Expression Of Cortistatin Research Articles

Evaluation of a Novel DNA Vaccine Double Encoding Somatostatin and Cortistatin for Promoting the Growth of Mice.

Simple SummaryGrowth trait is one of the most important economic traits for meat animals. Somatostatin DNA vaccine has been proven to enhance the growth rate of animals. However, the growth-promoting effect is not ideal. This study aimed to evaluate the immune effects of a novel eukaryotic dual expression vaccine known as pIRES-S/CST14-S/2SS in mice. Firstly, we demonstrated pIRES-S/CST14-S/2SS could functionally express in GH3 pituitary cells by regulating the growth hormone (GH) and prolactin (PRL) productions. Secondly, we observed that all concentrations of pIRES-S/CST14-S/2SS vaccine could evoke anti-somatostatin (SS) antibodies, leading to a higher level of GH concentration. Notably, pIRES-S/CST14-S/2SS (10 μg/100 μL) immunized mice obtained maximum body weight gain in a booster vaccination period. Our results are helpful for better understanding of the relationship between SS and CST, and pIRES-S/CST14-S/2SS vaccine may be used as a promising alternative for developing growth-promoting vaccine.Animal growth traits are directly linked with the economics of livestock species. A somatostatin DNA vaccine has been developed to improve the growth of animals. However, the growth-promoting effect is still unsatisfying. The current study aimed to evaluate the effect of a novel eukaryotic dual expression vaccine known as pIRES-S/CST14-S/2SS, which encodes the genes obtained by fusing somatostatin (SS) and cortistatin (CST) into hepatitis B surface antigen (HBsAg). After transfection into GH3 cells with pIRES-S/CST14-S/2SS, green fluorescence signals were observed by fluorescence microscopy, suggesting the effective expression of CST and SS in GH3 cells using the IRES elements. Subsequently, both GH and PRL levels were found to be significantly lower in pIRES-S/CST14-S/2SS-treated cells as compared to the control group (p < 0.05). Furthermore, the antibody level, hormone secretion, and weight gain in the mice injected with novel recombinant plasmids were also evaluated. The anti-SS antibodies were detectable in all vaccine treated groups, resulting in significantly higher levels of GH secretion (p < 0.05). It is worth mentioning that pIRES-S/CST14-S/2SS (10 μg/100 μL) vaccinated mice exhibited a higher body weight gain in the second immunization period. This study increases the understanding of the relationship between somatostatin and cortistatin, and may help to develop an effective growth-promoting DNA vaccine in animals.

Cortistatin attenuates titanium particle-induced osteolysis through regulation of TNFR1-ROS-caspase-3 signaling in osteoblasts.

Aseptic loosening is a major complication of prosthetic joint surgery and is associated with impaired osteoblast homeostasis. Cortistatin (CST) is a neuropeptide that protects against inflammatory conditions. In this study, we found that expression of CST was diminished in patients with prosthetic joint loosening and in titanium (Ti) particle-induced animal models. A Ti particle-induced calvarial osteolysis model was established in wild-type and CST gene knockout mice; CST deficiency enhanced, while exogenously added CST attenuated, the severity of Ti particle-mediated osteolysis. CST protected against inflammation as well as apoptosis and maintained the osteogenic function of MC3T3-E1 osteoblasts upon stimulation with Ti particles. Furthermore, CST antagonized reactive oxygen species production and suppressed caspase-3-associated apoptosis mediated by Ti particles in osteoblasts. Additionally, CST protects against Ti particle-induced osteolysis through tumor necrosis factor receptor 1. Taken together, CST might provide a therapeutic strategy for wear debris-induced inflammatory osteolysis.

Cortistatin regulates fibrosis and myofibroblast activation in experimental hepatotoxic- and cholestatic-induced liver injury.

Liver fibrosis induced by chronic hepatic injury remains a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis. We experimentally induced liver fibrosis in mice by chronic CCl4 exposure and bile duct ligation and evaluated the histopathological signs and fibrotic markers. Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged by hepatotoxic and cholestatic injury. Compared with wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury. We identify cortistatin as an endogenous molecular brake on liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that link with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various aetiologies.

Cortistatin protects against intervertebral disc degeneration through targeting mitochondrial ROS-dependent NLRP3 inflammasome activation.

