Effects of a somatostatin derivative (SMS 201-995) on postprandial hyperglycemia in insulin-dependent diabetics studied by means of a closed-loop device

We studied the effects of a premeal sc injection of an analog of somatostatin (SMS 201-995, Sandoz) on the postprandial glycemic excursions, insulin requirement and hormone profiles (GH, glucagon and C-peptide) in 8 IDDM patients (diabetes duration 14.0 +/- 6.5 yr, daily insulin requirement 36 +/- 6.4 U) maintained normoglycemic by connecting them to a closed-loop insulin infusion system (Betalike, Genoa). The morning of the test the patients were connected to the Betalike and their glucose levels stabilized for at least 4 h. At 13:00 h the study was begun with a sc injection of 50 micrograms of SMS 201-995 or placebo (randomly) and a standardized mixed meal (800 Kcal) was given. Blood samples were obtained 0, 15, 30, 60, 120 and 180 min after the injection. Each patient was tested both with SMS 201-995 and placebo. Postmeal glycemic peaks were decreased after SMS 201-995 (119.6 +/- 5.4 mg/dl vs 149.1 +/- 4.2; p less than 0.05) as well as insulin requirements (3.2 +/- 0.8 U vs 13.3 +/- 1.9; p less than 0.01) for the 180 min postprandial period. Similarly, glucagon level was reduced 30 min postprandially (24 +/- 6 pg/ml vs 59 +/- 24; p less than 0.05) and so GH level only 180 min after lunch (p less than 0.05). The premeal injection of SMS decreases postprandial glycemic excursions and the corresponding insulin requirement. The action of SMS 201-995 may be mainly mediated by the suppression of postprandial glucagon peak.     

Effect of a new long-acting somatostatin analogue (SMS 201-995) on glycemic and hormonal profiles in insulin-treated type II diabetic patients

Five type II diabetic patients were studied after secondary failure of oral agents, with and without the addition of the new long-acting somatostatin analogue SMS 201-995 to an intermediate-acting insulin regimen. SMS 201-995 was administered twice daily, before breakfast and dinner, as 100 micrograms sc injections, and resulted in a lowering of plasma glucose, as well as of plasma glucagon and serum C-peptide levels. SMS 201-995 abolished postprandial glycemic and xylosemic peaks related to meals and to oral d-xylose when they were taken shortly after the administration of the analogue, while it had no effect on glycemic and xylosemic increments that followed the midday meal. The new somatostatin analogue improves glucose tolerance in type II diabetic patients, both by inhibiting counterregulatory hormones and by delaying and reducing intestinal absorption of nutrients. Its administration could lead to a reduction of daily insulin requirements. Our findings indicate that SMS 201-995 may have a role as an adjunct to insulin in the management of type II diabetic patients after secondary failure of oral agents.     

THE SENSITIVITY OF GROWTH HORMONE AND PROLACTIN SECRETION TO THE SOMATOSTATIN ANALOGUE SMS 201–995 IN PATIENTS WITH PROLACTINOMAS AND ACROMEGALY

The somatostatin analogue SMS 201-995 has recently been shown to be effective in suppressing GH secretion in most acromegalic patients. In the present study it was investigated whether PRL release in prolactinoma and acromegalic patients might also be sensitive to SMS 201-995 and whether co-secretion of PRL in acromegaly plays a role in determining the sensitivity of GH secretion to SMS 201-995. The s.c. administration of 50 micrograms SMS 201-995 did not affect high plasma PRL levels in four microprolactinoma patients. Therapy of one of these patients for 3 d with 50 micrograms three times a day also did not affect PRL levels. The single administration of 50 micrograms SMS 201-995 in 22 acromegalic patients lowered plasma GH levels for 2-6 h to less than 5 micrograms/l in 14 patients and to less than 50% of control values in 16 patients. In 18 of these 22 patients the immunohistochemical picture of the pituitary tumour was known. Eleven patients had pure GH-containing tumours and in seven patients there were mixed GH/PRL-containing tumours. In two of these latter patients there was evidence for GH and PRL being secreted by the same tumour cells. The sensitivity of GH secretion to SMS 201-995 did not differ between the patients with pure GH or mixed GH/PRL-containing adenomas. Plasma PRL levels were not affected by SMS 201-995 in the patients with pure GH-secreting tumours, but were significantly suppressed in four of the seven patients with mixed GH/PRL containing tumours. Chronic treatment for 16 weeks of one patient with a mixed GH/PRL-containing tumour with SMS 201-995 (100 micrograms three times a day) resulted in normalization of both the increased GH and PRL levels. It is concluded that SMS 201-995 does not affect tumorous PRL secretion in patients with pure prolactinomas. In acromegalic patients with mixed GH/PRL-containing tumours PRL secretion in some patients is sensitive to SMS 201-995, making these patients good candidates for chronic treatment with the analogue. The simultaneous presence of PRL in the GH-secreting pituitary tumour or the presence of hyperprolactinaemia in acromegalics does not play a role in the sensitivity of GH secretion to the somatostatin analogue.     

