118 results on '"Glucagonoma metabolism"'
Search Results
2. Foxa2, a novel protein partner of the tumour suppressor menin, is deregulated in mouse and human MEN1 glucagonomas.
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Bonnavion R, Teinturier R, Gherardi S, Leteurtre E, Yu R, Cordier-Bussat M, Du R, Pattou F, Vantyghem MC, Bertolino P, Lu J, and Zhang CX
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- Animals, Gene Expression Regulation, Neoplastic, Glucagonoma genetics, Hepatocyte Nuclear Factor 3-beta genetics, Humans, Mice, Transgenic, Multiple Endocrine Neoplasia Type 1 genetics, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Pancreatic Neoplasms genetics, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Transfection, Tumor Cells, Cultured, Glucagonoma metabolism, Hepatocyte Nuclear Factor 3-beta biosynthesis, Multiple Endocrine Neoplasia Type 1 metabolism, Pancreatic Neoplasms metabolism
- Abstract
Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including, in particular, insulin and glucagon. However, its expression and biological role in adult pancreatic α-cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α-cell-specific Men1 mutant mice, at both the transcriptional level and the protein level. More importantly, immunostaining analyses showed its prominent nuclear accumulation, specifically in α-cells, at a very early stage after Men1 disruption. Similar nuclear FOXA2 expression was also detected in a substantial proportion (12/19) of human multiple endocrine neoplasia type 1 (MEN1) glucagonomas. Interestingly, our data revealed an interaction between Foxa2 and menin encoded by the Men1 gene. Furthermore, using several approaches, we demonstrated the relevance of this interaction in the regulation of two tested Foxa2 target genes, including the autoregulation of the Foxa2 promoter by Foxa2 itself. The current study establishes menin, a novel protein partner of Foxa2, as a regulator of Foxa2, the biological functions of which extend beyond the pancreatic endocrine cells. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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- 2017
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3. Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver-α-Cell Axis.
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Holst JJ, Wewer Albrechtsen NJ, Pedersen J, and Knop FK
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- Animals, Feedback, Glucagonoma metabolism, Humans, Mice, Mutation, Pancreatic Neoplasms metabolism, Receptors, Glucagon genetics, Urea metabolism, Amino Acids metabolism, Glucagon metabolism, Glucagon-Secreting Cells metabolism, Glucose metabolism, Liver metabolism
- Abstract
Glucagon is usually viewed as an important counterregulatory hormone in glucose metabolism, with actions opposing those of insulin. Evidence exists that shows glucagon is important for minute-to-minute regulation of postprandial hepatic glucose production, although conditions of glucagon excess or deficiency do not cause changes compatible with this view. In patients with glucagon-producing tumors (glucagonomas), the most conspicuous signs are skin lesions (necrolytic migratory erythema), while in subjects with inactivating mutations of the glucagon receptor, pancreatic swelling may be the first sign; neither condition is necessarily associated with disturbed glucose metabolism. In glucagonoma patients, amino acid turnover and ureagenesis are greatly accelerated, and low plasma amino acid levels are probably at least partly responsible for the necrolytic migratory erythema, which resolves after amino acid administration. In patients with receptor mutations (and in knockout mice), pancreatic swelling is due to α-cell hyperplasia with gross hypersecretion of glucagon, which according to recent groundbreaking research may result from elevated amino acid levels. Additionally, solid evidence indicates that ureagenesis, and thereby amino acid levels, is critically controlled by glucagon. Together, this constitutes a complete endocrine system; feedback regulation involving amino acids regulates α-cell function and secretion, while glucagon, in turn, regulates amino acid turnover., (© 2017 by the American Diabetes Association.)
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- 2017
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4. Zinc and skin biology.
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Ogawa Y, Kawamura T, and Shimada S
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- Acrodermatitis metabolism, Adenosine Triphosphate chemistry, Alopecia metabolism, Alopecia Areata metabolism, Animals, Cation Transport Proteins genetics, Cation Transport Proteins metabolism, Cell Differentiation, Cell Proliferation, Dermis metabolism, Epidermis metabolism, Glucagonoma metabolism, Humans, Keratinocytes cytology, Keratinocytes metabolism, Langerhans Cells metabolism, Mutation, Skin Diseases metabolism, Zinc deficiency, Zinc metabolism, Skin metabolism, Skin Physiological Phenomena, Zinc physiology
- Abstract
Of all tissues, the skin has the third highest abundance of zinc in the body. In the skin, the zinc concentration is higher in the epidermis than in the dermis, owing to a zinc requirement for the active proliferation and differentiation of epidermal keratinocytes. Here we review the dynamics and functions of zinc in the skin as well as skin disorders associated with zinc deficiency, zinc finger domain-containing proteins, and zinc transporters. Among skin disorders associated with zinc deficiency, acrodermatitis enteropathica is a disorder caused by mutations in the ZIP4 transporter and subsequent zinc deficiency. The triad acrodermatitis enteropathica is characterized by alopecia, diarrhea, and skin lesions in acral, periorificial, and anogenital areas. We highlight the underlying mechanism of the development of acrodermatitis because of zinc deficiency by describing our new findings. We also discuss the accumulating evidence on zinc deficiency in alopecia and necrolytic migratory erythema, which is typically associated with glucagonomas., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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5. Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells.
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Fielitz K, Althoff K, De Preter K, Nonnekens J, Ohli J, Elges S, Hartmann W, Klöppel G, Knösel T, Schulte M, Klein-Hitpass L, Beisser D, Reis H, Eyking A, Cario E, Schulte JH, Schramm A, and Schüller U
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- Animals, Cell Line, Tumor, Disease Models, Animal, Gene Expression Profiling, Glial Fibrillary Acidic Protein metabolism, Glucagonoma genetics, Glucagonoma metabolism, Glucagonoma pathology, Humans, Immunohistochemistry, Mice, Mice, Transgenic, N-Myc Proto-Oncogene Protein metabolism, Neuroendocrine Tumors genetics, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors pathology, Pancreatic Neoplasms pathology, Pituitary Neoplasms pathology, Transcriptome, Gene Expression, Glial Fibrillary Acidic Protein genetics, Glucagon biosynthesis, N-Myc Proto-Oncogene Protein genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism, Pituitary Neoplasms genetics, Pituitary Neoplasms metabolism
- Abstract
Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies.
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- 2016
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6. Delayed diagnosis of glucagonoma syndrome: a case report.
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Huo J, Liu P, Chen X, Wu J, An J, and Ren J
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- Adult, Delayed Diagnosis, Female, Glucagonoma complications, Humans, Pancreatic Neoplasms complications, Paraneoplastic Endocrine Syndromes complications, Glucagon metabolism, Glucagonoma diagnosis, Glucagonoma metabolism, Necrolytic Migratory Erythema etiology, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Paraneoplastic Endocrine Syndromes diagnosis
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- 2016
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7. The biology of glucagon and the consequences of hyperglucagonemia.
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Wewer Albrechtsen NJ, Kuhre RE, Pedersen J, Knop FK, and Holst JJ
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- Diabetes Mellitus metabolism, Diabetes Mellitus pathology, Glucagon blood, Glucagon chemistry, Glucagon-Like Peptide 1 metabolism, Glucagonoma diagnosis, Glucagonoma metabolism, Humans, Liver metabolism, Neoplasms metabolism, Neoplasms pathology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Oxyntomodulin metabolism, Pancreas metabolism, Receptors, Glucagon deficiency, Receptors, Glucagon genetics, Receptors, Glucagon metabolism, Glucagon metabolism, Glucagonoma pathology
- Abstract
The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, hyperglucagonemia, may contribute to diabetes. However, hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.
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- 2016
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8. Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model.
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Barbu A, Lejonklou MH, and Skogseid B
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- Animals, Blotting, Western, Cell Hypoxia, Cell Line, Cells, Cultured, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Glucagonoma genetics, Glucagonoma metabolism, Granulins, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins metabolism, MAP Kinase Signaling System genetics, Mice, Knockout, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Progranulins, Proto-Oncogene Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Cell Proliferation genetics, Intercellular Signaling Peptides and Proteins genetics, Islets of Langerhans metabolism, Neuroendocrine Tumors genetics, Pancreatic Neoplasms genetics, Proto-Oncogene Proteins genetics
- Abstract
Objectives: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1(+/−) mice., Methods: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis., Results: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade., Conclusions: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.
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- 2016
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9. Do glucagonomas always produce glucagon?
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Wewer Albrechtsen NJ, Challis BG, Damjanov I, and Holst JJ
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- Animals, Gastrointestinal Diseases metabolism, Gene Expression Regulation, Glicentin metabolism, Glucagon-Like Peptide 1 metabolism, Humans, Hypoglycemia metabolism, Oxyntomodulin metabolism, Pancreas metabolism, Peptide Fragments, Peptides chemistry, Phenotype, Proglucagon metabolism, Protein Domains, Glucagon biosynthesis, Glucagon-Secreting Cells metabolism, Glucagonoma metabolism, Islets of Langerhans cytology, Pancreatic Neoplasms metabolism
- Abstract
Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.
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- 2016
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10. Conditional deletion of Men1 in the pancreatic β-cell leads to glucagon-expressing tumor development.
