Of or pertaining to a space in the thoracic cavity behind the sternum and in between the two pleural sacs (containing the lungs).

Indolent tumor: Causing little or no pain; inactive or relatively benign.

Astrocytoma: A neuro-ectodermal tumor arising from astrocytes (The largest and most numerous neuroglial cells found in the brain and spinal cord).

Prosomatostatin: Precursor to somatostatin.

Pancreatic islets: Groups of cells found within the pancreas.

Cholecystokinin: A 33-amino acid peptide secreted by the upper intestinal mucosa and also found in the central nervous system. It causes gallbladder contraction, release of pancreatic exocrine (or digestive) enzymes, and affects other gastrointestinal functions.

Enteric nervous system: Local nervous system of the digestive tract.

Pepsin: Principal proteases in gastric secretions of adult mammals.

Gastrin: A major physiological regulator of gastric acid secretion.

Paracrine: Form of signaling in which the target cell is close to the signal releasing cell.

Oesophageal varices: Abnormal dilation of the veins in the oesophagus that occurs as the result of cirrhotic liver disease. Oesophageal varices are prone to bleed due to their fragility.

Portal hypertension: Any increase in the portal vein (in the liver) pressure due to anatomic or functional obstruction (for example alcoholic cirrhosis) to blood flow in the portal venous system.

Schistosomiosis: Disease caused by digenetic trematode worms of the genus Schistosoma, the adults of which live in the urinary or mesenteric blood vessels.

Fibrosis: The formation of fibrous tissue, fibroid or fibrous degeneration.

Oesophageal varices: Abnormal dilation of the veins in the oesophagus that occurs as the result of cirrhotic liver disease.

Rheumatoid arthritis: Chronic, multisystem autoimmune disease characterized by persistent synovitis.

Synovitis: Inflammation of a synovial membrane (a membrane which secretes a transparent, viscid, lubricating fluid which contains mucin.

Human lymphocytes: White blood cell, with two main classes: T lymphocytes and B lymphocytes.

Pannus: An aggressive inflammatory tissue where activated T lymphocytes, macrophages, B cells and the cytokines they produce, as well as active angiogenesis play a major part in the progressive destruction of the joints.

ACR 20: The criteria for improvement in rheumatoid arthritis according to the American College of Rheumatology (ACR).

Endocrine action: the hormone is distributed in blood and binds to distant target cells.

Paracrine action: the hormone acts locally by diffusing from its source to target cells in the neighborhood.

Online dictionary: http://cancerweb.ncl.ac.uk/omd/

=Articles and Web Pages for Review and Inclusion=