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Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
SOMATOSTATIN:
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PHYSIOLOGICAL AND CLINICAL SIGNIFICANCE Roger Guillemin, MD., Ph.D. The Salk Institute, La Jolla, California 92112
John E. Gerich, MD. Metabolic Research Unit and Department of Medicine, University of California, San Francisco, California 94143
INTRODUCTION In 1972,while searching in hypothalamic extracts for the releasing factor for growth hormone (at that time and still uncharacterizedl ), we observed that the material from some fractions of the purification sequence would powerfully inhibit the secre tion of immunoreactive growth hormone. Krulich & McCann (6) had previously observed such an inhibitory activity, but no attempt at its characterization had been reported. Our test system was composed of sets of identical tissue-culture plates in which anterior pituitary cells from normal rats were attached as a monolayer four to six days after placing in the dish after dispersion with collagenase and trypsin (7). The major component with the growth hormone release-inhibiting activity was isolated, characterized, reproduced by total synthesis, and named somatostatin. It has the following primary sequence (8-10):
I
I
H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH. Both the oxidized and the reduced forms of the peptide were shown to have the full biological activity in vitro or in vivo in various animal species (8, 10). IThe literature and proceedings of several symposia on growth hormone secretion (1-3) contain reports claiming the isolation and characterization of growth hormone-releasing hor mone (GHRH) as a decapeptide (4); biological activity was evidenced by a highly controversial assay based on pituitary "depletion" of bioassayable growth hormone. It was later shown that GHRH was identical to a fragment from the N-terminal
of the /3
(5)
chain of hemoglobin.
GHRH has no effect on the secretion of immunoreactive growth hormone, and is thus most likely an artifact.
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Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
LABORATORY STUDIES In laboratory animals, somatostatin inhibited growth hormone secretion acutely induced by all pharmacologic means, such as barbiturates, L-Dopa, arginine, and morphine (8, 11-13), as well as after electrical stimulation of the hypothalamus or amygdala (14) or catecholamine infusion in the third ventricle (12). Additionally, somatostatin was found to inhibit the secretion of thyrotropin induced by thyrotro pin-releasing factor (TRF), while not affecting the concomitant secretion of prolac tin triggered by the same dose of TRF (I5, 16). In some of the above studies, Koerker et al (12) noticed that infusion of somato statin in nonanesthetized baboons was accompanied by hypoglycemia, which was associated with the prompt inhibition by somatostatin of the (basal) secretion of glucagon and insulin. This effect was clearly shown to be directly at the pancreatic level by in vitro infusion of the isolated pancreas (17-21), as well as with tissue cultures of the endocrine pancreas (22). At both receptor sites (i.e. adenohypophysis and endocrine pancreas),somatosta tin is significantly active at similar concentrations: 10-9 M in vitro, > 200-400 ng/IOO g body weight in vivo (23). It had been observed in the earliest studies in vivo with somatostatin (8, II) that the peptide had a very short biological half-life « 4 min). Also,with an exquisitely sensitive bioassay (16), and later by radioimmunoassay (24,25), it was shown that somatostatin is present in parts of the central nervous system (eNS) other than the hypothalamus; indeed, the spinal cord appears to contain a high concentration. These observations led us to wonder whether the effects of somatostatin on the endocrine pancreas could, in physiological circumstances, truly be due to peptides of hypothalamic origin. A more satisfactory hypothesis would have been the possi ble release of somatostatin at (peptidergic) nerve endings in the neuroinsular com plexes of the endocrine pancreas. Indeed, somatostatin activity was found in aqueous extracts of the fetal rat pancreas by bioassays (23) and later by radioim munoassays (25). When this was investigated by histoimmunofluorescence,no nerve endings containing somatostatin were found; however, a discrete population of endocrine cells was found to contain somatostatin (2&-29). These are different from the a cells secreting glucagon and the 13 cells secreting insulin. Early evidence with the light microscope (2&-28),and more recently with the electron microscope (29), have assigned the somatostatin-secreting cells of the pancreas to be the so-called D cells, for which no well-established function was available thus far. In the same reports (2&-28), somatostatin-containing cells were observed (by immunofluores cence) in the duodenum, the fundic and antral mucosa of the stomach, and, al though in much more reduced numbers, in the glandular elements of the jejunum and ileum and occasionally as isolated elements or small clusters in the exocrine pancreas. These observations have been confirmed in all species of vertebrates studied thus far (26). Somatostatin has also been shown to inhibit the secretion of gastrin as induced by meals (30),and there are two reports that in relatively large doses, it can inhibit the secretion of secretin and of the exocrine pancreas as induced by HCI (31) and gastric secretion of HCI and pepsin (32), as induced by pentagastrin.
Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
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When administered to animals rendered diabetic by alloxan, streptozotocin, or pancreatectomy, somatostatin regularly produces dramatic lowering of hyper glycemia. This effect is always accompanied by inhibition of the basal elevated secretion of glucagon of either pancreatic or extrapancreatic origin (33). Somatosta tin has no effect on the peripheral utilization or distribution of glucose (12, 34), nor is there evidence that it acts at the hepatic level to inhibit glycogenolysis or gluconeogenesis (35). In early studies, somatostatin appeared to act distally to cyclic adenosine mono phosphate (cAMP), since it inhibits release of growth hormone normally produced by both (dibutyryl)cAMP and theophylline (36, 37). It has been reported to lower cAMP levels and elevate cyclic guanosine monophosphate (cGMP) in pituitary tissues (37, 38). In acute studies, although somatostatin inhibits the release of preformed growth hormone, it does not inhibit the biosynthesis of growth hormone in the same pituitary cells (36). With regard to earlier observations of somatostatin's presence in parts of the eNS other than the hypothalamus, there are recent reports of its effects on the spontane ous electrical activity of some neuronal systems as observed by microelectrode recordings (39) and on behavior (40, 41). It has been shown to counteract the seizure-inducing effects of strychnine (42) in the rat. All of the above studies, as well as the clinical studies discussed below, have been conducted with somatostatin prepared by total synthesis (10). Series of synthetic analogues have already been prepared, including molecules with biological potency greater than that of the native substance (43). Evidence for dissociation of several of the multiple biological activities of some analogues of somatostatin at some receptor sites has recently been achieved (79, 80). No evidence (macro- or microscopic) of toxicity, either acute or after 21-days' administration, has been seen in dogs, rats, mice, or Rhesus monkeys with well characterized synthetic preparations of somatostatin administered in doses ten- to a hundredfold the human clinical doses on a body weight basis.2 Baboons, in which somatostatin was chronically administered, were reported to have shown abnormal platelet function as well as various blood disorders with postmortem evidence of lung hepatization (44). A causal relationship, h owever, is not apparent. Substances other than somatostatin were also administered, and no strict controls are or were available to determine whether the animals, sitting for long periods of time in primate chairs and with multiple implanted catheters, may not have been prone to developing some type of coagulation disorder or latent septicemic infection responsi ble for death. This question is discussed further below.
CLINICAL STUDIES IN MAN Growth Hormone Somatostatin inhibits growth hormone responses to virtually all known physiologi cal and pharmacological stimuli such as arginine (45-47), L-Dopa (45), insulin2AIl studies were carried out in compliance with FDA regulations in an application for an IND number, which was granted to one of us (RG) in April 1973.