- Author
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Li F, Su Y, Cheng Y, Jiang X, Peng Y, Li Y, Lu J, Gu Y, Zhang C, Cao Y, Wang W, and Ning G
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- Animals, Female, Gene Deletion, Genotype, Glucagon-Secreting Cells physiology, Glucagonoma genetics, Male, Mice, Mice, Knockout, Pancreatic Neoplasms genetics, Transcription Factors, Gene Expression Regulation, Neoplastic physiology, Glucagon metabolism, Glucagonoma metabolism, Insulin-Secreting Cells metabolism, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins genetics
- Abstract
The tumor suppressor menin is recognized as a key regulator of β-cell proliferation. To induce tumorigenesis within the pancreatic β-cells, floxed alleles of Men1 were selectively ablated using Cre-recombinase driven by the insulin promoter. Despite the β-cell specificity of the RipCre, glucagon-expressing tumors as well as insulinomas developed in old mutant mice. These glucagon-expressing tumor cells were menin deficient and expressed the mature α-cell-specific transcription factors Brain-specific homeobox POU domain protein 4 (Brn4) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MafB). Moreover, the inactivation of β-cell-specific transcription factors was observed in mutant β-cells. Our work shows that Men1 ablation in the pancreatic β-cells leads to the inactivation of specific transcription factors, resulting in glucagon-expressing tumor development, which sheds light on the mechanisms of islet tumorigenesis.
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- 2015
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11. A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors.
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Halperin DM, Kulke MH, and Yao JC
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- Carcinoid Tumor metabolism, Carcinoid Tumor therapy, Gastrinoma metabolism, Gastrinoma therapy, Glucagonoma metabolism, Glucagonoma therapy, Humans, Insulinoma metabolism, Insulinoma therapy, Pancreatic Neoplasms metabolism, Vipoma metabolism, Vipoma therapy, Biomarkers, Tumor metabolism, Gastrointestinal Neoplasms therapy, Neuroendocrine Tumors therapy, Pancreatic Neoplasms therapy
- Abstract
Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.
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- 2015
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12. Necrolytic migratory erythema associated with alteration from predominantly gastrin-secreting to predominantly glucagon-secreting pancreatic neuroendocrine tumor.
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Kido-Nakahara M, Nakahara T, Miki M, Igarashi H, Ito T, and Furue M
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- Adult, Female, Gastrins blood, Glucagon blood, Glucagonoma complications, Humans, Neuroendocrine Tumors complications, Pancreatic Neoplasms complications, Paraneoplastic Syndromes etiology, Phenotype, Gastrinoma metabolism, Gastrins metabolism, Glucagon metabolism, Glucagonoma metabolism, Necrolytic Migratory Erythema etiology, Neuroendocrine Tumors metabolism, Pancreatic Neoplasms metabolism
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- 2014
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13. Enhanced glucagon-like peptide-1 secretion in a patient with glucagonoma: implications for glucagon-like peptide-1 secretion from pancreatic α cells in vivo.
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Yabe D, Rokutan M, Miura Y, Komoto I, Usui R, Kuwata H, Watanabe K, Hyo T, Kurose T, Nagamatsu T, Shimizu S, Kawai J, Imamura M, and Seino Y
- Subjects
- Adult, Arteries, Calcium Gluconate administration & dosage, Food, Glucagon blood, Glucagonoma surgery, Humans, Injections, Intra-Arterial, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 complications, Pancreatectomy, Glucagon-Like Peptide 1 metabolism, Glucagon-Secreting Cells metabolism, Glucagonoma metabolism
- Abstract
We examined GLP-1 secretion from the pancreas of a patient with glucagonoma and pancreatic resection by measuring GLP-1 after meal ingestion or selective arterial calcium injection, and immunohistochemical analysis. Our findings support the notion that GLP-1 is secreted from pancreatic α cells in humans., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
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- 2013
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14. Asymptomatic insulinoma: a case report and autopsy series.
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Kishi S, Sakamoto K, Mori M, Isogawa A, and Shiba T
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- Autopsy, Calcium Gluconate, Diagnosis, Differential, Early Detection of Cancer, Female, Glucagon metabolism, Glucagonoma diagnosis, Glucagonoma metabolism, Glucagonoma pathology, Glucagonoma physiopathology, Humans, Hypoglycemia etiology, Insulin blood, Insulin metabolism, Insulin Secretion, Insulinoma blood, Insulinoma pathology, Insulinoma physiopathology, Islets of Langerhans metabolism, Islets of Langerhans pathology, Islets of Langerhans physiopathology, Middle Aged, Pancreas metabolism, Pancreas pathology, Pancreas physiopathology, Pancreatic Neoplasms blood, Pancreatic Neoplasms pathology, Pancreatic Neoplasms physiopathology, Retrospective Studies, Tomography, X-Ray Computed, Insulinoma diagnostic imaging, Pancreas diagnostic imaging, Pancreatic Neoplasms diagnostic imaging
- Abstract
Aims: We investigated the prevalence and characterization of asymptomatic pancreatic tumors in response to our experience of asymptomatic insulinoma., Methods: A patient with a moderately low glucose level and pancreatic incidentaloma detected by CT was examined. Pancreas specimens from 423 autopsy cases were also pathologically examined systematically by hematoxylin-eosin staining., Results: The examined patient showed no profile characteristic of insulinoma by fasting or loading tests, however, ASVS led to diagnosis of insulin-producing tumor. The tumor was resected with the pancreatic body and tail and revealed to be 10 mm in diameter, with 98.5% of the cells positive for insulin. Pathological evaluation confirmed a well-differentiated endocrine pancreatic tumor, which was suggestive of an incidentally detected asymptomatic insulinoma. Microscopic evaluations of pancreatic specimens from 423 autopsy cases revealed pancreatic monotonous lesions in 6 cases (1.42%). In 4 autopsy specimens large enough for immuno-histochemical evaluation, the lesions were positive for glucagon but negative for insulin., Conclusions: As concerns the present study, retrospective immunohistochemical investigation in autopsy cases revealed the presence of asymptomatic glucagonoma but no asymptomatic insulinoma. Advances in diagnostic imaging, however, might raise the probability of detecting early asymptomatic stages of insulinoma incidentally. ASVS appears to be sensitive even for asymptomatic incidental insulinomas., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2012
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15. Diabetes Cured by Pancreaticoduodenectomy: A Case Report of Glucagonoma Masquerading as Carcinoma of the Head of Pancreas.
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Pandey D, Aiyer HM, and Pandey R
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- Adenocarcinoma diagnosis, Adenocarcinoma metabolism, Adult, Biomarkers, Tumor metabolism, Female, Glucagonoma diagnosis, Glucagonoma metabolism, Humans, Immunoenzyme Techniques, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Prognosis, Tomography, X-Ray Computed, Adenocarcinoma surgery, Diabetes Mellitus, Type 1 therapy, Glucagonoma surgery, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy
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- 2012
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16. Immunocytochemical staining for islet amyloid polypeptide in pancreatic endocrine tumors.
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Tomita T
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- Female, Glucagon analysis, Glucagon metabolism, Humans, Immunohistochemistry methods, Islet Amyloid Polypeptide analysis, Male, Somatostatin analysis, Somatostatin metabolism, Glucagonoma metabolism, Insulinoma metabolism, Islet Amyloid Polypeptide metabolism, Pancreatic Neoplasms metabolism
- Abstract
Aims/hypothesis: Islet amyloid polypeptide is originally identified as the chief constituent of amyloid in insulinomas and type 2 diabetic islets. This study aimed to identify islet amyloid polypeptide by immunocytochemical staining in pancreatic endocrine tumors including 30 cases of insulinomas and non-β-cell pancreatic endocrine tumors., Results: In normal islets, 62% of islet cells and 52% of insulin cells were granularly positive for insulin and IAPP, respectively, with more insulin positive cells than IAPP positive cells and some densely positive staining for insulin and IAPP in irregularly shaped a nuclear, degenerating islet β-cells. In pancreatic endocrine tumors, all 10 insulinomas were positive for islet amyloid polypeptide but 2 glucogonomas, 1 somatostatinoma, 6 of 7 pancreatic polypeptidomas, all 7 gastrinomas and all 3 non-functioning pancreatic endocrine tumors were negative for islet amyloid polypeptide whereas one pancreatic polypeptidoma was positive for islet amyloid polypeptide., Methods: Using commercially available rabbit anti-islet amyloid polypeptide antibody, immunocytochemical staining was performed on 30 cases of pancreatic endocrine tumors, consisting of 10 insulinomas, 2 glucagonomas, 1 somatostatinoma, 7 pancreatic polypeptidomas, 7 gastrinomas and 3 non-functioning pancreatic endocrine tumors. Pancreatic tissues containing pancreatic endocrine tumors were systematically immunostained for insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and chromogranin A, in addition to islet amyloid polypeptide. When normal pancreatic tissues adjacent to pancreatic endocrine tumors were present, insulin, glucagon, somatostatin and islet amyloid polypeptide positive cells were counted for a total of 20 islets, which were divided into large islets and medium islets for each case., Conclusions/interpretations: All 10 insulinomas and 1 pancreatic polypeptidoma were granularly positive for islet amyloid polypeptide, suggesting all 10 insulinomas contained enough insulin granules for IAPP whereas only one non-β-cell pancreatic endocrine tumor was co-localized with islet amyloid polypeptide in their secretary granules.
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- 2011
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17. Foetal proglucagon processing in relation to adult appetite control: lessons from a transplantable rat glucagonoma with severe anorexia.
