Somatostatin

Discovery

Somatostatin is a tetradecapeptide exerting a growth hormone (GH) release-inhibiting activity. SS also has a large variety of neuromodulatory and gastrointestinal actions, mostly as an inhibitory hormone. SS of 14 aa residues (SS-14) was first isolated from ovine hypothalamic extracts by Roger Guillemin’s group in 1973 and was originally named GH inhibiting factor. An N-terminally extended form of 28 aa residues (SS-28) was isolated later from the porcine gut. SS cDNA that encodes a precursor for SS-14 and SS-28, a product of the SS1 gene (approved symbol SST), was first cloned from the anglerfish pancreas in 1980. In this report, another SS cDNA encoding a different precursor (formerly called SSII), a product of the SS3 gene, was also isolated. Subsequently, cDNAs and genes encoding SS precursors have been identified in many animals by molecular cloning and bioinformatic analyses, and so far six paralogous genes (SS1, SS2, SS3, SS4, SS5, and SS6) have been identified in vertebrates. Accordingly, two SS-related peptides, cortistatin (CST)5 and neuronostatin, have been identified.

Structure

SS-14 and SS-28 contain a disulfide bridge and have a cyclic structure. CST, a product of the SS2/CST gene, is 14–17 aa residues in length, depending on the species, and contains the SS2 signature, a proline residue at position 2. CST in placental mammals exhibits an additional lysine residue at its C-terminal extremity. Neuronostatin is a 13-residue amidated peptide that is flanked with the signal peptide of the SS1 precursor, and is an acyclic peptide.  The aa sequence of SS-14 is fully conserved in vertebrates. SS-28 in mammals that contains the SS-14 moiety at its C-terminal shares 40%–66% sequence identity with its counterparts in fish. Mr 1638 (SS-14), 3149 (SS-28). Soluble in water, acid, and methanol. Stable in solution at -80°C for more than a year. Plasma half-life is <3min.

Gene, mRNA, and precursor

The human preproSS gene (SS1), SST, location 3q28, consists of two exons. Mammalian SS-14 and SS-28 are derived from preproSS1 of 116 aa residues by specific proprotein convertases (PCs) through tissue-specific posttranslational processing. In vertebrates, six SS genes have been identified, and all these paralogs are present in teleost fish while only SS1 and SS2/CST are present in tetrapods. Phylogenetic and comparative genomic analyses showed that whole-genome duplications, local duplications, and gene losses contribute to the divergent evolution of SS genes.

Clinical implications

Somatostatinoma is a malignant tumor that arises from transformed D cells in the pancreatic islets or duodenum. Somatostatinomas are associated with malabsorption, diabetes mellitus, steatorrhea, and cholelithiasis. In gastroenteropancreatic tumors, high levels of SS receptor expression have been found, and specifically designed analogs are used for tumor imaging and radiotherapy. SS deficiency causes persistent Helicobacter pylori infection in the patient with chronic gastritis.

Receptors

SS receptors belong to the family of seventransmembrane-domain GPCRs. There are five subtypes (sst1–sst5), and all these receptors bind to SS and CST with high affinity.7 The structural and functional characteristics of these receptors in humans, including signal transduction pathways, agonists, and antagonists.

Regulation of synthesis and release

SS secretion in the gastrointestinal tract is regulated by the autonomous nervous system and various gut regulatory peptides including gastrin, cholecystokinin (CCK), and substance P. The synthesis and release of hypothalamic SS are regulated by GH, growth hormone-releasing hormone (GHRH), and glucose.

Biological functions

In the anterior pituitary, SS inhibits the release of GH and thyroid-stimulating hormone (TSH). Pulsatile GH secretion reflects the pulsatile release of both SS and GHRH in a reciprocal fashion. In fish, SS-14 inhibits the release of GH, prolactin, and insulin. In the brain, SS has a variety of neuromodulatory roles in learning, cognitive functions, locomotor activity, anxiety, and depression. CST has physiological functions, such as depression of neuronal activity and induction of slowwave sleep. Moreover, SS exerts inhibitory effects on various gastrointestinal functions, including gastric acid secretion, gastric emptying, intestinal motility, and release of insulin, glucagon, and various gastrointestinal hormones.