The effects of SMS 201-995 (sandostatin) on metabolic profiles in insulin-dependent diabetes mellitus

GH has been implicated in the pathophysiology of various acute and chronic complications of diabetes mellitus. As a consequence, there has been a great deal of interest in developing methods for suppressing GH secretion in diabetes. SMS 201-995 is a long-acting somatostatin analog which inhibits the secretion of numerous hormones, including GH. To determine the metabolic and hormonal responses to SMS 201-995 independent of endogenous insulin suppression, we studied six patients with insulin-dependent diabetes mellitus while they received 150 micrograms SMS 201-995, sc, daily for an 8-week period. This treatment resulted in no change in 24-h glucose profiles, although the mean insulin dose decreased by 19%, while hemoglobin A1c decreased significantly (0.084 +/- 0.023 to 0.067 +/- 0.011, P = 0.04). The 24-h profiles of blood lactate, plasma free insulin, glucagon, FFA, blood glycerol, and beta-hydroxybutyrate were unchanged, whereas that of blood alanine increased significantly (7.8 +/- 0.4 to 10.6 +/- 0.9 mmol/L.h; P = 0.01). GH secretion declined in five of the six patients; the mean values before and during SMS 201-995 treatment were 102 +/- 23 and 68 +/- 12 micrograms/L.h, respectively (P = NS), for the six patients. [In the five patients in whom GH secretion declined, the mean values before and during SMS 201-995 treatment were 115 +/- 23 and 63 +/- 14 micrograms/L.h, respectively (P = 0.01).] These results suggest that SMS 201-995 may be administered to patients with insulin-dependent diabetes mellitus without a deleterious effect on metabolic control.     

SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile

OBJECTIVE: The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. DESIGN: A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. RESULTS: SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. CONCLUSION: We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.     

Somatostatin analog SMS 201-995 and insulin needs in insulin-dependent diabetic patients studied by means of an artificial pancreas

SMS 201-995 is a new somatostatin analog which is 10-60 times more potent and specific than somatostatin as an inhibitor of GH and insulin release. The aim of this study was to assess its value as an adjunct to insulin therapy in insulin-dependent diabetic- (IDD) patients. Six IDD patients were studied. Their average insulin doses ranged from 22-46 U/day, and hemoglobin A1c levels varied between 6.5-11.5%. Two patients had background retinopathy and mild sensorimotor neuropathy. After 12 h of glucemic stabilization, the patients were kept normoglycemic by connecting them to the Biostator-GCIIS. The study entailed two parts in random order, in which standardised mixed meals were administered at 0800, 1400, and 2000 h with or without sc bolus injections of 50 micrograms SMS 201-995 immediately before meal ingestion. Plasma free insulin, C-peptide, GH, and glucagon were measured by RIA. Postprandial hyperglycemia was significantly diminished by SMS 201-995 after breakfast, lunch, and dinner. Insulin requirements, both total and 2-h postprandially, decreased significantly with a parallel reduction in free insulin levels. Postprandial glucagon levels also significantly decreased, but GH profiles were similar. In conclusion, the somatostatin analog SMS 201-995 has a potential value as an adjunct to insulin in the management of IDD patients.     