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induced hypoglycemia (47, 48), exercise (49), sleep (50), and meals (51, 52) in normal man (45-50) and in human subjects with growth hormone-producing pitui tary tumors as in acromegaly (46-48,51, 53-55). Although several studies (45-49, 56-58) have failed to demonstrate an effect on basal growth hormone levels in normal man, there is usually a rebound upon discontinuation of the somatostatin infusion, suggesting that inhibition of basal hormone secretion had been present (45, 46,48,49,57). In pathological states associated with elevated basal growth hormone levels, such as acromegaly (46-48,51,53-55),protein-caloric malnutrition (55),and diabetes (49, 59), suppression is readily apparent. The cyclic and linear forms of synthetic somatostatin appear to be equally effec tive inhibitors of growth hormone secretion. With intravenous administration, inhi bition is demonstrable within 15 min (53, 54) and upon termination of the somatostatin infusion, growth hormone levels characteristically rebound above preinfusion levels. From the rapidity with which inhibition by somatostatin begins and its quick reversal after termination of the infusions, it is apparent that the action of somatostatin on growth hormone release is almost immediate and that it has a short biological half-life (4--8 min). When administered subcutaneously in doses up to 8 mg (57), the effect of somatostatin lasts for only 2 hr. Attempts to prolong its action by administering it subcutaneously in oil or gelatin (54) or after coupling it to protamine zinc (51) have not resulted in increases in activity beyond 4 hr. The time required for maximal suppression is a function of the fasting growth hormone level when conventional doses of somatostatin are used. In one study of acromegalic patients (54), doses between 100 and 1000 ,u.glhr were found to be maximally effective; a lesser response was observed with 25 ,u.g/hr, and none with 10 ,u.glhr. No comparable data are available concerning the sensitivity of normal pituitary tissue. Once suppressed, there has been no escape of growth hormone from inhibition during short-term studies and in longer studies carried out in acromegalic and diabetic subjects for as long as 28 hr (51, 59). It has been reported, however, that growth hormone responses to TRF and luteinizing hormone-releasing factor in acromegalic patients are not inhibited by somatostatin (60). OTHER PITUITARY HORMONES In normal man,somatostatin does not affect the secretion of luteinizing hormone and follicle-stimulating hormone (45, 48, 53), adrenocorticotropin (48, 61), and prolactin (45, 48, 58). Thyrotropin responses to TRF are inhibited by somatostatin (48, 58, 62); most (45, 48, 53, 58), but not all (63), studies indicate that basal levels are apparently not affected. Atypicai responses to somatostatin may occur in patients with pituitary tumors. Thus, somatostatin has been reported to lower fasting prolactin levels in patients with acromegaly (53) and to lower ACTH levels in patients with Nelson's syndrome (61),although somatostatin does not affect secretion of these hormones by normal pituitary tissue.
Pancreatic Hormones Somatostatin inhibits secretion of both insulin (34, 46, 47, 53, �4, 56, 64--69) and glucagon (34, 46,51, 52, 54,56,57,59,67-70) in man. Fasting insulin levels (34,
Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
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46,47, 53, 65, 68), as well as insulin responses to meals (51), oral and intravenous glucose (46, 51, 54, 57, 66, 68), arginine (47, 56), glucagon, and tolbutamide (69), are diminished or completely prevented by somatostatin. Similarly, basal glucagon secretion (34,46,51,52,54,59,67,68),as well as glucagon responses to meals (51, 52, 57), intravenous arginine (56), insulin-induced hypoglycemia (71), epinephrine (70), and insulin deprivation (59), are suppressed by somatostatin. The inhibitory effects of somatostatin on glucagon secretion occur with equal effectiveness in normal subjects (34,56,67,68,70),insulin-dependent diabetic subjects (52,56,57, 59), and patients with acromegaly (46, 51). The ability of somatostatin to inhibit insulin and glucagon secretion has provided a useful tool for studying the physiological and pathological effects of these hor mones (46, 52, 56, 57,59,67) on human metabolism (34). Infusion of somatostatin lowers plasma glucose levels in normal man despite concomitant lowering of both plasma insulin and glucagon levels (34,46, 67). These observations provided the first clear-cut evidence that glucagon has an important physiological role in human carbohydrate homeostasis. Somatostatin itself has no direct effect on either hepatic glucose production (72) or peripheral glucose utilization (34, 73), since the fall in plasma glucose levels could be prevented by exogenous glucagon (69). In juvenile-type diabetics, somatostatin diminishes fasting hyperglycemia by as much as 50% in the complete absence of circulating insulin (57, 74). Although somatostatin impairs carbohydrate tolerance after oral or intravenous glucose chal lenges in normal man by inhibiting insulin secretion (46,51,54,64,66), carbohy drate tolerance after ingestion of balanced meals is improved in patients with insulin-dependent diabetes mellitus through the suppression of excessive glucagon responses (52, 57). The combination of somatostatin and a suboptimal amount of exogenous insulin (which by itself had prevented neither excessive hyperglycemia nor hyperglucagonemia in response to meals) completely prevents plasma glucose levels from rising after meal ingestion in insulin-dependent diabetics (52). Through its suppression of glucagon and growth hormone secretion, somatostatin has also been shown to moderate or prevent completely the development of diabetic ketoacidosis after the acute withdrawal of insulin from patients with insulin-depend ent diabetes mellitus (59). Pancreatic tumors secreting either glucagon (54) or insulin (75) have been re ported to be responsive to somatostatin. Curiously, in patients with insulinomas, basal and glucagon-stimulated insulin secretion is inhibited by somatostatin, but that due to tolbutamide characteristically is not (75). Infusion of somatostatin in such patients must be performed cautiously since,despite lowering of basal insulin levels, plasma glucose levels fall precipitously.
Gastrointestinal Hormones Data concerning the effect of somatostatin on gastrointestinal hormones in man are presently available only for gastrin (30). Somatostatin suppressed fasting plasma gastrin levels approximately 40% in normal subjects and in subjects with acromeg aly during a 60-min infusion. Additionally, gastrin responses after ingestion of a balanced meal were completely suppressed. The markedly elevated fasting gastrin levels in two patients with pernicious anemia were diminished by more than 50%
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during a 75-min infusion of somatostatin. Finally, both gastric acid secretion and extreme hypergastrinemia of a patient with Zollinger-Ellison syndrome were sup pressed during a 20-min infusion of somatostatin (30).
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Side Effects and Toxicity Although some adverse hematological effects have been reported in baboons (44) and rabbits (76) receiving large amounts of somatostatin, no serious toxicity has been encountered in man during a two-year clinical experience in over 300 subjects. The most frequent side effects encountered are transient nausea, occasional diarrhea, and abdominal cramps (50, 56, 58). Transient falls in blood pressure (10 mm Hg for 10 min) and rises in pulse (10 beats per min lasting 10 min) are sometimes observed (49, 56). No significant hypoglycemia has been found, except in diabetics given exogenous insulin. No changes in white blood cell count (46, 48), platelet count (46, 77), bleeding time (77), prothrombin time (77), partial thromboplastin time (77), serum electrolyte levels (46, 48), or renal or hepatic function (46, 48) have been encountered either in acute studies or after prolonged (12 hr) infusions of somatostatin. All these values have been found to be normal after intermittent administration of somatostatin as frequently as once weekly for over a year (77). Although a recent report (78) suggested that somatostatin might diminish platelet aggregation, similar studies using higher doses of somatostatin found no effect (77); these discrepant results might have been due to the use of different preparations of somatostatin. Since bleeding times were unaffected in both studies, the clinical significance of the reported platelet abnormalities is unclear.
