Sst2 Receptor Research Articles

The human brain somatostatin interactome: SST binds selectively to P-type family ATPases.

Somatostatin (SST) is a cyclic peptide that is understood to inhibit the release of hormones and neurotransmitters from a variety of cells by binding to one of five canonical G protein-coupled SST receptors (SSTR1 to SSTR5). Recently, SST was also observed to interact with the amyloid beta (Aβ) peptide and affect its aggregation kinetics, raising the possibility that it may bind other brain proteins. Here we report on an SST interactome analysis that made use of human brain extracts as biological source material and incorporated advanced mass spectrometry workflows for the relative quantitation of SST binding proteins. The analysis revealed SST to predominantly bind several members of the P-type family of ATPases. Subsequent validation experiments confirmed an interaction between SST and the sodium-potassium pump (Na+/K+-ATPase) and identified a tryptophan residue within SST as critical for binding. Functional analyses in three different cell lines indicated that SST might negatively modulate the K+ uptake rate of the Na+/K+-ATPase.

T2-signal intensity, SST receptor expression and first-generation somatostatin analogues efficacy predict hormone and tumor responses to pasireotide in acromegaly

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-460 Pasireotide Treatment Inhibits Cytokine Release from Pituitary Adenoma-Associated Fibroblasts: Is This Mechanism Playing a Key Role in Its Effect?

Introduction: Tumour-associated fibroblasts (TAFs) are important elements of the tumour microenvironment (TME) well-studied in several cancers, but their role in pituitary adenomas (PAs) has never been shown. We aimed to study the role of TAFs in PAs and its response to somatostatin analogues (SSA). Methods: TAFs were isolated from 11 freshly-cultured NFPAs and 5 GHomas as confirmed by vimentin and αSMA immunostaining. TAF presence in PAs was confirmed by immunohistochemistry, and further assessed with the gene-signature based method xCELL on a different set of samples. Macrophage infiltration, angiogenesis and epithelial-to-mesenchymal pathways were evaluated by immunohistochemistry for CD68, CD163, HLA-DR, E-cadherin, ZEB1 and CD31. TAFs secretome was assessed in vitro on culture supernatants, at baseline and after treatment with pasireotide (10-7M) using Millipore MILLIPLEX human cytokine 42-plex. GH3 cells were treated with TAF-conditioned media (CM) and normal skin fibroblasts-CM (F-CM). Cell morphology (analysed by ImageJ), invasion and epithelial-to-mesenchymal pathways were assessed. Results: CCL2 and eotaxin-1 were identified as the top secreted cytokines in TAF supernatants, followed by VEGF-A, CCL22, IL-6, FGF-2 and IL-8. TAF secretomes from NFPAs and GHomas did not differ significantly. PAs with cavernous sinus invasion had higher TAF-derived IL-6 levels compared to non-invasive PAs (72.7±10.7 vs 43.9±6.3pg/mL; p=0.027), while there was a trend for TAFs from PAs with higher Ki67 to secrete more CCL2 (p=0.058). Correlation between macrophages and TAF-derived FGF-2 was found (r=0.499, p=0.049), and increased FGF-2 and CXCL1 levels were seen in PAs with a macrophage M2:M1 ratio≥2. CCL2 levels were correlated with microvessel area (r=0.672, p=0.004), whereas PDGF-AA was negatively correlated with E-cadherin immunoreactivity (r=-0.564, p=0.023). RT-qPCR analyses indicated that the sst1 receptor is the predominant somatostatin receptor expressed in TAFs, while sst2 and sst5 receptors are poorly expressed. Pasireotide treatment decreased TAF-derived IL-6 by 80% (p<0.001) and CCL2 by 35% (p=0.038). GH3 cells treated with TAF-CM showed epithelial-to-mesenchymal-like morphology and increased invasiveness in comparison to F-CM or untreated cells, as well as E-cadherin downregulation and ZEB1 upregulation. Conclusions: TAFs are present in the TME of PAs and display a biological role. TAF-derived cytokines may influence tumor and non-tumoral cells (such as macrophages) leading to increased invasiveness, as well as influence angiogenesis and epithelial-to-mesenchymal pathways in PAs, with IL-6 and CCL2 emerging as relevant mediators. The inhibitory effect of pasireotide on TAF secretome highlights a promising anti-tumoral effect of SSAs by directly targeting TAFs and thus modulating the TME in PAs.

