Circulating Somatostatin Levels Research Articles

The therapeutic effect of the neuropeptide hormone somatostatin on Schistosoma mansoni caused liver fibrosis

BackgroundThe neuropeptide somatostatin is one of the major regulatory peptides in the central nervous system and the digestive tract. Our recent work has delineated an association between fibrosis and low levels of endogenous somatostatin plasma levels in Schistosoma mansoni infected subjects. Based on these results this paper explores the therapeutic potential of somatostatin in a mouse model of hepatic fibrosis associated with S. mansoni infections.MethodsGroups of outbred Swiss mice were infected with 100 S. mansoni cercariae, infection maintained till weeks 10 or 14, and then somatostatin therapy delivered in two regimens – Either a one or a two-day treatment. All animals were sacrificed one week after therapy and controlled for liver, spleen and total body weight. Circulating somatostatin levels in mice plasma were measured at the time of sacrifice by means of a radio-immuno assay. GraphPad Prism® was used for statistical calculations.ResultsSomatostatin administration showed little toxicity, probably due to its short half-life. Total liver and spleen weights of S. mansoni infected animals increased over time, with no changes observed due to somatostatin therapy. Total body weights were decreased after infection but were not affected by somatostatin therapy. Snap frozen liver sections were stained with haematoxylin-eosin or Masson's trichrome to study parasite count, hepatocyte status, granuloma size and cellularity. After somatostatin treatment mean egg counts per liver section (43.76 ± 3.56) were significantly reduced as compared to the egg counts in untreated mice after 10 weeks of infection (56.01 ± 3.34) (P = 0.03). Similar significant reduction in parasite egg counts were also observed after somatostatin treatment at 14 weeks of infection (56.62 ± 3.02) as compared to untreated animals (69.82 ± 2.77)(P = 0.006). Fibrosis was assessed from the spectrophotometric determination of tissue hydroxyproline. Infection with S. mansoni caused increased hydroxyproline levels (9.37 ± 0.63 μmol at wk10; 9.65 ± 0.96 μmol at wk14) as compared to uninfected animals (1.06 ± 0.10 μmol). This significant increase in collagen content (P = 0.01; 0.007 respectively) marks the fibrosis observed at these time points. Treatment with somatostatin resulted in a significant decrease in hydroxyproline levels both at wk10 (4.76 ± 0.58 μmol) and at wk14 (5.8 ± 1.13 μmol) (P = 0.01; 0.03 respectively). Endogenous somatostatin levels were increased at wk10 (297 ± 37.24 pg/ml) and wk14 (206 ± 13.30 pg/ml) of infection as compared to uninfected mice (119 ± 11.99 pg/ml) (P = 0.01; 0.008 respectively). Circulating somatostatin levels in infected animals were not significantly affected by somatostatin treatment. Hepatocyte status remained unaltered and granulomas were not remarkably changed in size or cellularity.ConclusionOur experiments reveal an antifibrotic effect of somatostatin in schistosomiasis. We have previously shown that the somatostatin receptors SSTR2 and SSTR3 are present on the parasite egg and worms. We therefore hypothesize that somatostatin reduces either the number of parasite eggs or the secretion of fibrosis inducing-mediators. Our data suggest somatostatin may have therapeutic potential in S. mansoni mediated liver pathology.

Elevated circulating somatostatin levels in acromegaly.

GH increases hypothalamic somatostatin (SS) synthesis and secretion but it is unknown if chronic GH excess, as found in acromegaly, may influence circulating SS levels, that are mainly of enteropancreatic source and affect several gastrointestinal functions, including motility. Circulating SS occurs in several post-translational forms including somatostatin-14 (SS-14), somatostatin-28 (SS-28) and other small peptides. The aim of the present study was to characterize the fasting and postprandial pattern of plasma circulating somatostatin in normal subjects and patients with acromegaly. Fasting total SS and SS-28 levels were measured in 32 subjects, 16 acromegalic patients with a new diagnosis (A) (8 F, 8 M, median age 48) and 16 matched healthy volunteers (C) (8 F, 8 M, median age 45). SS was also determined after a standard solid-liquid meal (550 kCal) in 24 of the subjects (12 C and 12 A). Fasting SS and SS-28 were significantly higher in acromegalic patients as compared to healthy subjects. In the former, a positive correlation was found between IGF-I and SS levels (r = 0.525 p < 0.05). Furthermore, the ratio between SS (as pmol equivalent SS-14/I) and SS-28 was higher in the acromegalic patients than in the controls (3.4 +/- 2.1 vs 2.0 +/- 1.6, p < 0.05). The postprandial SS peak, as well as the incremental area above baseline values, was similar in the patients and controls. In conclusion, fasting but not postprandial hypersomatostatinemia, mainly due to an increase in SS-14, characterizes acromegaly. Excess GH/IGF-I could be a causal factor in somatostatin hypersecretion. Conceivably this abnormality might play a role in some alterations of gastrointestinal function of acromegalic patients such as prolonged bowel transit.