Therapeutic Implications From the foregoing description of the ability of somatostatin to inhibit the secretion of various hormones, it would appear that this agent may be of therapeutic use in certain clinical conditions such as acromegaly, pancreatic islet cell tumors, and diabetes mellitus. With regard to endocrine tumors, it must be emphasized that while somatostatin will inhibit hormone secretion by these tissues, it would not be expected to diminish tumor growth (36, 81). Thus, in these conditions it is unlikely that somatostatin will find use other than as a symptomatic or temporizing measure. In diabetes mellitus, however, somatostatin might be of considerable clinical value. First, it has already been demonstrated that it can acutely improve fasting (57) as well as postprandial hyperglycemia (52, 57) in insulin-requiring diabetics by inhibiting glucagon secretion. Second, since growth hormone has been implicated in the development of diabetic retinopathy, the inhibition of growth hormone secre tion by somatostatin may lessen this complication of diabetes. Finally, through suppression of both growth hormone and glucagon secretion, somatostatin may prevent or diminish the severity of diabetic ketoacidosis and find application in "brittle diabetes." These optimistic expectations must be tempered with the facts that the diverse effects of somatostatin on hormone secretion and its short duration of action make its clinical use impractical at the present time and that its long-term effectiveness and safety have not been established as yet.
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CONCLUSION Somatostatin, originally characterized on the basis of one well-defined biological activity and extracted from one well-defined area of the brain, has now been shown to exist in significant quantities outside the CNS and to be polyvalent in its ability to inhibit hormone secretion. Its tissue distribution is not random: the peptide is found both in the CNS and in highly specialized (neuro-) endocrine cells ontogeni cally derived from neural crest primordia. The multiple effects of the peptide are all consistent, as they appear to involve inhibition of the secretion of polypeptides; in all cases, the target or receptor is topographically closely related to the secretory element. Somatostatin may well represent the prototype of a new class of carriers of physiological information (for which one of us is proposing elsewhere the generic name of cybernins) different from classical hormones (e.g. ACTH, gonadotropins, insulin, etc) and different also from the classical neurotransmitters (e.g. catechola mines, dopamine, serotonin, and acetylcholine). The existence of such a new class of agents seems likely, but remains to be firmly established; methodology for this is just becoming available as this review is being prepared. Abnormalities in the metabolism or secretion of these agents could be significant in the etiology of malfunction or disease of various organic systems. For example, if somatostatin is actually synthesized in multiple areas of the CNS, as seems to be the case, local dysfunctions in the biosynthesis or release mechanism for somatostatin could be involved in the pathogenesis of some mental disorders. The possible clinical significance of somatostatin, particularly as a component of the treatment of diabetes, also remains to be established in further clinical studies. The multiplicity of target receptors for the peptide and its short duration of action will require careful assessment of dosage and timing of administration and knowl edge of differential affinities of the various receptors for the synthetic replicates of the native primary sequence or some of its synthetic analogues. ACKNOWLEDGMENTS
The fundamental research reviewed here and carried out at The Salk Institute has been supported by the McConnell Clark Foundation of New York City, the Ford and Rockefeller Foundations, and the National Institutes of Health (NIAMDD, AM 16707). The clinical investigations carried out at the University "of California, San Francisco, were supported in part by the Levi J. and Mary Skaggs Foundation of Oakland, Calif., the Susan Greenwall Foundation of New York City, and the Division of Research Resources, RR-79, of the US Public Health Service. Literature Cited 1. Sonenberg, M., ed. 1968. Growth hor mone. Ann. NY Acad. Sci. 148:289-571 2. Pecile, A., Miiller, E. E., eds. 1968. Growth Hormone. Proc. Int. Symp. Growth Horm.. 1st. Excerpta Med. Int. Congr. Ser. 158 3. Pecile, A., Miiller, E. E., eds. 1972. Growth and Growth Hormone. Proc. Int.
Symp. Growth Horm., 2nd. Excerpta Med. Int. Congr. Ser. 244 4. Schally, A. V., .Baba, Y., Nair, R. M. G., Bennett, C: D. 1971. The amino acid sequence of a peptide with growth hormone-releasing activity isolated from porcine hypothalamus. J. Bio/. Chern. 246:6647-50
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S. Veber, D. F. et al 1971. Synthesis of a
proposed growth hormone releasing factor. Biochem. Biophys. Res. Com mun. 45:235-39 Krulich, L., McCann, S. M. 1969. Effect of GH-releasing factor and GH inhibiting factor on the release and con centration of GH in pituitaries in cubated in vitro. Endocrinology 85: 319-24 Vale, W., Grant, G., Amoss, M., Black well, R., Guillemin, R. 1972. Culture of enzymatically dispersed anterior pitui tary cells: Functional validation of a method. Endocrinology 91 :562-72 Brazeau, P. et al 1973. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77-79 Burgus, R., Ling, N., Butcher, M., Guillemin, R. 1973. Primary structure of somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone. Proc. Natl Acad. Sci.