INTERACTION BETWEEN GROWTH HORMONE RELEASING FACTOR (GRF) AND SOMATOSTATIN ANALOGUE (SMS 201–995) IN NORMAL SUBJECTS

Continuous infusion or pulsatile administration of growth hormone releasing factor leads to decreasing GH levels and GH responses in normal subjects. We have given 50 micrograms GRF 1-44 i.v. four times in 2-hourly intervals to five normal subjects. After 1 week the same protocol was repeated after s.c. administration of 50 micrograms of the synthetic octapeptide somatostatin (SMS 201-995). The GH response to the same GRF doses was higher after the initial GRF pulse and blunted to the following GRF pulses (pulse I: 37:0 +/- 11.2 ng/ml; Pulse II: 5.3 +/- 1.2 ng/ml; pulse III: 5.9 +/- 2.5 ng/ml; pulse IV: 5.9 +/- 3.2 ng/ml; mean +/- SE). When SMS 201-995 was given 60 min before pulsatile GRF administration, the GH secretion pattern was reversed (pulse I: 2.4 +/- 0.7 ng/ml; pulse II: 2.0 +/- 0.9 ng/ml; pulse III: 4.4 +/- 2.1 ng/ml; pulse IV: 11.4 +/- 3.6 ng/ml). Radioimmunoassayable GRF levels were not different before and after administration of SMS 201-995. The half time of disappearance was 8.6 +/- 0.4 min before and 8.0 +/- 0.5 min after SMS 201-995. Basal thyrotrophin and insulin levels, which remained constant over the 8 h period with GRF only, decreased significantly after SMS 201-995 administration. These findings are compatible with a limited releasable GH pool which is exhausted by chronic GRF stimulation but can be conserved by prior administration of the somatostatin analogue. Thus, when somatostatin bioactivity tapers off, there is recovery of GRF-stimulated GH secretion.     

Acute effects of a somatostatin analogue on kidney function in type 1 diabetic patients

Suppression of growth hormone by means of somatostatin has been suggested as a possible adjunct therapy in Type 1 diabetes. To assess the acute effect of the somatostatin analogue SMS 201-995 on kidney function in uncomplicated Type 1 diabetes, 13 normoalbuminuric, normotensive diabetic patients were investigated before and during IV infusion of SMS 201-995 (8 micrograms h-1). A control experiment with infusion of carrier only was also performed. The SMS infusion induced a reduction in the glomerular filtration rate (clearance of 125I-iothalamate) and renal plasma flow (131I-hippuran) from 140 +/- 15 (mean +/- SD) and 550 +/- 69 to 131 +/- 14 (2p less than 0.005) and 492 +/- 73 ml min-1 1.73-m-2 (2p less than 0.001), while filtration fraction and total renal resistance rose (both 2p less than 0.001). Urinary albumin excretion rate, blood pressure, and blood glucose concentration were unchanged. Plasma growth hormone and glucagon were significantly suppressed. The reduction in glomerular filtration rate and renal plasma flow correlated with the fall in glucagon concentration (r = 0.57, 2p = 0.04, and r = 0.63, 2p = 0.02). The urinary flow rate was markedly reduced, urine osmolality increased, and fractional excretion of sodium, calcium, and phosphate were reduced. Arginine vasopressin, atrial natriuretic peptide, angiotensin II, and aldosterone were unchanged by the SMS infusion. Thus SMS 201-995 acutely reduces glomerular filtration rate and renal plasma flow in uncomplicated Type 1 diabetes and has an antidiuretic effect. The effects may be related to suppression of glucagon secretion.     