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Jensen PB, Larsen PJ, Karlsen C, Jensen HI, Holst JJ, and Madsen OD
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- Animals, Anorexia chemically induced, Appetite Regulation drug effects, Glucagon-Like Peptide 1 adverse effects, Glucagon-Like Peptide-1 Receptor, Glucagonoma complications, Male, Neoplasm Transplantation, Peptide Fragments administration & dosage, Rats, Anorexia metabolism, Glucagon-Like Peptide 1 blood, Glucagonoma metabolism, Pancreatic Neoplasms metabolism, Proglucagon metabolism, Receptors, Glucagon antagonists & inhibitors, Taste
- Abstract
We have previously reported severe anorexia abruptly induced in rats 2-3 weeks after they have been transplanted subcutaneously with the glucagonoma MSL-G-AN. Vagotomy did not affect the time of onset and severity of anorexia, and the anorectic state resembles hunger with strongly elevated neuropeptide Y (NPY) mRNA levels in the nucleus arcuatus. We now show that circulating levels of bioactive glucagon-like peptide-1 (GLP-1) (7-36amide) start to increase above control levels exactly at the time of onset of anorexia. At this time-point, bioactive glucagon as well as total glucagon precursors and GLP-1 metabolites are already vastly elevated compared to controls. We further show that intravenous administration of very high concentrations of GLP-1 to hungry schedule-fed rats causes anorexia in a dose-dependent manner, which is blocked by the GLP-1 receptor antagonist exendin (9-39). GLP-1 (7-36amide) has a well-characterized anorectic effect but also causes taste aversion when administered centrally. The anorectic effect is blocked in rats treated neonatally by monosodium glutamate (MSG). We show that MSG treatment does not prevent the MSL-G-AN-induced anorexia, thereby suggesting a different type of anorectic function. We show a very strong component of taste aversion as anorectic rats, when presented to novel or known alternative food items, will resume normal feeding for 1 day, and then redevelop anorexia. We hypothetize that the anorexia in MSL-G-AN tumour-bearing rats correlates with a foetal processing pattern of proglucagon to both glucagon and GLP-1 (7-36amide), and is due to taste aversion. The sudden onset is characterized by a dramatic increase in circulating levels of biologically active GLP-1 (7-36amide), suggesting eventual saturation of proteolytic inactivation of its N-terminus., (© 2011 Blackwell Publishing Ltd.)
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- 2011
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18. A case of a giant glucagonoma with parathyroid hormone-related peptide secretion showing an inconsistent postsurgical endocrine status.
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Shirai K, Inoue I, Kato J, Maeda H, Moribata K, Shingaki N, Ueda K, Deguchi H, Maekita T, Iguchi M, Yanaoka K, Tamai H, Oka M, Kawai M, Yamaue H, Yasuoka H, Nakamura Y, Iso-O N, and Ichinose M
- Subjects
- Bone Neoplasms diagnosis, Bone Neoplasms metabolism, Bone Neoplasms secondary, Female, Glucagon metabolism, Glucagonoma diagnosis, Humans, Liver Neoplasms diagnosis, Liver Neoplasms metabolism, Liver Neoplasms secondary, Middle Aged, Pancreatic Neoplasms diagnosis, Postoperative Period, Glucagonoma metabolism, Glucagonoma surgery, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms surgery, Parathyroid Hormone-Related Protein metabolism
- Abstract
A 53-year-old woman was admitted because of a giant pancreatic tumor. Hypercalcemia and a high serum parathyroid hormone-related peptide (PTHrP) level were observed. A hypoglycemic attack occurred during pancreatectomy, and the surgical specimen revealed a PTHrP-secreting glucagonoma. Liver metastases developed 1 and 5.5 years later, and bone metastases appeared 6 years after surgery. Her serum PTHrP concentrations remained normal after surgery, despite re-elevation of the serum glucagon concentration after recurrence. The clinical course of this case illustrates the process of development of neuroendocrine tumors secreting two or more hormones.
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- 2011
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19. Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development.
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Lu J, Herrera PL, Carreira C, Bonnavion R, Seigne C, Calender A, Bertolino P, and Zhang CX
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- Age Factors, Aging metabolism, Aging pathology, Animals, Biomarkers metabolism, Cell Fusion, Cell Lineage, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genotype, Glucagon-Secreting Cells pathology, Glucagonoma genetics, Glucagonoma pathology, Insulin metabolism, Insulin-Secreting Cells metabolism, Insulin-Secreting Cells pathology, Insulinoma genetics, Insulinoma pathology, Mice, Mice, Knockout, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Phenotype, Proto-Oncogene Proteins genetics, Transcription Factors metabolism, Cell Transdifferentiation, Cell Transformation, Neoplastic metabolism, Glucagon metabolism, Glucagon-Secreting Cells metabolism, Glucagonoma metabolism, Insulinoma metabolism, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins deficiency
- Abstract
Background & Aims: The tumor suppressor menin is recognized as a key regulator of pancreatic islet development, proliferation, and beta-cell function, whereas its role in alpha cells remains poorly understood. The purpose of the current study was to address this issue in relation to islet tumor histogenesis., Methods: We generated alpha cell-specific Men1 mutant mice with Cre/loxP technology and carried out analyses of pancreatic lesions developed in the mutant mice during aging., Results: We showed that, despite the alpha-cell specificity of the GluCre transgene, both glucagonomas and a large amount of insulinomas developed in mutant mice older than 6 months, accompanied by mixed islet tumors. Interestingly, the cells sharing characteristics of both alpha and beta cells were identified shortly after the appearance of menin-deficient alpha cells but well before the tumor onset. Using a genetic cell lineage tracing analysis, we demonstrated that insulinoma cells were directly derived from transdifferentiating glucagon-expressing cells. Furthermore, our data indicated that the expression of Pdx1, MafA, Pax4, and Ngn3 did not seem to be required for the initiation of this transdifferentiation., Conclusions: Our work shows cell transdifferentiation as a novel mechanism involved in islet tumor development and provides evidence showing that menin regulates the plasticity of differentiated pancreatic alpha cells in vivo, shedding new light on the mechanisms of islet tumorigenesis., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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20. C-type natriuretic peptide receptor expression in pancreatic alpha cells.
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Burgess MD, Moore KD, Carter GM, Alli AA, Granda CS, Ichii H, Ricordi C, and Gower WR Jr
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- Adult, Glucagonoma metabolism, Glucagonoma pathology, Humans, Insulinoma metabolism, Insulinoma pathology, Male, Middle Aged, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, RNA, Messenger biosynthesis, Young Adult, Atrial Natriuretic Factor metabolism, Glucagon-Secreting Cells metabolism, Receptors, Atrial Natriuretic Factor biosynthesis
- Abstract
Atrial natriuretic peptide (ANP), brain type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) comprise a family of natriuretic peptides that mediate their biological effects through three natriuretic peptide receptor subtypes, NPR-A (ANP, BNP), NPR-B (CNP) and NPR-C (ANP, BNP, CNP). Several reports have provided evidence for the expression of ANP and specific binding sites for ANP in the pancreas. The purpose of this study was to identify the ANP receptor subtype and to localize its expression to a specific cell type in the human pancreas. NPR-C immunoreactivity, but neither ANP nor NPR-A, was detected in human islets by immunofluorescent staining. No immunostaining was observed in the exocrine pancreas or ductal structures. Double-staining revealed that NPR-C was expressed mainly in the glucagon-containing alpha cells. NPR-C mRNA and protein were detected in isolated human islets by RT-PCR and Western blot analysis, respectively. NPR-C expression was also detected by immunofluorescent staining in glucagonoma but not in insulinoma. ANP, as well as BNP and CNP, stimulated glucagon secretion from perifused human islets (1,111 +/- 55% vs. basal [7.3 fmol/min]; P < 0.001). This response was mimicked by cANP(4-23), a selective agonist of NPR-C. In conclusion, the NPR-C receptor is expressed in normal and neoplastic human alpha cells. These findings suggest a role for natriuretic peptides in the regulation of glucagon secretion from human alpha cells.
- Published
- 2009
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21. Cervical metastases of glucagonoma in a patient with multiple endocrine neoplasia type 1: report of a case.
- Author
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Butte JM, Montero PH, Solar A, Torres J, Olmos PR, Goñi I, Quintana JC, Martínez J, and Llanos O
- Subjects
- Adult, Cholecystectomy, Duodenal Neoplasms pathology, Duodenal Neoplasms secondary, Female, Glucagonoma metabolism, Glucagonoma surgery, Humans, Hyperplasia, Hypoglycemia etiology, Immunohistochemistry, Lymphatic Metastasis, Neck, Pancreatectomy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Parathyroid Glands pathology, Parathyroid Glands surgery, Splenectomy, Glucagonoma pathology, Multiple Endocrine Neoplasia Type 1 pathology, Pancreatic Neoplasms pathology
- Abstract
Multiple endocrine neoplasia type 1 (MEN 1) is a syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, duodenum, and pituitary gland. We report a case of cervical metastases of glucagonoma with MEN 1. The patient was a 34-year-old woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolactinoma and two upper GI hemorrhages secondary to duodenal ulcers. Computed tomography (CT) showed two hypervascular lesions in the tail of the pancreas and cervical ultrasound showed multiple hypoechogenic ovoid images in the neck. A cervical CT scan confirmed two 15-mm lymph nodes in the left cervical region and 111In-DOTATOC imaging showed focal abnormal somatostatin expression in the pancreatic tail and the cervical nodes. The patient had asymptomatic hypoglycemic episodes, with blood sugar levels as low as 30 mg/dl, which raised our suspicion of MEN 1 associated with pancreatic insulinoma. Thus, we performed a distal pancreatectomy with bilateral cervical dissection and parathyroid gland resection. Histopathological examination revealed 12 pancreatic tumors as well as metastases in four cervical lymph nodes. The resected parathyroid glands had normal structure, suggesting parathyroid hyperplasia. A follow-up CT scan, 18 months after surgery, showed new tumors in the head of the pancreas and in the duodenal wall. A pancreatoduodenectomy was performed and histopathological examination revealed nine nonfunctioning endocrine tumors in the pancreas, one tumor in the duodenal wall, and metastases in two peripancreatic lymph nodes. The patient recovered well and remains asymptomatic.
- Published
- 2008
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22. Neuroendocrine tumors of the pancreas.