18. Curry, D. L., Bennett, L. L., Li, C. H. 1974. Direct inhibition of insulin secre tion by synthetic somatostatin. Bio chem. Biophys. Res. Commun. 58: 885-89 19. Efendic, S., Luft, R., Grill, V. 1974. Effect of somatostatin on glucose in duced insulin release in isolated per fused rat pancreas and isolated rat pan creatic islets. FEBS Lett. 42:169-72 20. Weir, G. C., Knowlton, S. D., Martin, D. B. 1974. Somatostatin inhibition of epinephrine-induced glucagon secre tion. Endocrinology 95:1744-46 21. Iversen, J. 1974. Inhibition of pan creatic glucagon release by somato statin: In vitro. Scand. J. Clin. Lab. In vest. 33:125-29 22. Fujimoto, W. Y., Ensinck, J. W., Wil liams, R. H. 1974. Somatostatin inhibits insulin and glucagon release by monolayer cell cultures of rat endocrine pancreas. Life Sci. 15:1999-2004 23. Vale, W. et al 1975. Somatostatin. Re
10. Rivier, J. E. F. 1974. Somatostatin. To tal solid phase synthesis. J. Am. Chem. Soc. 96:2986-- 92 II. Brazeau, P., Rivier, J., Vale, W., Guille min, R. 1974. Inhibition of growth hor mone secretion in the rat by synthetic somatostatin. Endocrinology 94:184-87 12. Koerker, D. J. et a1 1974. Somatostatin: Hypothalamic inhibitor of the endo crine pancreas. Science 184:482-84 13. Lovinger, R. et al 1974. Effect of syn thetic somatotropin release inhibiting factor on the increase in plasma growth hormone elicited by L-Dopa in the dog. Endocrinology 95:943-46 14. Martin, J. B. 1974. Inhibitory effect of somatostatin (SRIF) on the release of growth hormone (GH) induced in the rat by electrical stimulation. Endo crinology 94:497-502 15. Vale, W. et al 1973. Inhibitory hypo physiotropic activities of hypothalamic somatostatin. Fed. Proc. 32:211 16. Vale, W., Rivier, C., Brazeau, P., Guillemin, R. 1974. Effects of somato statin on the secretion of thyrotropin and prolactin. Endocrinology 95: 968-77 17. Gerich, J. E., Lovinger, R., Grodsky, G. M. 1975. Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to ar ginine, isoproterenol and theophylline: Evidence for a preferential effect on glucagon secretion. Endocrinology 96: 749-54
24. Arimura, A., Sato, H., Coy, D. H., Schally, A. V. 1975. Radioimmunoas say for GH-release inhibiting hormone. Proc. Soc. Exp. Bioi. Med. 148:784-89 25. Patel, Y. C., Weir, G. C., Reichlin, S. 1975. Anatomic distribution of somato statin (SRIF) in brain and pancreatic islets as studied by radioimmunoassay (RIA). Endocrinology 96:A127 26. Dubois, M. P. 1975. Immunoreactive somatostatin is present in discrete cells of the endocrine pancreas. Proc. Natl. Acad. Sci. USA 72:1340-43 27. Luft, R., Efendic, S., Hokfelt, T., Jo hansson, 0., Arimura, A. 1974. Im munohistochemical evidence for the lo calization of somatostatin-like im munoreactivity in a cell population of the pancreatic islets. Med. Biol 52: 428-30 28. Polak, J. M., Pearse, A. G. E. Grimelius, L., Bloom, S. R., Arimura, A. 1975. Growth-hormone release inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet I: 1220--22 29. Rufener, C., Amherdt, M., Dubois, M. P., Orci, L. 1975. Ultrastructural immunocytochemical localization of somatostatin in D-cells of rat pancreatic monolayer culture. J. Histochem. Cyto chern. In press 30. Bloom S. R. et al 1974. Inhibition of gastrin and gastric-acid secretion by growth-hormone release-inhibiting hor mone. Lancet 2:1106--9
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8.
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USA 70;684-88
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31. Boden, G. 1975. Somatostatin sup presses secretin and pancreatic exocrine secretion. Science. 190:163-65 32. Gomez-Pan, A. et al 1975. Direct inhi bition of gastric acid and pepsin secre tion by growth-hormone release-inhib iting hormone in cats. Lancet 1:888-90 33. Unger, R. H., Orci, L. 1975. The essen tial role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1:14-16 34. Gerich, J. E. et al 1975. Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin. Metab. Clin. Exp. 24:175-82 35. Gerich, J. E. et al 1975. In vitro and in vivo effects of somatostatin on glucose, alanine, and ketone body metabolism in the rat. Endocrinology 96:A128 36. Vale, W. et al 1972. Premieres observa tions sur Ie mode d'action de la somato statine, un facteur hypothalamique qui inhibe la secretion de I'hormone de croissance. C. R. Acad. Sci. D 275: 2913-16 37. Borgeat. P., Drouin, J., Belanger, A., Labrie, F. 1974. Inhibitory effect of growth hormone-release inhibiting hor mone on cyclic AMP accumulation in rat anterior pituitary gland in vitro. Fed. Proc. 33:263 (Abstr.) 38. Kaneko. T. et al 1974. Stimulation of guanosine 3',5'-cyclic monophosphate accumulation in rat anterior pituitary gland in vitro by synthetic somatosta tin. Diochem. Diophys. Res. Commun. 61:53-57 39. Renaud, L. P., Martin, J. B., Brazeau, P. 1975. Depressant action of TRH, LH-RH and somatostatin on activity of central neurons. Nature 255:233-35 40. Prange, A. J. et a1 1975. Modification of pentobarbital effects by natural and syn thetic polypeptides: Dissociation of brain and pituitary effects. Life Sci. 16:1907-14 41. Cohn, M. L., Cohn, M. 1975. "Barrel rotation" induced by somatostatin in the nonlesioned rat. Drain Res. In press 42. Brown, M., Vale, W. 1975. Central ner vous system effects of hypothalamic peptides. Endocrinology 96:1333-36 43. Rivier, J., Brown, J., Vale, W. 1975. o-Trp8-Somatostatin: An analog of somatostatin more potent than the na tive molecule. Dioch em. Diophys. Res. Commun. 65:746--51 44. Koerker, D. J., Harker, L. A., Goodner, C. J. 1975. Effects of somatostatin on hemostasis in baboons. N. EngL J. Med. 293:476--79
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45. Siler, T. M. et al 1973. Inhibition of growth hormone release in humans by somatostatin. J. Clin. EndocrinoL Metab. 37:632-35 46. Mortimer, C. H. et al 1974. Effects of growth-hormone release-inhibiting hor mone on circulating glucagon, insulin, and growth hormone in normal. dia betic, acromegalic, and hypopituitary patients. Lancet 1:697-701 47. Peracchi, M. et al 1974. Effect of somatostatin on blood glucose, plasma growth hormone, insulin, and free fatty acids in normal subjects and acrome galic patients. Metab. Clin. Exp. 23: 1009-15 48. Hall, R. et al 1973. Action of growth hormone-release inhibitory hormone in healthy men and in acromegaly. Lancet 2:581-84 49. Hansen, Aa. P., Orskov, H., Seyer Hansen, K., Lundbaek, K. 1973. Some actions of growth hormone release inhibiting factor. Dr. Med. J. 3: 523-24 50. Parker, D. C. et al 1974. Inhibition of the sleep-related peak in physiologic human growth hormone release by somatostatin. J. Clin. Endocrinol. Metab. 38:496--99 51. Besser, G. M. et al 1974. Long-term in fusion of growth hormone release inhib iting hormone in acromegaly: Effects on pituitary and pancreatic hormones. Dr. . Med. J. 4:622-27 52. Gerich, J. E., Lorenzi, M., Karam, J. H., Schneider, V., Forsham, P. H. 1975. The contribution of abnormal pancreatic glucagon secretion to post prandial hyperglycemia in human dia betes mellitus. J. Am. Med. Assoc. 234:159-65 53. Yen, S. S. C., Siler, T. M., DeVane, G. W. 1974. Effect of somatostatin in patients with acromegaly: Suppression of growth hormone, prolactin, insulin and glucose levels. N. Engl. J. Med. 290:935-38 54. Besser, G. M. et al 1974. Growth hor mone release inhibiting hormone in acromegaly. Dr. Med. J. 1:352-35 55. Pimstone, B. L., Becker, D., Kronheim, S. 1975. Disappearance of plasma growth hormone in acromegaly and protein-calorie malnutrition after so matostatin. J. Clin. EndocrinoL Metab. 40:168-71 56. Gerich, J. E. et al 1974. Inhibition of pancreatic glucagon responses to argi nine by somatostatin in normal man
