Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NOD/Lt mice harboring a hybrid rat insulin-promoter/SV40 large T-antigen gene spontaneously develop beta-cell adenomas. NIT-1 is a pancreatic beta-cell line established from one of these transgenic mice. Immunocytochemical staining of passage 18 cells showed most contained insulin, with less than 5% containing glucagon, and none containing pancreatic polypeptide or somatostatin. Glucagon content radioimmunoassayed in cell extracts was only 0.27% of the insulin content. Two-hour insulin secretion at 16.5 mM glucose was 638 ng/10(6) cells (41% of intracellular content) compared to only 1.3 ng glucagon (32% of intracellular content). Stimulated insulin secretion was consistently observed in response to 11 and 16.5 mM glucose between passages 11 and 19. At passage 19, both theophylline and tolbutamide stimulated insulin secretion at 5.5 mM glucose. Northern-blot analysis confirmed high levels of insulin mRNA but only trace glucagon mRNA and undetectable somatostatin mRNA. Interferon-gamma (IFN-gamma)-induced MHC class I RNA expression was correlated with markedly increased antigen expression at the cell surface. Similarly, a MHC-linked "occult" class I-like antigen detected by Cr release assay only after exposure of standard NOD/Lt islet cells to IFN-gamma was strongly induced by IFN-gamma in NIT-1 cells. Cell surface MHC class II antigen was not constitutively expressed on NIT-1 cells and could not be detected after IFN-gamma incubation, despite demonstration of IFN-gamma-induced Aa, Ab, and Li invariant-chain RNA transcripts. Similarly IFN-gamma induction of intercellular adhesion molecule 1 (Icam-1) transcripts was not accompanied by demonstrable cell surface expression of ICAM-1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. 164 94

The amounts of insulin, glucagon and somatostatin in the pancreas of NOD mice were determined and the results were compared with those of normal ICR-strain mice, and plasma antibodies to Coxsackie B-3 and reovirus types 1, 2 and 3 were measured. In the pancreas of NOD mice with fasting plasma glucose (FPG) less than 140 mg/100 ml, the insulin content of the male mice was similar to that of the normal controls, ranging to 3.55 +/- 0.31 U/g wet weight of pancreas, but it was already significantly decreased to 0.85 +/- 0.52 U/g in the female mice. In the NOD mice with FPG more than 201 mg/100 ml, it was 0.002 +/- 0.001 U/g. The glucagon content of the pancreas was 7.76 +/- 0.89 micrograms/g in the normal controls and it was decreased slightly in the NOD mice, but the values among the NOD mice were not significantly different. Pancreas somatostatin showed a tendency to be higher in the NOD mice with FPG more than 201 mg/100 ml. Histologically cell infiltration into the pancreatic islets was conspicuous in the hyperglycemic NOD mice, but it was found even in the normoglycemic NOD. Plasma antibodies to Coxsackie B-3 Virus and reovirus types 1, 2 and 3 were not detected at any stage of FPG.
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PMID:Insulin, glucagon and somatostatin content of the non-obese diabetic (NOD) mouse pancreas and plasma virus antibodies to Coxsackie B- and reoviruses. 286 17

Prophylactic insulin therapy prevents IDDM in spontaneous animal models of the disease and has shown promise in preventing the disease in humans. Although large clinical trials have been formed to use this therapy, a comparative analysis of the efficiency of different pharmaceutical forms and doses of insulin in preventing IDDM has not been performed, and the mechanism underlying the observed prevention of disease is unknown. In the NOD-scid/scid adoptive transfer model of IDDM (10(7) new-onset NOD splenocytes injected intravenously into 6- to 8-week NOD/scid-scid recipients; insulitis develops at 6-9 days post-transfer and 100% IDDM by 32 days post-transfer), life-table (log-rank) analyses revealed that IDDM can be delayed (compared with insulin-free diluent, once daily, n = 8) with equivalent efficiency by prophylactic administration (-9-50 days post-transfer) of high (metabolism-altering) doses of short-acting (0.5 U, once daily, regular, n = 13) or long-acting (0.5 U, once daily, ultralente, n = 9) insulin as well as non-metabolism-altering low-dose insulin (0.02 U, once daily, regular, n = 8). Furthermore, IDDM was delayed with somatostatin (0.2 microgram, twice daily, n = 11), an agent that suppresses endogenous insulin production. No significant difference was seen between the preventative effects of these agents. In an assessment of when therapies can be initiated and still maintain clinical efficiency, only prophylactic somatostatin therapy delayed IDDM (n = 10, P = 0.02) when initiated at 14 days post-transfer, whereas the short-acting insulin regimen did not retard the onset of IDDM (n = 8, P = 0.25) compared with diluent-treated controls. The 24-h urinary C-peptide levels were significantly reduced with short-acting (-56%, P = 0.01) and long-acting (-67%, P = 0.02) insulin products and somatostatin (-59%, P = 0.02) compared with diluent-treated controls. These results indicate that both immunological and metabolic (i.e., beta-cell rest) factors may contribute to the beneficial effects of prophylactic insulin therapy.
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PMID:Immunological and metabolic effects of prophylactic insulin therapy in the NOD-scid/scid adoptive transfer model of IDDM. 854 66