SAT-169 Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists Suppress Glucose- and Sulfonylurea-Induced Insulin Secretion in Rats

Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1/30,000 to 1/50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, near-total pancreatectomy may be required. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. Glucagon secretion from α-cells is inhibited through sst2 receptors and insulin secretion from β-cells is inhibited through activation of sst2, sst3, and sst5. The injectable peptide drugs octreotide and lanreotide are potent agonists at sst2 and are often deployed as the last medical intervention to prevent or delay pancreatectomy. These peptides’ sst2 activity leads to inhibition of glucagon secretion, potentially reducing their effectiveness and compromising a key defense mechanism against hypoglycemia. We hypothesize that agonists targeting sst5 but lacking sst2 activity will possess an optimal efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. These compounds also typically possess similar potency for the rat sst5 receptor. To probe their physiological consequences and to gain mechanistic insights, we compared the acute and chronic effects of these agonists to the peptide pasireotide, a pan-sst agonist that is most potent at sst5, on glycemic control in several rat models, which generally demonstrate a high degree of translation to humans. These preclinical studies evaluated the effects of the sst5 agonists during oGTT, ipGTT, sulfonylurea-induced hypoglycemia, and on blood glucose levels in both the fed and fasted states. In each model, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels while having minimal effects on glucagon secretion, as predicted by their in vitro pharmacology. These results support our efforts to develop potent nonpeptide selective sst5 agonists with pharmaceutical and safety profiles suitable for evaluation in human clinical trials.

SAT-260 Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists Suppress Induced Insulin Secretion in Pancreatic Islets from both Rats and Healthy Human Donors

Hyperinsulinemia is a heterogeneous condition in which dangerously low blood sugar levels are caused by improperly regulated insulin secretion from pancreatic ß-cells. The most severe form of hyperinsulinemia arises from congenital hyperinsulinism (CHI), a set of genetic disorders in which the underlying pathology is driven by mutations in key genes that regulate insulin secretion. CHI is the most common cause of persistent hypoglycemia in newborns and infants, and prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. The neuropeptide somatostatin is an important modulator of hormonal signaling from the pancreas mediated by different somatostatin receptor (sst) subtypes. Glucagon secretion from α-cells is inhibited through sst2 receptor activation and insulin secretion from β-cells is inhibited through sst2, sst3, and sst5. The injectable peptide drugs octreotide and lanreotide are primarily agonists at sst2 and are often prescribed for these patients in an attempt to reduce insulin secretion, but their efficacy is limited, and they carry the risk of impairing glucagon secretion, an important defense mechanism against hypoglycemia. We hypothesize that an orally available selective sst5 agonist may be a useful new approach to managing hyperinsulinemia. We launched an iterative medicinal chemistry program that led to the discovery of selective sst5 agonists, with multiple nonpeptide series possessing EC50s < 1 nM in cell-based assays of receptor activation (these compounds also routinely possess similar potencies for the rat sst5 receptor). We have shown that these sst5 agonists potently suppress insulin and raise plasma glucose in multiple glycemic studies in rats. To explore the mechanism of selective sst agonism and its translation from rat studies to humans, we undertook a series of studies using pancreatic islets isolated from human donors and from naïve Sprague Dawley rats. Selective sst5 agonists were compared to selective sst2 and selective sst3 agonists as well as somatostatin peptides for their capacity to suppress insulin and/or glucagon from islets under various conditions including increasing glucose concentrations and the presence of a sulfonylurea (the increased insulin secretion mimics many CHI patients). In both human and rat islets, we found that selective sst5 agonists potently suppressed insulin secretion more effectively than selective sst2 or sst3 agonists, while having little effect on glucagon secretion, demonstrating their potential efficacy in the human condition. These studies support our program to identify and develop potent nonpeptide selective sst5 agonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials.

