Somatostatin: Physiology and Clinical Applications

Symposium on The Brain and The Endocrine System

Somatostatin Physiology and Clinical Applications

John E. Gerich, M.D., * and Gloria S. Patton, Ph.D. **

In the late 1960's, studies by Krulich et al. 82-84 indicated the presence of a peptide-like substance within the hypothalamus which inhibited the secretion of growth hormone. In 1972, Guillemin and co_workers139-141 succeeded in isolating from ovine hypothalamus a similar or identical substance-a tetradecapeptide which they called somatostatin in the beliefthat it was a specific hypo thalamic factor which modulates the release of growth hormone (somatotropin), analogous to the factor which inhibits release of prolactin. The purity and yield of their isolation procedure permitted Guillemin and his colleagues to determine the amino acid sequence of somatostatin. 28 This breakthrough then led to the production of a biologically active synthetic replicate which in turn allowed the development of a radioimmunoassay4 and a host of pharmacologic and physiologic studies, which are the subject ofthis review. It is now known that somatostatin is present outside the hypothalamus, elsewhere in the central nervous system, in peripheral ganglia and in such extraneural tissue as the stomach, small intestine, pancreas, and thyroid gland. Moreover, it is now appreciated that somatostatin has many actions in addition to inhibiting the secretion of growth hormone, which suggests that this peptide may have considerable biologic importance beyond that of a hypothalamic releasing factor.

STRUCTURE, DISTRIBUTION, AND METABOLISM The primary sequence of ovine and porcine somatostatin is shown in Figure 1. 28 No data are presently available concerning the structure of somatostatin in other species, but several peptides 125. 139. 140 (? fragments, polymers, biosynthetic precursers, additional releasing factors) have • Associate Professor of Medicine and Physiology, Mayo Medical School; Director, Diabetes and Metabolism Research Laboratory, Mayo Foundation, Rochester, Minnesota **Research ASSOCiate, Diabetes and Metabolism Research Laboratory, Mayo Foundat~on, Rochester, Minnesota

Medical Clinics of North America-Vo1.62, No. 2, March 1978

375

376

JOHN

E.

GERICH AND GLORIA

S.

PAT TON

H- ALA- GLY- CYS-LYS-ASN-PHE- PHE

I

I

5

TRP

S

LYS

,

I

I

Figure 1. somatostatin.

Amino acid sequence of

I

HO-CYS-SER-THR-PHE-THR

been detected during the procedure used to isolate somatostatin. Preliminary evidence suggests that the biosynthesis of somatostatin may include a larger precurser molecule, "prosomatostatin," analogous to other polypeptide hormones. The reduced noncyclized form of synthetic somatostatin-dihydrosomatostatin and the native molecule are equipotent in various biologic systems. 86 . [39 This may result from oxidation of dihydrosomatostatin to somatostatin, since alkylation of its cysteine residues, or substitution of alanine for cysteine, which prevents cyclization, drastically reduces biologic activity.119 Table 1 summarizes the distribution of somatostatin in the rat as determined by radioimmunoassay5, 27 or by bioassay. 139 Differences may be seen in the results obtained by these two methods. The concomitant presence of growth hormone-releasing substances may lower values obtained by bioassay, and the presence of somatostatin-binding proteins97 may interfere with the radioimmunoassay of tissue extracts. Most somatostatin is found outside the central nervous system, predominantly in the pancreas5 , 4[, 74, [00 and the stomach. 1[3 Data indicating whether the peptide also occurs in the thyroid are conflicting. 112 The highest concentrations of somatostatin are found in certain hypothalamic areas 27 and in the pancreatic isletsY' 74, 87, 100, 113 Although it has not been possible to unequivocally demonstrate somatostatin in the systemic circulation,44 there is substantial evidence for its presence in portal venous effluent in dogs, [08, [09, [24 in the pituitary portal circulation, 6,7,46, [34 and in human cerebrospinal fluid. 106 Both somatostatin and dihydrosomatostatin have extremely short half-lives (approximately 1 minute).44 Catheterization studies during infusion of exogenous somatostatin in baboons indicate that the extremities, kidney, and liver may be major sites of degradation. 44 Few data are available on the actual metabolism of somatostatin. Inactivation of the peptide by an endopeptidase present in partially purified rat brain extracts has recently been reported. 90 In view ofits probable role as a local regulatorB 7, 138 or peptidergic neurotransmitter92 rather than a classic circulating hormone, it seems most likely at the present time that somatostatin is metabolized at sites in close proximity to its production.

BIOLOGIC ACTIONS Table 2 summarizes the reported biologic actions of somatostatin.

Pituitary Hormones In every species tested, synthetic somatostatin inhibits the response of growth hormone to all known physiologic and pharmacologic stimuli:

PG/JLG

2.1 309.1 44.6 23.7 17.3 14.6 10.4 8.6 8.0 5.4 4.9 4.4 4.3 30 25 18 9.8 9.5 4.5 3.2

CENTRAL NERVOUS SYSTEM

Hypothalamus Median eminence Arcuate nucleus Periventricular nucleus Ventricular premamillary nucleus Ventromedial nucleus Medial preoptic nucleus Anterior hypothalamic nucleus Suprachiasmatic nucleus Dorsomedial nucleus Lateral anterior nucleus Paraventricular nucleus Dorsal premamillary nucleus Cerebral cortex System/preoptic area Thalamus Brain stem Midbrain Cerebellum Striatum 39

NG/REGION

Pancreas Stomach Fundus Pylorus Duodenum Upper Lower Jejunum Heart Lung Thymus Liver Spleen Kidney Adrenal Ovary negligible

NERVOUS SYSTEM

TISSUES OUTSIDE THE CENTRAL

Table 1. Distribution and Content of Somatostatin in the Rat

33.8 11.7 9.5 9.7 1.6 1.6 1.3 1.6

PG/JLG

36

13

111 200

NG/ORGAN

VJ

c.>:l '-l '-l

Z

>-<

~

>-l

[Jl

o

>-l

~

o

378

JOHN

E.

GERICH AND GLORIA

S.

PAT TON

Table 2. Reported Biologic Activities of Somatostatin ENDOCRINE

NONENDOCRINE

Inhibition of secretion of:

Inhibition or diminution of:

Growth honnone Thyrotropin Adrenocorticotropin Gastrin Pancreozymin Secretin Human pancreatic polypeptide Vasoactive intestinal peptide Gastric inhibitory polypeptide Motilin Glucagon Insulin Renin Gut glucagon-like radioimmunoactivity (GLI) renal water reabsorption

Gastric acid secretion and emptying Pancreatic bicarbonate and enzyme release Gallbladder contraction Xylose absorption Splanchnic blood flow Electrical activity of central nervous system neurons LD50 of Phenobarbital Platelet aggregation Release of acetylcholine from the myenteric plexus and renal water reabsorption

sleep,t04 exercise,71 barbiturates,23 levodopa,t29 theophylline, 141 dibutyl cAMP, 110. 141 hypoglycemia,70 arginine,68, 96, 129 meals,60 and direct electrical stimulation of the hypothalamus. 91 Furthermore, in conditions in which basal levels of circulating growth honnone are elevated (acromegaly,12, 13, 50, 68, 70, 148 protein-calorie m:llnutrition,111 and diabetes mellitus 00, 58, 71) infusion of somatos tatin promptly suppresses these increased levels toward nonnal values. No escape from suppression has been observed for as long as 28 hours during infusion of somatostatin at maximally effective doses in acromegalic patients. 13 However, anomalous responses of growth hormone to gonadotropin-releasing hormone (GRH) and thyrotropin-releasing hormone (TRH) are sometimes not inhibited in these patients. 69 Somatostatin is also a potent inhibitor of thyrotropin (TSH) secretion, basal levels of thyrotropin in normal individuals 147 and in those with primary hypo thyroidism, 89 and thyrotropin responses to thyrotropinreleasing hormones_ 29 , 130, 146 Except in special conditions other pituitary hormones are not affected by somatostatin. Thus, in cultured pituitary cells,40,142 and in certain patients with acromegaly,148 but not in normal individuals,130 secretion of prolactin may be inhibited by somatostatin. Similarly, secretion of adrenocorticotropin (ACTH) is normally unaffected but in patients with Nelson's syndrome 137 or in patients with Addison's disease withdrawn from corticoid replacement therapY,45 levels of ACTH are suppressed by somatostatin.