Somatostatin infusion suppresses GH secretory burst frequency and mass in normal men

In attempting to elucidate the neuroendocrine mechanisms that regulate pulsatile growth hormone (GH) secretion, we measured serum GH concentrations by an ultrasensitive immunofluorometric method in blood collected every 10 min for 8 h in 11 young healthy male volunteers (age range 21-31 yr) before and during somatostatin (SS) administration (an iv bolus dose of 350 micrograms followed by a continuous infusion at the rate of 6 micrograms.kg-1.h-1, which increases the circulating SS levels to approximately 570 pg/ml). Pulsatile GH secretion was analyzed using the computer-assisted pulse detection program cluster method and deconvolution analysis. The area and frequency of GH peaks were significantly reduced during SS infusion compared with basal values, but detectable pulsatile episodes were still present. These data suggest that, in adult males, SS controls pulsatile GH secretion and can decrease the mass and frequency of GH secretory bursts.

Hypersomatostatinaemia in duodenal ulcer

Abstract A sensitive and specific radioimmunoassay of serum somatostatin has been developed that overcomes the problems encountered in earlier assays of peptide disintegration and the need for prior plasma extraction, which is known to result in artifactual loss of somatostatin. In 37 normal controls, a significant positive correlation between fasting serum gastrin and somatostatin concentrations, and a significant negative correlation between pentagastrin‐stimulated maximal acid output and fasting serum somatostatin levels were observed. In the majority of 134 patients with active duodenal ulcer in whom the fasting serum somatostatin levels were normal, these relationships were absent. In the remaining 25% in whom the fasting serum somatostatin levels were abnormally raised, these relationships were retained. Following a mixed meal, circulating somatostatin levels remained unchanged in controls and patients as a group. These results suggest that: (i) in the normal state, fasting levels of circulating gastrin and somatostatin are closely related, and that acid secretion may paradoxically exert an inhibitory effect on fasting somatostatin levels; (ii) hypersomatostatinaemia identifies a subgroup of patients with duodenal ulcer in whom these relationships are retained; and (iii) somatostatin may not have a significant hormonal role in the postprandial state in man.

Effects of short-term and prolonged infusions of somatostatin on endocrine pancreas, body weight and food intake in rats.

Infusion of cyclic somatostatin (700 mg/kg/min) for 4 h in rat fed and libitum suppressed basal insulin but not glucagon release. It was accompanied by hypoglycemia during the first hour whereas, at the end of the infusion, hyperglycemia was present. The same dose of somatostatin applied 60 min prior to and during a 30 min load of glucose or arginine significantly inhibited their effects on insulin and glucagon release. In contrast, when this dose of somatostatin was given during a 24 h period by the i.v. route it did not inhibit glucose induced insulin release though circulating somatostatin levels were constantly and markedly elevated. Furthermore, in rats continuously infused with somatostatin for 4 days, no effect was found either on plasma concentrations of glucose, insulin, glucagon, growth hormone and cyclic AMP, or on body weight gain, food consumption or water intake. The pancreases of these animals showed normal concentrations of insulin and glucagon and a normal nuclear area of D-cells. Our experiments demonstrate that, in short-term experiments in rats, somatostatin influences insulin and glucagon release as well as glucose homeostasis. Furthermore, they suggest that during prolonged i.v. administration of somatostatin, rats develop mechanisms counteracting the effect of the peptide, e.g., peripheral tachyphylaxis.

IMMUNOREACTIVE SOMATOSTATIN CHANGES DURING INSULIN‐INDUCED HYPOGLYCAEMIA AND OPERATIVE STRESS IN MAN

Little is currently known about the factors controlling somatostatin secretion. A radioimmunoassay has been developed that is sufficiently specific and sensitive to be used for physiological studies of circulating levels in man. During insulin-induced hypoglycaemia a rise in plasma somatostatin was seen in each of ten subjects studies. Although this paralleled the rise in circulating glucagon and growth hormone, no individual relationships were found either between these variables or to any change in cortisol or insulin C-peptide. In contrast no rise in somatostatin was seen during surgical stress. Thus, contrary to expectation, circulating somatostatin levels can be altered by metabolic stimuli. It seems likely that this peptide may serve an endocrine as well as a paracrine role since its modulating effects may occur not only near to but also at a distance from the site of secretion. It is not yet clear whether the somatostatin measured comes from the hypothalamus, any other part of the central nervous system or the gastrointestinal tract.

Enzymatic degradation of somatostatin by rat plasma and hypothalamus.

A highly sensitive and specific radioimmunoassay for somatostatin has been used to study inactivation of the neurohormone by plasma and hypothalamic peptidase(s). Specificity of the inactivation process was indicated by the absence of interference by addition of luteinizing hormone releasing hormone, thyrotropin-releasing hormone, oxytocin, or substance P. The inactivating ability of hypothalamic tissue and plasma was destroyed by heating and the protease inhibitor benzamidine prevented plasma activity, thus suggesting the enzymatic nature of the processes involved. The present data suggest that the inactivation of somatostatin by hypothalamus and plasma could be an important factor in the regulation of circulating somatostatin levels.