Background: Intervertebral disc (IVD) degeneration is a common degenerative disease that can lead to collapse or herniation of the nucleus pulposus (NP) and result in radiculopathy in patients.Methods: NP tissue and cells were isolated from patients and mice, and the expression profile of cortistatin (CST) was analysed. In addition, ageing of the NP was compared between 6-month-old WT and CST-knockout (CST-/-) mice. Furthermore, NP tissues and cells were cultured to validate the role of CST in TNF-α-induced IVD degeneration. Moreover, in vitro and in vivo experiments were performed to identify the potential role of CST in mitochondrial dysfunction, mitochondrial ROS generation and activation of the NLRP3 inflammasome during IVD degeneration. In addition, NF-κB signalling pathway activity was tested in NP tissues and cells from CST-/- mice.Results: The expression of CST in NP cells was diminished in the ageing- and TNF-α-induced IVD degeneration process. In addition, compared with WT mice, aged CST-/- mice displayed accelerated metabolic imbalance and enhanced apoptosis, and these mice showed a disorganized NP tissue structure. Moreover, TNF-α-mediated catabolism and apoptosis were alleviated by exogenous CST treatment. Furthermore, CST inhibited mitochondrial dysfunction in NP cells through IVD degeneration and suppressed activation of the NLRP3 inflammasome. In vitro and ex vivo experiments indicated that increased NF-κB pathway activity might have been associated with the IVD degeneration observed in CST-/- mice.Conclusion: This study suggests the role of CST in mitochondrial ROS and activation of the NLRP3 inflammasome in IVD degeneration, which might shed light on therapeutic targets for IVD degeneration.

RETRACTED: Overexpression of cortistatin alleviates oxygen/glucose-deprivation-induced ER stress and prompts neural stem cell proliferation via SSTR2

Cerebral infarction (CI), a blood circulatory disorder, causes a high mortality and disability rate worldwide. Intriguingly, a newly discovered neuropeptide, Cortistatin (CST), has been indicated to inhibit the cortical activity. In our research, we aimed to explore the functional relevance of CST in neural stem cells (NSCs) in CI rats. The expression of CST was determined in NSCs induced by oxygen-glucose deprivation (OGD). NSCs isolated from the embryonic rat brain were treated with OGD to establish an in vitro CI model while dithiothreitol (DTT) was introduced to induce endoplasmic reticulum stress (ERS), which were evaluated by assessment of GRP94, caspase-12 and CHOP expression. Then CST expression was restored by transfection of oe-CST, followed by assessment of NSC proliferation ability and cytotoxicity. Finally, the expression of CST and its receptor Somatostatin receptor subtype 2 (SSTR2) was quantified for mechanism exploration. CST was downregulated in CI, which was further confirmed in NSCs under OGD treatment. Overexpressed CST was found to promote cell activity and attenuate OGD-induced cytotoxicity of NSCs. Meanwhile, it was observed that the injured proliferation ability of NSCs was restored by CST overexpression. Besides, lower expression of GRP94, caspase-12 and CHOP was indicative of suppressed occurrence of ERS by CST. Mechanically, CST inhibited ERS through SSTR2. CST could facilitate the proliferation of NSCs in CI induced by OGD, ultimately highlighting a novel therapeutic target for CI treatment.

Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut.

Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg-1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells.

Cortistatin Improves Cardiac Function After Acute Myocardial Infarction in Rats by Suppressing Myocardial Apoptosis and Endoplasmic Reticulum Stress.

