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Sample records for insulinoma

  1. MRI in insulinomas

    International Nuclear Information System (INIS)

    Liessi, Guido; Pasquali, Claudio; Alfano D'Andrea, Alfonso; Pedrazzoli, Sergio; Scandellari, Cesare

    1992-01-01

    After establishing the diagnosis of an insulinoma, most surgeons prefer preoperative localization. Selective arteriography is usually considered the gold standard for this purpose. Recently, computed tomography (CT) and preoperative US have contended the role to angiography. MRI has been used in few cases of endocrine pancreatic tumors, and its role in this particular field has to be defined. Between November 1988-September 1990 7 adult patients who had undergone surgery were evaluated. Eight tumors were resected in 6 patients who were cured; in an 18-year-old woman surgical treatment was unsuccessful. Arterio-graphy, CT, preoperative US, MRI and intraoperative US detected 2, 6, 6, 5 and 6 tumors respectively. Two insulinomas (0.2 and 0.7 cm) were found at histologic examination in resected specimen. The ability of intra-operative US and careful surgical exploration to resolve more than 90 percent of cases makes the preoperative use of arteriography and CT questionable value. If further experience confirms these findings, US and MRI may suffice. (author). 13 refs.; 3 figs.; 1 tab

  2. An Atypical Presentation on Insulinoma

    Science.gov (United States)

    2017-06-16

    PUBLICATIONS/ PRESENTATIONS 1. TO: CLINICAL RESEARCH 2. FROM: (Author’s Name, Rank, Grade, Office Symbol) 3. GME/GHSE STUDENT: 4. PROTOCOL NUMBER: Kluesner...PROCESSING OF PROFESSIONAL MEDICAL RESEARCH/TECHNICAL PUBLICATIONS/ PRESENTATIONS 1st ENDORSEMENT (59 MDW/SGVU Use Only) TO: Clinical Research Division 24...CAPT JOSEPH KLUESNER FROM: 59 MDW/SGYU SUBJECT: Professional Presentation Approval 1. Your paper, entitled An Atypical Presentation of Insulinoma

  3. Insulinoma canino: relato de caso

    Directory of Open Access Journals (Sweden)

    L. Padovani

    Full Text Available RESUMO O insulinoma é um tumor das células β do pâncreas, que têm a função de produzir e secretar insulina e, geralmente são malignos em cães. O presente trabalho descreve o diagnóstico e o manejo terapêutico de três casos de insulinoma. Os sinais clínicos dos animais relatados variaram de acordo com a severidade e a duração da hipoglicemia. O diagnóstico presuntivo se deu através dos sinais clínicos e da dosagem de insulina sérica no momento de mais intensa hipoglicemia e, o diagnóstico definitivo foi obtido por meio de exame histopatológico nos três casos relatados. O tratamento realizado variou de acordo com a intensidade dos sinais clínicos.

  4. Insulinoma

    Science.gov (United States)

    After fasting, your blood may be tested for: Blood C-peptide level Blood glucose level Blood insulin level Drugs ... to lower insulin production and prevent hypoglycemia. A water pill (diuretic) is given with this medicine to ...

  5. Insulinoma-Induced Hypoglycemia in a Patient with Insulinoma after Gastrojejunostomy for Prepyloric Ulcer

    Directory of Open Access Journals (Sweden)

    Yavuz Savas Koca

    2015-01-01

    Full Text Available Hyperinsulinism due to dumping syndrome following gastric surgery is an uncommon condition. It is specified with hypoglycemic attacks. However, linking symptoms to dumping syndrome in each patient to whom gastric surgery was performed leads to inappropriate diagnosis and therapy. Insulinoma and other causes that give rise to hyperinsulinemia should not be ignored and these diagnoses should be excluded. In this paper, 71-year-old male patient who was followed up for 2 years with a false conclusion of dumping syndrome and operated on due to insulinoma diagnosed at endoscopic ultrasonography is presented in the light of the literature.

  6. Antitumorigenic effect of proteasome inhibitors on insulinoma cells

    DEFF Research Database (Denmark)

    Størling, Joachim; Allaman-Pillet, Nathalie; Karlsen, Allan E

    2004-01-01

    inhibition of the proteasome has an antitumorigenic potential in insulinoma cells. Exposure of mouse betaTC3 insulinoma cells to the proteasome inhibitor N-Acetyl-Leu-Leu-Nle-CHO (ALLN) reduced cell viability, activated caspase-3, induced apoptosis, and suppressed insulin release. Treatment with ALLN also...

  7. Tratamiento del insulinoma con diazóxido Insulinoma treated with diazoxide

    Directory of Open Access Journals (Sweden)

    M. V. Mateu

    2003-01-01

    Full Text Available Los insulinomas son tumores pancreáticos de las células beta que segregan insulina en cantidad suficiente como para producir hipoglucemia. Habitualmente benignos se manifiestan como adenomas solitarios, y en menor medida como microadenomas múltiples o carcinomas. Con una incidencia anual de un caso por millón de habitantes, generalmente en adultos de más de 30 años, se localizan con mayor frecuencia en el cuerpo y cola del páncreas. El diagnóstico se realiza sobre la base de los síntomas, la glucemia por debajo de 50mg% y niveles elevados de insulina plasmática y péptido C en ayunas. El mejor método preoperatorio para localizar el tumor es la arteriografía subselectiva del tronco celíaco. La mayoría de los adenomas que no logran evidenciarse por estudios por imágenes se diagnostican durante la cirugía. El tratamiento de elección del insulinoma es la cirugía. Cuando ésta fracasa o se contraindica, se utiliza tratamiento médico con diazóxido. Presentamos un caso de un paciente con un insulinoma que fue tratado médicamente, con excelente respuesta, realizando una actualización de las manifestaciones clínicas, los métodos diagnósticos y las opciones terapéuticas de una enfermedad muy poco frecuente.Insulinomas are islet cell tumors of the pancreas that produce hypoglycemia due to inappropriate insulin secretion. They appear generally as solitary adenomas, and less commonly as multifocal microadenomas or malignant insulinomas. Their incidence is approximately one case per 1 million population per year, and they appear mostly in patients above thirty years old. They are mainly situated in the pancreas tail or body. The diagnosis is based on the symptoms related to hypoglycemia, a blood glucose level under 50mg% and high levels of fast insulin and C-peptide. Selective angiography is the best preoperative procedure to localize the tumor. Occult adenomas, which cannot be represented by preoperative imaging diagnosis, are

  8. An unusual case of concurrent insulinoma and nesidioblastosis.

    Science.gov (United States)

    Bright, Elizabeth; Garcea, Giuseppe; Ong, Seok L; Madira, Webster; Berry, David P; Dennison, Ashley R

    2008-09-02

    Endogenous hyperinsulinaemic hypoglycaemia in adults is most commonly caused by an insulinoma. Adult nesidioblastosis is rarely reported. To the best of our knowledge the presence of both insulinoma and nesidioblastosis has not been reported before. We report a case of a 35-year-old female presenting with neuroglycaemic symptoms. A supervised 72-hour fast confirmed hypoglycaemia in the presence of hyperinsulinaemia. Thorough pre-operative biochemical and radiological investigations, including selective splenic, superior mesenteric and portal venous sampling inferred a tentative diagnosis of adult nesidioblastosis. However, a grossly elevated insulin level within the splenic vein on a second set of venous sampling produced a high index of suspicion for the presence of an insulinoma. At surgical exploration both an insulinoma and nesidioblastosis were identified and confirmed by histological examination. We report an even rarer entity of concurrent insulinoma and nesidioblastosis.

  9. Road Accident due to a Pancreatic Insulinoma

    Science.gov (United States)

    Parisi, Amilcare; Desiderio, Jacopo; Cirocchi, Roberto; Grassi, Veronica; Trastulli, Stefano; Barberini, Francesco; Corsi, Alessia; Cacurri, Alban; Renzi, Claudio; Anastasio, Fabio; Battista, Francesca; Pucci, Giacomo; Noya, Giuseppe; Schillaci, Giuseppe

    2015-01-01

    Abstract Insulinoma is a rare pancreatic endocrine tumor, typically sporadic and solitary. Although the Whipple triad, consisting of hypoglycemia, neuroglycopenic symptoms, and symptoms relief with glucose administration, is often present, the diagnosis may be challenging when symptoms are less typical. We report a case of road accident due to an episode of loss of consciousness in a patient with pancreatic insulinoma. In the previous months, the patient had occasionally reported nonspecific symptoms. During hospitalization, endocrine examinations were compatible with an insulin-producing tumor. Abdominal computerized tomography and magnetic resonance imaging allowed us to identify and localize the tumor. The patient underwent a robotic distal pancreatectomy with partial omentectomy and splenectomy. Insulin-producing tumors may go undetected for a long period due to nonspecific clinical symptoms, and may cause episodes of loss of consciousness with potentially lethal consequences. Robot-assisted procedures can be performed with the same techniques of the traditional surgery, reducing surgical trauma, intraoperative blood loss, and hospital stays. PMID:25816027

  10. [Double localization of pancreatic insulinoma. Diagnostic and therapeutic difficulties].

    Science.gov (United States)

    Ungureanu, C D; David, L; Braşoveanu, V; Herlea, V; Coculescu, M; Popescu, I

    2005-01-01

    Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. Because most of insulinomas are less than 2 cm in size and rarely they not may be visible by CT scan or transabdominal ultrasonography. Intraoperative ultrasonography may be a solution. Although as surgical method is preferred enucleation because operative time is shorter and easier and the low frequency postoperative complications, pancreaticoduodenectomy Whipple is indicated in selected cases. We report a case of double insulinoma located in the head of the pancreas in which the diagnosis and surgical treatment presented difficulties which determined a particular clinical evolution.

  11. Particular aspects of a pancreatic insulinoma case

    Directory of Open Access Journals (Sweden)

    Motoc R

    2016-06-01

    Full Text Available With a very low incidence (1-4 cases per 1 million per year, characterized by insulin hypersecretion, independent of the glycemia control system, insulinoma is a rare endocrine tumor, clinical with accentuated neuropsychological symptoms that hampers clinical diagnosis. We present a case of a 33 years old patient with no notable personal history, active lifestyle, non-smoker, a work environment that doesn’t involve professional toxicity; a remarkable family history of a brother with type 1 diabetes mellitus and grandmother with liver adenocarcinoma was noticed; in this particular case Whipple triad was strongly suggestive, gastrointestinal upper-ultrasonography endoscopy with tissue puncture as a tumor diagnostic tool was used and laparotomy was used successfully for removing the tumor, with favorable follow-up.

  12. Concurrent insulinoma with mosaic Turner syndrome: A case report.

    Science.gov (United States)

    Wang, Shaoyun; Yang, Lijuan; Li, Jie; Mu, Yiming

    2015-03-01

    Turner syndrome is a chromosomal abnormality in which the majority of patients have a 45XO karyotype, while a small number have a 45XO/47XXX karyotype. Congenital adrenal hyperplasia has been previously reported in patients with Turner syndrome. Although insulinomas are the most common type of functioning pancreatic neuroendocrine tumor and have been reported in patients with multiple endocrine neoplasias, the tumors have not been reported in patients with mosaic Turner syndrome. The present study reports the first case of an insulinoma in a patient with 45XO/47XXX mosaic Turner syndrome. The patient suffered from recurrent hypoglycemia, which was relieved following ingestion of glucose or food. A 5-h glucose tolerance test was performed and the levels of glucose, C-Peptide and insulin were detected. In addition, computed tomography (CT) and ultrasound scanning were performed to evaluate the possibility of an insulinoma. Pathological examination and karyotyping were performed on a surgical specimen and a whole blood sample, respectively. The patient was found to suffer from premature ovarian failure, and a physical examination was consistent with a diagnosis of Turner syndrome. An ultrasound scan demonstrated streak ovaries and the patient was found to have a 45XO/47XXX karyotype. Furthermore, a lesion was detected in the pancreas following CT scanning, which was identified as an insulinoma following surgical removal and histological examination. In conclusion, the present study reports the first case of an insulinoma in a patient with mosaic Turner syndrome. Since mosaic Turner syndrome and insulinoma are rare diseases, an association may exist that has not been previously identified.

  13. Laparoscopic surgery for solitary insulinoma in the absence of IOUS

    Directory of Open Access Journals (Sweden)

    Abhay Narendra Dalvi

    2018-01-01

    Full Text Available Background: Insulinomas are the most common pancreatic neuroendocrine neoplasms. In spite of adequate pre-operative localisation, conventional surgical methods rely on intraoperative palpation. Intraoperative ultrasonography (IOUS is said to aid in accurate localisation, decreases morbidity. Laparoscopic removal of pancreatic endocrine neoplasms is beneficial due to magnification and minimal invasion; however, in the absence of IOUS, error of judgement may lead to conversion to open surgery, thereby relying on 'palpation method' to localise the tumour. We combined laparoscopic surgical removal of insulinomas using an innovative method of 'laparoscopic finger palpation' with intraoperative blood glucose monitoring and frozen section for surgical cure. Materials and Methods: Patients were evaluated and investigated by the department of endocrinology and referred for surgical management of insulinoma. Pre-operative localisation of insulinoma was done by either contrast-enhanced computerised tomography angiogram – arterial and venous phase, or endoscopic ultrasound (EUS or DOTATATE scan. Intraoperative localisation was done by laparoscopic dissection and 'laparoscopic finger palpation'. After enucleation, the specimen was sent for frozen section, and in the interim period, serial monitoring of blood glucose was done by the anaesthetist. Maintenance of glucose levels for more than 45 min after enucleation and confirmation of neuroendocrine tumour on frozen section was the end point of surgical procedure. Results: A total of 19 patients were subjected to laparoscopic removal of solitary insulinomas. Enucleation was performed in 16 patients successfully. In three patients, laparoscopic distal pancreatectomy was performed. Three patients had pancreatic duct leak, of which two patients responded to conservative approach and the third patient required drainage by USG-guided pigtail catheter. All patients are cured of their disease and no patient has had

  14. Malignant insulinoma: The problems of tumour localization and ...

    African Journals Online (AJOL)

    Malignant insulinomas of the pancreas are rare tumours, accounting for 10% of ... Histological examination showed a R-cell malignant tumour of the pancreas with ... Associated vaso-. SA MEDICAL JOURNAL VOLUME 63 23 APRIL 1983 ... 52 cases of pancreatic endocrine malignant tumours, which have similar behaviour.