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NON-INSULIN-DEPENDENT DIABETES

The 24-h hormonal and metabolic profiles obtained in five non-insulin-dependent diabetics receiving twice daily s.c. injections of the long-acting somatostatin analogue SMS 201-995 (50 micrograms) have been compared with those obtained following placebo injection. Injections were given 30 min before breakfast and the evening meal. GH secretion was not suppressed by the analogue administered in this manner. Despite suppression of serum insulin levels following breakfast and the evening meal, blood glucose levels were similar during the two study periods with no evidence of worsening in diabetic control. Prolonged suppression of plasma glucagon levels was observed and the nocturnal elevation in serum TSH levels was abolished. Free T4 levels fell significantly following the analogue but total T3 levels were unaffected. Blood alanine levels were elevated throughout the study period following SMS 201-995 but changes in lactate, pyruvate, glycerol and 3-hydroxybutyrate were minor. All five subjects suffered gastrointestinal side-effects. SMS 201-995 (50 micrograms) given twice daily before meals does not cause a deterioration in metabolic control, does not suppress 24-h GH secretion and causes significant side-effects in patients with non-insulin-dependent diabetes mellitus.     

The effects of the somatostatin analogue SMS 201-995 on carbohydrate homeostasis of insulin-dependent diabetics as assessed by the artificial endocrine pancreas

On the basis of the inhibitory actions of the somatostatin analogue SMS 201-995 on growth hormone (GH) and glucagon (IRG) secretion we investigated its effects on carbohydrate metabolism of insulin-dependent diabetics. Six patients with no residual insulin secretion were connected to the artificial endocrine pancreas (AEP) and after the establishment of a steady state overnight they were injected either normal saline or 50 micrograms of SMS 201-995 s.c., t.i.d., or 100 micrograms of the same compound b.i.d. Insulin requirements were assessed by the AEP and compared during the 24 h and after the main meals. The inhibition of GH and IRG secretion was evaluated as well. 50 micrograms of SMS analogue t.i.d. induced a significant reduction of insulin requirement (mean +/- SEM) while no significant difference was observed between control and 100 micrograms s.c., b.i.d., nor between 50 micrograms and 100 micrograms. The curve of glucose fluctuations was smoother after 50 micrograms than after 100 micrograms and control. Postprandial IRG secretion was inhibited by both regimens of SMS after lunch and dinner. GH secretion was significantly inhibited after all meals during the days of analogue administration. SMS 201-995 analogue appears to have a remarkable antidiabetic activity as shown by the sparing of administered amount of insulin, suppression of counter-insulin hormones and smoothing of blood glucose curve. It may constitute a safe and effective adjunctive measure in the management of insulin-dependent diabetics.     

A CLOSE CORRELATION BETWEEN THE INHIBITORY EFFECTS OF INSULIN-LIKE GROWTH FACTOR-I AND SMS 201-995 ON GROWTH HORMONE RELEASE BY ACROMEGALIC PITUITARY TUMOURS IN VITRO AND IN VIVO

In the present study we compared the in-vitro effects of IGF-I and SMS 201-995 on GH release by cultured tumour cells obtained from seven acromegalic patients with the preoperative in-vivo GH dynamics, including the acute response to 50 micrograms SMS 201-995 subcutaneously. IGF-I and SMS 201-995 inhibited GH release during a 24 h incubation in four and five of the seven tumour cell preparations, respectively. The inhibitory effect of SMS 201-995 was greater than that exerted by IGF-I (P less than 0.01). There was a close correlation between the in-vitro inhibitory effects of IGF-I and SMS 201-995 (P less than 0.01). In addition, the acute inhibitory effect of 50 micrograms SMS 201-995 on circulating GH levels in vivo correlated with the inhibitory effects in vitro of both SMS 201-995 (P less than 0.01) and IGF-I (P less than 0.05). The inhibitory effects of IGF-I and SMS 201-995 on GH release in vitro were shown to be additive in two of four tumours. There was no relation between the in-vitro effects of IGF-I and/or SMS 201-995 and several in-vivo parameters, including fluctuations in GH levels, sleep-induced GH release, a paradoxical increase of GH in response to TRH, and the circulating IGF-I and PRL levels. In conclusion: (1) there is a close correlation between the sensitivity of GH release by cultured human adenoma cells to IGF-I and SMS 201-995. (2) There is also a close correlation between the in-vivo inhibitory effect on GH release of SMS 201-995 and the in-vitro inhibitory effects of both SMS 201-995 and IGF-I. (3) A subgroup of acromegalic patients harbour pituitary tumours in which the qualitative regulation of hormone secretion is similar to that of normal GH secretion.     

A randomized study of SMS 201-995 versus bromocriptine treatment in acromegaly: clinical and biochemical effects

Twenty-six acromegalic patients were randomized to treatment with either SMS 201-995 or bromocriptine in increasing doses and were investigated before treatment, after 2, 4, and 8 weeks of treatment, and 2 weeks after discontinuation of treatment. There were two dropouts from the bromocriptine group and one from the SMS 201-995 group. Amelioration of clinical signs and symptoms was seen in both groups during treatment. After 8 weeks mean 12-h GH concentrations had declined from 13.8 +/- 5.2 to 2.9 +/- 4.4 (mean +/- SEM) in SMS 201-995-treated and from 18.8 +/- 7.5 to 5.4 +/- 1.2 micrograms/L in bromocriptine-treated patients. Somatomedin-C concentrations fell from 3.04 +/- 0.36 to 1.43 +/- 0.36 in SMS 201-995-treated and from 2.93 +/- 0.40 to 2.13 +/- 0.27 U/mL in bromocriptine-treated patients. Size reduction of the pituitary tumor was seen in one patient receiving bromocriptine. Gastrointestinal glucose absorption was delayed, and insulin secretion suppressed during treatment with SMS 201-995. Hemoglobin-A1 concentrations remained unchanged in SMS 201-995-treated patients, but declined in the bromocriptine group. Side-effects were common, but usually tolerable, with both treatments. It is concluded that both drugs are of benefit in the treatment of acromegaly.     

The somatostatin analog SMS 201-995 induces long-acting inhibition of growth hormone secretion without rebound hypersecretion in acromegalic patients

The acute effect of the somatostatin analog SMS 201-995 (SMS) was investigated in eight acromegalic patients. This substance is an octapeptide [DPhe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-(ol)] that inhibits GH release in experimental animals and man. After a control day, 50 micrograms SMS were injected sc, and plasma GH and insulin and blood glucose levels were measured at multiple intervals for 24 h. GH significantly (P less than 0.001) decreased in seven of eight acromegalic patients from 30 +/- 5 (+/- SE) to an average of 10.7 +/- 4 micrograms/l from 1-10 h after drug administration. No rebound effect occurred. Postprandial blood glucose levels were significantly (P less than 0.01) higher between 2 and 4 h after SMS treatment compared with control day values, and there was a substantial reduction in insulin secretion, as estimated by the area under the curve (P less than 0.01), during the first 3 h after SMS administration. Circulating GH was not altered by SMS or the dopamine agonist mesulergine in one patient, but the combination of both substances (50 micrograms SMS, sc, and 0.5 mg mesulergine, orally) reduced GH to below 50% of basal. In vitro studies showed that 1 PM, 0.1 nM, and 10 nM SMS or natural somatostatin exerted a similar inhibitory effect (12-39% reduction; P less than 0.01 for all three strengths) on GH release by cultured human pituitary tumor cells. In conclusion, the somatostatin derivative SMS exerts a potent and prolonged inhibitory action on GH secretion and a shorter lasting suppression of insulin in acromegalic patients. Therefore, it may represent a useful tool in the chronic management of this condition.     

Inhibition of meal stimulated gastric acid secretion by an octapeptide somatostatin analogue SMS 201-995.

A dose response study of the effect of an octapeptide somatostatin analogue, SMS 201-995, on meal stimulated gastric acid secretion was carried out in 12 healthy volunteers. Infusion of SMS 201-995 in a dose of 50 pmol/kg/h almost completely abolished the acid response to the meal. Pl-gastrin was significantly decreased during infusion of 10 pmol/kg/h of SMS 201-995 and insulin was significantly inhibited during infusion of 50 pmol/kg/h. SMS 201-995 in a dose of 50 pmol/kg/h inhibited basal and submaximal pentagastrin stimulated acid secretion by 77% and 84% respectively (p less than 0.01). On a molar basis SMS 201-995 is substantially more potent than natural somatostatin in inhibiting gastric acid secretion.     