SAT-LB076 T2-Signal Intensity, SST Receptor Expression and First-Generation Somatostatin Analogues Efficacy Predict Hormone and Tumor Responses to Pasireotide in Acromegaly

Background: Previous studies indicate that PAS-LAR can achieve control of insulin-like growth factor I (IGF-I) levels and may reduce tumor size, however a subset of acromegaly patients responds poorly. T2-signal intensity, somatostatin receptor (SST) subtype 2 and 5 expression, and the response to first-generation somatostatin receptor ligands (SRLs) are recognized predictors of therapy response. Valid prediction of the response to PAS-LAR can alter treatment stratification. Aim: To analyze T2-signal intensity and SST receptor expression in relation to the hormone and tumor response during PAS-LAR treatment, and to determine to what extent this equals SRLs responsiveness. Methods: We included 45 patients initially receiving SRLs, followed by a combination therapy including pegvisomant, and finally treated with PAS-LAR. The hormone response to PAS-LAR was evaluated using IGF-I (x ULN) levels at 24 weeks. T2-weighted MRI signal intensity of the adenoma was visually assessed and quantified by region of interest measurement. A tumor volume change of ≥25% from baseline was considered significant. SST receptor expression in adenomas was evaluated in 13 out of 45 patients using a validated immunoreactivity score (IRS). The clinical characteristics and the hormone and tumor response to PAS-LAR were assessed using multivariable regressions. Results: Patients with the lowest percentage IGF-I (x ULN) reduction during SRLs also showed weak IGF-I (x ULN) control during PAS-LAR and, however, more significant tumor shrinkage (r=0.41, p=0.006; p=0.036). Lower IGF-I (x ULN) levels during PAS-LAR were associated with higher T2-signal intensity and less significant tumor shrinkage (ß=-0.29, p=0.045; ß=0.34, p=0.035). With regards to tumor response, adenoma volume at baseline was associated with higher random GH levels at diagnosis and greater absolute tumor shrinkage during PAS-LAR (ß=69, p=0.0018; ß=1.05, p=0.020). Significant tumor shrinkage was associated with female patients, higher IGF-I (x ULN) levels during PAS-LAR and borderline significant with non-hypointense adenomas at baseline (OR=6.35, 95% CI=1.42-36.4; OR=13.2, 95% CI=2.14-129.1; OR=5.97, 95% CI=0.91-65.5 respectively). Lower IGF-I (x ULN) levels after PAS-LAR correlated with higher (r=-0.68, p=0.011; r=-0.52, p=0.083), while significant tumor shrinkage correlated with lower SST2 levels as well as SST2/SST5 ratio expression (p=0.040; p=0.024). Conclusions: Patients not responding to somatostatin analogs with particularly large adenomas, low SST2 receptor expression and higher T2-signal intensity are more prone to show tumor shrinkage during PAS-LAR than patients with high SST2 receptor expression and T2-hypointense adenomas. Surprisingly, tumor shrinkage is not accompanied by lower IGF-I (x ULN) levels, which are associated with a high SST2 receptor expression and a higher T2-signal intensity. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-459 ONO-5788, a Novel Oral Small Molecule Somatostatin Receptor Type-2 (SST2) Agonist, Attenuates GH Hypersecretion in Human GH-Secreting, Pituitary Adenoma-Derived Cells

Somatostatin receptor ligands (SRL) and GHR antagonists are used for persistent or recurrent acromegaly following noncurative surgery and as primary therapy for patients unsuitable for surgery. We tested in vitro action of a novel oral SRL compound ONO-5788 and its active metabolite (ONO-ST1-641) which signals via SST2. With IRB approval and informed consent, 12 human somatotroph adenomas, obtained at transsphenoidal resection were cultured. In the 1st cohort, 8 somatotroph adenomas were treated with ONO-ST1-641 (0, 100, 1000 nM) and octreotide (OCT, 100 nM) for 24 h, and media collected at 2, 6, and 24 h respectively to assess GH and PRL concentrations by ELISA. Cells harvested at 24 h were used to measure mRNA levels of SST2 and SST5, hormone genes and cell cycle genes CDKN1A, CDKN1B by qPCR. Three of 8 tumors (38%) responded to ONO-ST1-641 and OCT as early as 2 and 6 h. GH was significantly reduced by OCT (18% to 58% reduction, P<0.05) and similarly attenuated by ONO-ST1-641 (28 to 59% reduction, P<0.05). GH secretion in 6 of 8 tumors (75%) was decreased at 24 h, showing reduction by OCT and ONO-ST1-641 by up to 48% (P<0.01) and 50% (P<0.01), respectively. PRL levels were undetectable, very low or unchanged by treatments. Related compound ONO-5788 showed similar responses. SST2 and SST5 expression was unchanged during treatments in the 6/8 responders as assessed by TaqMan qPCR using HPRT1 and GAPDH as controls. Neither was GH, PRL, CGA, CDKN1A and CDKN1B mRNA expression altered by ONO-ST1-641 or OCT for 24 h, as assessed by SYBR qPCR using RPL13A, GAPDH and 18S as controls, suggesting that ONO-ST1-641 did not affect these hormone genes and cell cycle regulator mRNA levels. In the 2nd cohort, pretreatment baseline SST2 and SST5 expression were assessed in 4 cultured tumors treated with ONO-ST1-641 (0, 100, 1000 nM) or OCT (100 nM) for 6 h. Untreated tumor cell mRNA was extracted at baseline to assess SST2 and SST5 expression and GH and PRL measured at 6 h. Two of 4 tumors were unresponsive to both ONO-ST1-641 and OCT, 1 showed mild GH reduction by ONO-ST1-641 (15%) but not by OCT. Notably, 1 specimen expressing highly abundant baseline SST2 exhibited marked GH suppression by ONO-ST1-641 and OCT at 6 h (63 and 62%, respectively, P<0.01). High baseline SST2 expression further validated by Western blot and confocal immunofluorescence, imply that SST receptor expression associates with ONO-ST1-641 responsiveness. Available SRLs and GHR antagonists are parenteral, requiring lifelong injection, with variable and suboptimal efficacy, necessitating development of novel oral small molecule drugs for acromegaly. Our study provides preclinical evidence that ONO-5788 and its active metabolite attenuate GH hypersecretion in primary somatotroph adenoma cells cultures, suggesting the potential application of ONO-5788 for acromegaly patients.