Description

Originally isolated from hypothalamic tissue, somatostatin is characterized as an inhibitor of growth hormone (GH) release. The structure was determined in 1971. Subsequent investigations led to the recognition that somatostatin also was released from the pancreas and has a role of inhibiting the secretion of both insulin and glucagon. A total of five somatostatin receptor subtypes have been characterized and cloned (sst1 to sst5). Subtype sst4 is associated with the inhibition of insulin release, and an sst4-selective inhibitor has been reported. The somatostatin analogue SOM230 has exhibited selectivity for sst1, sst2, sst3, and sst5 in rats and effectively decreased plasma GH and insulin-like growth factor-1 (IGF-1) levels by 75% without significant effects on insulin or glucagon. Another analogue, PT R3173, with selectivity for recombinant human somatostatin receptor (hsst2, hsst4, hsst5) was substantially more effective in inhibiting GH secretion compared to glucagon and insulin release in rats.

Uses

Somatostatin is a peptide hormone that regulates the endocrine system. Extensive SS analogs with improved pharmacokinetics, bioavailability, and receptor subtype selectivity have been developed. These include nonpeptidergic analogs and octapeptides such as octreotide and lanreotide. Octreotide and lanreotide are long-acting sst2-preferring agonists, and are used for the treatment of acromegaly, gastroenteropancreatic tumors, neuroendocrine tumors, and other gastrointestinal disorders such as secretory diarrhea and gastrointestinal bleeding.

Indications

Somatostatin (or somatotropin release–inhibiting factor [SRIF]) occurs primarily as a 14–amino acid peptide, although a 28–amino acid form also exists.As with the other hypothalamic peptides, it is formed by proteolytic cleavage of a larger precursor. Somatostatin, originally isolated from the hypothalamus, is also in many other locations, including the cerebral cortex, brainstem, spinal cord, gut, urinary system, and skin. Somatostatin inhibits the secretion of many substances in addition to growth hormone.

General Description

Somatostatin was discovered in the hypothalamus. It is elaboratedby the δ-cells of the pancreas and elsewhere in thebody. Somatostatin is an oligopeptide (14 amino acidresidues) and is referred to as somatotropin release–inhibitingfactor (SRIF).
Its primary action is inhibiting the release of GH from thepituitary gland. Somatostatin also suppresses the release ofboth insulin and glucagon. It causes a decrease in bothcAMP levels and adenylate cyclase activity. It also inhibitscalcium ion influx into the pituitary cells and suppressesglucose-induced pancreatic insulin secretion by activatingand deactivating potassium ion and calcium ion permeability,respectively. The chemistry, SARs, and potential clinicalapplications have been reviewed.

Mechanism of action

Somatostatin binds to 6 somatostatin receptor (SSTR) subtypes, which are G protein-coupled receptors (GPCRs) that inhibit adenylate cyclase after activation. It then inhibits intracellular cyclic adenosine monophosphate and Ca2+, while increasing outward potassium currents, ultimately reducing target tissue hormone secretion. Somatostatin can also achieve anti-tumor effects through anti-proliferation and cell inhibition.

Clinical Use

Somatostatin has a very brief half-life in serum and is not useful clinically.An 8–amino acid analogue with 2 D-amino acids substituted for the naturally occurring L-amino acids is more stable, and monthly injections of a depot form of this analogue (octreotide, Sandostatin LAR) have several uses. Long-acting octreotide is used to treat acromegaly, as described earlier. It is also used to counteract unpleasant effects caused by overproduction of secreted bioactive substances produced by neuroendocrine tumors, including hyperinsulinemia from insulinomas and secretions from carcinoid tumors that cause severe diarrhea. Octreotide may also control severe diarrhea associated with AIDS that has not responded to other treatments.

Side effects

Somatostatin analogues (SSA) are a common treatment for some forms of neuroendocrine tumours (NETs). Somatostatin analogues are usually well tolerated which means you may not have many side effects.
The main side effects are
Loss of appetite
Feeling sick
Feeling bloated
Stomach pain
Fatigue (tiredness)
Increased diarrhoea (this is rare)
Soreness at the injection site
Uncommon side effects include sinus bradycardia, asthenia, headache,pruritus, decreased libido, increased serum bilirubin, and constipation.
Transient side effects, gastrointestinal discomfort and decreased glucose tolerance, usually last only a few weeks after initiation of therapy.
The most significant side effect associated with prolonged use of octreotide is formation of gallstones resulting from reduced bile flow.

storage

-20°C