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GUILLEMIN & GERICH and in insulin-dependent diabetics. Dia betes 23;876-80 Gerich, J. E. et al 1974. Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mel litus: Pathophysiologic and therapeutic implications . N. Engl. J. Med. 2 91; 5 4 4-47 Siler, T. M., Yen, S. S. C., Vale, W., Guillemin, R. 1974. Inhibition by somatostatin on the release of TSH in duced in man by thyrotropin-releasing factor. J. Clin. Endocrinol. Metab. 38;742-45 Gerich, J. E. et al 1975. Prevention of human diabetic ketoacidosis by somato statin; Evidence for an essential role of glucagon. N. Engl. J. Med. 2 92;985-89 Giustina, G. et al 1974. Failure of somatostatin to suppress thyrotropin releasing factor and luteinizing hor mone releasing factor-induced growth hormone release in acromegaly. J. Clin. EndocrinoL Metab. 38: 906-9 Tyrrell, J. B., Lorenzi, M., Gerich, J. E., Forsham. P. H. 1975. Inhibition by somatostatin of ACTH secretion in Nel son's syndrome. J. Clin. Endocrinol. Metab. 4 0;1125 -27 Weeke, J., Hansen, Aa. P., Lundbaek, K. 1974. The inhibition by somatostatin of the thyrotropin response to thyrotro pin-releasing hormone in normal sub jects. Scand. J. Clin. Lab. Invest. 33:101-3 Weeke. J. Hansen. Aa. P Lundbaek. K. 1975. Inhibition by somatostatin of basal levels of serum thyrotropin (TSH) in normal men. J. Clin. EndocrinoL Metab. 4 1;168-71 Alberti, K. G. M. M. et a11973. Inhibi tion of insulin secretion by somatosta tin. Lancet 2:12 9 9-1301 DeVane, G. W., Siler, T. M., Yen, S. S. C. 1974. Acute suppression of insulin and glucose levels by synthetic somato statin in normal human subjects. J. Clin. Endocrinol. Metab. 38: 913-15 Efendic, S., Luft, R. 1975. Studies on the mechanism of somatostatin action on insulin release in man. I. Effect of blockade of a-adrenergic receptors. Acta EndocrinoL Copenhagen 78: 5 16-23 Alford, F. P. et al 1974. Glucagon con trol of fasting glucose in man. Lancet 2:974-77 Christensen, S. E. et al 1974. Somato statin as a tool in studies of basal car bohydrate and lipid metabolism in man: Modifications of glucagon and insulin .
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release. Scand. J. Clin. Lab. Invest. 34;321-25 Gerich, J. E., Lorenzi, M., Schneider, V., Forsham, P. H. 1974. Effect of somatostatin on plasma glucose and in sulin responses to glucagon and tolbuta mide in man. J. Clin. Endocrinol. Metab. 3 9:105 7-60 Lorenzi, M. et al 1975. Effect of somato statin on plasma glucose. free fatty acid. and glucagon responses to epinephrine in human diabetes Clin. Res. 23: 112A Chideckel, E. W. et a11975. Somatosta tin blockade of acute and chronic stimuli of the endocrine pancreas and the consequences of this blockade on glucose homeostasis. J. Clin. Invest. 5 5:754-62 Dobbs, R. et a11975. Glucagon: Role in the hyperglycemia of diabetes mellitus. Science 187:5 4 4-4 7 Haas, R. et al 1975. Effect of somatosta tin, insulin, and glucagon on glucose uptake and alanine release by the iso lated perfused rat hindlimb. Clin. Res. 23:IIOA Gerich, J. E. et al 1975. Prevention and reversal of human diabetic ketoacidosis by somatostatin: Evidence for an essen tial role of glucagon. Clin. Res. 23;421A ( Abstr.) Lorenzi, M., Gerich, J. E., Karam, J. H., Forsham. P. H. 1975. Failure of somatostatin to inhibit tolbutamide induced insulin secretion in patients with insulinomas; A possible diagnostic tool. J. Clin. EndocrinoL Metab. 1121-24 Chaing, T. M. et al 1975. The effect of somatostatin on platelet aggregation. Endocrinology 97:753-55 Mielke, C. H. Jr. et al 1975. The effect of somatostatin on coagulation and platelet function in man. N. EngL J. Med. 2 93:480-83 Besser, G. M. et a11975. Impairment of platelet function by growth-hormone release-inhibiting hormone. Lancet 1:1166-68 Sarantakis, W. A. et al 1975. Structure activity studies on somatostatin. In En docrinology 1975, ed. I. Mcintyre, vol. I. London: Academic Brown, M., Rivier, J., Vale, W. 1976. Somatostatin (SS) analogs with dis sociated biological activities. Fed. Proc. In press Brazeau, P., Guillemin, R. 1975. Somatostatin: Newcomer from the hypothalamus. N. Engl. J. Med. 290: 963-64
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Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
SOMATOSTATIN:
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PHYSIOLOGICAL AND CLINICAL SIGNIFICANCE Roger Guillemin, MD., Ph.D. The Salk Institute, La Jolla, California 92112
John E. Gerich, MD. Metabolic Research Unit and Department of Medicine, University of California, San Francisco, California 94143
INTRODUCTION In 1972,while searching in hypothalamic extracts for the releasing factor for growth hormone (at that time and still uncharacterizedl ), we observed that the material from some fractions of the purification sequence would powerfully inhibit the secre tion of immunoreactive growth hormone. Krulich & McCann (6) had previously observed such an inhibitory activity, but no attempt at its characterization had been reported. Our test system was composed of sets of identical tissue-culture plates in which anterior pituitary cells from normal rats were attached as a monolayer four to six days after placing in the dish after dispersion with collagenase and trypsin (7). The major component with the growth hormone release-inhibiting activity was isolated, characterized, reproduced by total synthesis, and named somatostatin. It has the following primary sequence (8-10):
I
I
H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH. Both the oxidized and the reduced forms of the peptide were shown to have the full biological activity in vitro or in vivo in various animal species (8, 10). IThe literature and proceedings of several symposia on growth hormone secretion (1-3) contain reports claiming the isolation and characterization of growth hormone-releasing hor mone (GHRH) as a decapeptide (4); biological activity was evidenced by a highly controversial assay based on pituitary "depletion" of bioassayable growth hormone. It was later shown that GHRH was identical to a fragment from the N-terminal
of the /3
(5)
chain of hemoglobin.
GHRH has no effect on the secretion of immunoreactive growth hormone, and is thus most likely an artifact.
