Physiology, Somatostatin

Article Author:
Timothy O'Toole
Article Editor:
Sandeep Sharma
Updated:
2/5/2019 10:33:29 PM
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Physiology, Somatostatin

Introduction

Somatostatin is a cyclic peptide well known for its strong regulatory effects throughout the body. Also known by the name of growth hormone inhibiting hormone, it is produced in many locations, which include the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS). Two active forms of the peptide exist, and they vary in length at fourteen amino acids and twenty-eight amino acids respectively. The two isoforms have considerable overlap in activity and differ primarily in their location of effect. The shorter isoform (14 amino acids) works primarily in the brain, while the longer (28 amino acids) form operates in the GI tract. Its half-life is between 1 to 3 minutes.

Somatostatin produces predominantly neuroendocrine inhibitory effects across multiple systems. It is known to inhibit GI, endocrine, exocrine, pancreatic, and pituitary secretions, as well as modify neurotransmission and memory formation in the CNS. It also prevents angiogenesis and has anti-proliferative effects on healthy and cancerous cells in human and animal models.

Due to its short half-life, somatostatin has been formulated exogenously in much more stable forms with a longer half-life; this allows for its primary clinical use, which is the treatment of neuroendocrine tumors (NET).[1][2]

Issues of Concern

Somatostatin plays an integral role in the regulation of exocrine, endocrine, and growth throughout the body. While there is no data relating to under-production of somatostatin, there are documented cases of over-production of somatostatin referred to as somatostatinoma. Otherwise, the main issue of concern regarding somatostatin is its exogenous use in the treatment of NETs.

Cellular

Somatostatin is produced in multiple locations in the body. It is most notably present in the islets of Langerhans within the pancreas. Within these specialized areas of the pancreas, somatostatin is produced by delta-cells, which comprise about 5% of the islet cells. The glucagon-producing alpha-cells and insulin-producing beta-cells make up the majority of the islets. Somatostatinproduciton is also in close proximity to the pancreas within the GI tract in D-cells, which contain the majority of somatostatin found in the entire body: roughly 65%. Lastly, somatostatin is produced by neurons in the anterior periventricular nucleus and arcuate nucleus within the hypothalamus, which was the first location within the body that somatostatin was identified.[3][4]

Development

As previously mentioned, the two types of somatostatin differ in length of amino acids. While they are a different length, they are both derived from pre-prosomatostatin. This precursor is cleaved into prosomatostatin, which subsequently undergoes post-translational processing at the C-terminal to create somatostatin-14 and somatostatin-28.[4]

Organ Systems Involved

Somatostatin is involved in the exocrine, endocrine, and CNS systems. Within these systems, there is a wide array of hormones that are affected. In the exocrine system, somatostatin inhibits bile secretion, colonic fluid secretions, gastric acid secretion, pancreatic enzymes, cholecystokinin, and vasoactive intestinal peptide (VIP). In the endocrine system, it inhibits growth hormone, thyroid-stimulating hormone (TSH), prolactin, gastrin, insulin, glucagon, and secretin. In the CNS, somatostatin is present as a neurotransmitter in the lateral septum, cortex, amygdala, hippocampus, the reticular nucleus of the thalamus, and numerous brainstem nuclei.[1]

Mechanism

Somatostatin binds to six different receptors in various systems and cells throughout the body to produce its regulatory effect. These receptors are specific to somatostatin and classify as G-protein coupled receptors (GPCR). When activated, somatostatin receptors decrease intracellular cyclic AMP and calcium while simultaneously increasing outward potassium currents. The overall effect observed is a decrease in hormone secretion of the target tissue.[1]

The other noteworthy effect to mention is the anti-proliferative and cytostatic forces that somatostatin can produce. It achieves these results from both direct and indirect mechanisms. Somatostatin activates phosphotyrosine phosphatase which directly inhibits the cell cycle progression in target cells. It provides indirect inhibition to cell growth by suppressing insulin-like growth factor I (IGF-1) and growth hormone which limits cells ability to thrive and survive.[1]

Related Testing

When evaluating for somatostatinoma, a blood level of somatostatin-like-immunoreactivity (SLI) is necessary to make the diagnosis. While an elevated plasma SLI can increase your suspicion, it is essential to rule out other illness that also elevates SLI, such as medullary thyroid cancer, lung cancer, pheochromocytoma, and paraganglioma.