Protective Role of the Somatostatin Receptor Subtype 4 in the Indomethacin‐Induced Gastrointestinal Mucosal Injury Model

Since gastrointestinal ulceration is still associated with high mortality despite advancements in the endoscopic and pharmacological management, precise understanding of the mucosal defensive and protective mechanisms is important. The neuropeptide somatostatin is present in the endocrine cells and sensory nerves, is analogues were shown to reduce mucosal blood flow, pepsin and gastric acid secretion. Its endocrine functions are mediated by the receptors sst2,3,5, and our group discovered that the anti‐inflammatory and analgesic actions are exerted via the sst4 receptor. Sst4 agonists are preclinically tested as novel drug candidates in theses areas. Therefore, we investigated the role of sst4 in gastrointestinal injury.Sst4 gene‐deleted (sst4 −/−) mice and wildtype counterparts (sst4 +/+) were treated s.c. with 35 mg/kg indomethacine (IDM) or its vehicle. Macroscopic and microscopic mucosal lesions in the stomach and small intestine were evaluated by the ImageJ program and semiquantitative histopathological scoring after 4 and 48 h, respectively. Small intestinal length, thymus, adrenal glands, spleen weight and plasma glucose levels were measured. Neutrophil myeloperoxidase (MPO) activity and plasma extravasation were measured by bioluminescent/fluorescent ex vivo imaging after 24 h.Macroscopic lesion area and MPO activity in the gastric mucosa were significantly greater in IDM‐treated sst4−/− mice than in wildtypes 4 h and 24 h after IDM administration, respectively. Similar tendency was observed in the duodenum and jejunum even after 48 h. However, IDM did not induce mucosal plasma extravasation in either group at the 24 h timepoint. Thymus weight was significantly less in sst4−/− mice than in sst4+/+ ones. Histopathological scores, small intestinal length, adrenal and spleen weight, and plasma glucose level were not altered by the sst4 deletion.These results provide evidence for a protective role of the sst4 receptor against chemical injury‐induced gastrointestinal mucosal damage. This shows the safety of sst4 agonist drug candidates in the gastrointestinal tract, and even highlights their potential use for gastroprotective indication.Support or Funding InformationGINOP‐2.3.2‐15‐2016‐00050 – PEPSYS, GINOP‐2.3.2 STAY ALIVE, EFOP‐3.6.2‐16‐2017‐00008, ÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Somatostatin-Mediated Changes in Microtubule-Associated Proteins and Retinoic Acid-Induced Neurite Outgrowth in SH-SY5Y Cells.