  15. Road accident due to a pancreatic insulinoma: a case report.

    Science.gov (United States)

    Parisi, Amilcare; Desiderio, Jacopo; Cirocchi, Roberto; Grassi, Veronica; Trastulli, Stefano; Barberini, Francesco; Corsi, Alessia; Cacurri, Alban; Renzi, Claudio; Anastasio, Fabio; Battista, Francesca; Pucci, Giacomo; Noya, Giuseppe; Schillaci, Giuseppe

    2015-03-01

    Insulinoma is a rare pancreatic endocrine tumor, typically sporadic and solitary. Although the Whipple triad, consisting of hypoglycemia, neuroglycopenic symptoms, and symptoms relief with glucose administration, is often present, the diagnosis may be challenging when symptoms are less typical. We report a case of road accident due to an episode of loss of consciousness in a patient with pancreatic insulinoma. In the previous months, the patient had occasionally reported nonspecific symptoms. During hospitalization, endocrine examinations were compatible with an insulin-producing tumor. Abdominal computerized tomography and magnetic resonance imaging allowed us to identify and localize the tumor. The patient underwent a robotic distal pancreatectomy with partial omentectomy and splenectomy. Insulin-producing tumors may go undetected for a long period due to nonspecific clinical symptoms, and may cause episodes of loss of consciousness with potentially lethal consequences. Robot-assisted procedures can be performed with the same techniques of the traditional surgery, reducing surgical trauma, intraoperative blood loss, and hospital stays.

  16. Insulinoma: A rare cause of hypoglycemia in a young female

    Directory of Open Access Journals (Sweden)

    Fnu Kelash

    2014-09-01

    Full Text Available Insulinoma is an exceedingly uncommon pancreatic islet cell neuroendocrine tumor. The estimated incidence is approximately four cases per million individuals per year and accounts for 60% of islets cell tumors. It causes glycopenic symptoms which includes headache, feeling irritable, confused, seizure or coma and leads to catecholamine excess which includes rapid heartbeat, sweating, palpitations and feelings of hunger. Early detection of the tumor prevents recurrent episodes of lethal hypoglycemia.

  17. Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.

    Science.gov (United States)

    Hamze, Z; Vercherat, C; Bernigaud-Lacheretz, A; Bazzi, W; Bonnavion, R; Lu, J; Calender, A; Pouponnot, C; Bertolino, P; Roche, C; Stein, R; Scoazec, J Y; Zhang, C X; Cordier-Bussat, M

    2013-12-01

    The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated β-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and β-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the β-cell differentiation/proliferation balance, which could contribute to tumorigenesis.

  18. Scaffold Architecture Controls Insulinoma Clustering, Viability, and Insulin Production

    Science.gov (United States)

    Blackstone, Britani N.; Palmer, Andre F.; Rilo, Horacio R.

    2014-01-01

    Recently, in vitro diagnostic tools have shifted focus toward personalized medicine by incorporating patient cells into traditional test beds. These cell-based platforms commonly utilize two-dimensional substrates that lack the ability to support three-dimensional cell structures seen in vivo. As monolayer cell cultures have previously been shown to function differently than cells in vivo, the results of such in vitro tests may not accurately reflect cell response in vivo. It is therefore of interest to determine the relationships between substrate architecture, cell structure, and cell function in 3D cell-based platforms. To investigate the effect of substrate architecture on insulinoma organization and function, insulinomas were seeded onto 2D gelatin substrates and 3D fibrous gelatin scaffolds with three distinct fiber diameters and fiber densities. Cell viability and clustering was assessed at culture days 3, 5, and 7 with baseline insulin secretion and glucose-stimulated insulin production measured at day 7. Small, closely spaced gelatin fibers promoted the formation of large, rounded insulinoma clusters, whereas monolayer organization and large fibers prevented cell clustering and reduced glucose-stimulated insulin production. Taken together, these data show that scaffold properties can be used to control the organization and function of insulin-producing cells and may be useful as a 3D test bed for diabetes drug development. PMID:24410263

  19. Embolization of an Insulinoma of the Pancreas with Trisacryl Gelatin Microspheres as Definitive Treatment

    International Nuclear Information System (INIS)

    Rott, Gernot; Biggemann, Martin; Pfohl, Martin

    2008-01-01

    Insulinomas are rare, mostly benign neuroendocrine tumors, originating in 99% of cases from the pancreas, that synthesize and secrete insulin, causing symptomatic hypoglycemia. Today the treatment of choice is surgical removal. We present the case of an 84-year-old woman with a symptomatic insulinoma who refused surgery and was treated with arterial embolization using trisacryl gelatin microspheres as definitive treatment

  20. Insulinoma in a black South African : a case report

    International Nuclear Information System (INIS)

    Huddle, K.R.L.; Mannell, A.; Hale, M.J.; Denath, F.M.

    1990-01-01

    A 69-year-old black woman with an insulinoma presented with recurrent episodes of sweating and confusion culminating in two episodes of hypoglycaemic coma. The diagnosis was confirmed by finding an inappropriately elevated serum insulin level in the presence of hypoglycaemia after a fast of 14 hours. Computed tomography revealed a large tumour in the head of the pancreas. Removal of the tumour necessitated partial resection of the head and body of the pancreas, which in turn necessitated certain repair and drainage procedures. Postoperative complications, while not insignificant, were acceptable. At 1-year follow-up the patient is well. 4 figs., 4 refs

  1. Severe deterioration of psoriasis due to an insulinoma.

    LENUS (Irish Health Repository)

    Field, S

    2008-03-01

    We report a case of a 56-year-old woman who presented with a severe exacerbation of psoriasis with concurrent hypoglycaemic episodes. Methotrexate 17.5 mg weekly was required to control her psoriasis. Investigation of her hypoglycaemia showed raised levels of insulin, C-peptide and proinsulin. Radiological investigation showed a tumour at the tail of the pancreas and the diagnosis was insulinoma. A spleen-preserving distal pancreatectomy was performed and the hypoglycaemic symptoms resolved. Immediately following the pancreatectomy, methotrexate was stopped and the patient\\'s psoriasis went into remission. During a 2-year follow-up, she has required only minimal topical treatment for her skin.

  2. Experiencia clínica sobre 37 casos de insulinoma Clinical experience in 37 cases of insulinoma

    Directory of Open Access Journals (Sweden)

    Adriana G. Diaz

    2006-12-01

    Full Text Available El insulinoma es el tumor neuroendocrino pancreático más frecuente. Se manifiesta por signos adrenérgicos y de neuroglucopenia. Su diagnóstico se confirma documentando la existencia de hipoglucemia junto a una inapropiada secreción de insulina. Desde 1988 fueron estudiados 23 mujeres (48 ± 18 años y 14 varones (45 ± 19 años con diagnóstico de insulinoma. La evolución de la enfermedad hasta el diagnóstico fue de 2.8 ± 2.1 años. Veintisiete pacientes (73% presentaron principalmente síntomas de neuroglucopenia, y el 27% refirió síntomas adrenérgicos. El laboratorio mostró glucemia en ayunas 32.4 ± 8.7 mg/dl, insulina (RIA 38.2 ± 39.7 µU/ml (n=11, insulina (quimioluminiscencia 23.8 ± 18.1 µU/ml (n=26, péptido C 1.15 ± 1.6 nmol/l (n=14. El test de ayuno prolongado fue diagnóstico a las 9.0 ± 5.2 horas (n=21. La localización preoperatoria fue posible en el 73% por imágenes, arteriografía con estimulación de calcio y/o ecografía intraoperatoria. Once casos fueron operados por laparoscopia, y el resto por vía convencional. El diagnóstico fue confirmado por histología e inmunohistoquímica. Veintidos pacientes (61.1% presentaron insulinomas únicos (16 en cuerpo y cola, 6 en la cabeza y proceso uncinado, 6 eran portadores de insulinomas múltiples, 5 de insulinomas malignos, 1 de nesidioblastosis del adulto y en 2 casos los hallazgos fueron incaracterísticos. En 3 pacientes se halló un glucagonoma asociado (1 de ellos con NEM1. Una paciente no fue operada recibiendo tratamiento con verapamilo, con buena respuesta clínica. El seguimiento postquirúrgico fue de 60.4 ± 59.9 meses.Insulinoma is the most frequent pancreatic islet cell tumor. Clinical manifestations include adrenergic and neuroglycopenic symptoms. Diagnosis is established through demonstration of inappropriately elevated insulin serum concentrations in the presence of hypoglycemia. The aim of this study is to show our experience in the management of

  3. Tumor thrombus formation in two dogs with insulinomas.

    Science.gov (United States)

    Hambrook, Lydia E; Kudnig, Simon T

    2012-10-15

    A 9-year-old sexually intact male Staffordshire Bull Terrier and a 9-year-old neutered male Boxer were evaluated for intermittent neurologic signs including muscle tremors, ataxia, episodic collapse, disorientation, and seizures. Both dogs had low blood glucose and high serum insulin concentrations. Results of abdominal ultrasonography were unremarkable for both dogs. Exploratory laparotomy revealed a mass that extended from the body of the pancreas into the pancreaticoduodenal vein in each dog. Marginal resection of pancreatic masses was performed, and tumor thrombi were removed via venotomy in both dogs. Histologic evaluation indicated the masses were pancreatic islet cell tumors with tumor thrombi. Clinical signs resolved following surgical resection of tumors and tumor thrombi, and the dogs were euglycemic during the follow-up period (17 and 45 months after surgery). Although gross tumor thrombus formation has been identified in humans with insulinomas, tumor thrombi have not been previously reported for dogs with insulinomas. Surgical removal of tumor thrombi via venotomy seemed to be well tolerated by the dogs. Tumor thrombus formation did not seem to adversely affect prognosis for the 2 dogs of this report.

  4. Andrographolide Suppress Tumor Growth by Inhibiting TLR4/NF-κB Signaling Activation in Insulinoma

    Science.gov (United States)

    Zhang, Qian-Qian; Ding, Yi; Lei, Yan; Qi, Cui-Ling; He, Xiao-Dong; Lan, Tian; Li, Jiang-Chao; Gong, Ping; Yang, Xuesong; Geng, Jian-Guo; Wang, Li-Jing

    2014-01-01

    Insulinomas are rare tumors, and approximately 10% of insulinomas are malignant. Accumulating evidence has implicated that we still lack effective therapy to treat the patients who are diagnosed with rare malignant insulinoma. Previous studies have reported that Andrographolide (Andro) could inhibit cell cycle progression, reduce cell invasion and induce cell apoptosis in many common cancer cells. However, the effects of andro are cell type-dependent. So we emplored the β-TC-6 cells and the RIP1-Tag2 transgenic mouse model of endogenously growing insulinoma model to elucidate the possible anti-cancer effect of Andro on insulinoma, an uncommon type of malignant cancers in this study. Our experiments revealed that Andro significantly inhibited tumor growth at both the early-stage and the advanced-stage of insulinoma through targeting the TLR4/NF-κB signaling pathway. This work initially provides the evidence that the TLR4/NF-κB signaling pathway might be vital as a potential therapeutic target, and also indispensable in Andro-mediated anti-cancer effect in insulinoma. PMID:24719558

  5. Recurrent insulinoma in a 10-year-old boy with Down’s syndrome

    Directory of Open Access Journals (Sweden)

    Noman Ahmad

    2017-05-01

    Full Text Available An insulinoma is a rare tumour with an incidence of four cases per million per year in adults. The incidence in children is not established. There is limited literature available in children with insulinoma, and only one case is reported in association with Down’s syndrome in adults. Insulinoma diagnosis is frequently missed in adults as well as in children. The Whipple triad is the most striking feature although it has limited application in young children. Hypoglycaemia with elevated insulin, C-peptide and absent ketones is highly suggestive of hyperinsulinism. We present a case of 10-year-old boy with Down’s syndrome with recurrent insulinoma. He was initially misdiagnosed as having an adrenal insufficiency and developed cushingoid features and obesity secondary to hydrocortisone treatment and excessive sugar intake. The tumour was successfully localised in the head of the pancreas with an MRI and octreotide scan on first presentation. Medical treatment with diazoxide and octreotide could not achieve normal blood glucose levels. The insulinoma was laparoscopically enucleated and pathological examination confirmed a neuroendocrine tumour. Subsequently, he had complete resolution of symptoms. He had a recurrence after 2 years with frequent episodes of hypoglycaemia. The biochemical workup was suggestive of hyperinsulinism. MRI and PET scan confirmed the recurrence at the same site (head of the pancreas. He had an open laparotomy for insulinoma resection. The pathology was consistent with benign insulinoma, and subsequently, he had complete resolution of symptoms.

  6. [Insulinoma of the pancreas: analysis of a clinical series of 30 cases].

    Science.gov (United States)

    Andronesi, D; Andronesi, A; Tonea, A; Andrei, S; Herlea, V; Lupescu, I; Ionescu-Târgovişte, C; Coculescu, M; Fica, S; Ionescu, M; Gheorghe, C; Popescu, I

    2009-01-01

    Insulinoma is the most frequent neuroendocrine pancreatic tumor and is the main cause for hypoglicemia due to endogenous hyperinsulinism. We performed an analysis of a clinical series in order to study the clinical and biological spectrum of presentation, the preoperatory imagistic diagnosis and results of the surgical approach. Between 1986-2009, 30 patients with symptoms suggesting an insulinoma were hospitalized in our department. Preoperatory localization of insulinomas was possible in 16 patients. The most sensitive imagistic methods were ecoendoscopy and magnetic resonance. Intraoperatory ultrasound was performed in 16 patients and its sensitivity in detection of insulinomas was 93%; the combination between intraoperative ultrasound and manual exploration of pancreas by the surgeon reached a 100% sensitivity. Before the intraoperatory ultrasound was used the tumor excision was predominantly done by extensive pancreatic resection, while after this was available in our centre more conservative (enucleo-resection) procedures were chosen. In 1 patient the resection was done by laparoscopy, and in 1 patient by robotic surgery. The dimensions of the tumor were less than 2 cm in most of the patients; 2 had nesidioblastosis and 2 had multiple insulinomas; all 28 patients proved to have benign insulinomas at histological specimens. Following surgery, the symptoms disappear in all patients. The most common complication following extensive pancreatic resections was acute pancreatitis, while after enucleation pancreatic fistula occurred more frequently. Due to small dimensions, the preoperative diagnosis of insulinomas is usually difficult, ecoendoscopy being the most sensitive method. Intraoperative ultrasound is essential for insulinoma localization and for chosing the optimal type of excision. Enucleation is the resection method to be chosen whenever this it is technical possible. In benign insulinomas the prognosis is excellent, surgical resection being curative in

  7. Tratamento cirúrgico dos insulinomas -- estudo de 59 casos Surgical treatment of insulinoma. Study of 59 cases

    Directory of Open Access Journals (Sweden)

    M.C.C. Machado

    1998-06-01

    Full Text Available Após a confirmação clínica e laboratorial de hiperinsulinismo, o principal problema consiste na localização precisa da lesão no parênquima pancreático, propiciando tratamento cirúrgico adequado. OBJETIVO: Analisar os métodos utilizados para o diagnóstico e localização pré e intra-operatório dos insulinomas, bem como as técnicas e os resultados do tratamento cirúrgico. MÉTODOS: Foram estudados 59 casos consecutivos de insulinoma submetidos a intervenção cirúrgica. Cada um dos métodos utilizados para a localização pré-operatória dessas lesões foi avaliado quanto à sua eficiência em confronto com os achados intra-operatórios. A palpação do pâncreas, isoladamente ou associada à ultra-sonografia intra-operatória, como métodos de localização dos insulinomas, foi também estudada. Os tipos de intervenção cirúrgica foram analisados quanto aos seus resultados imediatos e tardios. RESULTADOS: Dos 59 insulinomas, 55 eram benignos e quatro, malignos. Dos métodos utilizados para a localização pré-operatória, a ultra-sonografia foi eficiente em 28,1% dos casos, a tomografia computadorizada em 25%, a ultra-sonografia endoscópica em 27,2%, a arteriografia seletiva em 54,1% e a colheita de amostras de sangue portal para dosagem de insulina em 94,4% dos casos. A palpação bidigital, durante a intervenção cirúrgica, localizou as lesões em 54/55 casos (98,2%. A ultra-sonografia intra-operatória foi decisiva em apenas um caso. Cinco doentes apresentavam neoplasia endócrina múltipla tipo I e em todos as lesões pancreáticas eram múltiplas. Foram efetuadas 29 enucleações e 32 ressecções pancreáticas nos doentes com lesões benignas. Os doentes com lesões malignas foram submetidos a ressecções pancreáticas e quimioterapia. Não houve mortalidade, porém observaram-se complicações (fístulas em 29/59 casos. Os resultados foram bons em 98,1% dos doentes com lesões benignas. Apenas um dos doentes com

  8. Giant insulinoma in a 15-year-old man: A case report

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    Vasin Vasikasin

    2016-01-01

    Conclusion: We report the youngest case of a giant insulinoma. Despite the size of the tumor, the pathological report confirmed the benign characteristics. However, long-term follow-up is still essential to detect recurrence in the future.