The endoplasmic reticulum (ER) stress-induced apoptotic pathway is associated with the development of acute myocardial infarction (AMI). Cortistatin (CST) is a novel bioactive peptide that inhibits apoptosis-related injury. Therefore, we investigated the cardioprotective effects and potential mechanisms of CST in a rat model of AMI. Male Wistar rats were randomly divided into sham, AMI, and AMI + CST groups. Cardiac function and the degree of infarction were evaluated by echocardiography, cardiac troponin I activity, and 2,3,5-triphenyl-2H-tetrazolium chloride staining after 7 days. The expression of CST, ER stress markers, and apoptotic markers was examined using immunohistochemistry and Western blotting. Compared to the AMI group, the AMI + CST group exhibited markedly better cardiac function and a lower degree of infarction. Electron microscopy and terminal deoxynucleotidyl transferase dUTP nick end labeling confirmed that myocardial apoptosis occurred after AMI. Cortistatin treatment reduced the expression of caspase 3, cleaved caspase 3, and Bax (proapoptotic proteins) and promoted the expression of Bcl-2 (antiapoptotic protein). In addition, the reduced expression of glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding proteins homologous protein, and caspase 12 indicated that ER stress and the apoptotic pathway associated with ER stress were suppressed. Exogenous CST has a notable cardioprotective effect after AMI in a rat model in that it improves cardiac function by suppressing ER stress and myocardial apoptosis.

Cortistatin is dysregulated in skin tissue of patients with psoriasis vulgaris and suppresses keratinocyte proliferation in vitro.

Psoriasis is characterized by the unregulated proliferation of epidermal keratinocytes and increased expression of proinflammatory mediators in the skin. Cortistatin, an endogenous cyclic neuropeptide, inhibits the proliferation of inflammatory cells. We investigated the expression of cortistatin in patients with psoriasis vulgaris and examined its effects on keratinocyte growth in vitro. Serum levels of cortistatin were determined by enzyme-linked immunosorbent assay (ELISA) in 72 patients with psoriasis vulgaris and 76 age-matched healthy volunteers. Cortistatin expression was also examined by immunohistochemistry of skin biopsies from 14 patients and 14 healthy subjects. The effects of cortistatin on the proliferation of primary keratinocytes were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and BrdU incorporation assay. Intracellular levels of cAMP in keratinocytes in the presence or absence of cortistatin were determined by ELISA. Serum levels of cortistatin and expression levels in skin were significantly lower in patients with psoriasis than in healthy subjects. Cortistatin inhibited keratinocyte proliferation in vitro in a dose-dependent manner and substantially reduced intracellular cAMP levels in keratinocytes. Cortistatin is downregulated in the skin of patients with psoriasis vulgaris and suppresses keratinocyte growth in vitro.

Dietary fat alters the expression of cortistatin and ghrelin systems in the PBMCs of elderly subjects: putative implications in the postprandial inflammatory response.

Dietary fat influences systemic inflammatory status, which determines the progression of age-associated diseases. Since somatostatin (SST), cortistatin (CORT), and ghrelin systems modulate inflammatory response, we aim to comprehensively characterize the presence and regulation of the components of these systems in the peripheral blood mononuclear cells (PMBCs), a subset of white blood cells placed at the crossroad between diet and inflammation, in response to diets with different fat composition, and during the postprandial phase in elderly subjects. The applied nutrigenomic, inflammation-related PBMC-based approach revealed that the majority of components of SST/CORT and ghrelin systems are present in the human PBMCs. Particularly, CORT, SST/CORT receptors (sst2, sst3, sst5, and sst5TMD4), ghrelin, its acylating enzyme (GOAT), In1-ghrelin variant, and GHSR1b were detected in PBMCs. Their expression was altered in the long-term by diet composition, and in the short-term, during the postprandial phase. Of particular relevance is the postprandial elevation of CORT, sst2, and sst5 expression in PBMCs of subjects under n-3 PUFAs-enriched diet. Our results suggest a potential relevant role of CORT/ssts and ghrelin systems in regulating PBMCs response to nutrient intake, which could help to explain the positive effects of n-3 PUFAs-enriched diets in reducing the inflammatory response.

Dietary fat alters the expression of cortistatin and ghrelin systems in the PBMCs of elderly subjects: Putative implications in the postprandial inflammatory response

