Plasma Somatostatin Research Articles

Mutual Priming Effects of GHRH and Arginine on GH Secretion: Informative Procedure for Evaluating GH Secretory Dynamics.

To establish a single and reliable test for evaluating GH secretion, we examined successive GH provocation by two agents with different modes of action: GHRH and arginine (Arg). In 4 normal subjects, a bolus injection of 50 micrograms of GHRH followed by 0.5 g/kg Arg infusion after 90 min evoked two GH peaks and the priming of the GHRH potentiated Arg-induced GH peak by 88% of that by Arg alone. In contrast, Arg pretreatment suppressed the GHRH-induced GH peak to a level of 15%. This inhibitory effect of Arg priming was not recovered by an increase in the GHRH dose (100 micrograms) or by prolongation of the GHRH injection period to 180 min. During Arg infusion, plasma somatostatin (SRIH) was significantly reduced and there was a linear correlation between Arg-induced GH peaks and basal TSH levels. This suggests that GH release by Arg is mediated by suppression of hypothalamic SRIH. One subject showed a blunted GH peak in response to GHRH but a normal peak in response to Arg repeatedly, suggesting an endogenous hypertonicity of SRIH. In 4 other normal subjects, the effect of endogenous GH fluctuation on the GHRH-Arg test was examined in the morning, afternoon and evening. The GH secretory profile was fairly consistent in individuals, but in 2 of them, GH response to GHRH was exaggerated in the evening and Arg-unresponsiveness ensued. This potentiation of GH release appears to be due to an increase in endogenous GHRH secretion or a decrease in SRIH tone. The GHRH-Arg test is therefore able to evaluate GH secretory dynamics through two major mechanisms, GHRH stimulation and SRIH inhibition in a single procedure, reducing the incidence of false negative GH response to Arg.

Study of Somatostatin in Simple Obesi y

C-peptide, as a marker for pancreatic beta cells function, and somatostatin (SS) in plasma of obese males (n = 15) and a corresponding normal-weight control subjects (n = 10) are studied in this work. Fasting plasma SS and serum C-peptide are significantly higher in obese vs lean group, this can be explained by hypertrophy of both D- and B-cells of the pancreatic islets reported by other investigators. Post-prandial plasma SS in insignificantly increased in obese vs the control group wheres the increase in C-peptide levels is significant suggesting unequal response of B- and D-cells to meal in the obese group. We concluded that circulating SS may play important role in development of obesity. Hyperinsulinaemia, documented in obesity may be due to hypersecretion of insulin (marked by rise of serum C-peptide in this work), and this may contribute to increased somatomedin-C in obesity.

Morphometry and Function of Islet Cells after Different Forms of Drainage at Pancreatic Transplantation in Rats

The survival of endocrine cells of the islets is crucial for a successful transplantation of the pancreas in the treatment of diabetes mellitus. In the present investigation, we compared the effect of four techniques of whole pancreas transplantation in rats on the endocrine cells of islets of Langerhans. Impairment of the endocrine function of the pancreas with a decrease in the k value was seen after 6 months in the group with duct ligation, and after 12 months in the groups with latex and ethibloc occlusion. An open pancreatic duct maintains a more stable endocrine function than in duct-ligated or occluded grafts. Fasting plasma insulin and somatostatin were elevated in transplanted rats. Whichever method of transplantation we chose, the cell ratio remained unchanged compared with the control group, even after 12 months. Therefore, only intact islet architecture enables a normal endocrine pancreatic function.

Effect of rioprostil, a methylprostaglandin E1 analog, on basal and stimulated plasma pancreatic hormone levels in man

The effect of rioprostil, a methylprostaglandin E1 analog on circulating pancreatic hormones was evaluated in 13 healthy male subjects. Rioprostil administration, 300 micrograms twice daily resulted in a significant decrease of fasting insulin, C-peptide, glucagon, and pancreatic polypeptide. No change in fasting plasma glucose or somatostatin levels was observed. An oral glucose tolerance test induced similar increments in plasma glucose concentration before and during treatment, but a delayed rise of insulin and C-peptide levels occurred during the administration of the drug. On rioprostil, the glucose load no longer inhibited peripheral glucagon or somatostatin. Treatment with rioprostil remained without effect on mixed meal-induced changes in plasma glucose levels and concomitant increases in insulin, pancreatic polypeptide, and somatostatin levels. It is concluded that in healthy individuals rioprostil influences the basal and glucose-induced levels of glucagon, insulin, and somatostatin. In healthy men this effect did not, however, result in glucose intolerance.

Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs

The influence of acoustic stress on postprandial gastrointestinal motility, gastric emptying, and plasma gastrin, pancreatic polypeptide, motilin, and somatostatin was evaluated in conscious dogs. Six dogs were equipped with strain-gauge transducers and were exposed from 1–3 h after the meal to prerecorded music (80–90 dB broad frequency noise), which produced a significant (p ≤ 0.05) lengthening of the gastric (31.2%) and jejunal (37.0%) postprandial pattern. In 4 other dogs with gastric cannula, a 2-h session of acoustic stress beginning just after eating a radiolabeled standard meal induced a slowing of gastric emptying of both liquid (45.7%) and solid (47.1%) phases of the test meal when measured 0.5 h after feeding. In contrast, when measured 2 h after feeding, similar values of gastric emptying of liquids and solids were observed in stressed and control animals. Compared with controls, the postprandial increases of plasma gastrin and pancreatic polypeptide levels were significantly enhanced in stressed animals and occurred early (15 min after the meal). Although postprandial decrease in plasma motilin was unchanged by acoustic stress, the rise in plasma somatostatin level was significantly (p ≤ 0.05) prolonged in stressed dogs. These results indicate that acoustic stress affects gastric and intestinal postprandial motility in dogs, delaying the recovery of the migrating motor complex pattern, inducing a transient slowing of gastric emptying, and enhancing the feeding-induced release of gastrin, pancreatic polypeptide, and somatostatin. Such hormonal changes might be due to a direct effect of stress rather than being the consequence of acoustic stress-induced slowing of gastric emptying.

Relationship between gastric acid and elevated plasma somatostatinlike immunoreactivity after a mixed meal

The aim of this study was to examine whether hydrochloric acid plays a role mediating the postprandial increase in plasma somatostatinlike immunoreactivity in normal subjects. Intravenous infusion of cimetidine was found to reduce by 45% the postprandial increment in plasma somatostatin-like immunoreactivity. This effect was reversed by concomitant intragastric administration of 0.1 N hydrochloric acid, which in previous studies in fasted subjects had not affected plasma somatostatinlike immunoreactivity. The effects of cimetidine on postprandial plasma gastrin were the inverse of those observed on postprandial somatostatin. There was a greatly enhanced increment in postprandial plasma gastrin during cimetidine infusion, which was reduced significantly toward control levels by concomitant intragastric infusion of hydrochloric acid. To exclude direct inhibition by cimetidine of nutrient-stimulated plasma somatostatinlike immunoreactivity we studied the effect of cimetidine on plasma somatostatinlike immunoreactivity stimulated by an intraduodenal infusion of fat. Cimetidine did not alter the incremental response of somatostatinlike immunoreactivity to intraduodenal fat infusion. These data show that cimetidine does not invariably reduce nutrient-stimulated plasma somatostatinlike immunoreactivity and are consistent with the hypothesis that the action of cimetidine in reducing the plasma somatostatin response to ingestion of a meal is a consequence of reduction of postprandial acid secretion. These data suggest that the postprandial elevation in plasma somatostatin observed in humans is mediated in part through postprandial secretion of gastric acid, which in turn acts to elevate plasma somatostatin.

Enprostil reduces the increase of gastric corpus mucosal mass induced by the hydrogen-potassium-stimulated adenosine triphosphatase inhibitor BY 831-78 in the rat

We studied whether enprostil, a synthetic prostaglandin E2 derivative, might inhibit gastrin release and the trophic effects on gastric oxyntic mucosa induced by prolonged treatment with an inhibitor of hydrogen-potassium-stimulated adenosine triphosphatase, the substituted benzimidazole BY 831-78. Rats were treated intragastrically with enprostil (1 or 15 μg/kg b.i.d.), BY 831-78 (15 μmol/kg once daily), the combination of enprostil and BY 831-78, ranitidine (300 μmol/kg b.i.d.), and placebo. Plasma gastrin and somatostatin levels and gastric acid secretion were measured during a 1-day treatment in animals fitted with chronic gastric fistulas and repeatedly during 9 wk of treatment in intact rats. Despite inhibiting acid secretion, enprostil did not increase plasma gastrin. When combined with BY 831-78, enprostil transiently reduced the BY 831-78-induced increase of integrated plasma gastrin (1375 ± 206 vs. 2137 ± 256 pmol/L · 12 h, p < 0.05) in fasted rats with fistulas, but failed to prevent the marked hypergastrinemia following 9 wk of treatment with BY 831-78 (717 ± 80 vs. 731 ± 56 pmol/L) in intact rats. However, enprostil reduced the BY 831-78-induced increase of oxyntic mucosal volume (458 ± 31 vs. 567 ± 33 mm3, p < 0.01), whereas BY 831-78 prevented the enprostil-induced increase of antrat mucosal volume (42 ± 3 vs. 56 ± 3 mm3, p < 0.01). These results demonstrate that some of the trophic effects induced by a hydrogen-potassiumstimulated adenosine triphosphatase inhibitor are not exclusively governed by gastrin.