  9. Screening key candidate genes and pathways involved in insulinoma by microarray analysis.

    Science.gov (United States)

    Zhou, Wuhua; Gong, Li; Li, Xuefeng; Wan, Yunyan; Wang, Xiangfei; Li, Huili; Jiang, Bin

    2018-06-01

    Insulinoma is a rare type tumor and its genetic features remain largely unknown. This study aimed to search for potential key genes and relevant enriched pathways of insulinoma.The gene expression data from GSE73338 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified between insulinoma tissues and normal pancreas tissues, followed by pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. The expressions of candidate key genes were validated by quantitative real-time polymerase chain reaction (RT-PCR) in insulinoma tissues.A total of 1632 DEGs were obtained, including 1117 upregulated genes and 514 downregulated genes. Pathway enrichment results showed that upregulated DEGs were significantly implicated in insulin secretion, and downregulated DEGs were mainly enriched in pancreatic secretion. PPI network analysis revealed 7 hub genes with degrees more than 10, including GCG (glucagon), GCGR (glucagon receptor), PLCB1 (phospholipase C, beta 1), CASR (calcium sensing receptor), F2R (coagulation factor II thrombin receptor), GRM1 (glutamate metabotropic receptor 1), and GRM5 (glutamate metabotropic receptor 5). DEGs involved in the significant modules were enriched in calcium signaling pathway, protein ubiquitination, and platelet degranulation. Quantitative RT-PCR data confirmed that the expression trends of these hub genes were similar to the results of bioinformatic analysis.The present study demonstrated that candidate DEGs and enriched pathways were the potential critical molecule events involved in the development of insulinoma, and these findings were useful for better understanding of insulinoma genesis.

  10. A prospective evaluation of laparoscopic exploration with intraoperative ultrasound as a technique for localizing sporadic insulinomas.

    Science.gov (United States)

    Grover, Amelia C; Skarulis, Monica; Alexander, H Richard; Pingpank, James F; Javor, Edward D; Chang, Richard; Shawker, Thomas; Gorden, Phil; Cochran, Craig; Libutti, Steven K

    2005-12-01

    Preoperative imaging studies localize insulinomas in less than 50% of patients. Arteriography with calcium stimulation and venous sampling (ASVS) regionalizes greater than 90% of insulinomas but requires specialized expertise and an invasive procedure. This prospective study evaluated laparoscopic exploration with IOUS compared with the other localization procedures in patients with a sporadic insulinoma. Between March 2001 and October 2004, 14 patients (7 women and 7 men; mean age, 53) with an insulinoma were enrolled in an IRB-approved protocol. Computed tomography, magnetic resonance imaging, ultrasound scan, and arteriography with calcium stimulation and venous sampling were performed preoperatively. A surgeon, blinded to the results of the localizing studies, performed a laparoscopic exploration with intraoperative ultrasound (IOUS). At the completion of the exploration, the success of laparoscopy for localization was scored, and the tumor was resected. Twelve of 14 tumors were localized successfully before laparoscopy (noninvasive, 7 of 14; invasive, 11 of 14). Laparoscopic IOUS localized successfully 12 of 14 tumors. All lesions were resected, and all patients were cured (median follow-up, 36 months). Laparoscopic IOUS identified 86% of tumors. The authors consider laparoscopic IOUS to be equivalent to ASVS in localizing insulinomas. Further study is therefore warranted to determine the role of laparoscopy with IOUS in the localization and treatment algorithm for patients with sporadic insulinoma.

  11. Clinical Implications of Various Criteria for the Biochemical Diagnosis of Insulinoma

    Directory of Open Access Journals (Sweden)

    Chang Ho Ahn

    2014-12-01

    Full Text Available BackgroundAmong the various diagnostic criteria for insulinoma, the ratio criteria have been controversial. However, the amended insulin-glucose ratio exhibited excellent diagnostic performance in a recent retrospective cohort study, although it has not yet been validated in other patient cohorts. We examined the diagnostic performance of the current criteria of the Endocrine Society, insulin-glucose ratio, C-peptide-glucose ratio, and amended ratios in terms of differentiating insulinomas.MethodsWe reviewed the medical records of patients who underwent evaluation for hypoglycemia from 2000 to 2013. Fourteen patients with histopathologically confirmed insulinoma and 18 patients without clinical evidence of insulinoma were included. The results of a prolonged fast test were analyzed according to the abovementioned criteria.ResultsFulfilling all three Endocrine Society criteria-plasma levels of glucose (24.0 (pmol/L/(mmol/L] gave the highest area under the receiver operating characteristic curve, with 93% sensitivity and 94% specificity.ConclusionFulfilling the glucose, insulin, and C-peptide criteria of the Endocrine Society guidelines exhibited the best diagnostic performance for insulinoma. Nonetheless, the insulin-glucose ratio may still have a role in the biochemical diagnosis of insulinoma.

  12. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience.

    Science.gov (United States)

    Guettier, Jean-Marc; Kam, Anthony; Chang, Richard; Skarulis, Monica C; Cochran, Craig; Alexander, H Richard; Libutti, Steven K; Pingpank, James F; Gorden, Phillip

    2009-04-01

    Selective intraarterial calcium injection of the major pancreatic arteries with hepatic venous sampling [calcium arterial stimulation (CaStim)] has been used as a localizing tool for insulinomas at the National Institutes of Health (NIH) since 1989. The accuracy of this technique for localizing insulinomas was reported for all cases until 1996. The aim of the study was to assess the accuracy and track record of the CaStim over time and in the context of evolving technology and to review issues related to result interpretation and procedure complications. CaStim was the only invasive preoperative localization modality used at our center. Endoscopic ultrasound (US) was not studied. We conducted a retrospective case review at a referral center. Twenty-nine women and 16 men (mean age, 47 yr; range, 13-78) were diagnosed with an insulinoma from 1996-2008. A supervised fast was conducted to confirm the diagnosis of insulinoma. US, computed tomography (CT), magnetic resonance imaging (MRI), and CaStim were used as preoperative localization studies. Localization predicted by each preoperative test was compared to surgical localization for accuracy. We measured the accuracy of US, CT, MRI, and CaStim for localization of insulinomas preoperatively. All 45 patients had surgically proven insulinomas. Thirty-eight of 45 (84%) localized to the correct anatomical region by CaStim. In five of 45 (11%) patients, the CaStim was falsely negative. Two of 45 (4%) had false-positive localizations. The CaStim has remained vastly superior to abdominal US, CT, or MRI over time as a preoperative localizing tool for insulinomas. The utility of the CaStim for this purpose and in this setting is thus validated.

  13. Metastatic Insulinoma Following Resection of Nonsecreting Pancreatic Islet Cell Tumor

    Directory of Open Access Journals (Sweden)

    Anoopa A. Koshy MD

    2013-01-01

    Full Text Available A 56-year-old woman presented to our clinic for recurrent hypoglycemia after undergoing resection of an incidentally discovered nonfunctional pancreatic endocrine tumor 6 years ago. She underwent a distal pancreatectomy and splenectomy, after which she developed diabetes and was placed on an insulin pump. Pathology showed a pancreatic endocrine neoplasm with negative islet hormone immunostains. Two years later, computed tomography scan of the abdomen showed multiple liver lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine neoplasm, consistent with pancreatic origin. Six years later, she presented to clinic with 1.5 years of recurrent hypoglycemia. Laboratory results showed elevated proinsulin, insulin levels, and c-peptide levels during a hypoglycemic episode. Computed tomography scan of the abdomen redemonstrated multiple liver lesions. Repeated transarterial catheter chemoembolization and microwave thermal ablation controlled hypoglycemia. The unusual features of interest of this case include the transformation of nonfunctioning pancreatic endocrine tumor to a metastatic insulinoma and the occurrence of atrial flutter after octreotide for treatment.

  14. Kupffer cell blockade prevents rejection of human insulinoma cell xenograft in rats

    International Nuclear Information System (INIS)

    Lazar, G. Jr.; Farkas, G.; Lazar, G.

    1998-01-01

    Alloantigens are recognized by T-cells in the context of both class I and class II antigen, but class II antigens predominate in the recognition of xenoantigens. Since class II molecules bind peptides derived from exogenous proteins that have been phagocytized and digested into small fragments by antigen presenting cells, in the present studies the effect of gadolinium chloride (GdCl 3 )-induced Kupffer cell blockade on the survival of discordant insulinoma cell xenografts was investigated. Insulinoma cells isolated by means of collagenase from human insulinoma and cultured were transplanted through the v. portae into the liver of streptozotocin-induced diabetic, male, CFY inbred rats. In the control, streptozotocin-treated rats, the decrease in blood glucose level was only transitory, in contrast with the GdCl 3 -pretreated diabetic rats, which remained normoglycaemic during the 2-week observation period. Histologically, in the liver and lung of rats pre-treated with GdCl 3 , large areas of extensively proliferating insulinoma cells were seen, whereas no insulinoma cells were seen in either the liver or the lung of diabetic-control rats, not-treated with GdCl 3 . These studies suggest that the Kupffer cells play significant roles in the recognition of xenoantigens and the induction of xenograft rejection. (orig.)

  15. Value of fat suppression and dynamic contrast-enhanced MRI in the diagnosis of insulinoma

    International Nuclear Information System (INIS)

    Xu Zengbin; Ruan Lingxiang; Peng Zhiyi; Zhang Minming; Xu Shunliang; Zhang Xidao

    2003-01-01

    Objective: To evaluate the value of fat suppression and dynamic contrast-enhanced MRI in the preoperative localization of insulinoma. Methods: Twelve cases with pathologically proven insulinoma were evaluated with MRI. SE T 1 WI, FSE T 2 WI, T 1 WI and T 2 WI with fat suppression, dynamic contrast-enhanced FMPSPGR sequences were used in MR scanning. Results: On SE T 1 WI, the lesions displayed hypointense in 4, isointense in 8 cases. Lesions showed hyperintense in 4, isointense in 8 cases on FSE T 2 WI. In contrast, 7 cases appeared as hypointense on T 1 WI with fat suppression and 6 cases appeared as hyperintense on T 2 WI with fat suppression. With dynamic contrast-enhanced FMPSPGR sequence 11 of 12 insulinomas were detected. In the arterial phase, the lesions presented as hyperintense with different degrees in 11 cases and isointense in 1 case. 6 cases remained hyperintense and 6 cases were isointense in pancreatic parenchymal and portal phase. 4 lesions were identified only in dynamic enhancement images. The diagnostic accuracy of insulinoma by dynamic contrast-enhanced MRI was 91.7% (11/12) as compared with histological study. Conclusion: The results indicate that dynamic contrast-enhanced MRI is an sensitive and accurate method for the preoperative localization of insulinoma

  16. Usefulness of intraoperative echography for resection of a insulinoma located in the head of pancreas

    International Nuclear Information System (INIS)

    Cepero Valdes, Manuel; Hernandez Rivero, Hanoi; Ugarte Moreno, Dayana; Chao Gonzalez, Lissette

    2011-01-01

    The insulinoma is the more frequent neoplasms among the neuroendocrine tumors of pancreas. The aim of present paper is to describe the clinical picture, laboratory and imaging examinations and the surgical features as well as the complications in a patient diagnosed with insulinoma without evidences by preoperative images. Surgery was prescribed on the base of clinical and analytic evidences of hypoglycemia and hyperinsulinism and the carrying out of an exploratory laparatomy without any lesion with direct palpation of pancreas. Intraoperative echography was used to locate a 0,8 cm nodule in the head of pancreas. After enucleation the only postoperative complication was a low-flow pancreatic fistula with a spontaneous remission. The histological diagnosis was a benign insulinoma. Patient had a clinical reversion of symptoms in addition to normalization of glycemia values, compared to those intraoperative. (author)

  17. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1

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    O'Sullivan Brendan

    2009-02-01

    Full Text Available Abstract Background Gastrointestinal stromal tumours (GIST frequently occur in patients with neurofibromatosis type 1 (NF-1. It has been reported that GIST may co-exist with pancreatic endocrine tumors but this has only been in association with NF-1. Case presentation A 76 year old woman presented with a 12 month history of hypoglycaemia symptoms. Abdominal CT scan demonstrated a 13 mm insulinoma localized in the tail of her pancreas. She was commenced on diazoxide and later underwent surgery for enucleation of insulinoma when a small ( Conclusion This is the first case report of a pancreatic insulinoma co-existing with a GIST in a patient without NF-1. In addition, we make the first report of rapidly growing cystic GIST recurrence following resection of a primary GIST tumour.