Somatostatin (SST) is a growth hormone inhibitory peptide involved in regulation of several physiological responses of cells including neurotransmission, cell migration, maturation, and neurite formation. In the present study, we examined the role of SST in all-trans retinoic acid (RA)-induced progression of neurite outgrowth in SH-SY5Y cells. We also determined the morphological and developmental changes in prominent intracellular markers of neurite growth including microtubule-associated protein 2 (MAP2), neuron-specific III β-tubulin (TUJ1), and Tau. Here, we present evidence that SST is a molecular determinant in regulating the transition of SH-SY5Y cells from non-neuronal entity to neuronal phenotype in response to RA. The results from present study reveal that SST changes the distributional pattern of MAP2/Tau and TUJ1, and activates extracellular signal-regulated kinase (ERK1/2) signaling pathway through SST receptors (SSTRs). The expression of MAP2 and Tau remains elevated upon treatment with RA and SST alone or in combination. Importantly, we identified that the cells displaying strong co-expression of SST and TUJ1 are more likely to bear elongated neurite formation than cells devoid of such expression. These findings show that the site-specific expression of MAP2 and TUJ1 is an essential determinant of neurite outgrowth in SH-SY5Y cells in RA-mediated differentiation. Taken together, results presented here further substantiates the role of SST in the promotion of neurite formation and elongation in SH-SY5Y cells in combination with RA. Investigating how SST can improve neurite formation in neurodegenerative disease may help to develop new therapeutic approach in improving cognitive function and memory loss.

A Novel Role for Somatostatin in the Survival of Mouse Pancreatic Beta Cells.

Cross-talk between different pancreatic islet cell types regulates islet function and somatostatin (SST) released from pancreatic delta cells inhibits insulin secretion from pancreatic beta cells. In other tissues SST exhibits both protective and pro-apoptotic properties in a tissue-specific manner, but little is known about the impact of the peptide on beta cell survival. Here we investigate the specific role of SST in the regulation of beta cell survival in response to physiologically relevant inducers of cellular stress including palmitate, cytokines and glucose. Pancreatic MIN6 beta cells and primary mouse islet cells were pre-treated with SST with or without the Gi/o signalling inhibitor, pertussis toxin, and exposed to different cellular stress factors. Apoptosis and proliferation were assessed by measurement of caspase 3/7 activity, TUNEL and BrdU incorporation, respectively, and expression of target genes was measured by qPCR. SST partly alleviated upregulation of cellular stress markers (Hspa1a and Ddit3) and beta cell apoptosis in response to factors such as lipotoxicity (palmitate), pro-inflammatory cytokines (IL1β and TNFα) and low glucose levels. This effect was mediated via a Gi/o protein-dependent pathway, but did not modify transcriptional upregulation of the specific NFκB-dependent genes, Nos2 and Ccl2, nor was it associated with transcriptional changes in SST receptor expression. Our results suggest an underlying protective effect of SST which modulates the beta cell response to ER stress and apoptosis induced by a range of cellular stressors associated with type 2 diabetes.

Evaluation of expression of somatostatin receptor 1, 2, 3, 5 and dopamine D2 receptor in spindle cell oncocytomas of posterior pituitary.

Spindle cell oncocytomas (SCOs) are very rare tumors of the posterior pituitary with potential for locally aggressive behaviour. Their treatment includes surgery and possibly radiotherapy, however other options are lacking. Somatostatin receptors (SSTs) are a possible therapeutic target for somatostatin analogues and their expression has been demonstrated recently in closely related pituicytomas, but there are no data about their presence in SCOs. We collected five cases of SCO from four patients including one recurrent case. Immunohistochemical detection of TTF1, GFAP, CD68, SST1, SST2, SST3, SST5 and D2 dopamine receptor (D2DR) was performed. Intensity, percentage of positive cells and pattern of expression was evaluated in semiquantitative fashion. Protein expression of SST1-5 and D2DR was further evaluated by western blot. Mean patient age was 61.8years (range 47-71years) with male to female ratio 1:1. In one patient, samples from the original tumor and its recurrence 16years later were assessed. TTF1 was positive in all five cases, no expression of GFAP and CD68 was seen. Immunohistochemical expression of SST1 was noted in 1/5 cases, SST2 in 2/5 cases, including recurrent case but not the original case. SST3 was expressed in 3/5 tumors and D2 dopamine receptor in 4/5 cases. Western blot was successfully performed in four samples. SST2, SST3 and D2DR expression was identified in all the samples, including two cases originally negative for SST2 and one case negative for SST3 by immunohistochemistry. The number of positive cells and level of expression varied among different areas of the same tumors. No expression of SST5 was observed. In the patient with the recurrent tumor, intensity of SST2, SST3 and D2DR expression varied between original tumor and its recurrence. We demonstrated presence of different SST subtypes and D2DR in spindle cell oncocytomas. The most commonly expressed subtype was SST2 and SST3, while no expression of SST5 was observed. Expression showed spatial heterogeneity and temporal changes as seen in the recurrent case. The biological meaning of SSTs expression in SCOs is unclear as well as whether it may be exploited in treatment of selected cases.