Scope Dietary fat influences systemic inflammatory status, which determines the progression of age-associated diseases. Since somatostatin (SST), cortistatin (CORT), and ghrelin systems modulate inflammatory response, we aim to comprehensively characterize the presence and regulation of the components of these systems in the peripheral blood mononuclear cells (PMBCs), a subset of white blood cells placed at the crossroad between diet and inflammation, in response to diets with different fat composition, and during the postprandial phase in elderly subjects. Methods and results The applied nutrigenomic, inflammation-related PBMC-based approach revealed that the majority of components of SST/CORT and ghrelin systems are present in the human PBMCs. Particularly, CORT, SST/CORT receptors (sst2, sst3, sst5, and sst5TMD4), ghrelin, its acylating enzyme (GOAT), In1-ghrelin variant, and GHSR1b were detected in PBMCs. Their expression was altered in the long-term by diet composition, and in the short-term, during the postprandial phase. Of particular relevance is the postprandial elevation of CORT, sst2, and sst5 expression in PBMCs of subjects under n-3 PUFAs-enriched diet. Conclusion Our results suggest a potential relevant role of CORT/ssts and ghrelin systems in regulating PBMCs response to nutrient intake, which could help to explain the positive effects of n-3 PUFAs-enriched diets in reducing the inflammatory response.

Involvement of DDAH/ADMA pathway in the pathogenesis of rheumatoid arthritis in rats

Endothelial dysfunction is the early stage of atherosclerosis, which is typically associated with rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is not only an independent predictor for endothelial dysfunction but also a proinflammatory mediator. It has been shown that the level of ADMA was elevated in patients with RA. In the present study, we investigated the potential effect of ADMA on inflammation process in collagen-induced arthritis (CIA) animal model and primary cultured fibroblast-like synoviocytes (FLS) exposed to tumor necrosis factor-α (TNF-α). In CIA rats, the plasma levels of inflammatory cytokines TNF-α, interleukin-1β (IL-1β) and IL-6 were markedly increased, while the plasma levels of ADMA did not increase. The expression of dimethylarginine dimethylohydrolase2 (DDAH2), the key enzyme for ADMA degradation, was markedly reduced in inflamed joint synovium of CIA rats. Moreover, the expression of anti-inflammatory factor cortistatin (CST) was markedly decreased in joint synovium of CIA rats. Treatment of cultured FLS with TNF-α significantly increased the levels of ADMA, and decreased the expression of DDAH2 mRNA and protein accompany with an increase in the levels of IL-1β and IL-6 and a reduction in the expression of CST mRNA and protein, and the effects of TNF-α were abolished by DDAH2 overexpression. Treatment of FLS with ADMA also significantly increased the levels of IL-1β and IL-6, and reduced the expression of CST. These findings suggest that DDAH/ADMA participates in the pathogenesis of RA, and that the effect of DDAH/ADMA may be mediated by CST.

Cortistatin modulates calcitonin gene-related peptide release from neuronal tissues of rat. Comparison with somatostatin

Cortistatin (CST) is an endogenous neuropeptide bearing strong structural and functional analogies with somatostatin (SST). Gene expression of CST and its putative receptor MrgX2 in dorsal root ganglia (DRG) neurons in man suggests the involvement of CST in pain transmission. In this study we have investigated the effects of CST and SST on calcitonin gene-related peptide (CGRP, the main neuropeptide mediator of pain transmission) from primary cultures of rat trigeminal neurons. Moreover, here for the first time we used organotypic cultures of rat brainstem to investigate the release of CGRP form nucleus caudalis as a model of pre-synaptic peptide release. In both experimental paradigm CGRP release was evaluated in the presence of CST or SST, with or without the addition of known secretagogues (namely high KCl concentrations, veratridine and capsaicin). We found that CST and SST do not modify basal CGRP secretion from trigeminal neurons, but both peptides were able to inhibit in a concentration-dependent manner the release of CGRP stimulated by KCl, veratridine or capsaicin. Likewise, in brainstem organotypic cultures CST and SST did not modify baseline CGRP secretion. Of the secretagogues used, capsaicin proved to be most effective compared to KCl and veratridine (8-fold vs 2-fold increase, respectively). Thereafter, CST and SST were tested on capsaicin-stimulated CGPR release only. Under these conditions, CST but not SST was able to inhibit in a significant manner pre-synaptic CGRP release from the brainstem, providing further evidence in support of a role for CST in pain transmission.

Neuroendocrine‐Immune Interactions

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst(1-5)). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system.

Expression of cortistatin and MrgX2, a specific cortistatin receptor, in human neuroendocrine tissues and related tumours

Cortistatin (CST), a novel hormone originally described in the rat, mouse, and human cerebral cortex, displays structural and functional similarities to somatostatin (SRIF). CST binds to all five somatostatin receptors and, differently from SRIF, also binds to MrgX2, which has recently been identified as its specific receptor. Little is known about the distribution of CST and MrgX2 in peripheral non-tumour and neoplastic tissues. The aim of the present study was therefore to determine by immunohistochemistry and mRNA analysis (RT-PCR) the distribution of CST and MrgX2 in 56 human non-tumour and 108 tumour tissues, with special reference to neuroendocrine tissue types. Despite the high level of CST mRNA expression in non-tumour and tumour (both neuroendocrine and non-neuroendocrine) tissues, the presence of immunoreactive CST was confirmed in a subset of gastroenteropancreatic, parathyroid, and pituitary non-tumour cells only, and showed a predominantly focal pattern in most neuroendocrine tumours. Co-localization experiments in the gastroenteropancreatic system demonstrated that the normal CST-producing cells are delta cells, while in the adenohypophysis no preferential co-localization of CST with any of the pituitary hormones was observed. MrgX2 mRNA was variably detected in the hypothalamus, pituitary, thyroid, lung, gastroenteropancreatic tract, testis, and ovary, and was negative in the cerebral cortex, parathyroid, and adrenal, as well as in a variety of tumour types. Conversely, immunolocalization of MrgX2 protein was restricted to neurohypophysis and testis, whilst all tumours analysed were negative. A possible explanation for the discrepancy between RT-PCR and immunohistochemistry is that MrgX2 protein was widely detected in blood vessels, scattered lymphocytes, and gastrointestinal ganglia in both normal and neoplastic samples. The findings demonstrate a selective distribution of CST in normal and neoplastic neuroendocrine tissues, suggesting that CST might have a broader functional role than previously assumed, whereas possible autocrine/paracrine actions via its recently described specific receptor MrgX2 are restricted to selected tissues.

Distribution pattern of somatostatin and cortistatin mRNA in human central and peripheral tissues.

Somatostatin receptors (sst) and their endogenous ligand, somatostatin (SS), are widely expressed throughout the human body. Recently, the cDNA of a novel SS-like peptide, named cortistatin (CST), has been cloned. This CST was found to be expressed in more restricted areas, like brain cortex, testes, kidney, stomach and leucocytes. Further studies demonstrated a selective expression of CST in tissues and cells of the human immune system, while SS was not expressed. In the present study we investigated the expression pattern of both SS mRNA and CST mRNA in various human central and peripheral tissues by quantitative RT-PCR (Q-PCR), in order to evaluate whether CST is more widely expressed in man than described to date and to investigate the relationship between SS and CST expression levels in various tissues. Previously, two different CST mRNA isoforms have been described. Therefore, we investigated the expression of both isoforms by RT-PCR in the different tissues as well. We demonstrate for the first time that CST mRNA is widely expressed in the human body. Interestingly, a selective expression of CST mRNA and not SS mRNA was only found in isolated cells of the human immune system, whereas different tissues expressed both SS and CST mRNA. CST may have a broader functional role than previously assumed.

Presence of cortistatin in the human pancreas.

Cortistatin (CST), a 17-amino acid peptide partially homologous to somatostatin (SRIF), has been originally isolated from the cerebral cortex and recently found in monocytes and macrophages of the immune system. CST binds all 5 SRIF receptors, as well the GH secretagogue (GHS)/ghrelin receptors. CST exerts sleep promoting activities, acts on animal motility and behavior and inhibits GH and insulin secretion. To investigate the possible occurrence and activities in peripheral tissues, expression of CST at the mRNA and peptide level was analyzed in the human pancreas by means of RT-PCR, in situ hybridization and immunohistochemistry. The specific CST mRNA was found in 3 of 4 pancreatic RNA extracts and in the control cerebral cortex. By in situ hybridization, CST mRNA was localized in the pancreatic islets, but not in the exocrine pancreas. This finding was confirmed by immunostaining with a specific antibody to CST-17 which detected CST in single islet cells. These cells also expressed SRIF receptors types 2, 3 and 5, ghrelin and GHS receptors. Thus, our findings show the presence of CST in the human endocrine pancreas. Local autocrine or paracrine circuits, only in part overlapped with those of SRIF, may be active to modulate insulin and/or glucagon levels.