  18. Localization of Hidden Insulinomas with ⁶⁸Ga-DOTA-Exendin-4 PET/CT: A Pilot Study.

    Science.gov (United States)

    Antwi, Kwadwo; Fani, Melpomeni; Nicolas, Guillaume; Rottenburger, Christof; Heye, Tobias; Reubi, Jean Claude; Gloor, Beat; Christ, Emanuel; Wild, Damian

    2015-07-01

    (111)In-DOTA-exendin-4 SPECT/CT has been shown to be highly efficient in the detection of insulinomas. We aimed at determining whether novel PET/CT imaging with [Nle(14),Lys(40)(Ahx-DOTA-(68)Ga)NH2]exendin-4 ((68)Ga-DOTA-exendin-4) is feasible and sensitive in detecting benign insulinomas. (68)Ga-DOTA-exendin-4 PET/CT and (111)In-DOTA-exendin-4 SPECT/CT were performed in a randomized cross-over order on 5 patients with endogenous hyperinsulinemic hypoglycemia. The gold standard for comparison was the histologic diagnosis after surgery. In 4 patients histologic diagnosis confirmed a benign insulinoma, whereas one patient refused surgery despite a positive (68)Ga-DOTA-exendin-4 PET/CT scan. In 4 of 5 patients, previously performed conventional imaging (CT or MR imaging) was not able to localize the insulinoma. (68)Ga-DOTA-exendin-4 PET/CT correctly identified the insulinoma in 4 of 4 patients, whereas (111)In-DOTA-exendin-4 SPECT/CT correctly identified the insulinoma in only 2 of 4 patients. These preliminary data suggest that the use of (68)Ga-DOTA-exendin-4 PET/CT in detecting hidden insulinomas is feasible. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  19. Canine and Human Insulinoma : prognostic factors, druggable genes and cancer stem cells

    NARCIS (Netherlands)

    Buishand, F.O.|info:eu-repo/dai/nl/411880381

    2016-01-01

    Insulinoma (INS), which causes clinical signs associated with hypoglycaemia, is the most common pancreatic neuroendocrine tumour (pNET) of dogs and humans. Ten tot fifteen percent of human INS metastasise to regional lymph nodes and the liver, and these are referred to as ‘malignant INS’. Surgical

  20. High-dose calcium stimulation test in a case of insulinoma masquerading as hysteria.

    Science.gov (United States)

    Nakamura, Yoshio; Doi, Ryuichiro; Kohno, Yasuhiro; Shimono, Dai; Kuwamura, Naomitsu; Inoue, Koichi; Koshiyama, Hiroyuki; Imamura, Masayuki

    2002-11-01

    It is reported that some cases with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed as psychosis. Here we report a case of insulinoma masquerading as hysteria, whose final diagnosis could be made using high-dose calcium stimulation test. A 28-yr-old woman was referred presenting with substupor, mutism, mannerism, restlessness, and incoherence. Laboratory examinations revealed hypoglycemia (33 mg/dL) and detectable insulin levels (9.7 microU/mL), suggesting the diagnosis of insulinoma. However, neither imaging studies nor selective arterial calcium injection (SACI) test with a conventional dose of calcium (0.025 mEq/kg) indicated the tumor. High-dose calcium injection (0.05 mEq/kg) evoked insulin secretion when injected into superior mesenteric artery. A solitary tumor in the head of the pancreas was resected, and her plasma glucose returned to normal. Postoperatively, iv injection of secretin resulted in a normal response of insulin, which was not found preoperatively. This case suggests the usefulness of the SACI test with high-dose of calcium in the case of insulinoma when the standard dose fails to detect such a tumor.

  1. Studies on a novel peptide isolated and purified from rat insulinoma tissue

    Energy Technology Data Exchange (ETDEWEB)

    Al-Akhras, G N

    1987-01-01

    Rat insulinoma peptide (RIP) which appears to be either a fragment of, or an altered rat C-peptide was isolated and purified by dialysis. The purity of this peptide was investigated using polyacrylamide gel electrophoresis with sodium dodecyl sulfate, isoelectric focusing, and high performance liquid chromatography. RIP may contain two peptides similar to each other but differing in their isoelectric points. The molecular weight of RIP was found to be 1982 daltons by fast atoms bombardment mass spectrometry giving a chain length of approximately 22 amino acid residues. From information obtained using radioimmunoassay employing antiserum R901, RIP appears to share a common C-terminus with rat C-peptide. A radioimmunoassay for RIP was developed using the purified RIP as immunogen and for standards and tracers. An indirect enzyme linked immunosorbent assay (ELISA) for rat insulinoma peptide was developed using purified RIP for immunogen and semi-purified RIP as a standard.

  2. Intra-arterial digital subtraction angiography in the diagnosis of insulinomas

    International Nuclear Information System (INIS)

    Moulopoulou, A.; Vlahos, L.

    1988-01-01

    Two cases of surgically proved benign insulinoma of the pancreas were correctly localized with intra-arterial digital subtraction angiography (IA-DSA) of the coeliac and the superior mesenteric artery, while the respective dynamic computed tomography (CT) and ultrasound (US) examinations were negative. In a third case of organic hyperinsulinism, IA-DSA, CT and US suggested a pancreatic islet-cell tumor, but the histological examination of the resected suspicious area was that of focal hyperplasia. 17 refs.; 3 figs

  3. Insulinoma: A retrospective study analyzing the differences between benign and malignant tumors.

    Science.gov (United States)

    Câmara-de-Souza, A B; Toyoshima, M T K; Giannella, M L; Freire, D S; Camacho, C P; Lourenço, D M; Rocha, M S; Bacchella, T; Jureidini, R; Machado, M C C; Almeida, M Q; Pereira, M A A

    2018-04-01

    Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors. Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease. Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 μU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm. Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases. Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  4. Dynamic computed tomography of the pancreas in normal dogs and in a dog with pancreatic insulinoma.

    Science.gov (United States)

    Iseri, Toshie; Yamada, Kazutaka; Chijiwa, Kousaku; Nishimura, Ryohei; Matsunaga, Satoru; Fujiwara, Reina; Sasaki, Nobuo

    2007-01-01

    To establish optimal imaging conditions for enhanced computed tomography (CT) for canine pancreatic tumors, 10 healthy beagles were subjected to dynamic CT. This technique was then applied to a dog with suspected insulinoma. The changes in mean peak enhancement and the delay time of the aorta and pancreas were determined. In normal beagles, maximal arterial and pancreatic CT enhancement was observed at 15 +/- 2 s (795 +/- 52 Housfield unit [HU]) and 28 +/- 9 s (118 +/- 16HU) after contrast medium injection, respectively. Multiphase enhanced CT was performed in a pug with suspected insulinoma using the CT protocol defined for the normal beagles with some parameters modified; the images were acquired at the arterial (14 s after contrast medium injection), pancreatic (after 28 s), and equilibrium (after 90 s) phases; scanning was followed by exploratory laparotomy. CT images were characterized by an enhanced mass in the left pancreatic lobe at the arterial phase, during which the difference between the CT values of the mass and normal pancreas was the highest. Histopathologic diagnosis of the pancreatic mass was insulinoma. Thus, it appears that enhanced CT imaging can be used to delineate the pancreas from a pancreatic mass, and it may be helpful in deciding the need for surgery.

  5. [Usefullness of scintigraphy with somatostatin analogues in the imaging of insulinoma of the pancreas].

    Science.gov (United States)

    Owecki, Maciej; Czepczyriński, Rafał; Biczysko, Maciej; Stawny, Bolesław; Drews, Michał; Sowiński, Jerzy

    2006-01-01

    We present a case of a 74-years-old female with insulinoma of the pancreas. Neuroglycopenic symptoms (Whipple's triad) and a positive fast test established the diagnosis. The fast was terminated after 5 hours and 40 minutes because of neuroglycopenic symptoms with the serum glucose and insulin levels of 40 mg/dl and 34,01 microU/ml respectively. The tumor was invisible in ultrasound, abdominal CT scan and MRL The only means that enabled preoperative visualization was 111-Indium labeled octreotide scintigraphy (OctreoScan). Laparotomy was performed, and a tumor was disclosed in intraoperative ultrasonography within the head of the pancreas. The tumor of 37 mm diameter was excised. Histopatological examination revealed benign insulinoma. After surgery the symptoms alleviated completely. The patient with proper glucose levels and insulin concentration of 3,04 microU/ml was discharged in good health. This case confirms high usefulness of preoperative OctreoScan and intraoperative ultrasonography in the approach to a patient with insulinoma.

  6. Somatostatin receptor scintigraphy and intraoperative gamma probe detection in the localisation and treatment of pancreatic insulinoma

    International Nuclear Information System (INIS)

    Loh, Nelson K.; Macdonald, William B.; Dunne, Marina L.; Rao, Sudhakar

    2009-01-01

    Full text: Aims: We report a case of insulinoma that was successfully enucleated under radio-guidance after an initial unsuccessful laparotomy. This case highlights the utility of Somatostatin Receptor Scintigraphy (SRS) and gamma probe in the localisation and treatment of neuroendocrine tumours. Methods: The patient presented with recurrent hypoglycaemia. An abdominal CT scan identified a lesion in the uncinate process of the pancreas, however, laparotomy with use of intraoperative ultrasound failed to localise the lesion. SRS with SPECTICT was then requested by the surgical team with a view to radio-guided surgery. Results: SRS demonstrated an octreotide-avid tumour in the posterior uncinate process of the pancreas, and confirmed suitability for radio-guided surgery. At re-exploration, the surgeon was again unable to palpate the lesion or localise it with intraoperative ultrasound, however, the lesion was successfully detected and removed with the use of a gamma probe. A postoperative SRS confirmed complete excision and histopathology was diagnostic of insulinoma. Conclusion: This case highlights the utility of SRS in the intraoperative localisation and surgical excision of neuroendocrine tumours. The lesion was unable to be localised clinically or with intraoperative ultrasound but was successfully detected with scintigraphic techniques. The surgical team acknowledge that the use of a gamma probe enabled enucleation of the insulinoma, which obviated the need for an invasive Whipple's procedure.

  7. Sporadic insulinomas on volume perfusion CT: dynamic enhancement patterns and timing of optimal tumour-parenchyma contrast

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Liang; Xue, Hua-dan; Liu, Wei; Wang, Xuan; Sun, Hao; Li, Ping; Jin, Zheng-yu [Peking Union Medical College Hospital, Department of Radiology, Beijing (China); Wu, Wen-ming; Zhao, Yu-pei [Peking Union Medical College Hospital, Department of General Surgery, Beijing (China)

    2017-08-15

    To assess enhancement patterns of sporadic insulinomas on volume perfusion CT (VPCT), and to identify timing of optimal tumour-parenchyma contrast. Consecutive patients who underwent VPCT for clinically suspected insulinomas were retrospectively identified. Patients with insulinomas confirmed by surgery were included, and patients with familial syndromes were excluded. Two radiologists evaluated VPCT images in consensus. Tumour-parenchyma contrast at each time point was measured, and timing of optimal contrast was determined. Time duration of hyperenhancement (tumour-parenchyma contrast >20 Hounsfield units, HU) was recorded. Perfusion parameters were evaluated. Three dynamic enhancement patterns were observed in 63 tumours: persistent hyperenhancement (hyperenhancement time window ≥10 s) in 39 (61.9%), transient hyperenhancement (hyperenhancement <10 s) in 19 (30.2%) and non-hyperenhancement in 5 (7.9%). Timing of optimal contrast was 9 s after abdominal aorta threshold (AAT) of 200 HU, with tumour-parenchyma contrast of 77.6 ± 57.2 HU. At 9 s after AAT, 14 (22.2%) tumours were non-hyperenhancing, nine of which had missed transient hyperenhancement. Insulinomas with transient and persistent hyperenhancement patterns had significantly increased perfusion. Insulinomas have variable enhancement patterns. Tumour-parenchyma contrast is time-dependent. Optimal timing of enhancement is 9 s after AAT. VPCT enables tumour detection even if the hyperenhancement is transient. (orig.)

  8. Advanced diagnostic approaches and current medical management of insulinomas and adrenocortical disease in ferrets (Mustela putorius furo).

    Science.gov (United States)

    Chen, Sue

    2010-09-01

    Endocrine neoplasia is the most common tumor type in domestic ferrets, especially in middle-aged to older ferrets. Islet cell tumors and adrenocortical tumors constitute the major types of endocrine neoplasms. Insulinoma is a tumor that produces and releases excessive amounts of insulin. Evaluation of fasted blood glucose levels provides a quick diagnostic assessment for the detection of insulinomas. Use of glucocorticoids, diazoxide, and diet modification are some of the medical treatment options for insulinomas. Adrenocortical neoplasia in ferrets usually overproduces one or more sex hormones. Sex hormones which can result in progressive alopecia, vulvar swelling in females, and prostagomegaly in males. Abdominal ultrasonography and sex hormone assays can be used to diagnose adrenocortical neoplasms. Drugs such as leuprolide acetate, deslorelin acetate, and the hormone melatonin can be used to treat adrenocortical neoplasms in ferrets when surgery is not an option. Copyright 2010 Elsevier Inc. All rights reserved.

  9. {sup 18}F-FDOPA PET/CT imaging of insulinoma revisited

    Energy Technology Data Exchange (ETDEWEB)

    Imperiale, Alessio; Namer, Izzie-Jacques [University Hospitals of Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg (France); University of Strasbourg/CNRS and FMTS, Faculty of Medicine, ICube - UMR 7357, Strasbourg (France); Sebag, Frederic [Aix-Marseille University, Department of Endocrine Surgery, La Timone University Hospital, Marseille (France); Vix, Michel [University of Strasbourg, Department of General, Digestive, and Endocrine Surgery, IRCAD-IHU, Strasbourg (France); Castinetti, Frederic [Aix-Marseille University, Department of Endocrinology, Diabetes and Metabolic Disorders, La Timone University Hospital, Marseille (France); Kessler, Laurence; Moreau, Francois [University of Strasbourg, Department of Diabetology, University Hospital of Strasbourg, Strasbourg (France); Bachellier, Philippe [University Hospitals of Strasbourg, Department of Visceral Surgery and Transplantation, Strasbourg (France); Guillet, Benjamin; Mundler, Olivier [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Marseille (France); Taieb, David [Aix-Marseille University, Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Marseille (France); Aix-Marseille University, Biophysics and Nuclear Medecine, La Timone University Hospital, European Center for Research in Medical Imaging, Marseille (France)

    2014-11-01

    {sup 18}F-FDOPA PET imaging is increasingly used in the work-up of patients with neuroendocrine tumours. It has been shown to be of limited value in localizing pancreatic insulin-secreting tumours in adults with hyperinsulinaemic hypoglycaemia (HH) mainly due to {sup 18}F-FDOPA uptake by the whole pancreatic gland. The objective of this study was to review our experience with {sup 18}F-FDOPA PET/CT imaging with carbidopa (CD) premedication in patients with HH in comparison with PET/CT studies performed without CD premedication in an independent population. A retrospective study including 16 HH patients who were investigated between January 2011 and December 2013 using {sup 18}F-FDOPA PET/CT (17 examinations) in two academic endocrine tumour centres was conducted. All PET/CT examinations were performed under CD premedication (200 mg orally, 1 - 2 h prior to tracer injection). The PET/CT acquisition protocol included an early acquisition (5 min after {sup 18}F-FDOPA injection) centred over the upper abdomen and a delayed whole-body acquisition starting 20 - 30 min later. An independent series of eight consecutive patients with HH and investigated before 2011 were considered for comparison. All patients had a reference whole-body PET/CT scan performed about 1 h after {sup 18}F-FDOPA injection. In all cases, PET/CT was performed without CD premedication. In the study group, {sup 18}F-FDOPA PET/CT with CD premedication was positive in 8 out of 11 patients with histologically proven insulinoma (73 %). All {sup 18}F-FDOPA PET/CT-avid insulinomas were detected on early images and 5 of 11 (45 %) on delayed ones. The tumour/normal pancreas uptake ratio was not significantly different between early and delayed acquisitions. Considering all patients with HH, including those without imaging evidence of disease, the detection rate of the primary lesions using CD-assisted {sup 18}F-FDOPA PET/CT was 53 %, showing 9 insulinomas in 17 studies performed. In the control group (without