Clinical significance of serial biomarkers activity determination after acute heart failure decompensation: sST2 NT-proBNP role during long-term follow-up

Monitoring of concentrations of modern biomarkers to evaluate the efficacy of long‑term treatment of patients after acute decompensated HF (ADHF). The study included 100 patients with severe decompensated FC II-IV CHF and LV EF &lt;40 % due to IHD, DCMP or AH. At discharge from the hospital, patients were divided into groups of low (NT‑proBNP&lt;1400 pg / ml) (control, n=30) and high (NT‑proBNP≥1400 pg / ml) risk (n=70). Patients at high risk were randomized to two treatment groups, a group of NT‑proBNP monitoring (NPM) (n=35) and a group of standard therapy (n=35). At the end of the study, noncompliant patients were isolated from these two groups into a separate group (n=10). The aim of the treatment was decreasing theNT‑proBNP concentration to less than 1000 pg / ml and / or ≥50 % of the baseline level. In addition to the soluble suppression of tumorigenicity2(sST2) receptor, concentrations of copeptin, neutrophil gelatinase associated lipocalin (NCAL), galectin 3, and high‑sensitivity troponin T were measured at discharge from the hospital (baseline) and at three and 6 months of treatment. Thestrongest correlations were found between changes in concentrations (Δ%) of NT‑proBNP, copeptin, and sST2 and changes in CHF FC, 6‑min walk distance, CCS, quality of life, LV EF, and Е / Е' (р&lt;0.001). The incidence of cardiovascular events was directly related with thedegree of decrease and / or increase in biomarker concentration. Patients of the NPM group had the lowest risk of adverse clinical outcome upon a decrease in NT‑proBNP &lt;988.5 pg / ml at 6 months of treatment or &gt; 50 % of the baseline level at discharge from the hospital. For these patients, the mean Δ% was 60.7±8.5 % for NT‑proBNP, 34.03±17.6 % for sST2, and 32.41±8.8 % for copeptin [OR at 95 % CI 0.08 (0.02-0.36), р &lt;0.0001]. A significant increase in the risk for cardiovascular events was observed only at a considerable increase in NT‑proBNP &gt;50 % [OR at 95 % CI 3.8 (1.13-13.0), р=0.03], and the highest incidence of cardiovascular events was observed in the group of noncompliant patients (110 %). Besides NT‑proBNP, to significantly decrease the risk of cardiovascular events, it was necessary to achieve a decrease in sST2 concentration to less than 30 ng / ml or by more than 24.9 % (Δ%) at the end offollowup [ОR (95 % CI: 0.1 (0.02-0.5), р=0.004]. Among the modern biomarkers, changes inNT‑proBNP, sST2, and copeptin concentrations most accurately reflect changes in the clinical and functional status, quality of life, and EchoCG parameters in HF patients during long‑term monitoring. The lowest risk for adverse clinical outcomes was observed in post‑decompensation patients with a decrease in NT‑proBNP &lt;988.5 pg / ml after 6 months of treatment or ≥50 % of baseline upon discharge from the hospital. The sST2 concentration has to be reduced by more than 24.9 % of baseline and less than 30 ng / ml in the course of long‑term treatment after decompensated HF.

The safety of lanreotide for neuroendocrine tumor

ABSTRACTIntroduction: Lanreotide autogel is a synthetic somatostatin analogue which has been FDA and EMA approved for unresectable, well to moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumor. Its action is mediated by its affinity to somatostatin receptors, especially sst2 and sst5 receptors. Its longer half-life offers the convenience of 4-week dosing over the need for frequent injections of short-acting somatostatin analogues.Areas covered: Lanreotide ATG offers progression-free survival benefit in locally advanced or metastatic neuroendocrine tumor (NET) compared to placebo, reflecting a strong antiproliferative signal. As lanreotide is commonly used for management of NET, it is imperative to recognize and appropriately manage any drug-related toxicities. In this review, we will provide an overview of the toxicity with lanreotide and its management.Expert opinion: Lanreotide is highly effective in managing carcinoid symptoms and has a robust anti-tumor effect in NET. Overall, it is well tolerated with low rates of treatment discontinuation due to toxicity. It's toxicity profile is mostly predictable, and patients should be informed of the transient nature of some of the upfront toxicities.