Pancreatic islets of Langerhans exhibit an architecture and cellular organization ideal for rapid, yet finely controlled, responses to changes in blood glucose levels. In type I, insulin-dependent diabetes (IDD), this organization is lost as a result of the progressive autoimmune response which selectively destroys the insulin-producing pancreatic beta cells. Since beta cells are perceived as end-stage differentiated cells having limited capacity for regeneration in situ, individuals with IDD resulting from beta cell loss or dysfunction require life-long insulin therapy. Efforts to produce islet neogenesis or initiate islet growth in vitro from either fetal or adult tissue have had minimal success. We now report that pancreatic-derived, pluripotent islet-producing stem cells (IPSCs), isolated from prediabetic mice, can be grown in long-term cultures and differentiated into immature functional islet-like structures containing cells which express low levels of insulin, glucagon and/or somatostatin. When such in vitro grown islets were implanted into clinically diabetic NOD mice, the implanted mice were successfully weaned from insulin long-term (>50 days) without ill effects. The implanted mice maintained blood glucose levels just above euglycemic (180-220 mg/dl) and showed no signs of disease. Thus, this technical breakthrough provides new therapeutic approaches to diabetes as an alternative to insulin therapy.
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PMID:In vitro-generation of islets in long-term cultures of pluripotent stem cells from adult mouse pancreas. 923 Mar 48

We devised a real-time RT-PCR method for the quantification of preproinsulin 1 and 2, proglucagon, prosomatostatin, and GAD 65 and 67 mRNAs in the thymus, using specific primers and internal probes. Corresponding standard cRNA synthesis and normalization to 18S ribosomal RNA allowed direct quantification. Then, during the first month of life, the expression of each substance of interest was measured in the thymus of NOD mice (a spontaneous model of type 1 diabetes), C57BL/6, BALB/c and lymphocyte-deficient mice (NODscid, NODrag, BALB/cscid and C57BL/6rag). In all mouse thymuses, preproinsulin 1 and GAD 65 were undetectable, preproinsulin 2 and proglucagon showed low expression, whereas that of GAD 67 and somatostatin were high. In 7-day-old mice, GAD 67 and prosomatostatin thymic expressions were lower in NOD than in C57BL/6, and at the same age, the scid mutation but not the rag mutation induced higher expression of all investigated genes compared to control mice. In conclusion, our data allowed the quantification of the expression of pancreatic factors in the mouse thymus. Investigations are underway to quantify, at the cellular level, i.e., in thymic dendritic/macrophage cells, the RNA expression of potential autoantigens, such as preproinsulin 2 and GAD 67.
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PMID:Pancreatic hormone and glutamic acid decarboxylase expression in the mouse thymus: a real-time PCR study. 1135 61