  10. 18F-FDOPA PET/CT imaging of insulinoma revisited

    International Nuclear Information System (INIS)

    Imperiale, Alessio; Namer, Izzie-Jacques; Sebag, Frederic; Vix, Michel; Castinetti, Frederic; Kessler, Laurence; Moreau, Francois; Bachellier, Philippe; Guillet, Benjamin; Mundler, Olivier; Taieb, David

    2015-01-01

    18 F-FDOPA PET imaging is increasingly used in the work-up of patients with neuroendocrine tumours. It has been shown to be of limited value in localizing pancreatic insulin-secreting tumours in adults with hyperinsulinaemic hypoglycaemia (HH) mainly due to 18 F-FDOPA uptake by the whole pancreatic gland. The objective of this study was to review our experience with 18 F-FDOPA PET/CT imaging with carbidopa (CD) premedication in patients with HH in comparison with PET/CT studies performed without CD premedication in an independent population. A retrospective study including 16 HH patients who were investigated between January 2011 and December 2013 using 18 F-FDOPA PET/CT (17 examinations) in two academic endocrine tumour centres was conducted. All PET/CT examinations were performed under CD premedication (200 mg orally, 1 - 2 h prior to tracer injection). The PET/CT acquisition protocol included an early acquisition (5 min after 18 F-FDOPA injection) centred over the upper abdomen and a delayed whole-body acquisition starting 20 - 30 min later. An independent series of eight consecutive patients with HH and investigated before 2011 were considered for comparison. All patients had a reference whole-body PET/CT scan performed about 1 h after 18 F-FDOPA injection. In all cases, PET/CT was performed without CD premedication. In the study group, 18 F-FDOPA PET/CT with CD premedication was positive in 8 out of 11 patients with histologically proven insulinoma (73 %). All 18 F-FDOPA PET/CT-avid insulinomas were detected on early images and 5 of 11 (45 %) on delayed ones. The tumour/normal pancreas uptake ratio was not significantly different between early and delayed acquisitions. Considering all patients with HH, including those without imaging evidence of disease, the detection rate of the primary lesions using CD-assisted 18 F-FDOPA PET/CT was 53 %, showing 9 insulinomas in 17 studies performed. In the control group (without CD premedication, eight patients), the final

  11. Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation.

    Science.gov (United States)

    Druce, Maralyn R; Muthuppalaniappan, Vasantha M; O'Leary, Benjamin; Chew, Shern L; Drake, William M; Monson, John P; Akker, Scott A; Besser, Michael; Sahdev, Anju; Rockall, Andrea; Vyas, Soumil; Bhattacharya, Satya; Matson, Matthew; Berney, Daniel; Reznek, R H; Grossman, Ashley B

    2010-05-01

    Preoperative localisation of insulinoma improves cure rate and reduces complications, but may be challenging. To review diagnostic features and localisation accuracy for insulinomas. Cross-sectional, retrospective analysis. A single tertiary referral centre. Patients with insulinoma in the years 1990-2009, including sporadic tumours and those in patients with multiple endocrine neoplasia syndromes. Patients were identified from a database, and case notes and investigation results were reviewed. Tumour localisation by computed tomography (CT), magnetic resonance imaging (MRI), octreotide scanning, endoscopic ultrasound (EUS) and calcium stimulation was evaluated. Insulinoma localisation was compared to histologically confirmed location following surgical excision. Thirty-seven instances of biochemically and/or histologically proven insulinoma were identified in 36 patients, of which seven were managed medically. Of the 30 treated surgically, 25 had CT (83.3%) and 28 had MRI (90.3%), with successful localisation in 16 (64%) by CT and 21 (75%) by MRI respectively. Considered together, such imaging correctly localised 80% of lesions. Radiolabelled octreotide scanning was positive in 10 out of 20 cases (50%); EUS correctly identified 17 lesions in 26 patients (65.4%). Twenty-seven patients had calcium stimulation testing, of which 6 (22%) did not localise, 17 (63%) were correctly localised, and 4 (15%) gave discordant or confusing results. Preoperative localisation of insulinomas remains challenging. A pragmatic combination of CT and especially MRI predicts tumour localisation with high accuracy. Radionuclide imaging and EUS were less helpful but may be valuable in selected cases. Calcium stimulation currently remains useful in providing an additional functional perspective.

  12. Mesenteric vein thrombosis after percitaneous transhepatic portal vein catheterisation for the localisation of an insulinoma

    International Nuclear Information System (INIS)

    Luska, G.; Langer, H.E.; Le Blanc, S.; Medizinische Hochschule Hannover

    1984-01-01

    The authors report on a fatal mesenteric vein thrombosis following an uncomplicated percutaneous transhepatic portal vein catheterisation for the localisation of an insulinoma. Several hours after the procedure the patient developed an acute abdomen. An emergency laparotomy revealed a haemorrhagic infarct of the ileum. The resected specimen showed an acute phlebitis with fresh thrombus. The cause of the phlebothrombosis was thought to be intimal damage from high osmolar contrast medium. There was no evidence of damage due to the catheder, either on the phlebogram or pathologically. (orig.) [de

  13. Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas

    DEFF Research Database (Denmark)

    Møller, C J; Christgau, S; Williamson, M R

    1992-01-01

    The endocrine cells of the pancreas develop from the endoderm and yet display several characteristics of a neuronal phenotype. During embryonic life, ductal epithelial cells give rise to first the glugagon-producing cells (alpha-cells) and then cells that express insulin (beta-cells), somatostatin...... primary islet cells at all ages express unsialylated NCAM and E-cadherin, as do insulinomas, the glucagonomas express the polysialylated NCAM, which is characteristic for developing neurons. The glucagonomas also lose E-cadherin expression and instead express a cadherin which is similar to N...

  14. Unusual presentation of a pancreatic insulinoma in helical CT and dynamic contrast-enhanced MR imaging: case report

    Energy Technology Data Exchange (ETDEWEB)

    Iglesias, A.; Arias, M.; Brasa, J. [Unidad de Resonancia Magnetica (Medtec), Hospital Xeral-Cies, Vigo (Spain); Casal, M. [Unidad de Radiologia Intervencionista, Hospital Xeral-Cies, Vigo (Spain); Paramo, C. [Servicio de Endocrinologia, Hospital Xeral-Cies, Vigo (Spain); Fiano, C. [Servicio de Anatomia Patologica, Hospital Xeral-Cies, Vigo (Spain)

    2001-06-01

    Insulinomas are pancreatic neoplasms that can be radiologically characterized typically because of their tendency to present intense and early contrast enhancement with a wash-out phenomenon. In this sense, we report an unusual case of a hypovascular solid pancreatic insulinoma confirmed with surgery and pathologic analysis, in a patient with normal serum insulin levels. In the two-phase helical CT, the mass behaved as a hypodense lesion with respect to the surrounding pancreatic parenchyma during the arterial phase and as a hypointense lesion during the dynamic contrast-enhanced MR imaging. Pathologic examination demonstrated a hypercellular tumor with poor vascularization of intervening stroma which showed prominent amyloid deposits. (orig.)

  15. Unusual presentation of a pancreatic insulinoma in helical CT and dynamic contrast-enhanced MR imaging: case report

    International Nuclear Information System (INIS)

    Iglesias, A.; Arias, M.; Brasa, J.; Casal, M.; Paramo, C.; Fiano, C.

    2001-01-01

    Insulinomas are pancreatic neoplasms that can be radiologically characterized typically because of their tendency to present intense and early contrast enhancement with a wash-out phenomenon. In this sense, we report an unusual case of a hypovascular solid pancreatic insulinoma confirmed with surgery and pathologic analysis, in a patient with normal serum insulin levels. In the two-phase helical CT, the mass behaved as a hypodense lesion with respect to the surrounding pancreatic parenchyma during the arterial phase and as a hypointense lesion during the dynamic contrast-enhanced MR imaging. Pathologic examination demonstrated a hypercellular tumor with poor vascularization of intervening stroma which showed prominent amyloid deposits. (orig.)

  16. Isoattenuating insulinomas at biphasic contrast-enhanced CT: frequency, clinicopathologic features and perfusion characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Liang; Xue, Hua-dan; Sun, Hao; Wang, Xuan; He, Yong-lan; Jin, Zheng-yu [Peking Union Medical College Hospital, Department of Radiology, Beijing (China); Zhao, Yu-pei [Peking Union Medical College Hospital, Department of General Surgery, Beijing (China)

    2016-10-15

    We aimed to determine the frequency of isoattenuating insulinomas, to investigate their clinicopathological features and to assess their regional pancreatic perfusion characteristics. Institutional review board approval was obtained, and patient informed consent was waived. From July 2010 to June 2014, 170 patients (66 male, 104 female) with endogenous hyperinsulinemic hypoglycemia underwent biphasic contrast-enhanced CT before surgery, and 129 of those patients also received preoperative whole-pancreas CT perfusion. A total of 181 tumours were proved histopathologically after surgery. Enhancement pattern and regional pancreatic perfusion characteristics were analyzed. Clinical features, tumour size and pathological grading were investigated. The frequency of isoattenuating tumours was 24.9 %. Tumour size and WHO grading was not significantly different between isoattenuating and hyperattenuating tumours. Tumour-free regions had identical blood flow (BF) regardless of their location (p = 0.35). Isoattenuating tumour-harbouring regions had lower BF compared with hyperattenuating tumour-harbouring regions; both showed higher BF compared with tumour-free neighbourhood regions (all p < 0.01). For patients with isoattenuating tumours, the overall hospital stay was longer (p < 0.01). A substantial subset of insulinomas were isoattenuating on biphasic CT. CT perfusion showed higher BF in tumour-harbouring regions compared to tumour-free regions, providing a clue for tumour regionalization. (orig.)

  17. Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC- 99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma.

    Science.gov (United States)

    Sowa-Staszczak, Anna; Pach, Dorota; Mikołajczak, Renata; Mäcke, Helmut; Jabrocka-Hybel, Agata; Stefańska, Agnieszka; Tomaszuk, Monika; Janota, Barbara; Gilis-Januszewska, Aleksandra; Małecki, Maciej; Kamiński, Grzegorz; Kowalska, Aldona; Kulig, Jan; Matyja, Andrzej; Osuch, Czesław; Hubalewska-Dydejczyk, Alicja

    2013-04-01

    The objective of this article is to present a new method for the diagnosis of insulinoma with the use of [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4. Studies were performed in 11 patients with negative results of all available non-isotopic diagnostic methods (8 with symptoms of insulinoma, 2 with malignant insulinoma and 1 with nesidioblastosis). In all patients glucagon-like peptide-1 (GLP-1) receptor imaging (whole-body and single photon emission computed tomography/CT examinations) after the injection of 740 MBq of the tracer was performed. Both sensitivity and specificity of GLP-1 receptor imaging were assessed to be 100 % in patients with benign insulinoma. In all eight cases with suspicion of insulinoma a focal uptake in the pancreas was found. In six patients surgical excision of the tumour was performed (type G1 tumours were confirmed histopathologically). In one patient surgical treatment is planned. One patient was disqualified from surgery. In one case with malignant insulinoma pathological accumulation of the tracer was found only in the region of local recurrence. The GLP-1 study was negative in the other malignant insulinoma patient. In one case with suspicion of nesidioblastosis, a focal accumulation of the tracer was observed and histopathology revealed coexistence of insulinoma and nesidioblastosis. [Lys(40)(Ahx-HYNIC-(99m)Tc/EDDA)NH2]-exendin-4 seems to be a promising diagnostic tool in the localization of small insulinoma tumours, but requires verification in a larger series of patients.

  18. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells

    DEFF Research Database (Denmark)

    Billestrup, N; Møldrup, A; Serup, P

    1990-01-01

    The stimulation of insulin biosynthesis in the pancreatic insulinoma cell line RIN5-AH by growth hormone (GH) is initiated by GH binding to specific receptors. To determine whether the recently cloned rat hepatic GH receptor is able to mediate the insulinotropic effect of GH, we have transfected ...

  19. PDX-1 Is a Therapeutic Target for Pancreatic Cancer, Insulinoma and Islet Neoplasia Using a Novel RNA Interference Platform

    Science.gov (United States)

    Liu, Shi-He; Rao, Donald D.; Nemunaitis, John; Senzer, Neil; Zhou, Guisheng; Dawson, David; Gingras, Marie-Claude; Wang, Zhaohui; Gibbs, Richard; Norman, Michael; Templeton, Nancy S.; DeMayo, Francesco J.; O'Malley, Bert; Sanchez, Robbi; Fisher, William E.; Brunicardi, F. Charles

    2012-01-01

    Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a “drugable” target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNAPDX-1, was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNAhumanPDX-1 lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNAmousePDX-1 lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNAmousePDX-1 lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases. PMID:22905092

  20. Preparation and evaluation of Exendin radio conjugates for detecting insulinomas and gastrinomas by molecular nuclear medicine techniques

    International Nuclear Information System (INIS)

    Medina G, V.