A case of malignant insulinoma responsive to somatostatin analogs treatment

BackgroundInsulinoma is a rare tumour representing 1–2% of all pancreatic neoplasms and it is malignant in only 10% of cases. Locoregional invasion or metastases define malignancy, whereas the dimension (> 2 cm), CK19 status, the tumor staging and grading (Ki67 > 2%), and the age of onset (> 50 years) can be considered elements of suspect.Case presentationWe describe the case of a 68-year-old man presenting symptoms compatible with hypoglycemia. The symptoms regressed with food intake. These episodes initially occurred during physical activity, later also during fasting. The fasting test was performed and the laboratory results showed endogenous hyperinsulinemia compatible with insulinoma. The patient appeared responsive to somatostatin analogs and so he was treated with short acting octreotide, obtaining a good control of glycemia. Imaging investigations showed the presence of a lesion of the uncinate pancreatic process of about 4 cm with a high sst2 receptor density. The patient underwent exploratory laparotomy and duodenocephalopancreasectomy after one month.The definitive histological examination revealed an insulinoma (T3N1MO, AGCC VII G1) with a low replicative index (Ki67: 2%).ConclusionsThis report describes a case of malignant insulinoma responsive to octreotide analogs administered pre-operatively in order to try to prevent hypoglycemia. The response to octreotide analogs is not predictable and should be initially assessed under strict clinical surveillance.

Royal jelly coordinately enhances hippocampal neuronal expression of somatostatin and neprilysin genes conferring neuronal protection against toxic soluble amyloid-β oligomers implicated in Alzheimer’s disease pathogenesis

Hippocampal somatostatin (SST)-neprilysin (NEP) system functions as a defense system against neurotoxic soluble amyloid-β oligomers associated with onset of Alzheimer’s disease. However, it remains unknown whether royal jelly (RJ) could impact the defense system. In this study using primary cultures of hippocampal neurons, including SST-positive and NEP-positive neuronal subsets, we evaluated the ability of DMSO-soluble fraction of RJ (DRJ) to enhance SST and NEP genes expression. The DRJ potently facilitated CRE-mediated transcription, and raised SST-immunoreactivity in an SST-positive neuronal subset, where elevated phospho-CREB immunoreactivity was simultaneously observed. Chromatin immunoprecipitation-qPCR assays uncovered that the DRJ mechanistically facilitated CREB-binding to a CRE present at the promoter region of SST. Moreover, in a distinct NEP-positive neuronal subset, the DRJ led to elevation of NEP immunoreactivity, which was abolished by cyclosomatostatin, a non-selective SST receptors antagonist. Collectively, these findings provide the first evidence that the RJ possesses potential to activate the hippocampal SST-NEP system.

CLINICAL VALUE OF BLOOD BIOMARKERS IN PATIENTS WITH CHRONIC HEART FAILURE

Biomarkers (various laboratory biochemical markers), such as natriuretic peptides (NP), soluble ST2 receptor, copeptin, galectin-3, are widely studied in patients with chronic heart failure (CHF). The European Society of Cardiology recommends the determination of blood NP level in suspicion of HF and its use as one of the mandatory diagnostic criteria for CHF with preserved and mid-range ejection fraction. Dynamics of NP concentration may be predictor of the effectiveness of the therapy and the necessity of the titration of the dose of HF drugs. Neprilyzin destroys NP, but does not destroy their precursors, including NT-proBNP. Therefore, it is necessary to use NT-proBNP as a marker of therapeutic efficacy and prognosis when using neprilysine inhibitors (sacubitril). ST2 is a protein receptor for interleukin-33 (IL-33). The transmembrane ST2 (ST2L) binds to IL-33 and forms the IL-33/ST2L complex, which has a cardioprotective effect, prevents the development of myocardial hypertrophy, fibrosis and apoptosis. The soluble ST2 receptor (sST2) is a “trap” for IL-33 and neutralizes the protective effects of the IL-33/ST2L complex, which leads to hypertrophy and fibrosis of the myocardium, dilatation of the chambers and reduction of the contractility of the heart. It can be considered as a marker of unfavorable prognosis in heart failure, but it is not specific. Copeptin is a part of the arginine-vasopressin, or antidiuretic hormone, precursor which plays an important role in the pathogenesis of CHF. Since arginine-vasopressin has a short half-life and is unstable outside the body, copeptin is being actively investigated. Its level increases during the CHF decompensation and relates with the functional class of CHF. A combined measurement of the concentration of copeptin and NP may improve the risk stratification in CHF patients. Galectin-3 is a peptide that stimulates the activation of fibroblasts and the development of fibrosis. It increases in CHF patients and is associated with the severity of the condition, systolic and diastolic LV dysfunction and prognosis. Currently, NP are the best biomarkers that can and should be used in routine clinical practice. To prove the need for widespread use of other biomarkers, additional research is needed.

