Physiology of somatostatin and its analogues
- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
Somatostatin holds an interesting place in gastrointestinal endocrinology. Originally discovered as an inhibitor of growth hormone release , it is now known to inhibit a variety of gastrointestinal processes (table 1) . Somatostatin is produced by paracrine cells that are scattered throughout the gastrointestinal tract and inhibits gastrointestinal endocrine secretion. Somatostatin is also found in various locations in the nervous system and exerts neural control over many physiological functions. Given this vast array of effects, it is not surprising that somatostatin has been the subject of intensive investigation. The development of synthetic analogues has led to treatment of clinical disorders such as acromegaly, hormone-secreting tumors of the gastrointestinal tract, and portal hypertensive bleeding.
Biologically active somatostatin exits in two molecular forms: somatostatin-14 and somatostatin-28. Both are the products of post-translational processing of preprohormone . (See "Overview of gastrointestinal peptides in health and disease".) Somatostatin is a cyclic peptide (figure 1) that is remarkably well conserved in evolution. A disulfide bond between cysteine residues maintains the cyclic structure. Somatostatin-14 is identical to the carboxyl terminal 14 amino acids of somatostatin-28. The biological activity of S-14 and S-28 resides in the cyclic region of the mature peptide. The F-W-K-T portion of the ring structure is required for receptor occupancy. This finding made it possible to produce synthetic bioactive peptides such as octreotide acetate (SMS-201-995, Sandostatin) (figure 1).
Cortistatin is a neuropeptide that is structurally similar to somatostatin and binds to all somatostatin receptor subtypes. It can also bind the growth hormone secretagogue receptor (GHS-R, also known as the ghrelin receptor), but as yet its physiological function is unknown .
Somatostatin is distributed throughout the entire body, although it is particularly abundant in nervous tissue of the cortex, hypothalamus, brainstem, and spinal cord. It has also been localized in nerves of the heart, thyroid, skin, eye, and thymus. Somatostatin is abundant in the gastrointestinal tract and pancreas where it is produced by paracrine and endocrine-like D cells and by enteric nerves. Both S-14 and S-28 are expressed throughout regions of the gastrointestinal tract.
Somatostatin cells are morphologically diverse. In the gut mucosa, D-cells are flask-shaped and contain long cytoplasmic extensions that end in nerve terminal-like processes poised to participate in endocrine regulation either via release into the systemic circulation or direct secretion onto a neighboring cell. (See "Overview of gastrointestinal peptides in health and disease".) These cells appear uniquely suited to sample the luminal contents and influence local cell responses in a paracrine manner. In the central and peripheral nervous systems, nerves release somatostatin where it functions as a peptidergic neurotransmitter.
- Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179:77.
- Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334:246.
- Chiba T, Yamada T. Gut Somatostatin, 1st ed, Walsh J, Dockray G (Eds), Raven Press, New York 1994.
- Broglio F, Papotti M, Muccioli G, Ghigo E. Brain-gut communication: cortistatin, somatostatin and ghrelin. Trends Endocrinol Metab 2007; 18:246.
- Kidd M, Drozdov I, Joseph R, et al. Differential cytotoxicity of novel somatostatin and dopamine chimeric compounds on bronchopulmonary and small intestinal neuroendocrine tumor cell lines. Cancer 2008; 113:690.
- Raulf F, Pérez J, Hoyer D, Bruns C. Differential expression of five somatostatin receptor subtypes, SSTR1-5, in the CNS and peripheral tissue. Digestion 1994; 55 Suppl 3:46.
- Schonbrunn A. Selective agonism in somatostatin receptor signaling and regulation. Mol Cell Endocrinol 2008; 286:35.
- Rocheville M, Lange DC, Kumar U, et al. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J Biol Chem 2000; 275:7862.
- Yamada T, Soll AH, Park J, Elashoff J. Autonomic regulation of somatostatin release: studies with primary cultures of canine fundic mucosal cells. Am J Physiol 1984; 247:G567.
- Kumar U. Cross-talk and modulation of signaling between somatostatin and growth factor receptors. Endocrine 2011; 40:168.
- Reubi JC, Schonbrunn A. Illuminating somatostatin analog action at neuroendocrine tumor receptors. Trends Pharmacol Sci 2013; 34:676.
- Hipkin RW, Friedman J, Clark RB, et al. Agonist-induced desensitization, internalization, and phosphorylation of the sst2A somatostatin receptor. J Biol Chem 1997; 272:13869.