Effects of physiological increases in plasma noradrenaline on the human endocrine pancreas

The effect of plasma noradrenaline concentrations within the physiological range (less than 5-6 nM) on the endocrine pancreas was investigated in 9 nondiabetic volunteers. Noradrenaline significantly inhibited plasma insulin levels but did not change plasma glucagon and somatostatin concentrations.

The influence of human corticotropin-releasing hormone on somatostatin secretion in depressed patients and controls

Twenty subjects (10 patients with a major depressive episode and 10 individually matched healthy controls) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an i.v. bolus dose. Healthy subjects and depressed patients exhibited a significant increase of plasma somatostatin (SRIH) concentrations with no difference between both comparison groups. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, while cortisol secretion in response to hCRH was normal. No correlations were found among basal plasma concentrations of SRIH, ACTH or cortisol and SRIH, ACTH or cortisol responses following hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) hyperactivity in the depressive state may primarily be due to central hypersecretion of CRH and support the view of a hCRH-induced SRIH secretion which is not related to HPA dysfunction associated with major depression.

Long-acting somatostatin analog controls acid and gastrin secretion in benign, not in malignant, Zollinger-Ellison syndrome.

The long-acting somatostatin (SMS) analog, SMS 201-995 has beneficial effects on APUDomas. In two Zollinger-Ellison syndrome (ZES) patients we assessed basal acid output (BAO) and 24-h pH under SMS and compared them to controls. We also assessed total gastrin, gastrin 17, insulin, glucagon, C-peptide, and SMS by radioimmunoassay. In the benign gastrinoma, an acid-controlling action of SMS was shown, elevating the 24-h pH threshold over the pH range 1.5-5 of 55-10% compared with control. A parallel inhibition of the gastrins greater than 90% was apparent. We found no beneficial effect on gastric acid secretion and on tumor gastrin in the malignant gastrinoma despite a fourfold higher plasma SMS level. Non-tumor-related peptides were suppressed by approximately 50% and in contrast to gastrin they again reached pre-SMS levels before the next dose of the drug. We conclude that SMS is more effective in benign than in malignant gastrinomas, and may be exclusively so.

Basal and Tolbutamide‐induced Plasma Somatostatin in Healthy Subjects and in Patients with Diabetes and Impaired Glucose Tolerance

Peripheral levels of basal and tolbutamide-induced somatostatin have been measured in patients with diabetes or impaired glucose tolerance (IGT) and compared with those in normal individuals. Basal somatostatin was significantly higher in patients with Type 1 diabetes than in age-matched control subjects. This increase was most pronounced at diagnosis, and appeared to be related to metabolic control in insulin-treated patients. No increase was noted in patients with Type 2 diabetes or with IGT. Intravenous bolus injection of tolbutamide enhanced peripheral somatostatin levels in healthy volunteers in a biphasic manner. Patients with IGT also exhibited a biphasic response but the amplitude of the first phase was higher. No secretory response was detected in 27/29 Type 1 diabetic patients at diagnosis; a somatostatin response to tolbutamide became detectable again in Type 1 patients with normalization of their basal somatostatin levels but was then paradoxically related to poor blood glucose control. In Type 2 diabetes, basal somatostatin levels were similar to age-matched control subjects, but decreased upon intravenous tolbutamide administration.

Differential effect of bombesin on intraluminal and intravascular release of gastric gastrin and somatostatin in anaesthetized rats