Gastrointestinal Tract Both endocrine and exocrine functions of the gastrointestinal tract are influenced by somatostatin (for review see reference 80). Release of gastrin in the basal state and after meals in nonnal individuals, 18,114,127 in hypergastrinemia occurring in the Zollinger-Ellison syndrome and pernicious anemia,18 as well as in vitro secretion of gastrin73

379

SOMATOSTATIN

are suppressed by somatostatin. Secretin20 , 35, 81, 127 responses to ingestion of meals and administration of HCL, and pancreozymin35 , 81,127 responses to meal ingestion are inhibited by somatostatin. Other gastrointestinal hormones whose release is impaired by somatostatin include gastric inhibitory polypeptide, vasoactive intestinal peptide,87 motilin,19 GLI (gut glucagon-like immunoreactivity),123 and human pancreatic polypeptide. Gastric acid 18 and pepsin 114 secretion under a variety of conditions including administration of synthetic gastrin, 114, 127 and secretion of both pancreatic electrolytes,35, 127 and enzymes following ingestion of meals 127 or administration of secretin and pancreozymin, 35, 127 are partially or completely prevented by infusions of somatostatin in man. Other gastrointestinal effects of somatostatin that have been reported include diminution of gastric motility, 19 gallbladder contraction,17 splanchnic blood flow,144 and xylose absorption.144 Whether these actions represent direct effects of the peptide or changes secondary to inhibition of hormone secretion is unclear. Since somatostatin has been reported to diminish neuronal electrical activity' 16 and to impair release of acetylcholine from the myenteric plexus,66 pharmacologic denervation by somatostatin may also be involved.

Pancreatic Islet Hormones Perhaps the most extensively examined (and exploited) action of somatostatin is its inability to inhibit the secretion ofinsulin and glucagon (for review see references 51, 53, 143). In vivo (and in vitro as sh~wn in Figure 2),63 somatostatin is an effective inhibitor of virtually every known stimulus for secretion of these hormones at concentrations similar to those which suppress the release of growth hormone. For practical purposes somatostatin inhibits the release of insulin and glucagon to a sim-

--5.5mM

GLUCOSE

MINUTES

Figure 2. Effect of somatostatin on glucagon and insulin release from rat pancreases perfused in vitro. (From Gerich, J., Lovinger, R., and Grodsky, G.: Endocrinology, 96 :749,754, 1975. Reproduced with permission.)

380

JOHN

E.

GERICH AND GLORIA

S.

PATTON

ilar extent, and reports to the contrary probably reflect the relative potency of stimuli on pancreatic A and B cells rather than that of somatostatin as an inhibitor. 63,68.86 Secretion of insulin and glucagon from islet cell tumors is also blocked by somatostatin,36, 96, 125, 135 but curiously insulin responses to tolbutamide in patients with insulinomas are not,88 Miscellaneous Actions and Adverse Effects In several species, depending on the dose and the preparation used, variable inhibitory effects on platelet function have been observed. 14,32,78,95, ll5 The clinical significance of these findings is unclear, since no prolongation of bleeding time, a sensitive in vivo index of platelet function, has been reported. 78, 95, 115 In the rat, somatostatin. depresses electrical activity of central nervous system neurons, 116 lowers the LD50 of phenobarbital,26 and exerts other effects on behavior.72, 118, 133 None has been reported in man although patients receiving somatostatin appear unusually tolerant of uncomfortable and tedious procedures. Recently somatostatin has been reported to inhibit renin responses to administration of furosemide in man 121 and to have a direct diuretic effect on the canine kidney; 117 this is surprising, since previously the peptide has been observed to exert an action only in tissues where it has been found, Thus, parathyroid hormone,38 cortisol,70 and catecholamine34 responses to provocative stimuli are unaffected by somatostatin. No serious adverse effects have been reported during administration of so mat os tatin to human subjects for as long as 3 days,52 although transient nausea, abdominal cramps, and rarely vomiting and diarrhea are observed. Routine shortterm screening for possible hepatic, hematologic, renal, and cardiac toxicity have proven negative to date. 52

MECHANISM OF ACTION The exact mechanism by which somatostatin inhibits secretion is still under investigation. The peptide has been reported to lower cyclic AMP levels in the pituitary, 2I to block elevation of cyclic AMP during glucosestimulated insulin release in pancreatic islets,42 and to increase cyclic GMP levels in pituitary tissue. 77 Since cyclic AMP has been considered as a possible "second messenger" modulating secretion of hormones by both the pituitary and the pancreatic islets, it was originally suggested that the peptide might act by diminishing tissue cyclic AMP. However, this now seems unlikely: somatostatin not only blocks hormone responses to stimulants which elevate islet cAMP levels (e.g., isoproterenol63 ) but also hormone responses to agents which lower or do not alter tissue cAMP levels (e.g., arginine 63 and epinephrine62 ); insulin responses to agents which increase islet cAMP by activating adenylate cyclase (e.g., glucagon l25 ) are as effectively inhibited as responses to agents which elevated islet cAMP by inhibiting phosphodiesterase47 , 136 (e.g., theophylline 63 ); glucagon-stimulated release ofinsulin was reported to be inhibited by somatostatin without impairment of the activation of adenylate cyclase by glucagon; 125 and finally, hormonal responses to the cAMP analogue dibutyryl cAMP are also inhibited. llO, 132, 141

SOMATOSTATIN

381

At the present time it seems likely that somatostatin acts by interfering with some facet of calcium metabolism in target tissues: somatostatin impairs uptake of calcium by islet cells, 10,98 and its inhibition of hormone secretion by the islet cells is reversed by increasing extracellular calcium concentrations of calcium 10,37,47,132 or by using a divalent cationic ionophore to increase uptake of calcium. 48 Nevertheless, since potassium 15 and an alpha adrenergic receptor antagonist l31 have also been reported to reverse inhibition of the release of hormones, effected by somatostatin, it remains to be determined whether the effects observed during manipulation of the availability of calcium are indicative of a specific site of action for somatostatin. It is generally assumed that, as with other polypeptide hormones, the initial step in the mechanism of action of somatostatin involves its binding to membrane receptors on the external surface of target cells. However, to date no such receptors have been identified. Moreover an intracellular cytosolic somatostatin-binding protein has been identified in numerous tissues. 97 Whether this represents part of a degradative pathway for the peptide or a step in its action is unclear. Kinetic studies ofthe effect of somatostatin on the release of thyrotropin indicate that somatostatin does not interfere with the binding of thyrotropin-releasing hormone to thyrotrophs. The mechanism appears to be noncompetitive. Dose-response studies of glucose-induced release of insulin, on the other hand, seem to suggest a possible competitive interaction of so mat os tat in with glucose. 43 Finally, the increase in the frequency of electrical discharges from B cells usually observed during the release of insulin has been reported to be blocked while the release of insulin is being inhibited by somatostatin. 103 Whether this is the cause or the result of the inhibition is unclear.

