Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptides (GLP) 1 and 2 are hormones derived from the post-translational processing of proglucagon in the intestinal L cells that influence intestinal motility and small bowel growth, respectively. We describe a patient with a neuroendocrine tumor of unknown primary origin with peritoneal carcinomatosis and diffuse liver metastases, who presented with constipation and nocturnal itching for over 3 years. Small bowel follow-through showed decreased small intestinal motility and marked intestinal hypertrophy. Biopsies from mesenterial lymph nodes showed, histologically, a well-differentiated neuroendocrine tumor (G1), with positive immunostaining for chromogranin A, GLP-1, GLP-2 and polypeptide YY (PYY). Jejunal biopsy demonstrated marked intestinal mucosal hypertrophy. HPLC analysis combined with RIA of tumor and serum extracts revealed that the tumor was producing and releasing fasting levels of GLP-1 of 738+/-20.7 pg/ml (normal levels (nl) <100 pg/ml), GLP-2 of 3,150+/-9 pg/ml (nl <100 pg/ml) as well as PYY 550 pg/ml (nl <100 pg/ml). Octreotide administration decreased levels of GLP-1 and GLP-2 and reduced small intestinal transit time from 150 to 50 min. However, tumor growth was not inhibited by octreotide, interferon or dacarbazine therapy and the patient died 8 months later. This is the first case report demonstrating the overproduction of GLP-1, GLP-2 and PYY from an neuroendocrine tumor, in a patient with intestinal hypertrophy and delayed intestinal transit time.
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PMID:Intestinal proliferation and delayed intestinal transit in a patient with a GLP-1-, GLP-2- and PYY-producing neuroendocrine carcinoma. 1117 2

Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GLP-2 analogue, h[Gly2]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil. h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, h[Gly2]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GLP-2 receptor. These observations demonstrate that the antiapoptotic effects of GLP-2 on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis.
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PMID:Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. 1121 69

Glucagonoma syndrome is a paraneoplastic phenomenon characterized by an islet alpha-cell pancreatic tumor, necrolytic migratory erythema, diabetes mellitus, weight loss, anemia, stomatitis, thromboembolism, and gastrointestinal and neuropsychiatric disturbances. These clinical findings in association with hyperglucagonemia and demonstrable pancreatic tumor establish the diagnosis. Glucagon itself is responsible for most of the observed signs and symptoms, and its induction of hypoaminoacidemia is thought to lead to necrolytic migratory erythema. Liver disease and fatty acid and zinc deficiency states may also contribute to the pathogenesis of the eruption in some cases. Most patients are diagnosed too late in the clinical course for cure, but successful palliation of symptomatology can usually be achieved with surgical and medical intervention. This paper reviews the glucagonoma syndrome, paying particular attention to its cutaneous features, and provides new perspectives in our current understanding of this phenomenon.
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PMID:The glucagonoma syndrome: a review of its features and discussion of new perspectives. 1137 Jul 94

Glucagon excess causes catabolic changes, including enhanced glucose production, lipolysis, and amino acid oxidation. In this study, we evaluate the metabolic effects of debulking surgery on a patient with glucagon-producing tumor. Stable isotope tracer methods were used to measure glucose, glycerol, and alpha-ketoisocaproic acid (alpha KICA) rates of appearance (Ra) into plasma. Measurements were obtained 25 days after surgery in the basal state and during hormonal suppression of glucagon production by infusing somatostatin with insulin replacement. Basal plasma glucagon concentration (14,100 pg/mL) remained high after debulking surgery. Somatostatin infusion decreased plasma glucagon concentration to 6,735 pg/mL and basal substrate kinetics (alpha-KICA Ra from 1.97 to 1.48 micromol/kg/min; glucose Ra from 16.89 to 11.56 micromol/kg/min; and glycerol Ra from 3.33 to 2.74 micromol/kg/min). We conclude that debulking surgery fails to adequately suppress glucagon production and the alterations in substrate metabolism associated with excess glucagon. In these patients, somatostatin therapy can be an effective method to suppress secretion of glucagon and help attenuate its catabolic effects.
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PMID:Amino acid, glucose, and lipid kinetics after palliative resection in a patient with glucagonoma syndrome. 1139 51