    2015-01-01

    The gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) are named based on the secreted hormones. Among them, the insulinomas and gastrinomas represent a diagnostic challenge because of their slow metabolic rate, small size and anatomical location that have limited their detection in some imaging procedures. About 90% of insulinomas are benign and 10% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R) and low levels of somatostatin receptors (SSTR), while malignant insulinomas over express SSTR or GLP-1R in low levels. A kit for the preparation of Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39)/ 99m Tc-EDDA/HYNIC-Tyr 3 -Octreotide was developed to detect 100% of gastrinomas and insulinomas. In order to reach this aim, the peptides were radiolabeled and characterized. Stability studies will be completed and the in vitro and in vivo behavior was evaluated. The Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39)/ 99m Tc-EDDA/HYNIC-Tyr 3 -Octreotide can be labeled with 99m Tc, obtaining high radiochemical purities (>94%), high stability in human serum and affinity to GLP-1 and SST-2 receptor. This new formulation showed properties suitable for use as a target-specific agent for molecular imaging of GLP-1R/SSTR positive tumors. In vivo micro-SPECT/CT images of Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39), 99m Tc-EDDA/HYNIC-Tyr 3 -Octreotide and of the pharmaceutical formulation Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39)/ 99m Tc-EDDA/HYNIC-Tyr 3 -Octreotide showed the main elimination pathways, and tumors higher uptake compared to the background tissues. The biodistribution and imaging studies demonstrated properties suitable for its use as a target-specific agent for the simultaneous molecular imaging of GLP-1R and SSTR. (Author)

  1. Diagnosis of insulinoma in a patient with hypoglycemia without obvious hyperinsulinemia.

    Science.gov (United States)

    Coelho, Catarina; Druce, Maralyn R; Grossman, Ashley B

    2009-11-01

    A 41-year-old Maltese woman with a 12-month history of severe, morning episodes of confusion, blurred vision and sweating was referred to a specialist center for evaluation of fasting hypoglycemia. She was not taking medication and did not report any prior personal or familial history of endocrinopathy or other relevant pathology. Measurement of plasma glucose, insulin, C-peptide, and beta-hydroxybutyrate concentrations during a prolonged supervised fast; sulfonylurea screen; CT, MRI scan and endoscopic ultrasonography of the pancreas; calcium stimulation test; surgical exploration and intra-operative ultrasonography of the pancreas. Insulin-secreting lesion (insulinoma) in the tail of the pancreas. The tumor was resected with cure of symptoms.

  2. Embolization as an Alternative Treatment of Insulinoma in a Patient with Multiple Endocrine Neoplasia Type 1 Syndrome

    International Nuclear Information System (INIS)

    Peppa, Melpomeni; Brountzos, Elias; Economopoulos, Nicolaos; Boutati, Eleni; Pikounis, Vasilios; Patapis, Paul; Economopoulos, Theofanis; Raptis, Sotirios A.; Hadjidakis, Dimitrios

    2009-01-01

    Insulinoma is a rare neuroendocrine tumor, most commonly originating from the pancreas, which is either sporadic or familial as a component of multiple endocrine neoplasia type 1 syndrome (MEN1). It is characterized by increased insulin secretion leading to hypoglycemia. Surgical removal is considered the treatment of choice, with limited side effects and relatively low morbidity and mortality, both being improved by the laparoscopic procedure. We present the case of a 30-year-old patient with MEN1 and recurrent insulinoma with severe hypoglycemic episodes who could not be surgically treated due to the adherence of the tumor to large blood vessels and to prior multiple surgical operations. He was treated by repeated embolization using spherical polyvinyl alcohol particles, resulting in shrinkage of the tumor, improvement of the frequency and severity of the hypoglycemic episodes, and better quality of life.

  3. Enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1.

    Science.gov (United States)

    Bartsch, Detlef K; Albers, Max; Knoop, Richard; Kann, Peter H; Fendrich, Volker; Waldmann, Jens

    2013-01-01

    To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma. Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center. Thirteen (17%) of 74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus. Enucleation and limited resection provide long-term cure for MEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients. © 2013 S. Karger AG, Basel.

  4. ActivinB Is Induced in Insulinoma To Promote Tumor Plasticity through a β-Cell-Induced Dedifferentiation.

    Science.gov (United States)

    Ripoche, Doriane; Charbord, Jérémie; Hennino, Ana; Teinturier, Romain; Bonnavion, Rémy; Jaafar, Rami; Goehrig, Delphine; Cordier-Bussat, Martine; Ritvos, Olli; Zhang, Chang X; Andersson, Olov; Bertolino, Philippe

    2015-12-28

    Loss of pancreatic β-cell maturity occurs in diabetes and insulinomas. Although both physiological and pathological stresses are known to promote β-cell dedifferentiation, little is known about the molecules involved in this process. Here we demonstrate that activinB, a transforming growth factor β (TGF-β)-related ligand, is upregulated during tumorigenesis and drives the loss of insulin expression and β-cell maturity in a mouse insulinoma model. Our data further identify Pax4 as a previously unknown activinB target and potent contributor to the observed β-cell dedifferentiation. More importantly, using compound mutant mice, we found that deleting activinB expression abolishes tumor β-cell dedifferentiation and, surprisingly, increases survival without significantly affecting tumor growth. Hence, this work reveals an unexpected role for activinB in the loss of β-cell maturity, islet plasticity, and progression of insulinoma through its participation in β-cell dedifferentiation. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  5. Preparation and evaluation of Exendin radio conjugates for detecting insulinomas and gastrinomas by molecular nuclear medicine techniques; Preparacion y evaluacion de radioconjugados de Exendin para la deteccion de insulinomas y gastrinomas por tecnicas de medicina nuclear molecular

    Energy Technology Data Exchange (ETDEWEB)

    Medina G, V.

    2015-07-01

    The gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) are named based on the secreted hormones. Among them, the insulinomas and gastrinomas represent a diagnostic challenge because of their slow metabolic rate, small size and anatomical location that have limited their detection in some imaging procedures. About 90% of insulinomas are benign and 10% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R) and low levels of somatostatin receptors (SSTR), while malignant insulinomas over express SSTR or GLP-1R in low levels. A kit for the preparation of Lys{sup 27} ({sup 99m}Tc-EDDA/HYNIC)-Exendin(9-39)/{sup 99m}Tc-EDDA/HYNIC-Tyr{sup 3}-Octreotide was developed to detect 100% of gastrinomas and insulinomas. In order to reach this aim, the peptides were radiolabeled and characterized. Stability studies will be completed and the in vitro and in vivo behavior was evaluated. The Lys{sup 27}({sup 99m}Tc-EDDA/HYNIC)-Exendin(9-39)/{sup 99m}Tc-EDDA/HYNIC-Tyr{sup 3}-Octreotide can be labeled with {sup 99m}Tc, obtaining high radiochemical purities (>94%), high stability in human serum and affinity to GLP-1 and SST-2 receptor. This new formulation showed properties suitable for use as a target-specific agent for molecular imaging of GLP-1R/SSTR positive tumors. In vivo micro-SPECT/CT images of Lys{sup 27}({sup 99m}Tc-EDDA/HYNIC)-Exendin(9-39), {sup 99m}Tc-EDDA/HYNIC-Tyr{sup 3}-Octreotide and of the pharmaceutical formulation Lys{sup 27}({sup 99m}Tc-EDDA/HYNIC)-Exendin(9-39)/{sup 99m}Tc-EDDA/HYNIC-Tyr{sup 3}-Octreotide showed the main elimination pathways, and tumors higher uptake compared to the background tissues. The biodistribution and imaging studies demonstrated properties suitable for its use as a target-specific agent for the simultaneous molecular imaging of GLP-1R and SSTR. (Author)

  6. Carbohydrate metabolism and quality of life in patients after surgical treatment of insulinoma

    Directory of Open Access Journals (Sweden)

    2014-08-01

    Full Text Available Objectives. T study the quality of life and status of carbohydrate metabolism in patients after surgical treatment insulinoma. Methods: The study involved 20 patients divided in two groups: the first group with a catamnesis duration of up to five years; the second group with a catamnesis duration of more than five years. We studied anthropometric parameters and carbohydrate metabolism as well as psychological questioning of patients using SF-36 questionnaire, the data was considered statistically significant at p<0.05. Results. severe combined postoperative complications were more frequent in the first group (63.6% vs. 22.2%, p=0.07, due to extend of the performed surgery. Adrenergic symptoms prior to the surgery were detected in 90.9% of cases in the first group and in 77.7% of cases in the second group. After treatment these numbers decreased to 36.4% and 11.1% respectively (p=0.039 and 0.026. Neuroglycopeniс symptoms before treatment were detected in 90.9% of cases in the first group and for all patients in the second, while after treatment persisted only in 45.5% and 33.3% of cases respectively (p=0.045 and 0.036. Carbohydrate metabolism have normalized for the majority of patients. Two patients (18.2% of the first group showed impaired glucose tolerance. Improved carbohydrate metabolism was associated with a decrease in body weight in both groups. Results of psychological questionnaires were comparable with the survey data obtained in general population in the Russian Federation. Conclusion. Surgical treatment of insulinomas is highly effective. Physical and psychological status of patients in most cases corresponds with those typical for this age-sex group of the population of the Russian Federation. Long-term treatment results do not depend on duration of the catamnesis. Complications that developed from surgical treatment have the main influence on the health of patients.

  7. Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma

    Directory of Open Access Journals (Sweden)

    Laura Soucek

    2011-11-01

    Full Text Available Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. More-over, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non–Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

  8. Regulation of ATP-sensitive K+ channels in insulinoma cells: Activation by somatostatin and protein kinase C and the role of cAMP

    International Nuclear Information System (INIS)

    De Weille, J.R.; Schmid-Antomarchi, H.; Fosset, M.; Lazdunski, M.

    1989-01-01

    The actions of somatostatin and of the phorbol ester 4β-phorbol 12-myristate 13-acetate (PMA) were studied in rat insulinoma (RINm5F) cells by electrophysiological and 86 Rb + flux techniques. Both PMA and somatostatin hyperpolarize insulinoma cells by activating ATP-sensitive K + channels. The presence of intracellular GTP is required for the somatostatin effects. PMA- and somatostatin-induced hyperpolarization and channel activity are inhibited by the sulfonylurea glibenclamide. Glibenclamide-sensitive 86 Rb + efflux from insulinoma cells is stimulated by somatostatin in a dose-dependent manner (half maximal effect at 0.7 nM) and abolished by pertussis toxin pretreatment. Mutual roles of a GTP-binding protein, of protein kinase C, and of cAMP in the regulation of ATP-sensitive K + channels are discussed

  9. Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe (18)F-FBEM-Cys (39)-exendin-4.

    Science.gov (United States)

    Xu, Yuping; Pan, Donghui; Xu, Qing; Zhu, Chen; Wang, Lizhen; Chen, Fei; Yang, Runlin; Luo, Shineng; Yang, Min

    2014-09-01

    Glucagon-like peptide-1 receptor (GLP-1R) is a specific target for insulinomas imaging since it is overexpressed in the tumor. Exendin-4 exhibits high affinity for the GLP-1R. In this study, a novel (18)F-labeled exendin-4 analog, (18)F-FBEM-Cys(39)-exendin-4, was synthesized and its potentials for GLP-1R imaging were also evaluated. (18)F-FBEM was synthesized by coupling (18)F-fluorobenzoic acid ((18)F-FBA) with N-(2-aminoethyl) maleimide, and the reaction conditions were optimized. Cys(39)-exendin-4 was then conjugated with (18)F-FBEM to obtain (18)F-FBEM-Cys(39)-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracer were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model, respectively. Under the optimal conditions, the yield of radiolabeled (18)F-FBEM was 49.1 ± 2.0 % (based on (18)F-FBA, non-decay corrected). The yield of (18)F-FBEM-Cys(39)-exendin-4 was 35.1 ± 2.6 % (based on the starting (18)F-FBEM, non-decay corrected). The radiochemical purity of (18)F-FBEM-Cys(39)-exendin-4 is >95 %, and the specific activity was at least 35 GBq/μmol. The GLP-1R-positive INS-1 insulinoma xenograft was clearly visible with good contrast to background, whereas GLP-1R-negative MDA-MB435 breast tumor was barely visible. Low levels of radioactivity were also detected at pancreas and lungs due to few GLP-1R expressions. GLP-1R binding specificity was demonstrated by reduced INS-1 tumor uptake of the tracer after coinjection with an excess of unlabeled Cys(39)-exendin-4 at 1 h postinjection. The thiol-reactive reagent, (18)F-FBEM, was prepared with high yield and successfully conjugated to Cys(39)-exendin-4. Favorable preclinical data showing specific and effective tumor targeting by (18)F-FBEM-Cys(39)-exendin-4 suggest that the tracer may be a potential probe for insulinomas imaging.

  10. FO-SPR based dextrose sensor using Ag/ZnO nanorods/GOx for insulinoma detection.

    Science.gov (United States)

    Usha, Sruthi P; Shrivastav, Anand M; Gupta, Banshi D

    2016-11-15

    In this piece of work, a fiber optic sensor has been fabricated and characterized using surface plasmon resonance for dextrose sensing. The concentration range used in this study is for diagnosing the cases of hypoglycaemia especially in suppression tests of insulinoma. Insulinoma is a medical case in which the person is recognized being hypoglycaemic with the blood dextrose level falling down to 2.2mM or less. Thus, the sensor has been characterized for the dextrose concentration range of 0 mM-10mM including the cases of normal blood dextrose range. Coatings of silver layer and zinc oxide nanorods have been carried out on the bare core fiber with a dual role of zinc oxide followed by immobilization of glucose oxidase. A three stage optimization procedure has been adopted for the best performance of the sensor. Absorbance spectra have been plotted and peak absorbance wavelengths have been extracted for each concentration chosen along with the sensitivities. The results have been made conclusive with control experiments. The probe has also been tested on sample having blood serum to check the reliability of the sensor. The sensor shows better selectivity and response time along with its real time applications, online monitoring, remote sensing and reusability. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas

    International Nuclear Information System (INIS)

    Flatt, P.R.; Tan, K.S.; Powell, C.J.; Swanston-Flatt, S.K.; Marks, V.; Bailey, C.J.

    1986-01-01

    Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 10 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life. (author)

  12. Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma

    NARCIS (Netherlands)

    Robben, J.H.; Brom, W.E. van den; Mol, J.A.; Haeften, T.W. van; Rijnberk, A.

    2006-01-01

    The inhibitory effect of the somatostatin analogue octreotide on the secretion of insulin could be used in the treatment of insulinoma. However, current information on the effectiveness of octreotide in dogs is conflicting. Therefore, the endocrine effects of a single subcutaneous dose of 50 lg

  13. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

    International Nuclear Information System (INIS)

    Kiesewetter, Dale O.; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan; Gao, Haokao

    2012-01-01

    Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. We prepared 18 F radioligands for GLP-1R by the reaction of [ 18 F]FBEM, a maleimide prosthetic group, with [Cys 0 ] and [Cys 40 ] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. The [ 18 F]FBEM-[Cys x ]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [ 18 F]FBEM, and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [ 18 F]FBEM-[Cys 40 ]-exendin-4, had higher affinity for INS-1 tumor cells (IC 50 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [ 18 F]FBEM-[Cys 0 ]-exendin-4 (IC 50 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys x ]-exendin-4 (p 18 F]FBEM-[Cys 40 ]-exendin-4 and [ 18 F]FBEM-[Cys 0 ]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [ 18 F]FBEM-[Cys 40 ]-exendin-4 suggests that this compound would be the better tracer for imaging

  14. A case of insulinoma with non-alcoholic fatty liver disease: Roles of hyperphagia and hyperinsulinemia in pathogenesis of the disease.