PHYSIOLOGIC ROLE OF ENDOGENOUS SOMATOSTATIN Current evidence indicates that somatostatin released from the hypothalamus into the pituitary portal circulation probably acts as a physiologic regulator of the release of growth hormone and possibly also of the secretion of thyrotropin: the peptide is active in vitro at concentrations anticipated in vivo; administration of antiserum against somatostatin to rats elevates basal levels of growth hormone,6, 46 prevents stress-induced inhibition of the release of growth hormone,7.134 and augments both basal6. 46 and cold-induced release of thyrotropin;46 furthermore, hypophysectomy diminishes the hypothalamic content of somatostatin. 8 Factors regulating the release of somatostatin from hypothalamic nerve terminals and the localization of the cell bodies of these terminals requires further investigation. Since the peptide is found in nerve endings throughout the brain, spinal cord, and peripheral ganglia,27. 74, 139 and since it has been reported to alter neuronal function" 6 and cause behavior changes in some species,26. 72,118,133 it is quite possible that it may also function as a peptidergic neurotransmitter. 92 Somatostatin present in the stomach and small intestine could act as a local regulator, of gastrointestinal exocrine and endocrine function. It

382

JOHN

E.

GERICH AND GLORIA

S.

PATTON

seems unlikely that it acts as a conventional systemic hormone because of its diverse actions, short half-life, and the current failure to demonstrate its presence in the general circulation. Accordingly, it has been suggested that somatostatin may be the prototype of a new class of local chemical messengers called cybemins. 67 PANCREATIC

D

CELL FUNCTION

Somatostatin Regulation of Insulin and Glucagon Secretion Although somatostatin affects both exocrine and endocrine pancreatic function, within the parenchyma of this organ it is found only in islet cell tissue and has been localized by immunohistochemical means to a discrete population of cells identified as D cells. 41 , 74, 100, 113 These cells normally constitute approximately 10 per cent of the islet cell mass in man and rat, with A and B cells, respectively, making up 20 and 70 per cent. 102 As shown in Figure 3, D cells are not randomly distributed in islets but occur at the periphery in close association with A cells. Since there is no convincing evidence to date that A and B cells differ in their sensitivity to somatostatin, this asymmetric distribution of D cells suggests that somatostatin endogenously released from the islets may affect primarily the secretion of glucagon and be a more important regulator of A cell function than of B cell function. 99 , 102 Support for this stems from several recent observations: glucagon but not insulin' stimulates release of

Figure 3. Distribution of pancreatic A, B, and D cells. Serial sections of rat pancreatic islet stained with fluorescein-Iabelled antiserum. A, anti-insulin serum; B, antiglucagon serum; C, antisomatostatin serum. (Courtesy of L.Orci.)

383

SOMATOSTATIN

somatostatin in vitro (Fig. 4 108); islets incubated in the presence of antisomatostatin antiserum release more glucagon but not more insulin;l1 glucose, which suppresses secretion of glucagon while augmenting release ofinsulin, also stimulates secretion of so matos tat in in vitro; 75. 126 and epinephrine, which enhances secretion of glucagon while inhibiting release ofinsulin, also inhibits secretion of somatostatin in vitro. 75 Thus, the effects of glucose and epinephrine on A cell function could be accounted for by the reported effects of this agent on the release of somatostatin. Caution must be exercised in the interpretation of these data, however, since there have been few detailed studies ofD cell function, and conflicting results are already apparent. 10 Certain agents which augment the release of both insulin and glucagon (e.g. arginine,t°9 cAMP analogues,lO isoproterenoP24 also augment secretion of somatostatin; it is unclear whether this occurs as a direct action ofthe secretagogues or is secondary to augmentation of secretion of glucagon. Recently electrical stimulation of the ventromedial hypothalamus 9 has been reported to cause ultrastructural changes in islet D cells consistent with enhanced secretion of somatostatin, while stimulation of the lateral hypothalamus induced the opposite morphologic changes. These hypo thalamic areas, the ventromedial and lateral regions, respectively, are thought to contain sympathetic and parasympathetic regions capable of influencing islet A and B cell function. 56 Thus, these results and the recently reported effects of epinephrine and isoproterenol on in vitro pancreatic release of somatostatin suggest that the function of pancreatic D cells may be under autonomic control, as is the function of pancreatic A and B cells; furthermore, neurally induced changes in the secretion ofinsulin and glucagon may be mediated through alterations in the secretion of somatostatin. 56 Somatostatin in Diabetes Mellitus Alterations in D cell mass and content of somatostatin in the islet cells have been reported in human juvenile-onset diabetes,lol streptozotocininduced diabetes in rats, 101.107 and spontaneously occurring diabetes in BUFFER

BUFFER

GLUCAGON 10)Jg/ml

10mU/m1

I Ii

pg/ml

z

BUFFER

I I INSULIN I I I

500

r- 400
r- 200
0

,

20

i

40

I

,

60 BO MINUTES

,

lOO

,

120

,

140

Figure 4. Stimulation of the release of somatostatin by glucagon from dog pancreases perfused in vitro. (From Patton, G., Dobbs, R, Orci, L., et al.: Metabolism, 2S(Suppl. 1): 1499-1500, 1976. Reproduced with permission.)

384

JOHN

E.

GERICH AND GLORIA

S.

PATTON

OB/OB and DB/DB mice,99, 105 suggesting possible involvement ofD cells in the pathologic process. 138 In human juvenile-onset diabetes and streptozotocin-induced diabetes in the rat,107, 191 hypertrophy and hyperplasia of D cells and increased islet content of somatostatin has been found, implying some influence of chronic insulinopenia or hyperglycemia on D cell function. Whether these changes indicate excessive release of somatostatin remains to be determined; conceivably these findings could result from diminished release of somatostatin, which might be at least partially responsible for the hyperglucagonemia found in diabetes. In spontaneously diabetic obese OB/OB and DB/DB mice, an animal model resembling adult-onset diabetes in man, diminished somatostatin and insulin in the pancreatic islet cells, hyperinsulinemia, and increased glucagon in the pancreatic islets have been reported. 105, 107 The pathogenetic significance of these findings is unclear since parallel changes (increases and decreases) in A and D cell mass have been found in other strains of genetically diabetic obese mice using immunofluorescent techniques. 99 Conceivably, however, a primary deficiency of somatostatin could result in excessive secretion of insulin and glucagon and, ultimately, hyperplasia of both pancreatic A and B cells; in susceptible individuals, lack of appropriate B cell hyperplasia or a deficient insulin-secreting mechanism could lead to a syndrome resembling adult-onset diabetes in man. Circulating antibodies against human pancreatic D cells have been found in patients with adult-onset diabetes. 22 Conversely, excess somatostatin could cause diabetes by inhibiting the secretion of insulin. This is evidenced by two recent reports 49 , 85 of malignant tumors ofthe pancreatic D cells producing somatostatin associated with diabetes, hypoinsulinemia, and hypoglucagonemia. In one case,49 the diabetes went into remission following removal of the "somatostatinoma."