Glucose is a major metabolic fuel in mammals and is transported into organs and cells by a facilitated diffusion which involves binding of glucose to glucose transporters (GLUTs). Among several GLUTs so far indentified, GLUT-2 is specifically localized immunocytochemV cally in beta-islet cells. Using immunocytochemical staining, normal pancreases and 27 cases of islet cell tumors, including insulinomas, gastrinomas, glucagonomas, pancreatic polypeptide-omas (PPomas), and a nonfunctioning islet cells tumor, were systematically stained for four different pancreatic hormones, gastrin, and GLUT-2. GLUT-2 staining in beta-islet cells was more diffuse than that of insulin immunostaining, and corresponded with the positive staining in the lateral segments of beta-cell plasma membrane, that faced adjacent beta-cells. Glucagon, somatostatin (SRIF) and PP cells stained weakly for GLUT-2, weaker than that of beta-cells. Some nonbeta cells, especially extra-islet PP cells were not stained for GLUT-2. Among islet cell tumors, insulinomas stained less strongly for GLUT-2 than normal beta-cells from the adjacent normal pancreas. Gastrinomas, glucagonomas, and PPomas stained weaker than insulinomas. Even nonfunctioning islet cell tumors were weakly stained for GLUT-2. The positive staining for GLUT-2 observed for islets cells and all islet tumors is consistent with the notion that all pancreatic islet cells and islet cell tumors utilize glucose as a major fuel, requiring transporter-facilitated diffusion of glucose into the cells of normal organ and their tumors.
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PMID:Immunocytochemical Localization of Glucose Transporter-2 (GLUT-2) in Pancreatic Islets and Islet Cell Tumors. 1211 1

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments beta cell mass via activation of beta cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce beta cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced beta cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased beta cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat beta cells exposed to interleukin 1beta, tumor necrosis fator alpha, and interferon gamma in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of beta-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of beta cell mass in vivo.
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PMID:Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. 1240 92

Glucagonomas are rare tumors originating in alpha-cells of the pancreas. The most common clinical presentation is the association of diabetes mellitus, necrolytic erythema, weight loss and anemia. The diagnosis of pancreatic tumor is usually made by abdominal computed tomography and/or endoscopic ultrasonography. Indium-labeled octreotide scanning is useful for the localization of most neuroendocrine tumors and their metastases. Glucagon release can be confirmed by a high concentration of plasma glucagon. We report the case of a 74-year-old patient who had a glucagonoma with particular presentation of neurological impairment and weight loss. The diagnosis was confirmed by usual imaging procedures and plasma glucagon level. Medical treatment was started with long-acting repeatable octreotide (Sandostatin(R) LAR). After a one-year follow-up, the patient remained well. The original presentation and benefit of a new, long-acting somatostatin analog for the treatment of inoperable glucagonoma are discussed.
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PMID:[Clinical response of an atypical glucagonoma treated with a long-acting somatostatin analog]. 1243 3

Glucagon-like peptide-1 (GLP-1, 7-36) is capable of restoring normal glucose tolerance in aging, glucose-intolerant Wistar rats and is a potent causal factor in differentiation of human islet duodenal homeobox-1-expressing cells into insulin-releasing beta cells. Here we report stable isotope-based dynamic metabolic profiles of rat pancreatic epithelial (ARIP) and human ductal tumor (PANC-1) cells responding to 10 nM GLP-1 treatment in 48 h cultures. Macromolecule synthesis patterns and substrate flow measurements using gas chromatography/mass spectrometry (MS) and the stable [1,2-13C2]glucose isotope as the tracer showed that GLP-1 induced a significant 20% and 60% increase in de novo fatty acid palmitate synthesis in ARIP and PANC-1 cells, respectively, and it also induced a significant increase in palmitate chain elongation into stearate utilizing glucose as the primary substrate. Distribution of 13C in other metabolites indicated no changes in the rates of nucleic acid ribose synthesis, glutamate oxidation, or lactate production. Tandem high-performance liquid chromatography-ion trap MS analysis of the culture media demonstrated mass insulin secretion by GLP-1-treated tumor cells. Metabolic profile changes in response to GLP-1-induced cell differentiation include selective increases in de novo fatty acid synthesis from glucose and consequent chain elongation, allowing increased membrane formation and greater insulin availability and release.
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PMID:GLP-1 stimulates glucose-derived de novo fatty acid synthesis and chain elongation during cell differentiation and insulin release. 1277 69