Behavioral response to imipramine under chronic mild stress corresponds with increase of mRNA encoding somatostatin receptors sst2 and sst4 expression in medial habenular nucleus

Behavioral response to imipramine under chronic mild stress corresponds with increase of mRNA encoding somatostatin receptors sst2 and sst4 expression in medial habenular nucleus

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

Somatostatin 2 Receptor Activation in the Rostral Ventrolateral Medulla Does Not Mediate the Decompensatory Phase of Haemorrhage.

Decompensation, a critical phase in the response to hemorrhage, is characterized by profound sympathoinhibition and the overriding of baroreflex mediated compensation. As sympathoexcitatory neurons of the rostral ventrolateral medulla (RVLM) maintain vasomotor tone and are essential for sympathetic baroreceptor reflex function, the RVLM is the likely mediator. However, how decompensation occurs is a mystery. Our previous work demonstrated that the inhibitory neuropeptide somatostatin (SST), evokes potent sympathoinhibition. Here we test the hypothesis that, in response to hypovolemia, SST in the RVLM evokes sympathoinhibition, driving decompensation and suppressing baroreflex compensation. We evaluated neuronal activation at sites that contain SST mRNA and project to the RVLM and, in SST2A expressing neurons in the RVLM. We determined the effects on cardiovascular and sympathetic responses to haemorrhage, of bilateral blockade of SST2 receptors in both the RVLM and A1 regions. Haemorrhage in conscious rats evoked c-Fos immunoreactivity in the amygdala, periaqueductal gray, and parabrachial nuclei, regions previously associated with hemorrhage, shown to contain SST and project to the RVLM. Although c-Fos labeling was found throughout the ventrolateral medulla, only a small subset of RVLM SST2A receptor expressing neurons were activated, consistent with the idea that these neurons are inhibited during hemorrhage. However, SST2 receptor antagonists bilaterally injected in the RVLM or the A1 region did not affect the decompensation response to hemorrhage. Thus somatostatin in the RVLM does not mediate decompensation. The physiological role associated with somatostatin-induced sympathoinhibition in the RVLM together with the central mechanisms responsible for decompensation remain elusive.

Somatostatin Is Only Partly Required for the Glucagonostatic Effect of Glucose but Is Necessary for the Glucagonostatic Effect of KATP Channel Blockers.

The mechanisms of control of glucagon secretion are largely debated. In particular, the paracrine role of somatostatin (SST) is unclear. We studied its role in the control of glucagon secretion by glucose and KATP channel blockers, using perifused islets and the in situ perfused pancreas. The involvement of SST was evaluated by comparing glucagon release of control tissue or tissue without paracrine influence of SST (pertussis toxin-treated islets, or islets or pancreas from Sst-/- mice). We show that removal of the paracrine influence of SST suppresses the ability of KATP channel blockers or KATP channel ablation to inhibit glucagon release, suggesting that in control islets, the glucagonostatic effect of KATP channel blockers/ablation is fully mediated by SST. By contrast, the glucagonostatic effect of glucose in control islets is mainly independent of SST for low glucose concentrations (0-7 mmol/L) but starts to involve SST for high concentrations of the sugar (15-30 mmol/L). This demonstrates that the glucagonostatic effect of glucose only partially depends on SST. Real-time quantitative PCR and pharmacological experiments indicate that the glucagonostatic effect of SST is mediated by two types of SST receptors, SSTR2 and SSTR3. These results suggest that alterations of the paracrine influence of SST will affect glucagon release.