CURRENT AND POTENTIAL USES At the present time synthetic somatostatin is being used in human and animal studies as an experimental tool to induce deficiency of certain hormones in order to assess their physiologic or pathologic importance; for example, somatostatin has proven useful in establishing a physiologic role for glucagon in man and its importance in human diabetes mellitus (for review see reference 53). When somatostatin is infused in man 2. 59. 61.128.145 and in other species, 1.31.33.39.76.79.122 circulating glucose levels fall transiently 30 to 50 per cent as the result of a parallel fall in hepatic production of glucose,3. 16. :11. 76.128 an effect mediated by suppression of glucagon, since somatostatin itself has no direct effect on glucose metabolism. 30, 52, 54 This phenomenon occurs despite inhibition of the secretion of insulin, and is seen in normal as well as hypophysectomized individuals 61 and in diabetics requiring insulin. 61 It is reversed by infusion ofphysiologic amounts of glucagon (but not growth hormone 2. 58) and is not observed in patients who have undergone pancreatectomy and lack glucagon. 55 These results indicate a physiologic role for glucagon in sustaining normoglycemia.

385

SOMATOSTATIN

During prolonged infusion of somatostatin in normal man 128 and in insulin-dependent diabetic subjects,57 mild hyperglycemia occurs (Fig. 5) and is much less than that seen when unrestrained secretion of glucagon accompanies insulin deficiency. In addition to this role of glucagon in diabetic hyperglycemia, studies with somatostatin have provided evidence for participation of glucagon in exaggerating other metabolic consequences of insulin deficiency such as ketoacidosis 64 and postprandial hyperglycemia. 60 Infusion of somatostatin for 18 hours after acute withdrawal of insulin from juvenile-onset insulin-dependent diabetic subjects prevented the development of diabetic ketoacidosis by causing sustained suppression of anticipated hyperketonemia and hyperglycemia. 57 In nondiabetic individuals, glucose tolerance after oral glucose,96 intravenous glucose,l and meals 13 deteriorates during infusion of somatostatin because the release of insulin is inhibited; however, in diabetic patients receiving insulin who exhibit exaggerated glucagon responses to meals,60 postprandial hyperglycemia is diminished during infusion of somatostatin. 60.94 This action, which has been attributed to suppression of glucagon secretion but which clearly may also involve direct effects of somatostatin on gastrointestinal function,80. 144 has raised the possibility that an agent like somatostatin might prove useful as an adjunct to insulin in the management of diabetes mellitus. Two recent studies 52 . 94 support such a view; as shown in Figure 6, infusion of somatostatin continuously for 3 days in a diabetic requiring insulin resulted in marked improvement in control of the diabetes despite concurrent reduction of insulin dosage. . With enhanced specificity and longer duration of action, analogues of somatostatin may prove therapeutically useful in other disorders, as well. These include acromegaly, Zollinger-Ellison syndrome, Verner-Morrison syndrome, insulinoma, peptic ulcer, gastrointestinal hemorrhage, dumping syndrome, acute pancreatitis, and neuropsychiatric disorders. Most of these possible uses are of only theoretical interest at present, because of INSULIN

350

i

SALINE OR SOMATOSTATIN (500,.g/h) MEAN

w

g E :::>

±

SEM

N=7

V)

250

..... 0

C>9

«'ii; ~ E 150

V)

........«

50 .2

0

8

12

16

20

HOURS Figure 5. Effect of suppression of secretion of glucagon by somatostatin on hyperglycemia occurring after withdrawal of insulin from insulin-dependent diabetic patients. Data from Gerich, J., Lorenzi, M., Bier, D., et al.: New Eng. J. Med., 292:985-989, 1975.

386

JOHN

320

AM

!!...M

14U REG

10U REG

3ltUNPH

14UNPH

for 2d.y.

E.

GERICH AND GLORIA

A...!!!!

eJl!!

10 U REG

5 U REG

18 U HPH

8 U HPH

S.

PATTON

SO ..... TOSTATlN INFUSION

SERUM GLUCOSE

100 *,9/h tor 3 d.ys

240

i

0 0

..

..:::

110

E

10

0

,, ,, I11 I I

7_

I 11 I I

7_

, ,

I

1111 11 I I 70m

I

II1 I I

7.m

,,

I11 I I

7_

I I

, ,,

I 11 11 I I I I 7.m

I 11 I I

7.m

INSULIN MEALS

7.m

Figure 6. Effect of prolon~ed adrrrinistration of somatostatin on diabetic control of diabetes in a patient requiring insulin. (From Gerich, J. E.: Metabolism, 2S(Suppl. 1):1505-1508, 1976. Reproduced with permission.)

the short half-life and diverse actions of somatostatin, and because for most of these conditions other more definitive therapy is available. Nevertheless, where medical therapy has not proven satisfactory and surgery may be contraindicated, or not immediately feasible, e.g. acute pancreatitis, insulinoma, Zollinger-Ellison, and Verner-Morrison syndromes, an agent such as somatostatin may find temporary application. Indeed, somatostatin was recently used successfully to control gastrointestinal bleeding in a patient who was not a candidate for surgery.93 Behavioral effects of somatostatin, whose endogenous metabolism could be altered in some psychiatric disorders, have not been completely characterized, but these might possibly find therapeutic application at some future date. As indicated previously, the major limitations to the practical use of somatostatin are its short half-life and diverse actions. Attempts to solve these by the development oflonger-acting, more specific analogues have been only partially successful.25 Modifications, e.g., conjugation to protamine zinc, suspension in oil, amino acid substitutions, have not prolonged the action of so matos tatin much beyond 4 hours. However, several laboratories have reported the synthesis of analogues with increased potency120 and with some degree of selectivity.24. 65 This raises the intriguing possibility of there being different receptors for somatostatin in different tissues, and thus encourages hope for the future development of selective, clinically useful analogues.

REFERENCES 1. Alberti, K., Christensen, S., Iversen, J., et al.: Inhibition of insulin secretion by somatostatin. Lancet, 2:1299-1301, 1973. 2. Alford, F., Bloom, S., Nabarro, J., et aL: Glucagon control of fasting glucose levels in man. Lancet, 2:974-976, 1974.