The aim of the present investigation was to study how bombesin, gastrin-17, cholecystokinin-8 (CCK-8) and electrical vagal stimulation influence the release of gastrin and somatostatin into the gastric lumen. Bombesin (3 and 30 nmol kg-1 h-1), gastrin-17 and CCK-8 (10 nmol kg-1h-1) were infused i.v. and vagal stimulations at 5 V, 2 ms, 5 Hz were performed in anaesthetized rats, in which the stomach was perfused with a dextran solution (pH approximately 6 or approximately 1.5). pH, gastrin and somatostatin levels were measured in the perfusate after having passed the stomach. In addition, blood samples were drawn from the jugular vein in the experiments in which bombesin was infused. Gastrin and somatostatin levels were determined with radioimmunoassay, and gastrin- and somatostatin-like immunoreactivity will be referred to as gastrin and somatostatin below. Infusion of bombesin, 3 and 30 nmol kg-1 h-1, did not influence acid secretion as evidenced by an unchanged intraluminal pH. Nor was the intraluminal secretion of gastrin or somatostatin influenced by bombesin, whereas plasma gastrin and somatostatin levels were significantly increased at the higher dose. In contrast, infusion of CCK-8 and gastrin-17 (10 nmol kg-1 h-1), as well as electrical vagal stimulation, significantly decreased the pH and increased the somatostatin levels in the perfusate. Vagal activation in addition increased the gastrin levels. The present results, demonstrating that bombesin influences plasma and perfusate levels of gastrin and somatostatin differently, indicate that intraluminal and intravascular gastrin and somatostatin release may be separately regulated.

Plasma Somatostatin Activity in Medullary Cancer of the Thyroid

In a group consisting of 50 adults and 5 children with diagnosed or suspected medullary cancer of the thyroid, plasma somatostatin levels were measured in 77 samples with a sensitive radioimmunoassay. Only 2 patients had clearly enhanced plasma somatostatin immunoreactivity, both with highly active aggressive tumors. Other patients had plasma somatostatin levels of under 20 ng/l or undetectable ones. No evidence of response of somatostatin levels to pentagastrin stimulation was found.

Maternal and Fetal Endocrine Pancreas in the Spontaneously Diabetic BB Rat

The maternal and fetal endocrine pancreas were investigated in the diabetic BB rat on day 21 of pregnancy. The maternal pancreas of the diabetic rat contained practically no insulin-positive B cells. The A and D cell mass were also decreased, while plasma glucagon and somatostatin levels were normal or increased, confirming previous data. Six of 11 diabetic rats had B-cell-specific surface antibodies (ICSA), whereas only 1 of 10 nondiabetic rats was ICSA-positive. The volume density of insulin-positive cells was decreased in the fetal pancreas of diabetic BB rats compared to fetuses of nondiabetic rats, but the volume density of glucagon- and somatostatin-positive cells remained normal. The B cells of these fetuses were ultrastructurally less granulated and showed signs of increased cellular activity. Plasma insulin levels were decreased while plasma glucagon and somatostatin concentrations were normal. ICSA were not detected in fetuses of nondiabetic and diabetic rats. There were no differences in the histology of the spleen and thymus between both groups of fetuses. Metabolic characterization of the growth-retarded fetuses of diabetic rats revealed, besides lower plasma insulin concentrations, increased branched chain amino acid levels, and normal plasma Sm/IGF-I levels. The main conclusions from this study are: (1) Severe maternal diabetes decreases the pancreatic insulin-positive cell mass and plasma insulin levels in the fetus, but not the A and D cell mass and function; (2) ICSA are not detectable in fetal plasma; (3) the influence of maternal BB rat diabetes on fetal endocrine pancreas and metabolic environment resembles that of severe streptozotocin-induced diabetes.

Plasma somatostatin and vasoactive intestinal polypeptide responses to an oral mixed test meal in obese patients.

Ten obese and 10 control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Blood glucose, insulin, somatostatin (SLI) and vasoactive intestinal polypeptide (VIP) concentrations were determined before and 30, 60, 90, 120, 180 and 240 min after the start of the meal. Basal SLI levels in the obese (14.4 +/- 0.7 ng/l) were not significantly different from those in the controls (15.5 +/- 0.8 ng/l), whereas after the meal a blunted secretory response was recorded. Baseline plasma VIP levels were higher in the obese (29.7 +/- 1.5 ng/l) than in the control subjects (19.8 +/- 1.3 ng/l) and, similarly to the controls, were unaffected by meal ingestion. Data suggest that in the course of obesity an enhanced VIP secretion in association with a diminished SLI responsiveness to meals occurs.

Sleep patterns in the genetically obese Zucker rat: effect of acarbose treatment.

Sleep patterns were continuously recorded in the genetically obese Zucker rat. Under normal feeding conditions, Zucker rats showed large amounts of slow-wave sleep (SWS) and normal amounts of pardoxical sleep (PS). In addition, both SWS and PS were equally distributed throughout the nychthemeron. When acarbose (an alpha-glucosidase inhibitor that slows absorption of glucose, reduces plasma insulin, and increases plasma somatostatin) was added to food pellets, the daily duration of SWS was markedly decreased, whereas PS was significantly increased. These results clearly show that sleep in the Zucker rat differs substantially from that classically observed in normal lean rats. In addition, they suggest that anomalies of insulin and somatostatin production and/or levels may cause the sleep disturbances observed in Zucker rats.

A Case of Somatostatinoma

Plasma somatostatin response to food and the administration of the long-acting somatostatin analogue SMS 201-995, as well as pituitary responses to insulin-induced hypoglycemia, growth hormone-releasing hormone (GHRH) and thyrotropin-releasing hormone (TRH), were assessed in a 60-year-old woman with biopsy-proven metastatic somatostatinoma. SMS 201-995 alone did not change plasma somatostatin-like immunoreactivity (SRIF), but levels of low-molecular-weight forms (SRIF-14 and SRIF-28) more than doubled in response to a standard meal. This postprandial response was not affected by pretreatment with SMS 201-995. Although a growth hormone response to insulin-induced hypoglycemia and supramaximal GHRH was absent, the patient's thyroid-stimulating hormone response to TRH was normal. These results suggest that somatostatin analogues may not influence tumor autonomy and that a SRIF response to food may contribute to early satiety in patients with somatostatinoma. In addition, the long-term use of somatostatin analogues to suppress hormone production by other peptide-secreting tumors may not have predictable results.

Variations of plasma immunoreactive motilin, pancreatic polypeptide, gastrin and somatostatin along the duodenal motility cycle in the pig

The peripheral plasma concentrations of immunoreactive motilin, pancreatic polypeptide (PP), somatostatin and gastrin were measured in 7 pigs fasted to 24 h and subsequently fed a standard meal. Plasma motilin peaked during the last part of phase II activity of the migrating myoelectric complex (MMC) sequence (25.2 ± 2.3 pM), the lowest value being recorded during phase I (10.6 ± 1.5 pM) after a 24 h fast. Plasma motilin remained at a low level during the digestive pattern of duodenal activity, no fluctuation occurring when the first postprandial MMC recurred. At variance analysis, gastrin and PP were not released phasically with MMC in the fasting state, while at autocovariance both peptides tended to fluctuate during the MMC sequence with positive and negative peaks at regular intervals along MMC cycles. No variation of plasma somatostatin was observed in the fasting animals. These findings argue against a major role of circulating PP, gastrin and somatostatin-like components in the control of fasted and post absorptive duodenal motility in pigs while the role of motilin remains equivocal.

Calcitonin gene-related peptide: Enteric and cardiovascular effects in the dog

We have measured the effects of intravenous infusion of calcitonin gene-related peptide at doses of 2.5, 10, and 50 pmol/kg · min on net jejunal water and solute fluxes and on plasma somatostatin concentrations in dogs. The hemodynamic effects and the pharmacokinetics of the peptide were also assessed. Using the triple-lumen perfusion technique in unsedated restrained animals it was shown that the highest dose of the peptide stimulated a transient net jejunal water and electrolyte secretion, and induced diarrhea in 4 of 6 animals receiving it. The peptide also induced dose-dependent tachycardia, hypotension, and increases in plasma immunoreactive somatostatin. All three doses of calcitonin generelated peptide produced plasma immunoreactive peptide levels within the elevated range previously measured in human patients with medullary thyroid carcinoma. Calcitonin gene-related peptide may have a major role in the pathogenesis of secretory diarrhea in medullary thyroid carcinoma.

Mechanisms of terbutaline-induced inhibition of exocrine pancreatic secretion in humans.

Terbutaline, a selective beta 2-adrenoreceptor agonist, has recently been advocated as a potential agent for treating patients with pancreatic fistulae. In the present study, we attempted to quantify the presumed effects of terbutaline on exocrine pancreatic secretion in humans and to characterize possible mechanisms of action. In six healthy volunteers, the pancreas was stimulated by infusion of graded doses of secretin (15.5-250 ng/kg/h) or by infusion of secretin (15.5 ng/kg/h) plus graded doses of caerulein (3.3-30 ng/kg/h). The experiments were repeated in each subject without and with administration of terbutaline. Pancreatic secretion was assessed by a marker perfusion technique and plasma somatostatin and pancreatic polypeptide (PP) levels by radioimmunoassay. Terbutaline had no significant effect on secretin-stimulated pancreatic secretion, but significantly inhibited caerulein-stimulated pancreatic fluid secretion and trypsin output. Plasma somatostatin and PP levels were not affected by terbutaline. The inhibitory effect required the administration of pharmacologically large doses of terbutaline. We conclude that the weak inhibitory effect of terbutaline on exocrine pancreatic secretion is not mediated via somatostatin nor PP and that our data do not support a major role for beta-adrenergic mechanism as regulator of pancreatic secretion.