During insulin-dependent diabetes mellitus, islet invading immune cells destroy beta cells over a prolonged asymptomatic pre-diabetic period. Cytokines synthesised and secreted by specific immune cells within the islet infiltrate may be crucial effectors of beta cell destruction or protection during the disease. Interleukin-1beta may be a key cytokine which may act in concert with other cytokines in initiating and/or promoting beta cell destruction. We have examined this hypothesis in NOD mice by assessing the intra-islet expression and co-localization of interleukin-1beta at different time-points following cyclophosphamide administration. We have also tested the effects of long-term oral nicotinamide given to NOD mice in suppressing intra-islet expression of the cytokine in this accelerated model. Cyclophosphamide was administered to day 95 female NOD mice. Pancreatic tissues were examined by dual-label confocal immunofluorescence microscopy for the expression and co-localization of interleukin-1beta at days 0, 4, 7, 11 and at onset of diabetes (day 14). Diabetes developed in 7/11 mice 14 days after administration of cyclophosphamide while nicotinamide completely prevented the disease. At day 0, interleukin-1beta immunolabelling was observed in selective intra-islet macrophages, several somatostatin cells and in a few beta cells. However, at day 4, it was seen mostly in somatostatin and some beta cells. At day 7, an increasing number of interleukin-1beta cells were observed within the islets and co-localized to several somatostatin cells, beta cells and macrophages. The mean number of intra-islet interleukin-1beta cells reached a peak at day 11 and was significantly higher than at day 7 (p = 0.05) and at day 14 (onset of diabetes; p = 0.03). At day 11, interleukin-1beta immunolabelling was also present in selective macrophages which co-expressed inducible nitric oxide synthase. At onset of diabetes, some macrophages, residual beta cells and somatostatin cells showed immunolabelling for the cytokine. Exposure of NOD mice to oral nicotinamide was associated with a considerably reduced expression of interleukin-1beta cells within the islet at day 11 (p = 0.002). We conclude that cylophosphamide treatment enhances the expression of interleukin-1beta in selective macrophages, somatostatin and beta cells during the course of the disease. Its expression reaches a maximum immediately prior to onset of diabetes. Interleukin-1beta present in intra-islet macrophages, somatostatin and beta cells may influence its expression by autocrine and paracrine means. Interleukin-1beta expression within islet macrophages may also up-regulate inducible nitric oxide synthase within the same macrophage or adjacent macrophage populations. These intra-islet molecular events may corroborate with other local cytotoxic processes leading to beta cell destruction. Oral nicotinamide may attenuate intra-islet expression of interleukin-1beta and thus inducible nitric oxide synthase during prevention of Type 1 diabetes in this animal model. The expression of interleukin-1beta in specific islet endocrine cell-types shown in this study requires further investigation.
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PMID:Immunoexpression of interleukin-1beta in pancreatic islets of NOD mice during cyclophosphamide-accelerated diabetes: co-localization in macrophages and endocrine cells and its attenuation with oral nicotinamide. 1175 8

The expression of IL-1beta in the NOD mouse pancreas was examined following disease acceleration with cyclophosphamide (Cy). Female NOD mice were injected with Cy at day 95 and the pancreas examined immunohistochemically at days 0, 4, 7, 11, and 14 (Cy group). Cyclophosphamide was also administered to NOD mice that were given oral nicotinamide from day 21. At day 0 (Cy group), IL-1beta was expressed in selective intraislet macrophages but showed an increase from day 7 onwards in macrophages, a few beta cells, and somatostatin cells. Peak expression was seen at day 11, when it was significantly higher than in day-11 mice given nicotinamide. In the Cy group a proportion of macrophages coexpressed IL-1beta and inducible nitric oxide synthase (iNOS). IL-1beta expressed within the islet macrophages may act in concert with other cytokines, promote free radical generation including NO, and promote beta cell death during IDDM.
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PMID:IL-1beta expression in islet cells of the NOD mouse and its spatial relationship to beta cells and inducible nitric oxide synthase. 1202 Nov 4