SOMATOSTATIN

387

3. Altszuler, N., Gottlieb, B., and Hampshire, J.: Interaction of somatostatin, glucagon, and insulin on hepatic glucose output in the normal dog. Diabetes, 25:116-121,1976. 4. Arimura, A., Sato, H., Coy, D., et al.: Radioimmunoassay for GH-release inhibiting hormone. Proc. Soc. Exper. BioI. Med., 148: 784-789, 1975. 5. Arimura, A., Sato, H., Du Pont, A., et al.: Somatostatin: abundance of immunoreactive hormone in rat stomach and pancreas. Science, 189:1007-1008, 1975. 6. Arimura, A., and Schally, A.: Increase in basal and thyrotropin-releasing hormone (TRH)-stimulated secretion of thyrotropin (TSH) by passive immunization with antiserum to somatostatin in rats. Endocrinology, 98:1069-1072, 1976. 7. Arimura, A., Smith, W., and Schally, A.: Blockade of the stress-induced decrease in blood GH by anti-somatostatin serum in rats. Endocrinology, 98:540-543, 1976. 8. Baker, B., and Yen, Y.: The influence of hypophysectomy on the stores of somatostatin in the hypothalamus and pituitary stem. Proc. Soc. Exper. BioI. Med., 151 :599-602, 1976. 9. Ban, T.: Fiber connections in the hypothalamus and some autonomic functions. Pharmacol. Biochem. Behav., 3 (Suppl. 1):3-13, 1975. 10. Barden, N., Alvarado-Urbina, G., Cote, J., et al.: Cyclic AMP-dependent stimulation of somatostatin secretion by isolated rat islets of Langerhans. Biochem. Biophys. Res. Commun., 71 :840-844, 1976. 11. Barden, N., Lavoie, M., Dupont, A., et al.: Stimulation of glucagon release by addition of antisomatostatin serum to islets of Langerhans in vitro. Endocrinology, 101 :635-637, 1977. 12. Besser, G., Mortimer, C., Carr, D., et al.: Growth hormone release inhibiting hormone in acromegaly. Brit. Med. J., 1 :352-355, 1974. 13. Besser, G., Mortimer, C., McNeilly, A., et al.: Long-term infusion of growth hormone release inhibiting hormone in acromegaly: effects on pituitary and pancreatic hormones. Brit. Med. J., 4:622-627, 1974. 14. Besser, G., Paxton, A., Johnson, S., et al.: Impairment of platelet function by growthhormone release-inhibiting hormone. Lancet, 1 :1166-1169, 1975. 15. Bhathena, S., Peirino, P., Voyles, N., et al.: Reversal of somatostatin inhibition ofinsulin and glucagon secretion. Diabetes, 25: 1031-1040, 1976. 16. Blauth, C., Sonksen, P., Tompkins, C., et al.: The hypoglycemic action of somat os tatin in the anesthetized dog. Clin. Endocrinol., 6:17-25,1977. 17. Bloom, S. J offe, S., and Polak, J.: Effect of somatostatin on gallbladder contraction after a fat meal and administration of cholecystokinin-pancreozymin in pigs. GUT, 16:836 (abstract), 1975. 18. Bloom, S., Mortimer, C., Thorner, M., et al.: Inhibition ofgastrin and gastric acid secretion by growth-hormone release-inhibiting hormone. Lancet, 2:1106-1109, 1974. 19. Bloom, S., Ralphs, D., Besser, G., et al.: Effect of somatostatin on motilin levels and gastric emptying. Gut, 16:834, 1975. Abstract. 20. Boden, G., Sivitz, M., Owen, 0., et al.: Somatostatin suppresses secretin and pancreatic exocrine secretion. Science, 190:163-165, 1975. 21. Borgeat, P., Labrie, P., Drouin, J., et al.: Inhibition of adenosine 3',5' monophosphate accumulation in anterior pituitary gland in vitro by growth hormone release inhibiting hormone. Biochem. Biophys. Res. Commun., 56:1052-1059, 1974. 22. Bottazzo, G., and Lendrum, R.: Separate auto antibodies to human pancreatic glucagon and somatostatin cells. Lancet, 2 :873-876, 1976. 23. Brazeau, P., Rivier, J., Vale, W., et al.: Inhibition of growth hormone secretion in the rat by synthetic somatostatin. Endocrinology, 94:184-187, 1974. 24. Brown, M., Rivier, J., and Vale, W.: Somatostatin analogs with selected biologic activities. Metabolism, 25 (Suppl. 1): 1491-1494, 1976. 25. Brown, M., Rivier, J., Vale, W., et al.: Variability of the duration of inhibition of growth hormone release by Na acylated-des [ALA'-GLY2]-H, somatostatin analogues. Biochem. Biophys. Res. Commun., 65:752-756,1975. 26. Brown, M., and Vale, W.: Central nervous system effects of hypothalamic peptides. Endocrinology, 96:1333-1336, 1975. 27. Brownstein, M., Arimura, A., Sato, H., et al.: The regional distribution of somatostatin in the rat brain. Endocrinology, 96:1456-1461, 1975. 28. Burgus, R., Ling, N., Butcher, M., et al.: Primary structure of somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone. Proc. N at. Acad. Sci., U.S. 70:684-688, 1973. 29. Carr, D., Gomez-Pan, A., Weightman, D., et al.: Growth hormone release inhibiting hormone: actions on thyrotropin and prolactin secretion after thyrotropin-releasing hormone. Brit. Med. J., 3:67-69,1975. 30. Cherrington, A., Caldwell, M., Dietz, M., et al.: The effect of somatostatin on glucose uptake and production by rat tissues in vitro. Diabetes, in press. 31. Cherrington, A., Chiasson, J., Liljenquist, J., et al.: The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J. Clin. Invest., 58: 1407-1418, 1976.

388

JOHN

E.

GERICH AND GLORIA

S.

PATTON

32. Chiang, T., Duckworth, W., Beachey, E., et al.: The effect of somatostatin on platelet aggregation. Endocrinology, 97:753-755,1975. 33. Chideckel, E., Palmer, J., Koerker, D., et al.: Somatostatin blockade of acute and chronic stimuli of the endocrine pancreas and the consequences of this blockade on glucose homeostasis. J. Clin. Invest., 55:754-762,1975. 34. Christensen, N., Christensen, S., Hansen, A., etal.: The effect of so mat os tatin on plasma noradrenaline and plasma adrenaline concentrations during exercise and hypoglycemia. Metabolism, 24:1267-1272, 1975. 35. Creutzfeldt, W., Lankisch, P., and Folsch, V.: Hemmung der Sekretin- und Cholezystokinin-Pancreozymin-Induzierten Saft- und Enzymesekretion des Pankreas und der Gallenbliisenkontraktion beim Menschen durch Somatostatin. Dtsch. Med. Wschr., 100:1135-1138, 1975. 36. Curnow, R, Carey, R, Taylor, A., et al.: Somatostatin inhibition of insulin and gastrin hypersecretion in pancreatic islet-cell carcinoma. New Eng. J. Med., 292:1385-1386, 1975. 37. Curry, D., and Bennett, L.: Reversal of somatostatin inhibition of insulin secretion by calcium. Biochem. Biophys. Res. Commun., 60:1015-1019, 1974. 38. Deftos, L., Lorenzi, M., Bohannon, N., et al.: Somatostatin does not suppress plasma parathyroid hormone. J. Clin. Endocrinol. Metab., 43:205-207, 1976. 39. Dobbs, R, Sakurai, H., Sasaki, H., et al.: Glucagon: role in the hyperglycemia of diabetes mellitus. Science, 187:544-547, 1975. 40. Drovin, J., De Lean, A., Rainville, D., et al.: Characteristics of the interaction between thyrotropin-releasing hormone and somatostatin for thyrotropin and prolactin release. Endocrinology, 98:514-521, 1976. 41. Dubois, M.: Immunoreactive somatostatin is present in discrete cells of the endocrine pancreas. Proc. Nat. Acad. Sci., V.S., 72:1340-1343, 1975. 42. Efendic, S., Grill, V., and Luft, R: Inhibition by somatostatin of glucose-induced 3':5'monophosphate (cyclic AMP) accumulation and insulin release in isolated pancreatic islets of the rat. FEBS Lett., 55: 131-133, 1975. 43. Efendic, S., and Luft, R: Studies on the inhibitory effect of somatostatin on glucose induced insulin release in the isolated perfused rat pancreas. Acta Endocr. (KbH), 78:510-516, 1975. 44. Ensinck, J., Laschansky, E., Fnoeber, M., et al.: Distribution of so matos tatin measured by radioimmunoassay. Clin. Res., 24:155A, 1976. Abstract. 45. Fehm, H., Voigt, K., Lang, R, et al.: Somatostatin: a potent inhibitor of ACTHhypersecretion in adrenal insufficiency. Klin. Wschr., 54:173-175, 1976. 46. Ferland, L., Labrie, F., Jobin, M., et al.: Physiologic role of so matos tatin in the control of growth hormone and thyrotropin secretion. Biochem. Biophys. Res. Commun., 68: 149153, 1976. 47. Fujimoto, W.: Somatostatin inhibition of glucose-, tolbutamide-, theophylline, cytochalasin B-, and calcium-stimulated insulin release in monolayer cultures of rat endocrine pancreas. Endocrinology, 97:1494-1500, 1975. 48. Fujimoto, W., and Ensinck, J.: Somatostatin inhibition ofinsulin and glucagon secretion in rat islet culture: reversal by ionophore A23187. Endocrinology, 98:259-262, 1976. 49. Ganda, 0., Weig, G., Soeldner, J., et al.: Somatostatinoma: a somatostatin-containing tumor of the endocrine pancreas. New Eng. J. Med., 296:963-967, 1977. 50. Gerich, J.: Somatostatin: diabetes and acromegaly. Advances Intern. Med., 22 :251-252, 1976. 51. Gerich, J.: Somatostatin and the endocrine pancreas. In Labrie, F., Meites, J., and Pellitier, G., eds.: Current Topics in Molecular Endocrinology, Vol. Ill. Hypothalamus and Endocrine Function. New York, Plenum, 1976, pp. 127-143. 52. Gerich, J. E.: Metabolic effects oflong-term somatostatin infusion in man. Metabolism, 25 (Suppl. 1): 1505-1508, 1976. 53. Gerich, J. E.: Somatostatin-its possible role in carbohydrate homeostasis and the treatment of diabetes mellitus. Arch. Intern. Med., 1977, 137:657-666, 1977. 54. Gerich, J., Bier, D., Haas, R., et al.: In vitro and in vivo effects ofsomatostatin on glucose, alanine, and ketone body metabolism in the rat. Program of the 57th Annual Meeting of the Endocrine SOciety, New York, June 18-20, 1975, p. 128. 55. Gerich, J., Karam, J., and Lorenzi, M.: Diabetes without glucagon. Lancet, 1 :855,1976. 56. Gerich, J., and Lorenzi, M.: The role ofthe autonomic nervous system and somatostatin in the control of insulin and glucagon secretion. In Ganong, W., and Martini, L., eds.: Frontiers in Neuroendocrinology, Vol. 5. New York, Raven Press, 1977, in press. 57. Gerich, J., Lorenzi, M., Bier, D., et al.: Prevention of human diabetic ketoacidosis by somatostatin: evidence for an essential role of glucagon. New Eng. J. Med., 292:985989, 1975. 58. Gerich J., Lorenzi, M., Bier, D., et al.: Effects ofphysiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism: studies involving administra-

SOMATOSTATIN

59. 60. 61. 62. 63.

64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

389

tion of exogenous honnone during suppression of endogenous hormone secretion with somatostatin. J. Clin. Invest., 57:875-884, 1976. Gerich, J., Lorenzi, M., Hane, S., et a!.: Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: studies with somatostatin. Metabolism, 24:175-182,1975. Gerich, J., Lorenzi, M., Karam, J., et al.: Abnormal pancreatic glucagon secretion and postprandial hyperglycemia in diabetes mellitus. J.A.M.A., 234: 159-165, 1975. Gerich, J., Lorenzi, M., Schneider, V., et a!.: Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mellitus. New Eng. J. Med., 291 :544-547,1974. Gerich, J., Lorenzi, M., Tsalikian, E., et al.: Studies on the mechanism of epinephrineinduced hyperglycemia in man: evidence for participation of pancreatic glucagon secretion. Diabetes, 25 :65-71, 1976. Gerich, J., Lovinger, R., and Grodsky, G.: Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to arginine, isoproterenol, and theophylline: evidence for a preferential effect on glucagon secretion. Endocrinology, 96:749-754,1975. Gerich, J., Schneider, V., Lorenzi, M., et al.: Role of glucagon in human diabetic ketoacidosis: studies using somatostatin. Clin. Endocrinol., 5 (Suppl.):299s-305s, 1976. Grant, N., Clark, D., Garsky, V., et al.: Dissociation of somatostatin effects. Peptides inhibiting the release of growth honnone but not glucagon or insulin in rats. Life SCi., 19:629-632, 1976. Guillemin, R.: Somatostatin inhibits the release of acetylcholine induced electrically in the myenteric plexus. Endocrinology, 99:1653-1654, 1976. Guillemin, R., and Gerich, J. E.: Somatostatin: physiologic and clinical significance. Ann. Rev. Med., 27:379-388,1976. Giustina, G., Peracchi, M., Reschini, E., et al.: Dose-response study of the inhibiting effect of somatostatin on growth hormone and insulin secretion in normal subjects and acromegalic patients. Metabolism, 24 :807-815, 1975. Guistina, G., Reschini, E., Peracchi, M., et al.: Failure of somatostatin to suppress thyrotropin releasing factor and luteinizing hormone releasing factor-induced growth hormone release in acromegaly. J. Clin. Endocrinol. Metab., 38:906-908, 1974. Hall, R., Schally, A., Evered, D., et a!.: Action of growth-honnone-release inhibitory hormone in healthy men and in acromegaly. Lancet, 2 :581-584, 1973. Hansen, A., Orskov, H., Seyer-Hansen, K., et al.: Some actions of growth hormone release inhibiting factor. Brit. Med. J., 3 :523-524, 1973. Havlicek, V., Rezek, M., and Friesen, H.: Somatostatin and thyrotropin releasing hormone: central effects on sleep and motor system. Pharmacol. Biochem. Behav., 4:455459,1976. Hayes, H., Johnson, D., Koerker, D., et al.: Inhibition of gastrin release by somatostatin in vitro. Endocrinology, 96: 1374-1376, 1975. Hiikfelt, T., Efendic, S., Hellerstriim, C., et al.: Cellular localization of somatostatin in endocrine-like cells and neurons of the rat with special references to the A-cells of the pancreatic islets and to the hypothalamus. Acta Endocrinol., 80(Suppl. 200): 1-41, 1975. Ipp, E., Patton, G., Dobbs, R., et al.: Endogenous immunoreactive somatostatin secretion by the pancreas. Diabetes, 26 (SuppI. 1), 1977 in press. Jennings, A., Cherrington, A., Liljenquist, J., et al.: The roles of insulin and glucagon in the regulation of gluconeogenesis in the postabsorptive dog. Diabetes, 26, 1977, in press. Kaneko, T., Oka, H., Munemura, M., et al.: Stimulation of guanosine 3', 5'-cyclic monophosphate accumulation in rat anterior pituitary gland in vitro by synthetic somatostatin. Biochem. Biophys. Res. Commun., 61 :53-57, 1974. Koerker, D., Harker, L., and Goodner, C.: Effects of somatostatin on hemostasis in baboons. New Eng. J. Med., 293:476-479, 1975. Koerker, D., Ruch, W., Chideckel, E., et al.: Somatostatin: hypothalamic inhibitor of the endocrine pancreas. Science, 184:482-484, 1974. Konturek, S.: Somatostatin and the gastrointestinal secretions. Scand. J. Gastroenterol., 11:1-4,1976. Konturek, S., Tasler, J., Obtulowicz, W., et al.: Effect of growth-hormone-release inhibiting hormone on hormones stimulating exocrine pancreatic secretion. J. Clin. Invest., 58:1-6,1976. Krulich, L., Dhariwal, A., and Mc Cann, S.: Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology, 83: 783-790, 1968. Krulich, L., Illner, P., Fawcett, C., et al.: Dual hypothalamic regulation of growth hormone secretion. Proceedings of the second international symposium on growth honnone Milan, May 5-7, 1971 Excerpta Medica International Congress Series 244:306-316, 1972.