Long term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin- and growth hormone-secreting pituitary adenoma

A patient with a mixed pituitary tumor secreting TSH and GH was treated, starting 3 months after partial adenomectomy, with the somatostatin analog SMS 201-995 for 8 months. Somatostatin itself inhibited TSH, GH, and alpha-subunit release by the tumor both in vivo and in vitro. Long term treatment with twice daily sc injections of SMS 201-995 resulted in decreased TSH secretion and lower serum thyroid hormone levels. However, euthyroidism was achieved only when the patient was treated with three daily 200-micrograms injections of SMS 201-995. After 30 weeks of SMS 201-995 therapy, TSH secretion increased, while GH secretion remained suppressed. After withdrawal for 6 months, SMS 201-995 (100 micrograms, sc, twice daily) again completely inhibited TSH secretion. SMS 201-995 did not alter the volume of the residual adenomatous tissue. We conclude that SMS 201-995 may be a valuable therapeutic agent for the management of patients with a thyrotroph adenoma. However, desensitization may occur during long term treatment.     

EFFECT OF OCTAPEPTIDE SOMATOSTATIN ANALOGUE (SMS 201-995) ON PLASMA 7B2 (A NEUROENDOCRINE POLYPEPTIDE) LEVELS IN PATIENTS WITH ACROMEGALY

We studied the sequential changes of plasma levels of immunoreactive '7B2' (IR-7B2), a neuroendocrine polypeptide, after a subcutaneous injection of 50 micrograms of synthetic octapeptide somatostatin analogue (SMS 201-995) in seven patients with acromegaly due to GH-producing pituitary adenoma. Compared to the basal levels, mean plasma IR-7B2 and GH levels significantly decreased, until 5 and 10 h respectively after the administration of SMS 201-995. The mean (+/- SEM) nadir levels of plasma IR-7B2 and GH were 68.1 +/- 10.1 and 13.1 +/- 6.9%, respectively, compared to mean plasma levels before treatment (100%). Plasma IR-7B2 as well as GH levels did not change significantly when saline was administered subcutaneously to three acromegalic patients. In addition, plasma IR-7B2 levels did not change significantly after the administration of SMS 201-995 in normal subjects or in patients with primary hypothyroidism in whom SMS 201-995 induced a decrease of plasma TSH levels. These results strongly suggest that SMS 201-995 has an unequivocal suppressive effect on the synthesis and/or the secretion of 7B2 in human somatotroph adenoma cells.     

THE GROWTH HORMONE RELEASING HORMONE (GHRH) RESPONSE TO A MIXED MEAL IS BLUNTED IN YOUNG ADULTS WITH INSULIN-DEPENDENT DIABETES MELLITUS WHEREAS THE SOMATOSTATIN RESPONSE IS NORMAL

Following a standard mixed meal, plasma concentrations of growth hormone releasing hormone (GHRH), somatostatin (SMS) and growth hormone (GH) were measured every 30 min for 300 min in six young adults with type I insulin-dependent diabetes mellitus (IDDM) and five normal controls. Mean blood glucose concentrations were higher and mean free insulin levels lower in the diabetics compared with controls both in fasting specimens and at all times following the mixed meal. Basal concentrations (mean +/- SEM) of GHRH were similar in diabetic (12.7 +/- 1.8 pg/ml) and control subjects (11.8 +/- 1.1 pg/ml). Following ingestion of the mixed meal, a rise in GHRH was observed in the control subjects maximal between 30 and 240 min (P less than 0.025) but the response was blunted in the diabetics. Mean GHRH concentrations were greater in the controls than in the diabetic subjects at all stages during the test, the maximum difference being noted at 120 mins (P less than 0.04). Basal SMS concentrations and those observed after the mixed meal were similar in diabetic and control subjects. These results indicate that glucose and insulin may play a role in the regulation of GHRH release following a mixed meal but circulating levels of GHRH and SMS are unlikely to be relevant to the abnormal regulation of GH in IDDM.     