    Science.gov (United States)

    Rokutan, Mariyo; Yabe, Daisuke; Komoto, Izumi; Kurose, Takeshi; Kawai, Jun; Nakamura, Takefumi; Imamura, Masayuki; Seino, Yutaka

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious health-related condition all over the world; the number of patients is increasing in Asian countries including Japan. Better understanding of its pathophysiology is required to develop effective therapeutics, as patients may go on to develop non-alcoholic steatohepatitis and hepatocellular carcinomas. While NAFLD is believed to be associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia, its etiology remains largely unknown and the development or co-existence of NAFLD in patients with insulinoma has not been investigated. A 33-year-old male with an insulinoma, who had been hypoglycemic during the previous four years, developed abnormally elevated levels of liver enzymes and histological fatty liver characteristic of NAFLD by the time of admission to our hospital for resection of an insulinoma. His medical records for the previous eight years revealed that his bodyweight had increased gradually from 60 kg to 71 kg for seven years and then acutely increased to 79 kg in the latest one-year period. This sudden increase was thought to be due to the patient's self-described overeating of fruits to forestall hypoglycemia. Fresh fruits are rich in fructose, and the patient's triglycerides, alanine and aspartate transaminases showed an acute increase in the previous one-year period. After resection of the insulinoma, the levels of these parameters all were mostly restored, which suggests that hyperinsulinemia and subsequent hyperphagia played a role in the development of NAFLD in this case. This is the first report of patient with NAFLD and an insulinoma.

  15. A freeze-dried kit formulation for the preparation of Lys27(99mTc-EDDA/HYNIC)-Exendin(9-39)/99mTc-EDDA/HYNIC-Tyr3-Octreotide to detect benign and malignant insulinomas

    International Nuclear Information System (INIS)

    Medina-García, Veronica; Ocampo-García, Blanca E.; Ferro-Flores, Guillermina; Santos-Cuevas, Clara L.; Aranda-Lara, Liliana; García-Becerra, Rocio; Ordaz-Rosado, David; Melendez-Alafort, Laura

    2015-01-01

    About 90% of insulinomas are benign and 5%–15% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R) and low levels of somatostatin receptors (SSTR), while malignant insulinomas over-express SSTR or GLP-1R in low levels. A kit for the preparation of Lys 27 ( 99m Tc-EDDA/HYNIC)-Exendin(9-39)/ 99m Tc-EDDA/HYNIC-Tyr 3 Octreotide was formulated to detect 100% of insulinomas. The formulation showed radiochemical purity of 97 ± 1%, high stability in human serum, and GLP-1R and SSTR affinity. The biodistribution and imaging studies demonstrated properties suitable for its use as a target-specific agent for the simultaneous molecular imaging of GRP-1R- and/or SSTR-positive tumors.

  16. A freeze-dried kit formulation for the preparation of Lys(27)(99mTc-EDDA/HYNIC)-Exendin(9-39)/99mTc-EDDA/HYNIC-Tyr3-Octreotide to detect benign and malignant insulinomas.

    Science.gov (United States)

    Medina-García, Veronica; Ocampo-García, Blanca E; Ferro-Flores, Guillermina; Santos-Cuevas, Clara L; Aranda-Lara, Liliana; García-Becerra, Rocio; Ordaz-Rosado, David; Melendez-Alafort, Laura

    2015-12-01

    About 90% of insulinomas are benign and 5%-15% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R) and low levels of somatostatin receptors (SSTR), while malignant insulinomas over-express SSTR or GLP-1R in low levels. A kit for the preparation of Lys(27)((99m)Tc-EDDA/HYNIC)-Exendin(9-39)/(99m)Tc-EDDA/HYNIC-Tyr(3)Octreotide was formulated to detect 100% of insulinomas. The formulation showed radiochemical purity of 97±1%, high stability in human serum, and GLP-1R and SSTR affinity. The biodistribution and imaging studies demonstrated properties suitable for its use as a target-specific agent for the simultaneous molecular imaging of GRP-1R- and/or SSTR-positive tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Antioxidant effect of mogrosides against oxidative stress induced by palmitic acid in mouse insulinoma NIT-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Q.; Chen, S.Y.; Deng, L.D.; Feng, L.P.; Huang, L.Z.; Yu, R.R. [Department of Pharmacy, Guilin Medical University, Guilin (China)

    2013-11-18

    Excessive oxidative stress in pancreatic β cells, caused by glucose and fatty acids, is associated with the pathogenesis of type 2 diabetes. Mogrosides have shown antioxidant and antidiabetic activities in animal models of diabetes, but the underlying mechanisms remain unclear. This study evaluated the antioxidant effect of mogrosides on insulinoma cells under oxidative stress caused by palmitic acid, and investigated the underlying molecular mechanisms. Mouse insulinoma NIT-1 cells were cultured in medium containing 0.75 mM palmitic acid, mimicking oxidative stress. The effects of 1 mM mogrosides were determined with the dichlorodihydrofluorescein diacetate assay for intracellular reactive oxygen species (ROS) and FITC-Annexin V/PI assay for cell apoptosis. Expression of glucose transporter-2 (GLUT2) and pyruvate kinase was determined by semi-quantitative reverse-transcription polymerase chain reaction. Palmitic acid significantly increased intracellular ROS concentration 2-fold (P<0.05), and decreased expression of GLUT2 (by 60%, P<0.05) and pyruvate kinase (by 80%, P<0.05) mRNAs in NIT-1 cells. Compared with palmitic acid, co-treatment with 1 mM mogrosides for 48 h significantly reduced intracellular ROS concentration and restored mRNA expression levels of GLUT2 and pyruvate kinase. However, mogrosides did not reverse palmitic acid-induced apoptosis in NIT-1 cells. Our results indicate that mogrosides might exert their antioxidant effect by reducing intracellular ROS and regulating expression of genes involved in glucose metabolism. Further research is needed to achieve a better understanding of the signaling pathway involved in the antioxidant effect of mogrosides.

  18. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma

    Science.gov (United States)

    Sowa-Staszczak, Anna; Trofimiuk-Müldner, Małgorzata; Stefańska, Agnieszka; Tomaszuk, Monika; Buziak-Bereza, Monika; Gilis-Januszewska, Aleksandra; Jabrocka-Hybel, Agata; Głowa, Bogusław; Małecki, Maciej; Bednarczuk, Tomasz; Kamiński, Grzegorz; Kowalska, Aldona; Mikołajczak, Renata; Janota, Barbara; Hubalewska-Dydejczyk, Alicja

    2016-01-01

    Introduction The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. Materials and Methods Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. Results Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). Conclusions 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective

  19. Role of aryl hydrocarbon receptor nuclear translocator in KATP channel-mediated insulin secretion in INS-1 insulinoma cells

    International Nuclear Information System (INIS)

    Kim, Ji-Seon; Zheng Haifeng; Kim, Sung Joon; Park, Jong-Wan; Park, Kyong Soo; Ho, Won-Kyung; Chun, Yang-Sook

    2009-01-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) has been known to participate in cellular responses to xenobiotic and hypoxic stresses, as a common partner of aryl hydrocarbon receptor and hypoxia inducible factor-1/2α. Recently, it was reported that ARNT is essential for adequate insulin secretion in response to glucose input and that its expression is downregulated in the pancreatic islets of diabetic patients. In the present study, the authors addressed the mechanism by which ARNT regulates insulin secretion in the INS-1 insulinoma cell line. In ARNT knock-down cells, basal insulin release was elevated, but insulin secretion was not further stimulated by a high-glucose challenge. Electrophysiological analyses revealed that glucose-dependent membrane depolarization was impaired in these cells. Furthermore, K ATP channel activity and expression were reduced. Of two K ATP channel subunits, Kir6.2 was found to be positively regulated by ARNT at the mRNA and protein levels. Based on these results, the authors suggest that ARNT expresses K ATP channel and by so doing regulates glucose-dependent insulin secretion.

  20. Suppression of the Nuclear Factor Eny2 Increases Insulin Secretion in Poorly Functioning INS-1E Insulinoma Cells

    Directory of Open Access Journals (Sweden)

    P. Dames

    2012-01-01

    Full Text Available Eny2, the mammalian ortholog of yeast Sus1 and drosophila E(y2, is a nuclear factor that participates in several steps of gene transcription and in mRNA export. We had previously found that Eny2 expression changes in mouse pancreatic islets during the metabolic adaptation to pregnancy. We therefore hypothesized that the protein contributes to the regulation of islet endocrine cell function and tested this hypothesis in rat INS-1E insulinoma cells. Overexpression of Eny2 had no effect but siRNA-mediated knockdown of Eny2 resulted in markedly increased glucose and exendin-4-induced insulin secretion from otherwise poorly glucose-responsive INS-1E cells. Insulin content, cellular viability, and the expression levels of several key components of glucose sensing remained unchanged; however glucose-dependent cellular metabolism was higher after Eny2 knockdown. Suppression of Eny2 enhanced the intracellular incretin signal downstream of cAMP. The use of specific cAMP analogues and pathway inhibitors primarily implicated the PKA and to a lesser extent the EPAC pathway. In summary, we identified a potential link between the nuclear protein Eny2 and insulin secretion. Suppression of Eny2 resulted in increased glucose and incretin-induced insulin release from a poorly glucose-responsive INS-1E subline. Whether these findings extend to other experimental conditions or to in vivo physiology needs to be determined in further studies.

  1. {sup 18}F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kiesewetter, Dale O.; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Gao, Haokao [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Fourth Military Medical University, Department of Cardiology, Xijing Hospital, Xi' an (China)

    2012-03-15

    Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic {beta}-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic {beta}-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. We prepared {sup 18}F radioligands for GLP-1R by the reaction of [{sup 18}F]FBEM, a maleimide prosthetic group, with [Cys{sup 0}] and [Cys{sup 40}] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. The [{sup 18}F]FBEM-[Cys{sup x}]-exendin-4 analogs were obtained in good yield (34.3 {+-} 3.4%, n = 11), based on the starting compound [{sup 18}F]FBEM, and had a specific activity of 45.51 {+-} 16.28 GBq/{mu}mol (1.23 {+-} 0.44 Ci/{mu}mol, n = 7) at the end of synthesis. The C-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4, had higher affinity for INS-1 tumor cells (IC{sub 50} 1.11 {+-} 0.057 nM) and higher tumor uptake (25.25 {+-} 3.39 %ID/g at 1 h) than the N-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 (IC{sub 50} 2.99 {+-} 0.06 nM, uptake 7.20 {+-} 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys{sup x}]-exendin-4 (p < 0.05). [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4 and [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors

  2. Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells

    Directory of Open Access Journals (Sweden)

    Han Sung Kim

    2016-01-01

    Full Text Available 2-DG triggers glucose deprivation without altering other nutrients or metabolic pathways and then activates autophagy via activation of AMPK and endoplasmic reticulum (ER stress. We investigated whether 2-DG reduced intracellular insulin increased by melatonin via autophagy/EDC3 in insulinoma INS-1E cells. p-AMPK and GRP78/BiP level were significantly increased by 2-DG in the presence/absence of melatonin, but IRE1α level was reduced in 2-DG treatment. Levels of p85α, p110, p-Akt (Ser473, Thr308, and p-mTOR (Ser2481 were also significantly reduced by 2-DG in the presence/absence of melatonin. Mn-SOD increased with 2-DG plus melatonin compared to groups treated with/without melatonin alone. Bcl-2 was decreased and Bax increased with 2-DG plus melatonin. LC3II level increased with 2-DG treatment in the presence/absence of melatonin. Intracellular insulin production increased in melatonin plus 2-DG but reduced in treatment with 2-DG with/without melatonin. EDC3 was increased by 2-DG in the presence/absence of melatonin. Rapamycin, an mTOR inhibitor, increased GRP78/BiP and EDC3 levels in a dose-dependent manner and subsequently resulted in a decrease in intracellular production of insulin. These results suggest that melatonin-mediated insulin synthesis during 2-DG treatment involves autophagy and EDC3 protein in rat insulinoma INS-1E cells and subsequently results in a decrease in intracellular production of insulin.

  3. A novel dual-color reporter for identifying insulin-producing beta-cells and classifying heterogeneity of insulinoma cell lines.

    Directory of Open Access Journals (Sweden)

    Nan Sook Lee

    Full Text Available Many research studies use immortalized cell lines as surrogates for primary beta- cells. We describe the production and use of a novel "indirect" dual-fluorescent reporter system that leads to mutually exclusive expression of EGFP in insulin-producing (INS(+ beta-cells or mCherry in non-beta-cells. Our system uses the human insulin promoter to initiate a Cre-mediated shift in reporter color within a single transgene construct and is useful for FACS selection of cells from single cultures for further analysis. Application of our reporter to presumably clonal HIT-T15 insulinoma cells, as well as other presumably clonal lines, indicates that these cultures are in fact heterogeneous with respect to INS(+ phenotype. Our strategy could be easily applied to other cell- or tissue-specific promoters. We anticipate its utility for FACS purification of INS(+ and glucose-responsive beta-like-cells from primary human islet cell isolates or in vitro differentiated pluripotent stem cells.

  4. Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist.

    Directory of Open Access Journals (Sweden)

    Mi-Kyung Kim

    Full Text Available Beta cell death caused by endoplasmic reticulum (ER stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1 reversed by exenatide, 2 exaggerated by exenatide, and 3 unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.

  5. Loss of Serglycin Promotes Primary Tumor Growth and Vessel Functionality in the RIP1-Tag2 Mouse Model for Spontaneous Insulinoma Formation.

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    Andrew Hamilton

    Full Text Available The serglycin proteoglycan is mainly expressed by hematopoietic cells where the major function is to retain the content of storage granules and vesicles. In recent years, expression of serglycin has also been found in different forms of human malignancies and a high serglycin expression level has been correlated with a more migratory and invasive phenotype in the case of breast cancer and nasopharyngeal carcinoma. Serglycin has also been implicated in the development of the tumor vasculature in multiple myeloma and hepatocellular carcinoma where reduced expression of serglycin was correlated with a less extensive vasculature. To further investigate the contribution of serglycin to tumor development, we have used the immunocompetent RIP1-Tag2 mouse model of spontaneous insulinoma formation crossed into serglycin deficient mice. For the first time we show that serglycin-deficiency affects orthotopic primary tumor growth and tumor vascular functionality of late stage carcinomas. RIP1-Tag2 mice that lack serglycin develop larger tumors with a higher proliferative activity but unaltered apoptosis compared to normal RIP1-Tag2 mice. The absence of serglycin also enhances the tumor vessel functionality, which is better perfused than in tumors from serglycin wild type mice. The presence of the pro-angiogenic modulators vascular endothelial growth factor and hepatocyte growth factor were decreased in the serglycin deficient mice which suggests a less pro-angiogenic environment in the tumors of these animals. Taken together, we conclude that serglycin affects multiple aspects of spontaneous tumor formation, which strengthens the theory that serglycin acts as an important mediator in the formation and progression of tumors.