When considering the many NETs that are treatable with synthetic somatostatin analogs, increased plasma levels of the hormone associated with the particular tumor (i.e., insulin for insulinoma, VIP for VIPoma, etc.), along with the clinical picture, will confirm the diagnosis. It is then up to the physician to determine whether the patient is a surgical candidate or requires treatment with somatostatin analog.[5]

Pathophysiology

The pathologic process associated with somatostatin is the somatostatinoma. It is a rare NET that develops in the pancreas or duodenum and releases large amounts of somatostatin. This illness presents a distinct clinical picture that includes cholelithiasis, diabetes mellitus, weight loss, and steatorrhea. The inhibitory effect of somatostatin leads to decreased gallbladder emptying as well as reduced cholecystokinin production, which results in gallstones. Increased somatostatin reduces insulin production resulting in diabetes. Lastly, the inhibition of pancreatic enzymes leads to the development of steatorrhea and weight loss.[6]

Clinical Significance

Due to the short half-life of endogenous somatostatin, synthetic analogs have been created that have a much longer half-life and are more useful in the management of the disease. These analogs include lanreotide, octreotide, seglitide, and vapreotide. While these medications can be extremely effective in reducing symptoms in patients, they are not 100% effective in all patients. Some patients only develop partial relief while others seem to be completely unaffected. In these patients who experience partial or zero relief, it appears the relative concentration and pattern of expression of the six somatostatin receptors to one another dictate the response to the synthetic analogs. This response is an area of potential research in treatment as the synthetic analogs must be developed to be more specific to the patient's unique somatostatin receptor pattern and receptor concentrations.

These somatostatin analogs are useful in the management of acromegaly and numerous NETs including, insulinoma, growth hormone releasing factor tumor (GRFoma), glucagonoma, pheochromocytoma, somatostatinoma, carcinoid tumors, many pituitary adenomas, VIPoma, and gastrinoma. Within this spectrum of disease, the synthetic somatostatin analogs are used to downregulate the overproduction of specific hormones. For example, somatostatin is used to decrease the insulin production in insulinoma or to decrease the TSH production from a pituitary adenoma. Ultimately, surgical resection of these tumors is curative, but in advanced metastasis or non-surgical candidates, medical treatment with somatostatin is the preferred treatment.[2]

Diabetic retinopathy resulting in neovascularization of the retina, which eventually leads to vision loss if untreated, is a common cause of blindness in patients with diabetes. Due to its anti-proliferative and anti-angiogenesis properties, somatostatin is frequently employed to hinder or reverse the vessel proliferation seen in this illness.[7]


References

[1] Cakir M,Dworakowska D,Grossman A, Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways. Journal of cellular and molecular medicine. 2010 Nov;     [PubMed PMID: 20629989]
[2] Cakir M,Dworakowska D,Grossman A, Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 2--clinical implications. Journal of cellular and molecular medicine. 2010 Nov;     [PubMed PMID: 20629988]
[3] Gunawardane K,Krarup Hansen T,Sandahl Christiansen J,Lunde Jorgensen JO, Normal Physiology of Growth Hormone in Adults 2000;     [PubMed PMID: 25905284]
[4] Rorsman P,Huising MO, The somatostatin-secreting pancreatic δ-cell in health and disease. Nature reviews. Endocrinology. 2018 Jul;     [PubMed PMID: 29773871]
[5] Ito T,Igarashi H,Jensen RT, Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best practice     [PubMed PMID: 23582916]
[6] Yee LF,Mulvihill SJ, Neuroendocrine disorders of the gut. The Western journal of medicine. 1995 Nov;     [PubMed PMID: 8533409]
[7] Gábriel R, Neuropeptides and diabetic retinopathy. British journal of clinical pharmacology. 2013 May;     [PubMed PMID: 23043302]