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LABORATORY STUDIES In laboratory animals, somatostatin inhibited growth hormone secretion acutely induced by all pharmacologic means, such as barbiturates, L-Dopa, arginine, and morphine (8, 11-13), as well as after electrical stimulation of the hypothalamus or amygdala (14) or catecholamine infusion in the third ventricle (12). Additionally, somatostatin was found to inhibit the secretion of thyrotropin induced by thyrotro pin-releasing factor (TRF), while not affecting the concomitant secretion of prolac tin triggered by the same dose of TRF (I5, 16). In some of the above studies, Koerker et al (12) noticed that infusion of somato statin in nonanesthetized baboons was accompanied by hypoglycemia, which was associated with the prompt inhibition by somatostatin of the (basal) secretion of glucagon and insulin. This effect was clearly shown to be directly at the pancreatic level by in vitro infusion of the isolated pancreas (17-21), as well as with tissue cultures of the endocrine pancreas (22). At both receptor sites (i.e. adenohypophysis and endocrine pancreas),somatosta tin is significantly active at similar concentrations: 10-9 M in vitro, > 200-400 ng/IOO g body weight in vivo (23). It had been observed in the earliest studies in vivo with somatostatin (8, II) that the peptide had a very short biological half-life « 4 min). Also,with an exquisitely sensitive bioassay (16), and later by radioimmunoassay (24,25), it was shown that somatostatin is present in parts of the central nervous system (eNS) other than the hypothalamus; indeed, the spinal cord appears to contain a high concentration. These observations led us to wonder whether the effects of somatostatin on the endocrine pancreas could, in physiological circumstances, truly be due to peptides of hypothalamic origin. A more satisfactory hypothesis would have been the possi ble release of somatostatin at (peptidergic) nerve endings in the neuroinsular com plexes of the endocrine pancreas. Indeed, somatostatin activity was found in aqueous extracts of the fetal rat pancreas by bioassays (23) and later by radioim munoassays (25). When this was investigated by histoimmunofluorescence,no nerve endings containing somatostatin were found; however, a discrete population of endocrine cells was found to contain somatostatin (2&-29). These are different from the a cells secreting glucagon and the 13 cells secreting insulin. Early evidence with the light microscope (2&-28),and more recently with the electron microscope (29), have assigned the somatostatin-secreting cells of the pancreas to be the so-called D cells, for which no well-established function was available thus far. In the same reports (2&-28), somatostatin-containing cells were observed (by immunofluores cence) in the duodenum, the fundic and antral mucosa of the stomach, and, al though in much more reduced numbers, in the glandular elements of the jejunum and ileum and occasionally as isolated elements or small clusters in the exocrine pancreas. These observations have been confirmed in all species of vertebrates studied thus far (26). Somatostatin has also been shown to inhibit the secretion of gastrin as induced by meals (30),and there are two reports that in relatively large doses, it can inhibit the secretion of secretin and of the exocrine pancreas as induced by HCI (31) and gastric secretion of HCI and pepsin (32), as induced by pentagastrin.
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When administered to animals rendered diabetic by alloxan, streptozotocin, or pancreatectomy, somatostatin regularly produces dramatic lowering of hyper glycemia. This effect is always accompanied by inhibition of the basal elevated secretion of glucagon of either pancreatic or extrapancreatic origin (33). Somatosta tin has no effect on the peripheral utilization or distribution of glucose (12, 34), nor is there evidence that it acts at the hepatic level to inhibit glycogenolysis or gluconeogenesis (35). In early studies, somatostatin appeared to act distally to cyclic adenosine mono phosphate (cAMP), since it inhibits release of growth hormone normally produced by both (dibutyryl)cAMP and theophylline (36, 37). It has been reported to lower cAMP levels and elevate cyclic guanosine monophosphate (cGMP) in pituitary tissues (37, 38). In acute studies, although somatostatin inhibits the release of preformed growth hormone, it does not inhibit the biosynthesis of growth hormone in the same pituitary cells (36). With regard to earlier observations of somatostatin's presence in parts of the eNS other than the hypothalamus, there are recent reports of its effects on the spontane ous electrical activity of some neuronal systems as observed by microelectrode recordings (39) and on behavior (40, 41). It has been shown to counteract the seizure-inducing effects of strychnine (42) in the rat. All of the above studies, as well as the clinical studies discussed below, have been conducted with somatostatin prepared by total synthesis (10). Series of synthetic analogues have already been prepared, including molecules with biological potency greater than that of the native substance (43). Evidence for dissociation of several of the multiple biological activities of some analogues of somatostatin at some receptor sites has recently been achieved (79, 80). No evidence (macro- or microscopic) of toxicity, either acute or after 21-days' administration, has been seen in dogs, rats, mice, or Rhesus monkeys with well characterized synthetic preparations of somatostatin administered in doses ten- to a hundredfold the human clinical doses on a body weight basis.2 Baboons, in which somatostatin was chronically administered, were reported to have shown abnormal platelet function as well as various blood disorders with postmortem evidence of lung hepatization (44). A causal relationship, h owever, is not apparent. Substances other than somatostatin were also administered, and no strict controls are or were available to determine whether the animals, sitting for long periods of time in primate chairs and with multiple implanted catheters, may not have been prone to developing some type of coagulation disorder or latent septicemic infection responsi ble for death. This question is discussed further below.
CLINICAL STUDIES IN MAN Growth Hormone Somatostatin inhibits growth hormone responses to virtually all known physiologi cal and pharmacological stimuli such as arginine (45-47), L-Dopa (45), insulin2AIl studies were carried out in compliance with FDA regulations in an application for an IND number, which was granted to one of us (RG) in April 1973.
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induced hypoglycemia (47, 48), exercise (49), sleep (50), and meals (51, 52) in normal man (45-50) and in human subjects with growth hormone-producing pitui tary tumors as in acromegaly (46-48,51, 53-55). Although several studies (45-49, 56-58) have failed to demonstrate an effect on basal growth hormone levels in normal man, there is usually a rebound upon discontinuation of the somatostatin infusion, suggesting that inhibition of basal hormone secretion had been present (45, 46,48,49,57). In pathological states associated with elevated basal growth hormone levels, such as acromegaly (46-48,51,53-55),protein-caloric malnutrition (55),and diabetes (49, 59), suppression is readily apparent. The cyclic and linear forms of synthetic somatostatin appear to be equally effec tive inhibitors of growth hormone secretion. With intravenous administration, inhi bition is demonstrable within 15 min (53, 54) and upon termination of the somatostatin infusion, growth hormone levels characteristically rebound above preinfusion levels. From the rapidity with which inhibition by somatostatin begins and its quick reversal after termination of the infusions, it is apparent that the action of somatostatin on growth hormone release is almost immediate and that it has a short biological half-life (4--8 min). When administered subcutaneously in doses up to 8 mg (57), the effect of somatostatin lasts for only 2 hr. Attempts to prolong its action by administering it subcutaneously in oil or gelatin (54) or after coupling it to protamine zinc (51) have not resulted in increases in activity beyond 4 hr. The time required for maximal suppression is a function of the fasting growth hormone level when conventional doses of somatostatin are used. In one study of acromegalic patients (54), doses between 100 and 1000 ,u.glhr were found to be maximally effective; a lesser response was observed with 25 ,u.g/hr, and none with 10 ,u.glhr. No comparable data are available concerning the sensitivity of normal pituitary tissue. Once suppressed, there has been no escape of growth hormone from inhibition during short-term studies and in longer studies carried out in acromegalic and diabetic subjects for as long as 28 hr (51, 59). It has been reported, however, that growth hormone responses to TRF and luteinizing hormone-releasing factor in acromegalic patients are not inhibited by somatostatin (60). OTHER PITUITARY HORMONES In normal man,somatostatin does not affect the secretion of luteinizing hormone and follicle-stimulating hormone (45, 48, 53), adrenocorticotropin (48, 61), and prolactin (45, 48, 58). Thyrotropin responses to TRF are inhibited by somatostatin (48, 58, 62); most (45, 48, 53, 58), but not all (63), studies indicate that basal levels are apparently not affected. Atypicai responses to somatostatin may occur in patients with pituitary tumors. Thus, somatostatin has been reported to lower fasting prolactin levels in patients with acromegaly (53) and to lower ACTH levels in patients with Nelson's syndrome (61),although somatostatin does not affect secretion of these hormones by normal pituitary tissue.