390

JOHN

E.

GERICH AND GLORIA

S.

PATTON

84. Krulich, L., and Mc Cann, S.: Effect of GH-releasing factor and GH-inhibiting factor on the release and concentration of GH in pituitaries incubated in vitro. Endocrinology, 85 :319-324, 1969. 85. Larsson, L., HoIst, J., Kiihl, C., et al.: Pancreatic somatostatinoma: clinical features and physiologic implications. Lancet, 1 :666-668, 1977. 86. Leblanc, H., and Yen, S.: Comparison of cyclic and linear forms of somatostatin in the inhibition of growth hormone, insulin and glucagon secretion. J. Clin. Endocrinol. Metab., 40:906-908, 1975. 87. Lennon, J., Sircus, W., Bloom, S., et al.: Investigation and treatment of a recurrent VIPoma. GUT, in press. 88. Lorenzi, M., Gerich, J., Karam, J., et al.: Failure of somat ostatin to inhibit tolbutamideinduced insulin secretion in patients with insulinomas: a possible diagnostic tool. J. Clin. Endocrinol. Metab., 40:1121-1124, 1975. 89. Lucke, C., Hiiffken, B., and von zur Miihlen, A.: The effect of somatostatin on TSH levels in patients with primary hypothyroidism. J. Clin. Endocrinol. Metab., 41 : lO821084, 1975. 90. Marks, N., and Stern, F.: Inactivation of somatostatin (GH-RIH) and its analogues by crude and partially purified rat brain extracts. FEBS Lett., 55 :220-224, 1975. 91. Martin, J. B.: Inhibitory effect of somatostatin (SRIF) on the release of growth hormone (GH) induced in the rat by electrical stimulation. Endocrinology, 94:497-502,1974. 92. Martin, J., Renaud, L., and Brazeau, P.: Hypothalamic peptides: new evidence for "peptidergic" pathways in the C.N.S. Lancet, 2:393-395, 1975. 93. Mattes, P., Raptis, S., Heil, T., et al.: Extended somatostatin treatment of a patient with bleeding ulcer. Horm. Metab. Res., 7:508-511, 1975. 94. Meissner, C., Thum, C., Beischer, W., et al.: Antidiabetic action of somatostatin-assessed by the artificial pancreas. Diabetes, 24:988-996, 1975. 95. Mielke, C., Gerich, J., Lorenzi, M., et al.: The effect of somat os tatin on coagulation and platelet function in man. New Eng. J. Med., 293 :480-483, 1975. 96. Mortimer, C., Carr, D., Lind, T., Effects of growth-hormone release-inhibiting hormone on circulating glucagon, insulin, and growth hormone in normal, diabetic acromegalic and hypopituitary patients. Lancet, 1 :697-701, 1974. 97. Ogawa, N., Thompson, T., and Friesen, H.: Soluble somatostatin binding protein. Clin. Res., 24:661A, 1976. 98. Oliver, J.: Inhibition of calcium uptake by somatostatin in isolated rat islets of Langerhans. Endocrinology, 99:9lO-913, 1976. 99. Orci, L.: The micro anatomy of the islets of Langerhans. Metabolism, 25 (Suppl. 1): 1303-1313, 1976. 100. Orci, L., Baetens, D., and Rufener, C.: Evidence for the D-cell of the pancreas secreting somatostatin. Horm. Metab. Res., 7:400-406, 1975. 101. Orci, L., Baetens, D., Rufener, C., et al.: Hypertrophy and Hyperplasia of somatostatincontaining DOcells in diabetes. Proc. Natl. Acad. Sci., U.S.A. 73:1338-1342, 1976. lO2. Orci, L., and Unger, R.: Functional subdivision of the islets of Langerhans and possible role of D cells. Lancet, 2: 1243-1244, 1975. lO3. Pace, C., Conant, S., and Murphy, M.: Somatostatin inhibition of electrical activity in cultured rat islet cells (abstract). Diabetes, 25 (Suppl. 1):380, 1976. lO4. Parker, D., Rossman, L., Siler, T., et al.: Inhibition of the sleep-related peak in physiologic human growth hormone release by somatostatin. J. Clin. Endocrinol. Metab., 38:496499,1974. 105. Patel, Y., Orci, L., Bankier, A., et al.: Decreased pancreatic somatostatin (SRIF) concentration in spontaneously diabetic mice. Endocrinology, 99:1415-1418, 1976. 106. Patel, Y., Rao, K., and Reichlin, S.: Somatostatin in human cerebrospinal fluid. New Eng. J. Med., 296:529-533, 1977. 107. Patel, Y., and Weir, G.: Increased somatostatin content of islets from streptozotocindiabetic rats. Clin. Endocrinol., 5: 191-194, 1976. 108. Patton, G., Dobbs, R., Orci, L., et al.: Stimulation of pancreatic immunoreactive somatostatin release by glucagon. Metabolism, 25 (Suppl. 1):1499-1500, 1976. 109. Patton, G., Ipp, E., Dobbs, R., et al.: Response of pancreatic immunoreactive somatostatin to arginine. Life. Sci., 19: 1957-1960, 1976. 110. Peracchi, M., Reschini, E., Cantalamessa, L., et al.: Inhibitory effect of somat os tatin on dibutyryl cyclic AMP-induced insulin and growth hormone release in human subjects. Metabolism, 25:321-328, 1976. Ill. Pinstone, B., Becker, D., and Kronheim, S.: Disappearance of plasma growth hormone in acromegaly and protein-calorie malnutrition after somatostatin. J. Clin. Endocrinol. Metab., 40:168-17l, 1975. 112. Pimstone, B., Berelowitz, M., and Kronheim, S.: Somatostatin, 1976. S. Afr. Med. J., 50:147l-1474,1976. 113. Polak, J., Grimelius, L., Pearse, A., et al.: Growth-hormone release-inhibiting hormone in gastrointestinal and pancreatic D-cells. Lancet, 1: 1220-1222, 1975.