PP omas are rare, usually malignant tumours of the PP cells of the Langerhan's islets which secrete pancreatic polypeptide. The authors present two women operated for PP-omas of the pancreas. The first was 55 year-old woman in whom we did a cephalic duodenopancreatectomy (Whipple's procedure) for the tumor of the head of the pancreas with central cavity containing gas due to communication with the duodenum. Immunohistochemistry showed a PP oma with strong generalised immunoreactivity with antibodies against Chromogramin A, neuron specific enolasa and PP with more the 95% of tumor cells and coexpression of somatostatine in 35% and VIP in less then 5% of tumor cells. Following uneventful recovery the patient stayed symptom free so far and put 20 kilograms in weight. The second patient was 19 year-old girl with a multinodal tumor of almost the entire pancreas in whom a local excision of the nodal mass of the head of the pancreas had been carried out in the other hospital, three years ago and relaparotomy and tumor biopsy a month before admission to our institution. In her we did a total duodenopancreatectomy and standard lymphadenectomy for a multinodal mass occupying almost the entire pancreas. Immunohistochemistry showed a strong generalised immunoreactivity with antibodies against Chromographin A, Neuron specific enolasa and PP for more then 95% of tumors, cells. Glucagon was expressed in few focuses (in less then 1% of cells), somatostatin was expressed very rarely in single cells while the rest of tumor markers did not show a visible immunologic reactions in the majority of tumors, cells. Three years after surgery she died due to multiple liver secondaries.
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PMID:[Two cases of pancreatic head polypeptide tumors, one with a central cavity which fistulized into the duodenum]. 1469 35

Two patients with incidentally discovered adrenocortical adenomas underwent a series of pharmacological and physiological tests after pretreatment with dexamethasone. Illicit plasma cortisol responses to the serotonin (5-HT)4 receptor agonist cisapride were observed in the two patients. Significant increases in plasma cortisol levels were also noticed after glucagon and combined TRH/GnRH/GHRH stimulation tests in patient 1 and after administration of the lysine vasopressin precursor terlipressin in patient 2. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured tumor cells to serotonergic ligands and peptide hormones. In the two cases, 5-HT stimulated cortisol secretion from tumor cells with increased efficacy and/or potency to activate steroidogenesis by comparison with normal adrenocortical cells. The corticotropic effect of 5-HT was inhibited by the specific 5-HT4 receptor antagonist GR 113808 and more potently by methiothepin, a nonspecific serotonergic antagonist having no affinity for the 5-HT4 receptor. These results show that the hypersensitivity of the tumors to 5-HT was related to tissue expression of an ectopic serotonergic receptor in addition to the eutopic 5-HT4 receptor. In the two adenoma tissues, immunohistochemical studies revealed the presence of 5-HT-like immunoreactivity within clusters of steroidogenic cells, suggesting that 5-HT acted through an autocrine/paracrine mechanism to stimulate steroidogenesis. Glucagon and GnRH but not TRH, GHRH, and human chorionic gonadotropin stimulated cortisol secretion from tumor 1 cells. In conclusion, this study provides the first observation of adrenocortical cortisol-producing adenomas hypersensitive in vivo and in vitro to serotonergic agonists. Our results also show that cortisol-producing adenomas can express simultaneously several illegitimate receptors.
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PMID:Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies. 1613 68


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