Pancreatic Hormones Somatostatin inhibits secretion of both insulin (34, 46, 47, 53, �4, 56, 64--69) and glucagon (34, 46,51, 52, 54,56,57,59,67-70) in man. Fasting insulin levels (34,
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46,47, 53, 65, 68), as well as insulin responses to meals (51), oral and intravenous glucose (46, 51, 54, 57, 66, 68), arginine (47, 56), glucagon, and tolbutamide (69), are diminished or completely prevented by somatostatin. Similarly, basal glucagon secretion (34,46,51,52,54,59,67,68),as well as glucagon responses to meals (51, 52, 57), intravenous arginine (56), insulin-induced hypoglycemia (71), epinephrine (70), and insulin deprivation (59), are suppressed by somatostatin. The inhibitory effects of somatostatin on glucagon secretion occur with equal effectiveness in normal subjects (34,56,67,68,70),insulin-dependent diabetic subjects (52,56,57, 59), and patients with acromegaly (46, 51). The ability of somatostatin to inhibit insulin and glucagon secretion has provided a useful tool for studying the physiological and pathological effects of these hor mones (46, 52, 56, 57,59,67) on human metabolism (34). Infusion of somatostatin lowers plasma glucose levels in normal man despite concomitant lowering of both plasma insulin and glucagon levels (34,46, 67). These observations provided the first clear-cut evidence that glucagon has an important physiological role in human carbohydrate homeostasis. Somatostatin itself has no direct effect on either hepatic glucose production (72) or peripheral glucose utilization (34, 73), since the fall in plasma glucose levels could be prevented by exogenous glucagon (69). In juvenile-type diabetics, somatostatin diminishes fasting hyperglycemia by as much as 50% in the complete absence of circulating insulin (57, 74). Although somatostatin impairs carbohydrate tolerance after oral or intravenous glucose chal lenges in normal man by inhibiting insulin secretion (46,51,54,64,66), carbohy drate tolerance after ingestion of balanced meals is improved in patients with insulin-dependent diabetes mellitus through the suppression of excessive glucagon responses (52, 57). The combination of somatostatin and a suboptimal amount of exogenous insulin (which by itself had prevented neither excessive hyperglycemia nor hyperglucagonemia in response to meals) completely prevents plasma glucose levels from rising after meal ingestion in insulin-dependent diabetics (52). Through its suppression of glucagon and growth hormone secretion, somatostatin has also been shown to moderate or prevent completely the development of diabetic ketoacidosis after the acute withdrawal of insulin from patients with insulin-depend ent diabetes mellitus (59). Pancreatic tumors secreting either glucagon (54) or insulin (75) have been re ported to be responsive to somatostatin. Curiously, in patients with insulinomas, basal and glucagon-stimulated insulin secretion is inhibited by somatostatin, but that due to tolbutamide characteristically is not (75). Infusion of somatostatin in such patients must be performed cautiously since,despite lowering of basal insulin levels, plasma glucose levels fall precipitously.
Gastrointestinal Hormones Data concerning the effect of somatostatin on gastrointestinal hormones in man are presently available only for gastrin (30). Somatostatin suppressed fasting plasma gastrin levels approximately 40% in normal subjects and in subjects with acromeg aly during a 60-min infusion. Additionally, gastrin responses after ingestion of a balanced meal were completely suppressed. The markedly elevated fasting gastrin levels in two patients with pernicious anemia were diminished by more than 50%
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during a 75-min infusion of somatostatin. Finally, both gastric acid secretion and extreme hypergastrinemia of a patient with Zollinger-Ellison syndrome were sup pressed during a 20-min infusion of somatostatin (30).
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Side Effects and Toxicity Although some adverse hematological effects have been reported in baboons (44) and rabbits (76) receiving large amounts of somatostatin, no serious toxicity has been encountered in man during a two-year clinical experience in over 300 subjects. The most frequent side effects encountered are transient nausea, occasional diarrhea, and abdominal cramps (50, 56, 58). Transient falls in blood pressure (10 mm Hg for 10 min) and rises in pulse (10 beats per min lasting 10 min) are sometimes observed (49, 56). No significant hypoglycemia has been found, except in diabetics given exogenous insulin. No changes in white blood cell count (46, 48), platelet count (46, 77), bleeding time (77), prothrombin time (77), partial thromboplastin time (77), serum electrolyte levels (46, 48), or renal or hepatic function (46, 48) have been encountered either in acute studies or after prolonged (12 hr) infusions of somatostatin. All these values have been found to be normal after intermittent administration of somatostatin as frequently as once weekly for over a year (77). Although a recent report (78) suggested that somatostatin might diminish platelet aggregation, similar studies using higher doses of somatostatin found no effect (77); these discrepant results might have been due to the use of different preparations of somatostatin. Since bleeding times were unaffected in both studies, the clinical significance of the reported platelet abnormalities is unclear.
Therapeutic Implications From the foregoing description of the ability of somatostatin to inhibit the secretion of various hormones, it would appear that this agent may be of therapeutic use in certain clinical conditions such as acromegaly, pancreatic islet cell tumors, and diabetes mellitus. With regard to endocrine tumors, it must be emphasized that while somatostatin will inhibit hormone secretion by these tissues, it would not be expected to diminish tumor growth (36, 81). Thus, in these conditions it is unlikely that somatostatin will find use other than as a symptomatic or temporizing measure. In diabetes mellitus, however, somatostatin might be of considerable clinical value. First, it has already been demonstrated that it can acutely improve fasting (57) as well as postprandial hyperglycemia (52, 57) in insulin-requiring diabetics by inhibiting glucagon secretion. Second, since growth hormone has been implicated in the development of diabetic retinopathy, the inhibition of growth hormone secre tion by somatostatin may lessen this complication of diabetes. Finally, through suppression of both growth hormone and glucagon secretion, somatostatin may prevent or diminish the severity of diabetic ketoacidosis and find application in "brittle diabetes." These optimistic expectations must be tempered with the facts that the diverse effects of somatostatin on hormone secretion and its short duration of action make its clinical use impractical at the present time and that its long-term effectiveness and safety have not been established as yet.
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CONCLUSION Somatostatin, originally characterized on the basis of one well-defined biological activity and extracted from one well-defined area of the brain, has now been shown to exist in significant quantities outside the CNS and to be polyvalent in its ability to inhibit hormone secretion. Its tissue distribution is not random: the peptide is found both in the CNS and in highly specialized (neuro-) endocrine cells ontogeni cally derived from neural crest primordia. The multiple effects of the peptide are all consistent, as they appear to involve inhibition of the secretion of polypeptides; in all cases, the target or receptor is topographically closely related to the secretory element. Somatostatin may well represent the prototype of a new class of carriers of physiological information (for which one of us is proposing elsewhere the generic name of cybernins) different from classical hormones (e.g. ACTH, gonadotropins, insulin, etc) and different also from the classical neurotransmitters (e.g. catechola mines, dopamine, serotonin, and acetylcholine). The existence of such a new class of agents seems likely, but remains to be firmly established; methodology for this is just becoming available as this review is being prepared. Abnormalities in the metabolism or secretion of these agents could be significant in the etiology of malfunction or disease of various organic systems. For example, if somatostatin is actually synthesized in multiple areas of the CNS, as seems to be the case, local dysfunctions in the biosynthesis or release mechanism for somatostatin could be involved in the pathogenesis of some mental disorders. The possible clinical significance of somatostatin, particularly as a component of the treatment of diabetes, also remains to be established in further clinical studies. The multiplicity of target receptors for the peptide and its short duration of action will require careful assessment of dosage and timing of administration and knowl edge of differential affinities of the various receptors for the synthetic replicates of the native primary sequence or some of its synthetic analogues. ACKNOWLEDGMENTS
The fundamental research reviewed here and carried out at The Salk Institute has been supported by the McConnell Clark Foundation of New York City, the Ford and Rockefeller Foundations, and the National Institutes of Health (NIAMDD, AM 16707). The clinical investigations carried out at the University "of California, San Francisco, were supported in part by the Levi J. and Mary Skaggs Foundation of Oakland, Calif., the Susan Greenwall Foundation of New York City, and the Division of Research Resources, RR-79, of the US Public Health Service. Literature Cited 1. Sonenberg, M., ed. 1968. Growth hor mone. Ann. NY Acad. Sci. 148:289-571 2. Pecile, A., Miiller, E. E., eds. 1968. Growth Hormone. Proc. Int. Symp. Growth Horm.. 1st. Excerpta Med. Int. Congr. Ser. 158 3. Pecile, A., Miiller, E. E., eds. 1972. Growth and Growth Hormone. Proc. Int.
Symp. Growth Horm., 2nd. Excerpta Med. Int. Congr. Ser. 244 4. Schally, A. V., .Baba, Y., Nair, R. M. G., Bennett, C: D. 1971. The amino acid sequence of a peptide with growth hormone-releasing activity isolated from porcine hypothalamus. J. Bio/. Chern. 246:6647-50
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S. Veber, D. F. et al 1971. Synthesis of a
proposed growth hormone releasing factor. Biochem. Biophys. Res. Com mun. 45:235-39 Krulich, L., McCann, S. M. 1969. Effect of GH-releasing factor and GH inhibiting factor on the release and con centration of GH in pituitaries in cubated in vitro. Endocrinology 85: 319-24 Vale, W., Grant, G., Amoss, M., Black well, R., Guillemin, R. 1972. Culture of enzymatically dispersed anterior pitui tary cells: Functional validation of a method. Endocrinology 91 :562-72 Brazeau, P. et al 1973. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77-79 Burgus, R., Ling, N., Butcher, M., Guillemin, R. 1973. Primary structure of somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone. Proc. Natl Acad. Sci.
18. Curry, D. L., Bennett, L. L., Li, C. H. 1974. Direct inhibition of insulin secre tion by synthetic somatostatin. Bio chem. Biophys. Res. Commun. 58: 885-89 19. Efendic, S., Luft, R., Grill, V. 1974. Effect of somatostatin on glucose in duced insulin release in isolated per fused rat pancreas and isolated rat pan creatic islets. FEBS Lett. 42:169-72 20. Weir, G. C., Knowlton, S. D., Martin, D. B. 1974. Somatostatin inhibition of epinephrine-induced glucagon secre tion. Endocrinology 95:1744-46 21. Iversen, J. 1974. Inhibition of pan creatic glucagon release by somato statin: In vitro. Scand. J. Clin. Lab. In vest. 33:125-29 22. Fujimoto, W. Y., Ensinck, J. W., Wil liams, R. H. 1974. Somatostatin inhibits insulin and glucagon release by monolayer cell cultures of rat endocrine pancreas. Life Sci. 15:1999-2004 23. Vale, W. et al 1975. Somatostatin. Re
10. Rivier, J. E. F. 1974. Somatostatin. To tal solid phase synthesis. J. Am. Chem. Soc. 96:2986-- 92 II. Brazeau, P., Rivier, J., Vale, W., Guille min, R. 1974. Inhibition of growth hor mone secretion in the rat by synthetic somatostatin. Endocrinology 94:184-87 12. Koerker, D. J. et a1 1974. Somatostatin: Hypothalamic inhibitor of the endo crine pancreas. Science 184:482-84 13. Lovinger, R. et al 1974. Effect of syn thetic somatotropin release inhibiting factor on the increase in plasma growth hormone elicited by L-Dopa in the dog. Endocrinology 95:943-46 14. Martin, J. B. 1974. Inhibitory effect of somatostatin (SRIF) on the release of growth hormone (GH) induced in the rat by electrical stimulation. Endo crinology 94:497-502 15. Vale, W. et al 1973. Inhibitory hypo physiotropic activities of hypothalamic somatostatin. Fed. Proc. 32:211 16. Vale, W., Rivier, C., Brazeau, P., Guillemin, R. 1974. Effects of somato statin on the secretion of thyrotropin and prolactin. Endocrinology 95: 968-77 17. Gerich, J. E., Lovinger, R., Grodsky, G. M. 1975. Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to ar ginine, isoproterenol and theophylline: Evidence for a preferential effect on glucagon secretion. Endocrinology 96: 749-54
24. Arimura, A., Sato, H., Coy, D. H., Schally, A. V. 1975. Radioimmunoas say for GH-release inhibiting hormone. Proc. Soc. Exp. Bioi. Med. 148:784-89 25. Patel, Y. C., Weir, G. C., Reichlin, S. 1975. Anatomic distribution of somato statin (SRIF) in brain and pancreatic islets as studied by radioimmunoassay (RIA). Endocrinology 96:A127 26. Dubois, M. P. 1975. Immunoreactive somatostatin is present in discrete cells of the endocrine pancreas. Proc. Natl. Acad. Sci. USA 72:1340-43 27. Luft, R., Efendic, S., Hokfelt, T., Jo hansson, 0., Arimura, A. 1974. Im munohistochemical evidence for the lo calization of somatostatin-like im munoreactivity in a cell population of the pancreatic islets. Med. Biol 52: 428-30 28. Polak, J. M., Pearse, A. G. E. Grimelius, L., Bloom, S. R., Arimura, A. 1975. Growth-hormone release inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet I: 1220--22 29. Rufener, C., Amherdt, M., Dubois, M. P., Orci, L. 1975. Ultrastructural immunocytochemical localization of somatostatin in D-cells of rat pancreatic monolayer culture. J. Histochem. Cyto chern. In press 30. Bloom S. R. et al 1974. Inhibition of gastrin and gastric-acid secretion by growth-hormone release-inhibiting hor mone. Lancet 2:1106--9
6.
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7.
8.
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USA 70;684-88
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Annu. Rev. Med. 1976.27:379-388. Downloaded from www.annualreviews.org by University of California - San Diego on 09/16/14. For personal use only.
SOMATOSTATIN
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