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.
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