SOMATOSTATIN

391

114. Raptis, S., Dollinger, H., von Berger, L., et al.: Effects ofsomatostatin on gastric secretion and gastrin release in man. Digestion, 13:15-26, 1975. 115. Rasche, H., Raptis, S., Scheck, R, and Pfeiffer, E.: Coagulation studies and platelet function after somatostatin. Klin. Wschr., 54:977-982, 1976. 116. Renaud, L., Martin, J., and Brazeau, P.: Depressant action ofTRH, LH-RH, and somatostatin on activity of central neurons. Nature, 255 :233-235, 1975. 117. Reid, 1., and Rose, J.: An intrarenal effect of somatostatin on water excretion. Endocrinology, 100:782-785, 1977. 118. Rezek, M., Havlicek, V., Hughes, K., et al.: Central site of action of so matos tatin (SRIF): Role of Hippocampus. Neuropharmacology, 15:499-504,1976. 119. Rivier, J., Brazeau, P., Vale, W., et al.: Somatostatin analogues: relative importance of the disulfide bridge and of the Ala-Gly side chain for biologic activity. J. Med. Chem., 18:123-126,1975. 120. Rivier, J., Brown, M., and Vale, W.: D-TRP'-somatostatin: an analogue of somat os tatin more potent than the native molecule. Biochem. Biophys. Res. Commun., 65 :746-751, 1975. 121. Rosenthal, J., Escobar-Jiminez, F., Raptis, S., et al.: Inhibition of furosemide-induced hyperreninaemia by growth-hormone release-inhibiting hormone in man. Lancet, 1 :772-774,1976. 122. Sakurai, H., Dobbs, R, and Unger, R: Somatostatin-induced changes in insulin and glucagon secretion in normal and diabetic dogs. J. Clin. Invest., 54:1395-1402,1974. 123. Sakurai, H., Dobbs, R., and Unger, R.: The effect of so mat ostatin on the response ofGLI to intraduodenal administration of glucose, protein and fat. Diabetologia, 11 :427-439, 1975. 124. Samols, E., Weir, G., Patel, Y., et al.: Autonomic control of somatos tatin and pancreatic polypeptide secretion by the isolated perfused canine pancreas. Clin. Res., 1977, in press. 125. Shapiro, S., Sumiya, E., Fleischer, N., et al.: Regulation ofin vitro insulin release from a transplantable Syrian hamster insulinoma. Endocrinology, 97:442-447,1975. 126. Schauder, P., Mc Intosh, C., Arends, J., et al.: Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose. FEBS. Lett., 68:225-227, 1976. 127. Schlegel, W., Raptis, S., Dollinger, H., et al.: Inhibition of secretin-pancreozymin and gastrin release and their biological activities by somatostatin in First International Symposium on hormonal receptors in Digestive tract Physiology. Inserm Symposium No. 3. Bonfils, S., Fromageot, P., and Rosselin, G., eds., New York, Elsevier North Holland Publishing Co., 1977, pp. 361-377. 128. Sherwin, R, Hendler, R, De Fronzo, R, et al.: Glucose homeostasis during prolonged suppression of insulin and glucagon by somatostatin. Proc. Natl. Acad. Sci. (U.S.A.), 74:348-352, 1977. 129. Siler, T., Vandenberg, G., and Yen, S.: Inhibition of growth hormone release in humans by somatostatin. J. Clin. Endocrinol. Metab., 37:632-634, 1973. 130. Siler, T., Yen, S., Vale, W., et al.: Inhibition by somatostatin of the release ofTSH induced in man by thyrotropin-releasing factor. J. Clin. Endocrinol. Metab., 38:742-745, 1974. 131. Smith, P., Woods, S., and Porte, D.: Phentolamine blocks the somatostatin-mediated inhibition of insulin secretion. Endocrinology, 98:1073-1076,1976. 132. Taminoto, T., Seino, Y., Goto, Y., et al.: Interaction of somatostatin and calcium in regulating insulin release from isolated pancreatic islets. Biochem. Biophys. Res. Commun., 66:928-934, 1975. 133. Terenius, L.: Somatostatin and ACTH are peptides with partial antagonistic-like selectivity for opiate receptors. Eur. J. Pharmacol., 38:211-213, 1976. 134. Terry, L., Willoughby, J., Brazeau, P., et al.: Antiserum to somatostatin prevents stressinduced inhibition of growth hormone secretion in the rat. SCience, 192 :565-566, 1976. 135. Tiengo, A., Fedele, D., Marchiori, E., et al.: Suppression and stimulation mechanisms controlling glucagon secretion in a case of islet-cell tumor producing glucagon, insulin, and gastrin. Diabetes, 25 :408-412, 1976. 136. Turcot-Lemay, L., Lemay, A., and Lacy, P.: Somatostatin inhibition of insulin release from freshly isolated and organ cultured rat islets of Langerhans in vitro. Biochem. Biophys. Res. Commun., 63:1130-1138,1975. 137. Tyrrell, J., Lorenzi, M., Gerich, J., et al.: Inhibition by somatostatin ofACTH secretion in Nelson's syndrome. J. Clin. Endocrinol. Metab., 40:1125-1127, 1975. 138. Unger, R, and Orci, L.: Possible roles of pancreatic D-cell in normal and diabetic states. Diabetes, 26:241-244, 1977. 139. Vale, W., Brazeau, P., Rivier, C., et al.: Somatostatin. Rec. Prog. Horm. Res., 34:365397, 1975. 140. Vale, W., Ling, N., Rivier, J., et al.: Anatomic andphylogenetic distribution of somatos tatin. Metabolism, 25 (Suppl. 1):1491-1494, 1976. 141. Vale, W., Brazeau, P., Grant, G., et al.: Premieres observations sur le mode d'action de la somatostatin, un facteur hypothalamique qui inhibe la secretion de I'hormone de croissance. C. R Acad. Sc. Paris, 275:2913-2916, 1972.

392

JOHN

E.

GERICH AND GLORIA

S.

PATTON

142. Vale, W., Rivier, C., Brazeau, P., et al.: Effects of somatostatin on the secretion of thyrotropin and proclatin. Endocrinology, 95:968-977, 1975. 143. Wahren, J.: Somatostatin and diabetes mellitus: the role of glucagon in diabetic hyperglycemia and glucose intolerance. Scand. J. Clin. Lab. Invest., 36 :497-503, 1976. 144. Wahren, J., and Felig, P.: Influence of somatostatin on carbohydrate disposal and absorption in diabetes melIitus. Lancet, 2: 1213-1216, 1976. 145. Ward, F., Leblanc, H., and Yen, S.: The inhibitory effect of somatostatin on growth hormone, insulin and glucagon secretion in diabetes melIitus. J. Clin. Endocrinol. Metab., 41 :527-531, 1975. 146. Weeke, J., Hansen, A., and Lundbaek, K.: The inhibition by somatostatin of the thyrotropin response to thyrotropin-releasing hormone in normal subjects. Scand.J. Clin. Lab. Invest., 33:101-103, 1974. 147. Weeke, J., Hansen, A., and Lundbaek, K.: Inhibition by somatostatin of basal levels of serum thyrotropin (TSH) in normal man. J. Clin. Endocrinol. Metab., 41 : 168-1 71, 1975. 148. Yen, S., Siler, T., and Devane, G.: Effect of somatostatin in patients with acromegaly. New Eng. J. Med., 290:935-938, 1974. Diabetes and Metabolism Research Laboratory Mayo Foundation Rochester, Minnesota 55901