- Author
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Dadan J, Wojskowicz P, and Wojskowicz A
- Subjects
- Carcinoma, Islet Cell metabolism, Gastrinoma diagnosis, Gastrinoma metabolism, Gastrinoma therapy, Glucagonoma diagnosis, Glucagonoma metabolism, Glucagonoma therapy, Humans, Insulinoma diagnosis, Insulinoma metabolism, Insulinoma therapy, Pancreatic Neoplasms metabolism, Somatostatinoma diagnosis, Somatostatinoma metabolism, Somatostatinoma therapy, Vipoma diagnosis, Vipoma metabolism, Vipoma therapy, Carcinoma, Islet Cell diagnosis, Carcinoma, Islet Cell therapy, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms therapy
- Abstract
The neuroendocrine tumors (NET) of the pancreas are very rare lesions with frequency of about 3 to 10 per 1 000 000 inhabitants. The neuroendocrine tumors composes a heterogeneous group of tumors. The gastro-entero-pancreatic tumors (GEP) constitute 70% of all NET and 2% of all digestive system tumors. There have been several attempts to classify those lesions and since 2000 exists WHO classification which divides NET according to malignancy and histologic structure. The most often NET of the pancreas are insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma. There is a recommendation to assay hormonal activity, measure concentration of specific peptides, biogenic amines and hormones produced by NET cells to establish diagnosis. Those tests are useful in monitoring treatment and in prognostication course of the disease. Imaging methods especially useful in localization GEP-NET are: ultrasound (US), endoscopic ultrasound (EUS), somatostatin receptor scintigraphy (SRS), computer tomography (CT), magnetic resonance (MR) and angiography. The most sensitive method in preoperative diagnosis seems to be EUS or less accessible intra ductal ultrasonography (IDUS). Surgical treatment depends on progression of disease as well as on localization of tumor and consists in both radical methods and palliative operations. The gold standard in pharmacological treatment are somatostatin analogs which can induce long-term remission even in inoperable lesions. Although NET of pancreas are very rare. they are still important diagnostic and therapeutic problem and requires interdisciplinary co-operation. The neuroendocrine tumors should be treated in centers with highest rank of references.
- Published
- 2008
23. Pancreatic glucagonoma presenting as necrolytic migratory erythema.
- Author
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Colombo E, Zuccoli R, Ugolini M, Dardano F, and Leigheb G
- Subjects
- Cell Movement, Glucagonoma diagnosis, Glucagonoma metabolism, Humans, Male, Middle Aged, Necrosis, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Erythema complications, Glucagonoma complications, Pancreatic Neoplasms complications
- Published
- 2007
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24. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years.
- Author
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Kindmark H, Sundin A, Granberg D, Dunder K, Skogseid B, Janson ET, Welin S, Oberg K, and Eriksson B
- Subjects
- Adult, Aged, Combined Modality Therapy, Erythema diagnosis, Female, Glucagon blood, Glucagonoma complications, Glucagonoma metabolism, Glucagonoma mortality, Glucagonoma pathology, Humans, Interferons, Liver Neoplasms secondary, Male, Middle Aged, Pancreatic Neoplasms complications, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Receptors, Somatostatin metabolism, Retrospective Studies, Sex Factors, Survival Analysis, Treatment Outcome, Antineoplastic Agents therapeutic use, Erythema complications, Glucagonoma therapy, Pancreatic Neoplasms therapy
- Abstract
Background: Glucagon-secreting endocrine pancreatic tumor is a rare disease, hence controlled studies on clinical management are lacking. In an attempt to assess the efficacy of diagnostic and therapeutic measures in patients with glucagonoma, a retrospective study was performed using the archives of a tertiary care center., Patients and Methods: Records from 340 patients with endocrine pancreatic tumors were reassessed and 23 patients with malignant endocrine pancreatic tumor and elevated plasma glucagon levels were identified., Results: About 7% of patients with histologically verified tumors fullfilled our criteria for glucagonoma. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma. Seventy eight percent had metastatic disease to the liver at diagnosis. Necrolytic migratory erythema was diagnosed or clinically suspected in 52%. Somatostatin receptor scintigraphy was positive in 95%. Nineteen patients received chemotherapy at some point, in 18 cases streptozotocin and 5 FU. With this treatment, objective radiological responses were seen in 50% of evaluable patients. Other treatment modalities used were interferon, somatostatin analogs, hepatic artery embolization, radio-frequency ablation of liver metastases, and radiolabeled somatostatin analogs. During the study period, 11 patients died at a median of 80 months from diagnosis whereas 11 patients are still alive after a median follow up of 52 months. One patient was lost to follow-up., Conclusions: Glucagonomas represent 7% of our comprehensive referral material of endocrine pancreatic tumors. Necrolytic migratory erythema was a common finding (52%) and diabetes less frequent at presentation than previously reported. Tumors were positive on somatostatin receptor scintigraphy and objective responses were seen to chemotherapy.
- Published
- 2007
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25. Metastatic glucagonoma: treatment with liver transplantation.
- Author
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Radny P, Eigentler TK, Soennichsen K, Overkamp D, Raab HR, Viebahn R, Mueller-Horvart C, Sotlar K, and Rassner G
- Subjects
- Antineoplastic Agents, Hormonal therapeutic use, Glucagon blood, Glucagonoma diagnostic imaging, Glucagonoma metabolism, Glucagonoma pathology, Humans, Immunohistochemistry, Liver Neoplasms diagnostic imaging, Liver Neoplasms metabolism, Liver Neoplasms pathology, Male, Middle Aged, Octreotide administration & dosage, Pancreatectomy, Pancreatic Neoplasms surgery, Radionuclide Imaging, Receptors, Somatostatin metabolism, Splenectomy, Glucagonoma secondary, Glucagonoma surgery, Liver Neoplasms secondary, Liver Neoplasms surgery, Liver Transplantation, Pancreatic Neoplasms pathology
- Abstract
Glucagonoma is a rare pancreatic endocrine tumor that is often both well developed and malignant at detection. In the case of metastatic spread the patient has a poor long-term prognosis. We hope to familiarize dermatologists and other specialists with this rare and potentially fatal disorder because early recognition of necrolytic migratory erythema, a clinical feature that may appear in patients with glucagonoma, can lead to possible cure, whereas delayed identification of the disease is associated with metastatic disease and a poor prognosis. We report the case of a 57-year-old patient with a metastatic glucagon-producing tumor; necrolytic migratory erythema was diagnosed and was successfully treated by a multimodal intervention including liver transplantation. Currently, 72 months after transplantation, our patient is in complete remission, which has been verified by somatostatin receptor scintigraphy monitoring, computed tomographic scanning and glucagon serum control. Increased awareness of the clinical symptoms and visible polymorphic mucocutaneous and nonspecific histopathologic features of glucagonoma syndrome is needed to avoid unnecessary delay in the diagnosis of this syndrome.
- Published
- 2006
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26. Glucagon release is regulated by tyrosine phosphatase and PI3-kinase activity.
- Author
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Chen J and Ostenson CG
- Subjects
- Androstadienes pharmacology, Animals, Arginine pharmacology, Cell Line, Tumor, Cricetinae, Enzyme Inhibitors pharmacology, Glucagon antagonists & inhibitors, Glucagonoma metabolism, Hypoglycemic Agents pharmacology, Immunoprecipitation, Insulin metabolism, Insulin Secretion, Male, Phosphoinositide-3 Kinase Inhibitors, Protein Tyrosine Phosphatases antagonists & inhibitors, Rats, Rats, Inbred Strains, Rats, Wistar, Signal Transduction, Vanadates pharmacology, Wortmannin, Glucagon metabolism, Phosphatidylinositol 3-Kinases metabolism, Protein Tyrosine Phosphatases metabolism
- Abstract
Since inhibition of protein tyrosine phosphatase (PTPase) activity by peroxovanadate (pV) affects insulin release and phosphorylation of pancreatic islet proteins in the insulin signaling pathway, we studied whether pV also modulates glucagon release. At 3.3mM glucose, pV (0.1-1mM) enhanced glucagon release in a dose-dependent manner in islets of normal Wistar and diabetic GK rats. Arginine-stimulated glucagon responses were higher in GK than in Wistar islets. These responses were inhibited by pV (0.01-0.1mM), also after islet exposure to pertussis toxin (PTX), but were abolished by 1 microM wortmannin. Moreover, in GK but not Wistar islets, wortmannin significantly stimulated basal glucagon secretion (p<0.05) and inhibited arginine-induced glucagon secretion (p<0.001). In In-R1-G9 glucagonoma cells, the inhibitory effect of pV (0.01 mM) on glucagon response to arginine was also observed and paralleled by increased IRS-1 and IRS-2 associated PI3-kinase activity. In conclusion, inhibition of PTPase activity by pV stimulates basal and inhibits arginine-induced glucagon release. The inhibitory effect of 0.01-0.1mM pV seems not to be accounted for by islet peptides acting on PTX sensitive G(i)-proteins. PI3-kinase activity seems to play an important role in pV-induced inhibition of glucagon release.
- Published
- 2004
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27. Cyclin-dependent kinase (cdk6) and p16 in pancreatic endocrine neoplasms.
- Author
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Tomita T
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Carcinoma, Islet Cell pathology, Cyclin-Dependent Kinase 6, Female, Gastrinoma metabolism, Gastrinoma pathology, Glucagonoma metabolism, Glucagonoma pathology, Humans, Immunoenzyme Techniques, Insulinoma metabolism, Insulinoma pathology, Islets of Langerhans pathology, Male, Middle Aged, Pancreatic Neoplasms pathology, Pancreatic Polypeptide metabolism, Carcinoma, Islet Cell metabolism, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Cyclin-Dependent Kinases metabolism, Islets of Langerhans metabolism, Pancreatic Neoplasms metabolism
- Abstract
Aims: p16 and p27, the inhibitors of cyclin-dependent kinases, have been reportedly decreased in certain human tumours, including a few endocrine tumours. The current study used immunocytochemical staining to compare the staining intensity of cdk6 and its inhibitor, p16, in pancreatic endocrine neoplasms with normal pancreatic islets., Methods: Twenty-four primary pancreatic endocrine neoplasms, consisting of 12 insulinomas, one glucagomoma, three pancreatic polypeptide (PP)-omas, five gastgrinomas and three non-fuctioning tumours, were immunocytochemically studied for cdk6 and p16 compared with the adjacent non-neoplastic islets., Results: In the normal islets, cdk6 staining was strongly positive for islet cell nuclei and cytoplasms, whereas p16 was strongly positively stained for islet cell cytoplasms. Insulinomas, glucagonoma, PP-omas and non-functioning tumours were weakly stained for cdk6 and p16. Among five gastrinomas, three tumours were moderately stained and two tumours were more weakly stained for cdk6 and p16. Thus, tumour cells were weaker stained for cdk6 and p16 compared with the strong staining of normal islet cells. No distinct immunostaining difference was observed among five kinds of pancreatic endocrine neoplasms., Conclusions: The decreased immunocytochemical staining for cdk6 and p16 is consistently observed in five kinds of pancreatic endocrine neoplasms. This decreased cdk6 and p16 in pancreatic endocrine neoplasms may be a part of the cell cycle event in tumour transformation and progression, and the same process may involve other endocrine tumours.
- Published
- 2004
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28. Glucagonoma and pseudoglucagonoma syndrome.
- Author
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Echenique-Elizondo M, Tuneu Valls A, Elorza Orúe JL, Martinez de Lizarduy I, and Ibáñez Aguirre J
- Subjects
- Aged, Diagnosis, Differential, Female, Glucagon metabolism, Glucagonoma epidemiology, Glucagonoma metabolism, Humans, Male, Middle Aged, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms metabolism, Retrospective Studies, Treatment Outcome, Glucagonoma diagnosis, Pancreatic Neoplasms diagnosis
- Abstract
Context: Glucagonoma syndrome may present either associated with a pancreatic neoplasm which secretes glucagon or as a pseudo-glucagonoma associated with other diseases. It is extremely infrequent but well-known with a current prevalence estimated at 1/20,000,000., Design: A retrospective review of glucagonoma and pseudoglucagonoma cases observed between January 1998 and December 2003 in three hospitals., Patients: Five cases: 3 with a demonstrable glucagon-secreting tumor and 2 cases without an associated neoplasm., Main Outcome Measures: Age, sex, initial diagnosis, associated symptoms, and pathology were analyzed as were procedures employed in diagnosis, imaging studies, laboratory data, surgery and follow-up., Results: Hyperglycemia and elevated plasma glucagon levels were found in all cases. In 3 cases, hypo-aminoacidemia and a descrease in fatty acids were found. No changes of zinc levels were observed. Abdominal ultrasound studies were of no value except in evaluating pancreatitis. A CT-scan was conclusive when a pancreatic neoplasm existed and 3 patients were operated on a curative basis., Discussion: Necrolytic migratory erythema was the key diagnosis in all cases. Surgery was intended to be curative. The follow-up was of 8, 37 and 57 months in the cases of true glucagonoma syndrome., Conclusions: A real prevalence of glucagonoma syndrome could be greater than currently estimated. In our series, it was 13.5/20,000,000. Pseudoglucagonoma syndrome remains a rarity.
- Published
- 2004
29. Genetic regulation of mouse glycosylphosphatidylinositol-phospholipase D.
- Author
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Flores-Borja F, Kieszkievicz J, Church V, Francis-West PH, Schofield J, Rademacher TW, and Lund T
- Subjects
- Amino Acid Sequence, Animals, Brain metabolism, DNA, Complementary, Diabetes Mellitus, Type 1 genetics, Glucagonoma metabolism, Glucagonoma pathology, Insulin metabolism, Liver embryology, Mice, Mice, Inbred C57BL, Mice, Inbred NOD embryology, Molecular Sequence Data, Phospholipase D metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Ribonucleases metabolism, Sequence Homology, Amino Acid, Gene Expression Regulation, Developmental, Liver enzymology, Phospholipase D genetics
- Abstract
Glycosylphosphatidylinositol phospholipase D (GPI-PLD) has been proposed to be responsible for cleaving membrane-associated glycosylphosphatidyl inositol (GPI) molecules to generate inositol phosphoglycan (IPGs), which have growth factor-mimetic properties. We have cloned the mouse liver GPI-PLD cDNA, which has a sequence that differs from that previously isolated from a mouse glucagonoma cell library. Using a highly specific and very sensitive RNase protection assay, we found that the GPI-PLD expressed in adult/post-natal brain, antrum and insulin-producing cells is identical to that isolated from liver. The expression of mouse GPI-PLD in liver shows a complex genetic regulation with a mouse strain-specific variation. In addition, GPI-PLD mRNA levels were higher in 4-week old animals compared to older animals, and the GPI-PLD mRNA levels increased in mice that developed insulin dependent type 1 diabetes spontaneously. This suggests that the expression of liver GPI-PLD in mice is highly regulated.
- Published
- 2004
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30. [Pancreatic islet cell endocrinopathies with carbohydrate metabolism disorders. Part I: Glucagonoma].
- Author
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Bronisz A and Junik R
- Subjects
- Diagnosis, Differential, Humans, Risk Factors, Glucagonoma diagnosis, Glucagonoma metabolism, Glucagonoma physiopathology, Glucagonoma therapy, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms physiopathology, Pancreatic Neoplasms therapy, Paraneoplastic Endocrine Syndromes diagnosis, Paraneoplastic Endocrine Syndromes physiopathology, Paraneoplastic Endocrine Syndromes therapy
- Published
- 2004
31. [Necrolytic migratory erythema revealing glucagonoma without diabetes].
- Author
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Marty C, Bennet A, Bayle P, Danjoux M, Lalande T, Marguery MC, and Bazex J
- Subjects
- Aged, Blood Glucose analysis, Erythema pathology, Follow-Up Studies, Glucagon blood, Glucagonoma blood, Glucagonoma metabolism, Glucagonoma surgery, Humans, Insulin metabolism, Insulin Secretion, Male, Necrosis, Pancreatic Neoplasms blood, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms surgery, Skin pathology, Syndrome, Time Factors, Erythema etiology, Glucagonoma diagnosis, Pancreatic Neoplasms diagnosis
- Abstract
We report a case of glucagonoma syndrome, revealed by a necrolytic migratory erythema that had developed for four Years, associated with anorexia, severe weight loss, anemia, hypoprotidemia, and hypoaminoacidemia. The fasting blood glucose level tended paradoxically to be low (0.6 g/l). Elevated plasma glucagon levels confirmed our diagnosis. The absence of diabetes was explained by an independent insulin secretion derived from this composite pancreatic tumor, authenticated by the histological analysis and the proinsulin level. This level was similar to those typically observed in insulinomas. Six Months after a complete surgical exeresis, symptoms disappeared and biological results returned to normal values.
- Published
- 2003
32. Amylin in pancreatic islets and pancreatic endocrine neoplasms.
- Author
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Tomita T
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Glucagon metabolism, Glucagonoma pathology, Humans, Immunoenzyme Techniques, Insulin metabolism, Insulinoma pathology, Islet Amyloid Polypeptide, Male, Middle Aged, Pancreatic Neoplasms pathology, Pancreatic Polypeptide metabolism, Somatostatin metabolism, Amyloid metabolism, Biomarkers, Tumor metabolism, Glucagonoma metabolism, Insulinoma metabolism, Islets of Langerhans metabolism, Pancreatic Neoplasms metabolism
- Abstract
Amylin is a chief constituent of the amyloid present in insulinomas, and is colocalized in beta islet cells. By immunocytochemical staining, all four islet cells including insulin, glucagon, somatostatin (SRIF) and pancreatic polypeptide (PP) cells were positively stained for amylin. The strongly insulin-positive cells corresponded with the strongly amylin-positive cells, and glucagon cells appeared to be strongly positive for amylin, whereas SRIF and PP cells were weakly positive for amylin. Among 37 cases of pancreatic endocrine neoplasms, insulinomas were more stronger stained for amylin than other islet cell tumors; however, amylin staining was the same or weaker than insulin staining. Glucagonomas and PP-omas were weakly positive for amylin, whereas six of 11 gastrinomas were weakly positive for amylin. It is concluded that three orthoendocrine tumors including insulinomas, glucagonomas and PP-omas were all positive for amylin, whereas ectopic hormone secreting gastrinomas were positive for amylin in six of 11 cases (55%). This colocalization of amylin with insulin, glucagon and PP may support a structure-function relationship of amylin and pancreatic hormones. The lesser immunoreactive amylin in pancreatic endocrine neoplasms than in normal islet cells may contribute to autonomous hypersecretion of hormones by pancreatic endocrine neoplasms.
- Published
- 2003
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33. Reproduction of features of the glucagonoma syndrome with continuous intravenous glucagon infusion as therapy for tumor-induced hypoglycemia.