Somatostatin has diverse functions, including immunomodulatory functions. In humans, sites of active inflammation can be visualized by the administration of 111In-DTPA(0)-octreotide, a radiolabelled somatostatin analogue. We wished to establish an animal model for preclinical evaluation of the effects of somatostatin analogues on the immune system. However, most animal models for immunological diseases are murine. This report is a preliminary study of the distribution of somatostatin receptors in mouse tissues, with emphasis on the immune system. Tissue distribution of octreotide binding receptors in normal (BALB/c) mice was determined in vivo by receptor binding of 111In-DTPA(0)-octreotide and in vitro and ex vivo by receptor autoradiography. Additionally, we investigated the tissue distribution of octreotide binding receptors in inflammatory lesions in a murine model of immune mediated disease, i.e. pre-diabetic pancreatic infiltration in the non-obese diabetic mouse strain. High specific uptake of radioactivity was seen in the thymus (range 1-1.7% ID/g) and the pituitary (1-1.6% ID/g) in all mouse strains. Specific uptake was also found in the stomach (0.1-0.7% ID/g), in the adrenal glands (0.1-0.3% ID/g) and in the pancreas (0.1-0.3% ID/g). However, we did not detect increased uptake of radiolabelled octreotide in the pancreas of pre-diabetic NOD mice. Autoradiography on tissue sections confirmed the presence of octreotide binding sites in the tissues that showed specific uptake. Moreover, by using autoradiography we could localize the cortex of the thymus and the anterior part of the pituitary as the localization of specific and high affinity, octreotide binding sites. A high, but not a receptor mediated, uptake of radioactivity was seen in the kidneys and was significantly higher in females than in males (12-19% vs 4% ID/g, respectively). Our results point to profound species differences in the tissue distribution of octreotide binding receptors. Of particular interest is the high uptake of 111In-DTPA(0)-octreotide in the cortex of the mouse thymus. This offers perspectives for the use of this animal in studies concerning the effect of somatostatin analogues on the immune system. To our knowledge, this is the first report on the tissue distribution of octreotide binding receptors in mice.
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PMID:Tissue distribution of octreotide binding receptors in normal mice and strains prone to autoimmunity. 1235 1

During insulin-dependent diabetes mellitus, immune cells which infiltrate pancreatic islets mediate beta cell destruction over a prolonged asymptomatic prediabetic period. The molecular mechanisms of beta cell death in vivo remain unresolved. At least two major molecular processes of destruction have been proposed. One involves the Fas-FasL (Fas-Fas ligand) system and the other, the perforin pathway. Here, dual-label immunohistochemistry was employed to examine the intra-islet expression, distribution and cellular sources of Fas and FasL in the NOD mouse, during spontaneous diabetes (days 21, 40 and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11 and 14 after cyclophosphamide administration). The expression of the proteins was correlated with advancing disease. FasL was expressed constitutively in most beta cells but not in glucagon or somatostatin cells or islet inflammatory cells and paralleled the loss of insulin immunolabelling with advancing disease. It was also expressed in beta cells of non-diabetes prone CD-1 and C57BL/6 mice from a young age (day 21). Strong immunolabelling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and non-diabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than CD4 and CD8 T cells, concomitant with advancing insulitis. In cyclophosphamide-treated mice, the proportion of Fas-positive intra-islet CD4 and CD8 T cells at day 14 (with and without diabetes) was considerably higher than at days 0, 4, 7 and 11. At days 11 and 14, a proportion of Fas-positive intra-islet macrophages co-expressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detectable in beta cells and other islet endocrine cells during spontaneous and cyclophosphamide induced diabetes. Our results show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. Interleukin-1beta in intra-islet macrophages may induce Fas and inducible nitric oxide synthase expression in an autocrine and paracrine manner and mediate beta cell destruction or even death of some macrophages and T cells. However, other mechanisms of beta cell destruction during spontaneous and cyclophosphamide-accelerated diabetes and independent of Fas-FasL, require examination.
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PMID:Fas and Fas ligand immunolocalization in pancreatic islets of NOD mice during spontaneous and cyclophosphamide-accelerated diabetes. 1236 94

During insulin-dependent diabetes mellitus, beta cell destruction may involve activation of the Fas-Fas ligand (Fas-FasL) system. Here, we employed dual-label immunohistochemistry to examine the intra-islet expression, distribution, and cellular sources of Fas and FasL in the NOD mouse. Pancreatic tissues were studied during spontaneous diabetes (days 21, 40, and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11, and 14 after cyclophosphamide administration). Our results show that FasL was expressed constitutively in most beta cells of NOD mice and in nondiabetes-prone mice, but not in glucagon or somatostatin cells or in islet inflammatory cells. It paralleled the loss of insulin immunolabeling with advancing disease. Immunolabeling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and nondiabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than in CD4 and CD8 cells. In the cyclophosphamide group, Fas expression in intra-islet CD4 and CD8 cells showed an increase close to the onset of diabetes. At days 11 and 14, several intra-islet macrophages with immunolabeling for Fas also coexpressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detected in beta cells and other endocrine cells during spontaneous and cyclophosphamide diabetes. We show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. The role of Fas-FasL in beta cell destruction in the NOD mouse requires further clarification.
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PMID:Fas and Fas ligand immunoexpression in pancreatic islets of NOD mice during spontaneous and cyclophosphamide-accelerated diabetes. 1467 52


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