  6. Evaluation of an [18F]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma

    Directory of Open Access Journals (Sweden)

    Dale O. Kiesewetter, Ning Guo, Jinxia Guo, Haokao Gao, Lei Zhu, Ying Ma, Gang Niu, Xiaoyuan Chen

    2012-01-01

    Full Text Available Introduction: The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of exendin-4 prepared by conjugation with [18F]FBEM (N-[2-(4-[18F]fluorobenzamideethyl]maleimide. Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [18F]fluoride complexation.Methods: Cys40-exendin-4 was conjugated with NOTA mono N-ethylmaleimide. [18F]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results.Results: The radiosynthesis provided [18F]AlF-NOTA-MAL-cys40-exendin-4 in 23.6 ± 2.4 % radiochemical yield (uncorrected, n = 3 after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci/µmol. Tumor uptake had reached its maximum (16.09 ± 1.18% ID/g, n = 4 by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component.Conclusion: The radiotracer is prepared in

  7. The H+/K+ ATPase Inhibitor SCH-28080 Inhibits Insulin Secretion and Induces Cell Death in INS-1E Rat Insulinoma Cells

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    Martin Jakab

    2017-10-01

    Full Text Available Background/Aims: Glucose-stimulated insulin secretion (GSIS of pancreatic β-cells involves glucose uptake and metabolism, closure of KATP channels and depolarization of the cell membrane potential (Vmem, activation of voltage-activated Ca2+ currents (ICav and influx of Ca2+, which eventually triggers hormone exocytosis. Beside this classical pathway, KATP-independent mechanisms such as changes in intracellular pH (pHi or cell volume, which also affect β-cell viability, can elicit or modify insulin release. In β-cells the regulation of pHi is mainly accomplished by Na+/H+ exchangers (NHEs. To investigate if other proton extrusion mechanisms than NHEs are involved in pH regulation, we tested for the presence of the non-gastric H+/K+ ATPase in rat insulinoma cells and assessed effects of the H+/K+ ATPase inhibitor SCH-28080 on insulin secretion, cell viability and apoptosis. Methods: In INS-1E cell cultures, H+/K+ ATPase gene and protein expression was analyzed by reverse transcription PCR and Western blotting. Intracellular pH (pHi recovery after acute acidic load was measured by NH4Cl prepulsing using BCECF. Insulin secretion was determined by ELISA from the cell culture supernatant. Vmem, K+ and Ca2+ currents were recorded using patch clamp. Overall cell responses were determined using resazurin (viability and cytotoxicity assays. The mean cell volume (MCV, cell granularity (side-scatter; SSC, phosphatidylserine (PS exposure, cell membrane integrity, caspase activity and the mitochondrial membrane potential (ΔΨm were measured by flow cytometry. Results: We found that the α-subunit of the non-gastric H+/K+ ATPase (HKα2 is expressed on mRNA and protein level. However, compared to rat colon tissue, in INS-1E cells mRNA abundance was very low. In NH4Cl prepulsing experiments no K+-dependent pHi recovery was observed under Na+-free extracellular conditions. Nonetheless within 1 h, 20 µM SCH-28080 inhibited GSIS by ∼50%, while basal release

  8. Though active on RINm5F insulinoma cells and cultured pancreatic islets, recombinant IL-22 fails to modulate cytotoxicity and disease in a protocol of streptozotocin-induced experimental diabetes.

    Directory of Open Access Journals (Sweden)

    Anika eBerner

    2016-01-01

    Full Text Available Interleukin (IL-22 is a cytokine displaying tissue protective and pro-regenerative functions in various preclinical disease models. Anti-bacterial, pro-proliferative, and anti-apoptotic properties mediated by activation of the transcription factor signal transducer and activator of transcription (STAT-3 are key to biological functions of this IL-10 family member. Herein, we introduce RINm5F insulinoma cells as rat ß-cell line that, under the influence of IL-22, displays activation of STAT3 with induction of its downstream gene targets Socs3, Bcl3, and Reg3ß. In addition, IL-22 also activates STAT1 in this cell type. To refine those observations, IL-22 biological activity was evaluated using ex vivo cultivated murine pancreatic islets. In accord with data on RINm5F cells, islet exposure to IL-22 activated STAT3 and upregulation of STAT3-inducible Socs3, Bcl3, and STEAP4 was evident under those conditions. As these observations supported the hypothesis that IL-22 may exert protective functions in toxic ß-cell injury, application of IL-22 was investigated in murine multiple-low-dose streptozotocin (STZ-induced diabetes. For that purpose, recombinant IL-22 was administered thrice either immediately before and at disease onset (at d4, d6, d8 or closely thereafter (at d8, d10, d12. These two IL-22-treatment periods coincide with two early peaks of ß-cell injury detectable in this model. Notably, none of the two IL-22-treatment strategies affected diabetes incidence or blood glucose levels in STZ-treated mice. Moreover, pathological changes in islet morphology analyzed 28 days after disease induction were not ameliorated by IL-22 administration. Taken together, despite being active on rat RINm5F insulinoma cells and murine pancreatic islets, recombinant IL-22 fails to protect pancreatic ß-cells in the tested protocols from toxic effects of STZ and thus is unable to ameliorate disease in the widely used model of STZ-induced diabetes.

  9. Cord blood insulinoma-associated protein 2 autoantibodies are associated with increased risk of type 1 diabetes in the population-based Diabetes Prediction in Skåne study.

    Science.gov (United States)

    Lundgren, Markus; Lynch, Kristian; Larsson, Christer; Elding Larsson, Helena

    2015-01-01

    The aim of this study was to examine the effect of cord blood autoantibodies on the risk for type 1 diabetes in children followed prospectively from birth. The Diabetes Prediction in Skåne (DiPiS) study consists of 35,853 children from the general population born during 2000-2004. Samples were collected at birth and analysed for HLA genotypes and autoantibodies to glutamate decarboxylase 65 (GAD65), insulin and insulinoma-associated protein 2 (IA-2). After adjusting for HLA, sex, maternal age and parental type 1 diabetes, independent associations with risk of diabetes were assessed using multivariate Cox proportional hazards models. In total, 151 children (0.4%) had developed type 1 diabetes by the end of 2013 at a median age of 5.8 years (0.8-12.2 years). In the multivariate analysis, the presence of IA-2 autoantibodies (IA-2A) in cord blood (HR 6.88, 95% CI 1.46,32.4; p = 0.003), but not maternal diabetes (HR 1.38, 95% CI 0.24,7.84; p = 0.71), was associated with risk of developing type 1 diabetes. No increased risk could be seen for the presence of autoantibodies to GAD65 or insulin. Our study indicates that the presence of cord blood IA-2A superimposes maternal diabetes and other cord blood islet autoantibodies as a predictor of type 1 diabetes development in the child. These findings may be of significance for future screening and study protocols on type 1 diabetes prediction.

  10. Studies of insulin secretory responses and of arachidonic acid incorporation into phospholipids of stably transfected insulinoma cells that overexpress group VIA phospholipase A2 (iPLA2beta ) indicate a signaling rather than a housekeeping role for iPLA2beta.

    Science.gov (United States)

    Ma, Z; Ramanadham, S; Wohltmann, M; Bohrer, A; Hsu, F F; Turk, J

    2001-04-20

    A cytosolic 84-kDa group VIA phospholipase A(2) (iPLA(2)beta) that does not require Ca(2+) for catalysis has been cloned from several sources, including rat and human pancreatic islet beta-cells and murine P388D1 cells. Many potential iPLA(2)beta functions have been proposed, including a signaling role in beta-cell insulin secretion and a role in generating lysophosphatidylcholine acceptors for arachidonic acid incorporation into P388D1 cell phosphatidylcholine (PC). Proposals for iPLA(2)beta function rest in part on effects of inhibiting iPLA(2)beta activity with a bromoenol lactone (BEL) suicide substrate, but BEL also inhibits phosphatidate phosphohydrolase-1 and a group VIB phospholipase A(2). Manipulation of iPLA(2)beta expression by molecular biologic means is an alternative approach to study iPLA(2)beta functions, and we have used a retroviral construct containing iPLA(2)beta cDNA to prepare two INS-1 insulinoma cell clonal lines that stably overexpress iPLA(2)beta. Compared with parental INS-1 cells or cells transfected with empty vector, both iPLA(2)beta-overexpressing lines exhibit amplified insulin secretory responses to glucose and cAMP-elevating agents, and BEL substantially attenuates stimulated secretion. Electrospray ionization mass spectrometric analyses of arachidonic acid incorporation into INS-1 cell PC indicate that neither overexpression nor inhibition of iPLA(2)beta affects the rate or extent of this process in INS-1 cells. Immunocytofluorescence studies with antibodies directed against iPLA(2)beta indicate that cAMP-elevating agents increase perinuclear fluorescence in INS-1 cells, suggesting that iPLA(2)beta associates with nuclei. These studies are more consistent with a signaling than with a housekeeping role for iPLA(2)beta in insulin-secreting beta-cells.

  11. Quick insulin radioimmunoassay and its utilization for intra operative localization of insulinoma

    International Nuclear Information System (INIS)

    Ursich, M.J.M.; Fukui, R.T.; Aguiar Pupo, A. de; Machado, M.C.C.

    1988-01-01

    A quick insuLin radioimmunoassay performed in 90 minutes is described and the results are compared with those obtained with the conventional method. The realibility of the new procedure is pointed. (M.A.C.) [pt

  12. Insulinoma in a third-trimester pregnant woman combined with pre-eclampsia

    DEFF Research Database (Denmark)

    Christiansen, Poul Erik; Vestergaard, Henrik

    2008-01-01

    week due to slurred speech, weakness and slow reaction patterns. An electroencephalogram and computed tomography scan of the brain and blood samples were normal. Blood pressure was 170-145/110-95 mmHg, albuminuria was moderate and there was moderate edema of the ankles. Labor started spontaneously...

  13. Tissue-specific expression of transfected human insulin genes in pluripotent clonal rat insulinoma lines induced during passage in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Madsen, O.D.; Andersen, L.C.; Michelsen, B.; Owerbach, D.; Larsson, L.I.; Lernmark, A.; Steiner, D.F. (Hagedorn Research Laboratory, Gentofte (Denmark))

    1988-09-01

    The pluripotent rat islet tumor cell line MSL-G2 expresses primarily glucagon or cholecystokinin and not insulin in vitro but changes phenotype completely after prolonged in vivo cultivation to yield small-sized hypoglycemic tumors composed almost entirely of insulin-producing beta cells. When a genomic DNA fragment containing the coding and upstream regulatory regions of the human insulin gene was stably transfected into MSL-G2 cells no measurable amounts of insulin or insulin mRNA were detected in vitro. However, successive transplantation of two transfected clones resulted in hypoglycemic tumors that efficiently coexpressed human and rat insulin as determined by human C-peptide-specific immunoreagents. These results demonstrate that cis-acting tissue-specific insulin gene enhancer elements are conserved between rat and human insulin genes. The authors propose that the in vivo differentiation of MSL-G2 cells and transfected subclones into insulin-producing cells reflects processes of natural beta-cell ontogeny leading to insulin gene expression.

  14. Tissue-specific expression of transfected human insulin genes in pluripotent clonal rat insulinoma lines induced during passage in vivo

    International Nuclear Information System (INIS)

    Madsen, O.D.; Andersen, L.C.; Michelsen, B.; Owerbach, D.; Larsson, L.I.; Lernmark, A.; Steiner, D.F.

    1988-01-01

    The pluripotent rat islet tumor cell line MSL-G2 expresses primarily glucagon or cholecystokinin and not insulin in vitro but changes phenotype completely after prolonged in vivo cultivation to yield small-sized hypoglycemic tumors composed almost entirely of insulin-producing beta cells. When a genomic DNA fragment containing the coding and upstream regulatory regions of the human insulin gene was stably transfected into MSL-G2 cells no measurable amounts of insulin or insulin mRNA were detected in vitro. However, successive transplantation of two transfected clones resulted in hypoglycemic tumors that efficiently coexpressed human and rat insulin as determined by human C-peptide-specific immunoreagents. These results demonstrate that cis-acting tissue-specific insulin gene enhancer elements are conserved between rat and human insulin genes. The authors propose that the in vivo differentiation of MSL-G2 cells and transfected subclones into insulin-producing cells reflects processes of natural beta-cell ontogeny leading to insulin gene expression

  15. Islet Cell Tumors of the Pancreas: A Variety of Multiphase Dynamic Imaging Findings with Pathologic Correlations Focusing on Nonfunctioning Tumors and Insulinomas

    International Nuclear Information System (INIS)

    Hong, Yoo Jin; Yu, Jeong Sik; Park, Chan Il; Kwon, Ji Eun; Chung, Jae Joon; Kim, Joo Hee; Kim, Ki Whang

    2010-01-01

    Islet cell tumors (ICTs) are rare pancreatic neoplasms of neuroendocrine origin, posing a diagnostic challenge to radiologists. We illustrated a spectrum of features of pancreatic ICTs that could be found on multiphase dynamic CT or MRI, and elucidated the histopathologic characteristics by determining the contrast enhancement pattern of the lesions. Various enhancement patterns were dependant on the internal composition of the tumor, that is, the proportion of vascular densities for early enhancement and non-hypervascular interstitial tissue for late enhancement regardless of the size or functional behavior. This knowledge of the imaging-pathologic spectrum of ICTs could be helpful for the proper differential diagnosis from other pancreatic tumors

  16. Glucose-stimulated insulin secretion of insulinoma INS-1E cells is associated with elevation of both respiration and mitochondrial membrane potential

    Czech Academy of Sciences Publication Activity Database

    Špaček, Tomáš; Šantorová, Jitka; Zacharovová, K.; Berková, Z.; Hlavatá, Lydie; Saudek, F.; Ježek, Petr

    2008-01-01

    Roč. 40, č. 8 (2008), s. 1522-1535 ISSN 1357-2725 R&D Projects: GA MZd(CZ) NR7917 Institutional research plan: CEZ:AV0Z50110509 Keywords : in situ mitochondrial membrane potential * in situ mitochondrial respiration * glucose-stimulated insulin secretion Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 4.178, year: 2008

  17. Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

    Science.gov (United States)

    2017-04-18

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma

  18. Hyperinsulinaemic hypoglycaemia - a diagnostic challenge. A report of two atypical cases.

    Directory of Open Access Journals (Sweden)

    Renata Baronaite Hansen

    2015-07-01

    Patient 2 was diagnosed with a benign insulinoma and 5 years later with metastatic disease. Conclusion: The authors conclude that insulinomas are rare entities which often present a diagnostic and therapeutic challenge. In such cases, patient referral to tertiary multidisciplinary centers is recommended.

  19. Adult-onset hyperinsulinaemic hypoglycaemia in clinical practice: diagnosis, aetiology and management.

    Science.gov (United States)

    Challis, Benjamin G; Powlson, Andrew S; Casey, