Physiology of somatostatin

This chapter is related to Section U1(ii) from the 2017 CICM Primary Syllabus, which asks the exam candidate to  "describe the physiology of insulin, glucagon and somatostatin". Somatostatin is probably too obscure to appear in the CICM exams all by itself, but somatostatin physiology has previously managed to sneak to the exam by wearing the skin of octreotide (Question 6 from the first paper of 2015). That is perhaps the best way to learn about its effects, as there is some clinical relevance attached; whereas otherwise the discussion becomes an abstract list of discouraged glands and smothered intracellular signals.

That list:

  • Synthesis and release of somatostatin
    • Produced from preprosomatostatin and prosomatostatin by numerous tissues, including intestine (65%), brain (25%) and pancreatic islet δ-cells (5%)
    • Two main versions of the same hormone (14 and 28-amino-acid peptides)
    • Stored in granules; very short half life (1-2 minutes)
  • Stimulus for the release of somatostatin
    • Acidic duodenal pH (most potent stimulus)
    • Raised levels of insulin, glucagon, gastrin, cholecystokinin, GIP, VIP
    • Sympathetic stimulation and β-agonists
    • Duodenal lumen contents (carbohydrate, fat and protein)
  • Inhibition of the release of somatostatin
    • α-agonists
    • Muscarinic agonists, and vagal tone
    • Fasting
  • Somatostatin receptors and intracellular signalling
    • Six species of G-protein (Gi) coupled transmembrane receptors
    • Inhibit adenylyl cyclase and therefore reduce intracellular cAMP, which is what decreases the exocytosis of other hormones
  • Physiological effects of somatostatin
    • Inhibitory effects on secretion of endocrine glands:
      • Decreased secretion of all hormones, including pancreatic, pituitary, thyroid, gastrointestinal, and renal (eg. renin and aldosterone)
    • Inhibitory effects on secretion of exocrine glands:
      • Decreased bile, pancreatic juice, and gastric acid secretion
      • Decreased colonic mucus secretion
    • Vasoactive effects:
      • Decreased splanchnic blood flow
      • Decreased splanchnic vascular activity in response to a meal
    • Neurological effects:
      • Decreased contractility of the gall bladder and decreased peristalsis
      • Diminished nociception by peripheral nerves
      • Poorly characterised behavioural and cognitive effects
    • Pro-absorptive effects
      • Increased intestinal absorption of glucose, fructose, galactose, lactose, amino acids, calcium, glycerol, xylose, and triglycerides
      • Increased intestinal absorption of water and electrolytes
    • Cellular proliferation effects
      • Inhibition of mucosal cell proliferation
      • Inhibition of immune cell activation
      • Promotion of apoptosis

Fortunately or unfortunately, there is no shortage of quality literature on the subject of somatostatin physiology, and even a lackadaisical Google search will immediately reveal several excellent papers such as Bloom & Polak (1987)Kumar & Grant (2009),

Barnett (2003) or Martinez (2013). The main problem here is that most people who are preparing for a physiology exam will probably be unable to summon enough enthusiasm to read them all, as somatostatin is a fairly distant endocrine province, and is unlikely to be well-represented in questions. The best recommendation would therefore have to be the short StatPearls page by O'Toole & Sharma (2021), as unlike what follows, it wastes none of the reader's time. 

Production of somatostatin

Somatostatin is a 14-amino-acid peptide (tetradecapeptide!), grouped by CICM with other pancreatic hormones, but actually produced by many tissues. The granules of pancreatic δ-cells are probably the least important source of this hormone, as it can also come from the stomach, the small intestine, the brain, retina, peripheral and enteric nerves, thyroid gland, adrenal glands, submandibular salivary glands, kidney, prostate, placenta, immune cells, vascular endothelium and probably numerous other cell types. It will suffice to say that the pancreas is really in the minority here, producing less than 5% of somatostatin in rats, with the gut and brain accounting for 65% and 25% of total secretion respectively.

 Like insulin, somatostatin appears to be some kind of fundamental right for higher animals, as basically all vertebrates have some sort of somatostatin-like molecule doing somatostatin-like things, and they are all very similar in their structure, remaining preserved through millions of years of evolution. There is apparently 100% homology of the somatostatin-14 amino acid sequence across all vertebrates, for example, which suggests that even a minor variation in its molecular structure will curse your heirs and doom your house to ruin. As with all such peptides, somatostatin is the end product of a process that begins with a much larger molecule (preprosomatostatin), and which is subject to several steps of post-translational enzymatic cleavage, at the end producing somatostatin and a pile of peptide offcuts which do not appear to have any physiological role. A larger (double) version of somatostatin, a 28-amino-acid peptide unimaginatively named SST-28, is also produced in the course of this process, and some somatostatin-secreting tissues (eg. intestine) produce more of it then others.   

Secretion of somatostatin

The release of somatostatin from granules is generally a regulatory response, in the sense that it is usually triggered by the increase in the circulating levels of the hormonal thing somatostatin is expected to suppress. Additionally there are some stimuli for somatostatin secretion which are related to its metabolic and nutritional effects. In the exciting early days of somatostatin research, Arimura & Fishback (1981) tested a whole range of different stimuli and determined their effect on somatostatin secretion from the CNS of anaesthetised rats, providing us with a helpful list:

  • Somatostatin release is stimulated by:
    • Dietary carbohydrate, and hyperglycaemia
    • Dietary fat
    • Dietary protein
    • Increased gastric and duodenal acidity (these appear to be the most potent stimuli, quantitatively)
    • Hormones:
      • Gastrin
      • Cholecystokinin
      • Secretub
      • GIP
      • VIP
      • Insulin and glucagon
    • Autonomic nervous system effects:
      • β-agonists
  • Somatostatin release is inhibited by:
    • ​​​​​​​α-agonists
    • Muscarinic agonists, and vagal tone
    • Fasting

Looking at the sort of things that trigger somatostatin release, one comes to the conclusion that it was probably just a hormone with only limited local gastrointestinal importance, but then accidentally happened to become involved in a million other regulatory pathways through the inattentive negligence of evolution. For example, its pharmacokinetics suggests that it must obviously be intended as mainly a paracrine signalling molecule.  Its half-life in the circulation is extremely short (perhaps one or two minutes, like adrenaline), but the things it influences (exocytosis, hormone synthesis, cell proliferation) are medium-term goals, unlike adrenaline (which influences the physiology of phenomena occurring over seconds and minutes, like contractility and vessel tone). From this it follows that somatostatin secretion is probably meant to wash over some local structures. Specifically the local structures of the gut, it would seem - in mammals most of the somatostatin in the body is hanging out in the gut mucosa, mainly the gastric antrum, duodenum and jejunum. Considering the potency of duodenal pH as a stimulus for somatostatin release, many authors have come to the conclusion that its main role in the gastrointestinal tract is to stop further gastric acid secretion from continuing after a meal has completed its tour of the stomach. This is supported by the finding that postprandial peaks of somatostatin release tend to be the highest physiological  levels overall (i.e., using the day, the highest systemic somatostatin level you will ever get will probably after lunch); and all of the somatostatin found in the systemic circulation after a meal appears to have originated from the upper GI tract (Yamada, 1987). How this peptide also ended up involved in pituitary and CNS function boggles the imagination

Somatostatin receptors

There are six main varieties of somatostatin receptors, all of which are G-protein coupled transmembrane receptors. It's a Gi protein, where the subscripted "i" stands for "inhibitory". The activation of these receptors results in the decrease in adenylyl cyclase activity and therefore a decrease in all kinds of cAMP-dependent processes, of which the most important would have to be exocytosis. More detail on the specific effects and tissue distribution of somatostatin receptors is probably irrelevant to most of the target audience of this page, but those who might want to know more can find it in this 2013 article by Theodoropoulou & Stalla from Frontiers in neuroendocrinology.

Physiological effects of somatostatin

In the interest of saving some space, it would be fair and reasonable to say that somatostatin is the hormone that hates other hormones, and to just leave it at that. No joke; Bloom and Polack referred to it as "endocrine cyanide".  Clinically relevant effects can be broadly divided into:

  • Inhibitory effects on secretion of endocrine glands,
  • Inhibitory effects on secretion of exocrine glands, and
  • Vasoactive effects, mainly related to the inhibition of nitric oxide synthesis

Specific applications of somatostatin analogues are described well enough in the chapter on octreotide, and are only listed here for convenience:

  • Splanchnic vasoconstriction (for GI bleeding or hepatorenal syndrome)
  • Intestinal antisecretory activity (mainly to control diarrhoea)
  • Decreased flow of chyle (eg. to reduce the accumulation of chylothorax)
  • Inhibition of insulin release (for sulfonylurea toxicity)
  • Inhibition of various hormones (GH, TSH, serotonin, etc) mainly in the context of neuroendocrine tumours (for example in a state of carcinoid crisis)

If you're a hormone, chances are somatostatin will decrease your rate of synthesis and secretion, and from this it follows that to list all the effects of somatostatin would probably mean to list all possible and impossible hormones, a task the thought of which fills this author with the opposite of joy. Still, someone else has already prepared a list of the more important somatostatin effects, and there would be no shame in borrowing it and reproducing a slightly modified form:

  • Inhibition of hormone secretion
    • Pituitary
      • Growth hormone
      • ACTH
      • TSH
      • Prolactin
    • Pancreatic
      • Insulin
      • Glucagon
    • Gastrointestinal
      • Gastrin
      • Secretin
        cholecystokinin
      • VIP
      • gastric inhibitory polypeptide
      • motilin
      • neurotensin
    • Misc
      • Calcitonin
      • Interferon-γ
      • Renin and aldosterone
  • Gastrointestinal regulatory functions
    • Vasoactive effects
      • Decreased splanchnic blood flow
      • Decreased splanchnic vascular activity in response to a meal
    • Inhibition of motility:
      • Decreased gastric emptying
      • Decreased gall bladder contractility
    • Inhibition of secretory functions:
      • Inhibition of gastric acid secretion
      • Inhibition of pancreatic exocrine secretion (bicarbonate and digestive enzymes)
      • Inhibition of bile production
      • Inhibition of colonic mucus secretion
    • Stimulation of absorptive functions:
      • Increased intestinal absorption of glucose, fructose, galactose, lactose, amino acids, calcium, glycerol, xylose, and triglycerides
      • Increased intestinal absorption of water and electrolytes
  • Proliferative and antiproliferative cellular effects
    • Inhibition of mucosal cell proliferation
    • Inhibition of immune cell activation
    • Promotion of apoptosis
  • Effects on the nervous system
    • Inhibition of peripheral nerve nociceptive activity
    • Behavioural and cognitive effects (which remain obscure, but there's clearly some role)

References

Bloom, S. R., and J. M. Polak. "Somatostatin.British Medical Journal (Clinical Research Ed.) 295.6593 (1987): 288.

Martinez, Vicente. "Somatostatin." Handbook of biologically active peptides. 2013. 1320-1329.

Liu, Yun, et al. "The evolution of somatostatin in vertebrates." Gene 463.1-2 (2010): 21-28.

Kumar, Ujendra, and Michael Grant. "Somatostatin and somatostatin receptors." Cellular peptide hormone synthesis and secretory pathways (2009): 97-120.

Theodoropoulou, Marily, and Günter K. Stalla. "Somatostatin receptors: from signaling to clinical practice." Frontiers in neuroendocrinology 34.3 (2013): 228-252.

Arimura, Akira, and James B. Fishback. "Somatostatin: regulation of secretion." Neuroendocrinology 33.4 (1981): 246-256.

Yamada, Tadataka. "Gut somatostatin." Somatostatin. Springer, Boston, MA, 1987. 221-228.

Tostivint, Hervé, Isabelle Lihrmann, and Hubert Vaudry. "New insight into the molecular evolution of the somatostatin family." Molecular and cellular endocrinology 286.1-2 (2008): 5-17.