Effect of intermittent physiologic hyperglucagonemia on postprandial plasma glucose levels in normal man

The ability of glucagon to impair glucose tolerance has been questioned by studies involving infusion of exogenous glucagon during a glucose load. Since such hormone administration may not reflect the physiologic pattern of glucagon secretion and may result in hepatic downregulation to glucagon, the present experiments have examined the effects of intermittent andogenous hyperglucagonemia (induced by episodic infusion of arginine) on plasma glucose profiles of normal man following ingestion of mixed meals. In control studies following meal ingestion, plasma glucose, insulin and glucagon increased respectively 15–30 mg/dl, 30–60 uU/ml and 25–50 pg/ml. When meals were accompanied by arginine infusions, plasma glucagon responses were augmented three to fourfold (p < 0.05). Amplitudes of glycemic excursions during infusion of arginine (345 ± 40 mg/dl) were significantly augmented compared to those observed in control studies (286 ± 34 mg/dl, p < 0.02). These results indicate that intermittent increases in plasma glucagon within the physiologic range can adversely affect postprandial glucose profiles in normal man despite concomitant hyperinsulinemia and suggest that such hyperglucagonemia may contribute to impaired postprandial glucose tolerance in diabetic individuals in whom insulin secretion is deficient.     

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs

The acute GH inhibitory effects of 50 micrograms SMS 201-995, a somatostatin analog, and 2.5 mg bromocriptine were compared in 17 acromegalic patients. SMS 201-995 suppressed plasma GH levels after 2-6 h to 5 micrograms/liter or less in 10 of these 17 patients, while bromocriptine did the same in only 5 of them. There was much variation in the responsiveness to both drugs in these patients, but the GH-lowering effect of 50 micrograms SMS 201-995 was significantly greater than that of 2.5 mg bromocriptine. SMS 201-995 and bromocriptine together significantly suppressed plasma GH levels in 2 of 3 acromegalic patients who were insensitive to both compounds when tested separately. We conclude that most acromegalic patients respond better to SMS 201-995, while a few patients are more sensitive to the GH-lowering effect of bromocriptine. In addition, the combination of SMS 201-995 and bromocriptine can be of value in a few acromegalic patients who do not respond to either drug alone.     

CONTINUOUS SUBCUTANEOUS PUMP INFUSION OF SOMATOSTATIN ANALOGUE SMS 201-995 VERSUS SUBCUTANEOUS INJECTION SCHEDULE IN ACROMEGALIC PATIENTS

Diurnal serum GH patterns were determined in 10 acromegalic patients before treatment, after 3 d continuous s.c. pump infusion and then after 3 d with three equal daily s.c. injections in both instances totalling 100 μg/24 h. Subcutaneous injections (33 μg) induced impressive suppression of serum GH lasting 3-6 h in eight patients followed by escape to pretreatment values before the next injection. In contrast, continuous infusion resulted in greater and more stable 24 h suppression to the levels reached at the nadir between injections. Suppression of mean 24 h serum GH below 5 ng/ml was achieved by pump treatment in four patients, while two patients had mean values between 5 rig/ml and 10 ng/ml. In four patients occasional or all levels were above 10 ng/ml (24 h average 12.4-102 ng/ml) implying either that adequate suppression by the SMS 201-995, was impossible during the 3 d pump infusion period, or that the dose administered was inadequate. Carbohydrate tolerance was unaffected in either regimen, indicating that reduction in insulin antagonistic hormones balanced inhibition of insulin release. Interestingly, and in contrast to somatostatin, SMS 201-995 did not inhibit TSH release. No untoward effects were observed at the moderate dosage and blood clinical chemistry was unchanged. Fairly constant diurnal serum SMS 201-995 values were obtained during pump infusion, while levels undulated inversely with serum GH during injection treatment. Average diurnal serum somatostatin-C immunoreactivity (all patients) decreased from 496 ± 129 (mean ± SD) to 385 ± 100 ng/ml ( P < 0 003) during pump treatment and did not decrease further during the following 3 d injection treatment (363 ± 76 ng/ml).