- Stengel A, Taché Y. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications. Front Endocrinol (Lausanne) 2012; 3:178.
- Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2005; 21:636.
- Arnold R, Frank M, Kajdan U. Management of gastroenteropancreatic endocrine tumors: the place of somatostatin analogues. Digestion 1994; 55 Suppl 3:107.
- Mosdell KW, Visconti JA. Emerging indications for octreotide therapy, Part 1. Am J Hosp Pharm 1994; 51:1184.
- van der Hoek J, Hofland LJ, Lamberts SW. Novel subtype specific and universal somatostatin analogues: clinical potential and pitfalls. Curr Pharm Des 2005; 11:1573.
- Cello JP, Grendell JH, Basuk P, et al. Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial. Ann Intern Med 1991; 115:705.
- Harris AG, O'Dorisio TM, Woltering EA, et al. Consensus statement: octreotide dose titration in secretory diarrhea. Diarrhea Management Consensus Development Panel. Dig Dis Sci 1995; 40:1464.
- Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986; 315:663.
- Valenzuela JE, Schubert T, Fogel MR, et al. A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. Hepatology 1989; 10:958.
- Korula J. Review: somatostatin and its analogues do not reduce mortality in acute bleeding esophageal varices. ACP J Club 2005; 143:16.
- Andriulli A, Leandro G, Niro G, et al. Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis. Gastrointest Endosc 2000; 51:1.
- Greenberg R, Haddad R, Kashtan H, Kaplan O. The effects of somatostatin and octreotide on experimental and human acute pancreatitis. J Lab Clin Med 2000; 135:112.
- Yeo CJ, Cameron JL, Lillemoe KD, et al. Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial. Ann Surg 2000; 232:419.
- Alvarez C, McFadden DW, Reber HA. Complicated enterocutaneous fistulas: failure of octreotide to improve healing. World J Surg 2000; 24:533.
- Stevens P, Foulkes RE, Hartford-Beynon JS, Delicata RJ. Systematic review and meta-analysis of the role of somatostatin and its analogues in the treatment of enterocutaneous fistula. Eur J Gastroenterol Hepatol 2011; 23:912.
- Connor S, Alexakis N, Garden OJ, et al. Meta-analysis of the value of somatostatin and its analogues in reducing complications associated with pancreatic surgery. Br J Surg 2005; 92:1059.
- Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med 1996; 125:26.
- Teunissen JJ, Kwekkeboom DJ, Valkema R, Krenning EP. Nuclear medicine techniques for the imaging and treatment of neuroendocrine tumours. Endocr Relat Cancer 2011; 18 Suppl 1:S27.
- Florio T. Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci 2008; 13:822.
- Hasskarl J, Kaufmann M, Schmid HA. Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors. Future Oncol 2011; 7:895.
- Tomassetti P, Migliori M, Caletti GC, et al. Treatment of type II gastric carcinoid tumors with somatostatin analogues. N Engl J Med 2000; 343:551.
- Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 1998; 42:442.
- Raderer M, Hejna MH, Muller C, et al. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int J Oncol 2000; 16:1197.
- Oberg K. State of the art and future prospects in the management of neuroendocrine tumors. Q J Nucl Med 2000; 44:3.
- Abdel-Rahman O, Lamarca A, Valle JW, Hubner RA. Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations. Endocr Relat Cancer 2014; 21:R485.
- Frilling A, Clift AK. Therapeutic strategies for neuroendocrine liver metastases. Cancer 2015; 121:1172.
- Raj N, Reidy-Lagunes D. Current clinical trials of targeted agents for well-differentiated neuroendocrine tumors. Pancreas 2014; 43:1185.
- Fogar P, Greco E, Basso D, et al. Killer genes in pancreatic cancer therapy. Cell Mol Biol (Noisy-le-grand) 2005; 51:61.
- Grant MB, Caballero S Jr. The potential role of octreotide in the treatment of diabetic retinopathy. Treat Endocrinol 2005; 4:199.
- Taylor BK. Spinal inhibitory neurotransmission in neuropathic pain. Curr Pain Headache Rep 2009; 13:208.
- Pan HL, Wu ZZ, Zhou HY, et al. Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther 2008; 117:141.
- Camilleri M, Andresen V. Current and novel therapeutic options for irritable bowel syndrome management. Dig Liver Dis 2009; 41:854.