- Author
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Case CC and Vassilopoulou-Sellin R
- Subjects
- Drug Eruptions pathology, Female, Glucagon administration & dosage, Glucagon adverse effects, Hemangioma complications, Humans, Infusions, Intravenous, Insulinoma complications, Lung Neoplasms complications, Male, Meningeal Neoplasms complications, Middle Aged, Pancreatic Neoplasms complications, Pleural Neoplasms complications, Sarcoma complications, Glucagon therapeutic use, Glucagonoma metabolism, Hypoglycemia drug therapy, Hypoglycemia etiology, Insulinoma metabolism, Pancreatic Neoplasms metabolism
- Abstract
Objective: To describe the adverse effects of continuous intravenous infusion of glucagon as therapy for tumor-induced hypoglycemia and to correlate these treatment-related effects with symptoms of endogenous hyper-glucagonemia., Methods: We reviewed three cases in which patients received continuous glucagon therapy for tumor-induced hypoglycemia and experienced adverse side effects to the treatment. We noted that these adverse events were consistent with changes that are described in the literature as symptoms of the glucagonoma syndrome., Results: Continuous intravenous glucagon infusion has evolved as a reliable and efficacious modality for the treatment of tumor-induced hypoglycemia. We report the adverse events of venous thromboembolism, necrolytic migratory erythema, and angular cheilitis in conjunction with continuous intravenous glucagon treatment. These complications resemble symptoms that characterize the human model of hyperglucagonemia--the glucagonoma syndrome--which is associated with hyperglucagonemia and alpha-islet cell neoplasms of the pancreas., Conclusion: Symptoms that characterize the islet cell neoplasm-related glucagonoma syndrome may develop in patients receiving an infusion of exogenous glucagon. This observation lends support to the suggestion that glucagon may have a direct, causative role.
- Published
- 2003
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34. Ghrelin expression in islet cell tumors: augmented expression of ghrelin in a case of glucagonoma with multiple endocrine neoplasm type I.
- Author
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Iwakura H, Hosoda K, Doi R, Komoto I, Nishimura H, Son C, Fujikura J, Tomita T, Takaya K, Ogawa Y, Hayashi T, Inoue G, Akamizu T, Hosoda H, Kojima M, Kangawa K, Imamura M, and Nakao K
- Subjects
- Adult, Blotting, Northern, Female, Ghrelin, Glucagonoma chemistry, Glucose Tolerance Test, Humans, Immunohistochemistry, Male, Middle Aged, Pancreatic Neoplasms chemistry, Peptide Hormones blood, RNA analysis, Reverse Transcriptase Polymerase Chain Reaction, Adenoma, Islet Cell metabolism, Gene Expression, Glucagonoma metabolism, Multiple Endocrine Neoplasia Type 1 genetics, Pancreatic Neoplasms metabolism, Peptide Hormones genetics
- Abstract
Ghrelin is a 28-amino acid peptide that regulates GH release together with GHRH and somatostatin. The expression of ghrelin has been detected in the stomach, small intestine, hypothalamus, pituitary gland, kidney, placenta, and testis. Recently it was reported that ghrelin is present in pancreatic alpha-cells and that it stimulates insulin secretion. In this study, we examined the ghrelin expression in two cases of glucagonoma and two cases of insulinoma by Northern blot analysis and immunohistochemistry. Ghrelin expression was identified in a case of glucagonoma associated with multiple endocrine neoplasm type I both by Northern blot analysis using total RNA and by immunohistochemistry, although the plasma ghrelin level was not elevated. This is the first case of tumor in which ghrelin gene expression was detected by Northern blot analysis using total RNA.
- Published
- 2002
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35. Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours.
- Author
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Cohen T, Herzog Y, Brodzky A, Greenson JK, Eldar S, Gluzman-Poltorak Z, Neufeld G, and Resnick MB
- Subjects
- Adenoma, Islet Cell diagnosis, Diagnosis, Differential, Gastrinoma diagnosis, Gastrinoma metabolism, Glucagonoma diagnosis, Glucagonoma metabolism, Humans, Immunoenzyme Techniques, Insulinoma diagnosis, Insulinoma metabolism, Neuroendocrine Tumors diagnosis, Neuroendocrine Tumors metabolism, Neuropilin-1, Pancreatic Neoplasms diagnosis, Receptors, Cell Surface metabolism, Adenoma, Islet Cell metabolism, Biomarkers, Tumor metabolism, Islets of Langerhans metabolism, Nerve Tissue Proteins metabolism, Pancreatic Neoplasms metabolism
- Abstract
Neuropilin-2 (NP-2) is a cell surface transmembrane protein originally characterized as a receptor for the type 3 semaphorins, and more recently for a number of vascular endothelial growth factor (VEGF) isoforms. NP-2 expression has been recently localized to a subset of neuroendocrine cells in the gastrointestinal tract. The aim of this study was to define the expression pattern of NP-2 in normal pancreatic islets and to determine the utility of NP-2 expression as a diagnostic marker of pancreatic endocrine tumours. Paraffin-embedded tissue sections from 30 endocrine pancreatic tumours (EPTs) and from normal pancreas were immunostained with a rabbit polyclonal antibody generated towards NP-2. Nineteen of the tumours were hormonally functional (nine insulinomas, nine gastrinomas, and one glucagonoma). The NP-2 staining pattern was correlated with islet cell hormone expression. In addition, NP-2 expression was evaluated in other normal neuroendocrine tissues and neuroendocrine neoplasms. In normal pancreas, NP-2 stained a distinct subset of islet cells situated primarily at the islet periphery. Double immunohistochemical staining revealed co-localization with glucagon-expressing cells. Moderate to strong NP-2 staining was present in 27 of 30 EPTs. Serial staining of the pancreatic tumours with insulin, gastrin, glucagon, pancreatic polypeptide (PP) or somatostatin did not reveal a distinct pattern of co-localization. NP-2 expression was not detected in neuroendocrine cells outside the gastroenteropancreatic system, or in their corresponding neoplasms, except for focal staining in one bronchial carcinoid tumour. In conclusion, the vast majority of EPTs examined expressed NP-2, suggesting its utility as a diagnostic marker for these tumours. The function of NP-2 in islet cell biology or tumourigenesis remains to be elucidated., (Copyright 2002 John Wiley & Sons, Ltd.)
- Published
- 2002
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36. Immunohistochemical localization of human kallikreins 6 and 10 in pancreatic islets.
- Author
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Petraki CD, Karavana VN, Revelos KI, Luo LY, and Diamandis EP
- Subjects
- Glucagonoma metabolism, Humans, Immunohistochemistry, Insulinoma metabolism, Pancreatic Neoplasms metabolism, Staining and Labeling, Islets of Langerhans metabolism, Kallikreins biosynthesis, Pancreatic Diseases metabolism
- Abstract
Tissue kallikreins are thought to be present in the pancreatic islets of Langerhans and to aid in the conversion of proinsulin to insulin. In recent immunohistochemical studies, we observed strong staining of the newly identified human kallikreins 6 and 10 (hK6 and hK10) in the islets of Langerhans. Here, we examine hK6 and hK10 immunoexpression in different types of islet cells of the endocrine pancreas, in order to obtain clues for hK6 and hK10 function in these cells. Ten cases of normal pancreatic tissue, two cases of nesidioblastosis, five insulin-producing tumours and one case of multiple endocrine neoplasia 1 syndrome, containing an insulin-, a somatostatin- and several glucagon-producing tumours, as well as tiny foci of endocrine dysplasia with different predominance of the secreted hormones (mainly glucagon and pancreatic polypeptide) were included in the study. A streptavidin--biotin--peroxidase and an alkaline phosphatase protocol, as well as a sequential immunoenzymatic double staining method were performed, using specific antibodies against hK6, hK10, insulin, glucagon, somatostatin, pancreatic polypeptide, and serotonin. hK6 and hK10 immunoexpression was observed in the islets of Langerhans, including the pancreatic polypeptide-rich islets, in the normal pancreas. Scattered hK6 and hK10 positive cells were localized in relationship with pancreatic acinar cells. In the exocrine pancreas, a cytoplasmic and/or brush border hK6 and hK10 immunoexpression was observed in the median and small sized pancreatic ducts, while the acinar cells were negative. Foci of nesidioblastosis and endocrine dysplasia expressed both kallikreins. hK6 and hK10 were also strongly and diffusely expressed throughout all insulin-, glucagon- and somatostatin-producing tumours. The double staining method revealed co-localization of each hormone and hK6/hK10 respectively, in the same cellular population, in the normal as well as in the diseased pancreas. Our results support the view that hK6 and hK10 may be involved in insulin and other pancreatic hormone processing and/or secretion, as well as in physiological functions related to the endocrine pancreas.
- Published
- 2002
- Full Text
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37. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior.
- Author
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Canavese G, Azzoni C, Pizzi S, Corleto VD, Pasquali C, Davoli C, Crafa P, Delle Fave G, and Bordi C
- Subjects
- Adenoma, Islet Cell pathology, Adult, Aged, Biomarkers, Tumor metabolism, Carcinoid Tumor pathology, Cell Division, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Cyclins metabolism, Female, Gastrinoma metabolism, Gastrinoma pathology, Gastrointestinal Neoplasms pathology, Glucagonoma metabolism, Glucagonoma pathology, Humans, Immunohistochemistry, Insulinoma metabolism, Insulinoma pathology, Ki-67 Antigen metabolism, Male, Middle Aged, Pancreatic Neoplasms pathology, Tumor Suppressor Protein p53 metabolism, Adenoma, Islet Cell metabolism, Carcinoid Tumor metabolism, Cell Cycle Proteins metabolism, Gastrointestinal Neoplasms metabolism, Pancreatic Neoplasms metabolism, Tumor Suppressor Proteins metabolism
- Abstract
The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53. p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors. p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P =.02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases. Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors., (Copyright 2001 by W.B. Saunders Company)
- Published
- 2001
- Full Text
- View/download PDF
38. Amino acid, glucose, and lipid kinetics after palliative resection in a patient with glucagonoma syndrome.
- Author
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Bernstein M, Jahoor F, Townsend CM Jr, and Klein S
- Subjects
- Combined Modality Therapy, Female, Glucagonoma surgery, Humans, Infusions, Intravenous, Insulin administration & dosage, Insulin therapeutic use, Lipolysis drug effects, Middle Aged, Palliative Care, Pancreatic Neoplasms surgery, Somatostatin administration & dosage, Somatostatin therapeutic use, Amino Acids metabolism, Glucagonoma metabolism, Glucose metabolism, Lipid Metabolism, Pancreatic Neoplasms metabolism
- Abstract
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., (Copyright 2001 by W.B. Saunders Company)
- Published
- 2001
- Full Text
- View/download PDF
39. Synthesis of gamma-carboxylated polypeptides by alpha-cells of the pancreatic islets.
- Author
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Stenberg LM, Nilsson E, Ljungberg O, Stenflo J, and Brown MA
- Subjects
- 1-Carboxyglutamic Acid immunology, Animals, Antibodies, Monoclonal, Clone Cells, Glucagonoma metabolism, Humans, Immunohistochemistry, Insulinoma metabolism, Mice, Pancreatic Neoplasms metabolism, Protein S metabolism, Prothrombin metabolism, Vitamin K metabolism, 1-Carboxyglutamic Acid metabolism, Islets of Langerhans metabolism, Protein Biosynthesis, Proteins chemistry
- Abstract
gamma-Carboxylated proteins were detected in normal human pancreas by immunohistochemistry with a monoclonal antibody (M3B) specific for gamma-carboxyglutamyl residues. Staining appeared to be localized to the glucagon-secreting alpha-cells in the islets of Langerhans. Consistent with this, sections from a glucagonoma were stained much more intensely with the M3B antibody than those from an insulinoma. A murine alpha-cell line (alphaTC1 Clone 9) was cultured and gamma-carboxylated polypeptides, identified immunologically as prothrombin, protein S and (tentatively) Gas6, were isolated from the intracellular compartment by chromatography on an M3B-coupled resin. As in liver, prothrombin is synthesized by alpha-cells as a gamma-carboxylated zymogen that can be cleaved by ecarin to form an active serine protease that is inhibited by hirudin. The pancreas thus appears to be a novel site of synthesis for certain vitamin K-dependent proteins.
- Published
- 2001
- Full Text
- View/download PDF
40. Immunohistochemical assessment of an asymptomatic glucagonoma in a patient with hypergastrinemia and marked antral angiodysplasia.
- Author
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Weitgasser R, Sungler P, Hauser-Kronberger C, Dietze O, Sattlegger P, and Hacker GW
- Subjects
- Diagnosis, Differential, Gastric Antral Vascular Ectasia pathology, Glucagon metabolism, Glucagonoma pathology, Humans, Immunohistochemistry, Male, Middle Aged, Multiple Endocrine Neoplasia Type 1 diagnosis, Pancreatic Neoplasms pathology, Pyloric Antrum pathology, Gastric Antral Vascular Ectasia etiology, Gastrins blood, Glucagonoma complications, Glucagonoma metabolism, Pancreatic Neoplasms complications, Pancreatic Neoplasms metabolism
- Abstract
A 58-year-old patient had been treated for recurrent gastritis. Numerous gastroscopies indicated hemorrhagic gastritis combined with increasingly severe anemia. The patient was admitted with a hemoglobin of 4.4 g/dL. Gastroscopy showed marked antral angiodysplasia. Serum samples for gastrin were taken and found to be elevated (170-250 U/mL). The search for a gastrin-producing tumor with abdominal ultrasound, computed tomography, octreotide scan, and secretin test was negative, but angiography detected a pancreas tumor with a 2-cm diameter. Partial pancreatectomy and partial gastrectomy were performed. Immunohistochemical examination of the tumor did not show a gastrinoma but did show glucagon-reactive tissue. Further tumors or elevated plasma hormone levels were not detected, and a multiple endocrine neoplasia type I syndrome could be excluded. We thus found antral angiodysplasia with hypergastrinemia leading to detection of a glucagonoma diagnosed by immunohistochemistry. After more than 4 years of follow-up, the patient is without any symptoms or signs of relapse or secondary hormone syndrome.
- Published
- 2001
41. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells.
- Author
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Perren A, Komminoth P, Saremaslani P, Matter C, Feurer S, Lees JA, Heitz PU, and Eng C
- Subjects
- Adult, Aged, Aged, 80 and over, Base Sequence genetics, DNA Mutational Analysis, Female, Gene Expression, Glucagonoma genetics, Glucagonoma pathology, Humans, Immunohistochemistry, Insulinoma genetics, Insulinoma pathology, Loss of Heterozygosity, Male, Middle Aged, PTEN Phosphohydrolase, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Phosphoric Monoester Hydrolases genetics, Polymorphism, Single-Stranded Conformational, Reference Values, Tissue Distribution, Glucagonoma metabolism, Insulinoma metabolism, Islets of Langerhans metabolism, Pancreatic Neoplasms metabolism, Phosphoric Monoester Hydrolases metabolism, Subcellular Fractions metabolism, Tumor Suppressor Proteins
- Abstract
The pathogenesis of sporadic endocrine pancreatic tumors (EPTs) is still primarily unknown. Comparative genomic hybridization studies revealed loss of 10q in a significant number (nine of 31) of EPTs. The tumor suppressor gene PTEN lies on 10q23, and so, is a candidate to play some role in EPT pathogenesis. Germline PTEN mutations are found in Cowden and Bannayan-Riley-Ruvalcaba syndromes, whereas somatic mutations and deletions are found in a variety of sporadic cancers. The mutation and expression status of PTEN in EPTs has not yet been examined. Mutation analysis of the entire coding region of PTEN including splice sites was performed in 33 tumors, revealing one tumor with somatic L182F (exon 6). Loss of heterozygosity of the 10q23 region was detected in eight of 15 informative malignant (53%) and in none of seven benign EPTs. PTEN expression was assessed in 24 available EPTs by immunohistochemistry using a monoclonal anti-PTEN antibody. Of these 24, 23 tumors showed strong immunoreactivity for PTEN. Only the EPTs with PTEN mutation lacked PTEN protein expression. Although normal islet cells always exhibited predominantly nuclear PTEN immunostaining, 19 of 23 EPTs had a predominantly cytoplasmic PTEN expression pattern. Exocrine pancreatic tissue was PTEN-negative throughout. PTEN mutation is a rare event in malignant EPTs and PTEN protein is expressed in most (23 of 24) EPTs. Thus, intragenic mutation or another means of physical loss of PTEN is rarely involved in the pathogenesis of EPTs. Instead, either an impaired transport system of PTEN to the nucleus or some other means of differential compartmentalization could account for impaired PTEN function. Loss of heterozygosity of the 10q23 region is a frequent event in malignant EPTs and might suggest several hypotheses: a different tumor suppressor gene in the vicinity of PTEN might be principally involved in EPT formation; alternatively, 10q loss, including PTEN, seems to be associated with malignant transformation, but the first step toward neoplasia might involve altered subcellular localization of PTEN.
- Published
- 2000
- Full Text
- View/download PDF
42. [Glucagon-secreting malignant neuroendocrine tumor of the pancreas].
- Author
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Wickenhauser C, Aichelmann E, Neuhaus H, Hölscher AH, and Dienes HP
- Subjects
- Adrenal Gland Neoplasms secondary, Aged, Diabetes Mellitus diagnosis, Diagnosis, Differential, Glucagonoma metabolism, Humans, Liver Neoplasms secondary, Male, Multiple Endocrine Neoplasia diagnosis, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Adrenal Gland Neoplasms diagnosis, Glucagon metabolism, Glucagonoma diagnosis, Glucagonoma secondary, Liver Neoplasms diagnosis, Pancreatic Neoplasms diagnosis
- Abstract
Background: Glucagonoma is a rare pancreatic tumor of islet alpha 2 cells. Fewer than 200 cases have been reported worldwide, with an estimated incidence of 1 in 20 million. In general, the disease is characterized by a well-defined clinical syndrome which typically shows as necrotic migratory erythema of the skin, weight loss, diabetes mellitus, anemia, cheilosis and stomatitis. Since pancreatic glucagonomas are predominantly located in the tail and findings of radiographic or sonographic examination can remain unspecific, patients often present already metastasis when diagnosis is first established., Case Report: We report the case of a 67-year-old man with an extended malignant glucagonoma of the pancreas infiltrating already the hilus of the spleen and, additionally, presenting metastatic lesions in the liver and the left adrenal gland. A monohormonal expression of glucagon could be ascertained by serological and immunohistochemical analysis. The special feature of this case is that the tumor was not associated with the characteristic skin rash., Conclusion: An unclear migratory erythema combined with diabetes mellitus and stomatitis/cheilosis should lead to the differential diagnosis of glucagonoma. Isolated glucagonomas are very difficult to find out and often diagnosed already presenting metastasis.
- Published
- 2000
- Full Text
- View/download PDF
43. [Pancreatic endocrine tumor--from clinic to calcium sensing receptor].
- Author
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Imamura M
- Subjects
- Calcium metabolism, Gastrins blood, Humans, Infusions, Intra-Arterial, Pancreatic Function Tests methods, Receptors, G-Protein-Coupled, Receptors, Gastrointestinal Hormone metabolism, Secretin administration & dosage, Calcium-Binding Proteins physiology, Gastrinoma diagnosis, Gastrinoma metabolism, Glucagonoma diagnosis, Glucagonoma metabolism, Insulinoma diagnosis, Insulinoma metabolism, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Vipoma chemically induced, Vipoma metabolism
- Published
- 2000
44. A particularly aggressive combined glucagonoma and gastrinoma syndrome.
- Author
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Balian A, Fromont C, Naveau S, Bonte E, Belloula D, Giraud V, Montembault S, Capron F, and Chaput JC
- Subjects
- Adult, Diabetic Ketoacidosis etiology, Fatal Outcome, Female, Gastrinoma complications, Gastrinoma metabolism, Glucagonoma complications, Glucagonoma metabolism, Humans, Neoplasms, Multiple Primary metabolism, Pancreatic Neoplasms metabolism, Peptic Ulcer etiology, Gastrinoma diagnosis, Glucagonoma diagnosis, Neoplasms, Multiple Primary diagnosis, Pancreatic Neoplasms diagnosis
- Abstract
Duodeno-pancreatic biochemically polyfunctional endocrine tumour is a well known entity. Usually, only one hormone is responsible for the clinical features. We report a case of aggressive combined glucagonoma and gastrinoma tumour without metastases, causing respectively diabetic ketoacidosis and fulminant peptic ulcer, and death. Occasional patients can present with clinical features of both glucagonoma and gastrinoma. Diabetic patients exhibiting migratory skin lesions should be suspected of glucagonoma. In addition, a multidisciplinary approach to such patients including dermatologists, surgeons, radiologists and endoscopists is mandatory.
- Published
- 1999
- Full Text
- View/download PDF
45. The entero-insular axis in glucagonoma. A report of 2 cases.
- Author
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Ranganath L, Bayoumi H, Ghatei M, and Morgan L
- Subjects
- Aged, Female, Humans, Insulin Secretion, Male, Middle Aged, Dietary Carbohydrates, Glucagonoma metabolism, Insulin metabolism, Pancreatic Neoplasms metabolism
- Published
- 1999
- Full Text
- View/download PDF
46. Protein metabolism in glucagonoma.
- Author
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Barazzoni R, Zanetti M, Tiengo A, and Tessari P
- Subjects
- Adult, Amino Acids blood, Blood Glucose metabolism, C-Peptide blood, Deuterium, Female, Glucagon blood, Glucagonoma blood, Humans, Infusions, Intravenous, Insulin blood, Leucine administration & dosage, Leucine metabolism, Male, Middle Aged, Pancreatic Neoplasms blood, Phenylalanine administration & dosage, Phenylalanine metabolism, Protein Biosynthesis, Reference Values, Tyrosine administration & dosage, Tyrosine metabolism, Amino Acids metabolism, Glucagonoma metabolism, Pancreatic Neoplasms metabolism, Proteins metabolism
- Abstract
Although protein wasting and reduced amino acid concentrations are common findings in glucagonoma patients, the mechanisms underlying these alterations are unclear. Therefore, we studied basal postabsorptive leucine, phenylalanine and tyrosine turnover following L-[D3]-Leucine, L-[D5]-Phenylalanine and L-[D2]-Tyrosine i.v. infusions in one male and one female patient with glucagonoma, compared with healthy control volunteers. Plasma amino acid concentrations were reduced (-40 to 80%, delta >2 SD vs. control subjects) in both patients. Plasma leucine, phenylalanine and tyrosine rates of appearance in patients with glucagonoma were similar to values in the control subjects, except leucine rate of appearence in the female patient with glucagonoma (+ approximately 30%, delta >2 SD). In contrast, the intracellular leucine rate of appearence, reflecting protein degradation, was considerably increased in both patients (+60-80%, delta >2 SD). Phenylalanine hydroxylation was moderately higher only in the male patient with glucagonoma (+ approximately 30%, delta >2 SD). Leucine, phenylalanine and tyrosine clearances (+100-300%), as well as phenylalanine hydroxylative clearance (+75-100%) were also increased in the patients. In conclusion, whole-body protein breakdown is enhanced in patients with glucagonoma compared with healthy control subjects. Phenylalanine hydroxylative clearance is also higher. Reduced plasma amino acid concentrations are probably due, at least in part, to their increased clearance. These alterations could contribute to the determination of the catabolic state of the glucagonoma syndrome.
- Published
- 1999
- Full Text
- View/download PDF
47. Asymptomatic glucagonoma presenting with an isolated hepatic nodule.
- Author
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De Giorgio R, Migliori M, Lalli S, Montini GC, Gullo L, Corinaldesi R, Bordi C, and Tomassetti P
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Adult, Biomarkers, Tumor metabolism, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Glucagonoma metabolism, Humans, Immunohistochemistry, Liver Neoplasms metabolism, Magnetic Resonance Imaging, Male, Neoplasms, Multiple Primary metabolism, Neoplasms, Multiple Primary pathology, Glucagonoma pathology, Liver Neoplasms pathology
- Abstract
A 37-year-old male patient, without any particular symptoms apart from moderate right upper quadrant postprandial pain, was found to have a liver mass identified as a glucagon-producing tumor. Plasma glucagon levels were slightly increased, whereas those of other gut peptides were within the normal range. Despite an extensive pre- and intraoperative diagnostic work-up, a presumed primary glucagonoma remained undetected. This unusual presentation with the absence of any symptoms typical of glucagonoma, as well as the presence of histopathological features characteristic of both benign and malignant forms of glucagonoma, make this case very peculiar. A clinically silent, apparently unrelated adenocarcinoma of the left colon was also found. The concomitant presence of a glucagonoma and a carcinoma of the large intestine has not been previously reported, and its significance remains unclear.
- Published
- 1998
48. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours.
- Author
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Terris B, Scoazec JY, Rubbia L, Bregeaud L, Pepper MS, Ruszniewski P, Belghiti J, Fléjou J, and Degott C
- Subjects
- Adult, Aged, Antibodies, Monoclonal metabolism, Blotting, Western, Carcinoma, Islet Cell pathology, Female, Gastrinoma metabolism, Gastrinoma pathology, Gastrointestinal Neoplasms pathology, Glucagonoma metabolism, Glucagonoma pathology, Humans, Immunohistochemistry, Insulinoma metabolism, Insulinoma pathology, Male, Middle Aged, Pancreatic Neoplasms pathology, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Carcinoma, Islet Cell metabolism, Endothelial Growth Factors biosynthesis, Gastrointestinal Neoplasms metabolism, Lymphokines biosynthesis, Pancreatic Neoplasms metabolism
- Abstract
Aims: Angiogenesis is a complex multistep process essential for tumour growth. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and vascular permeability-inducing agent. Recent studies have shown that VEGF expression is correlated to microvessel density and tumour progression. The aim of this study was to analyse VEGF expression in a series of gastrointestinal neuroendocrine tumours., Methods and Results: Surgical specimens from 28 gastrointestinal carcinoids and 20 pancreatic endocrine tumours were examined for VEGF expression by immunohistochemistry. Intense cytoplasmic staining for VEGF was observed in several cells of the islets of Langerhans and in neuroendocrine cells of normal digestive mucosa. All midgut carcinoids showed strong VEGF expression in tumoral cells. Positive VEGF immunostaining was observed in 16 of 20 neuroendocrine pancreatic tumours but it was usually much lower than in midgut carcinoids. Western blotting analysis in eight cases identified a major band at 30-32 kDa. No correlation between VEGF expression and tumour stage was found., Conclusions: This study demonstrates that neuroendocrine cells are a major source of VEGF, particularly in midgut carcinoids. This finding suggests that the presence of VEGF may be required to maintain the differentiated state of capillary vessels in these hypervascular tumours. Such secretion, in conjunction with the other growth factors synthesized by these neuroendocrine tumours, may have an important role in tumour growth.
- Published
- 1998
- Full Text
- View/download PDF
49. Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus.
- Author
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Jensen PB, Blume N, Mikkelsen JD, Larsen PJ, Jensen HI, Holst JJ, and Madsen OD
- Subjects
- Animals, Female, Glucagon blood, Glucagon-Like Peptide 1, Glucagonoma metabolism, Male, Neoplasm Transplantation, Peptide Fragments blood, Protein Precursors blood, Rats, Weight Loss, Anorexia etiology, Arcuate Nucleus of Hypothalamus metabolism, Drinking, Glucagonoma complications, Neuropeptide Y genetics, Pancreatic Neoplasms complications, RNA, Messenger analysis
- Abstract
We have isolated a stable, transplantable, and small glucagonoma (MSL-G-AN) associated with abrupt onset of severe anorexia occurring 2-3 wk after subcutaneous transplantation. Before onset of anorexia, food consumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventually resulting in reduction of food and water intake of 100 and 80%, respectively. During the anorectic phase, the rats eventually become hypoglycemic and hypothermic. The tumor-associated anorexia shows no sex difference, and is not affected by bilateral abdominal vagotomy, indicating a direct central effect. The adipose satiety factor leptin, known to suppress food intake by reducing hypothalamic neuropeptide Y (NPY) levels, was not found to be expressed by the tumor, and circulating leptin levels were reduced twofold in the anorectic phase. A highly significant increase in hypothalamic (arcuate nucleus) NPY mRNA levels was found in anorectic rats compared with control animals. Since elevated hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude that the MSL-G-AN glucagonoma releases circulating factor(s) that overrides the hypothalamic NPY-ergic system, thereby eliminating the orexigenic effect of NPY. We hypothesize a possible central role of proglucagon-derived peptides in the observed anorexia.
- Published
- 1998
- Full Text
- View/download PDF
50. [Glucagonoma and somatostatinoma].
- Author
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Totsuka Y
- Subjects
- Glucagon metabolism, Glucose metabolism, Humans, Insulin metabolism, Insulin Secretion, Insulinoma complications, Glucagonoma metabolism, Pancreatic Neoplasms metabolism, Somatostatinoma metabolism
- Published
- 1998
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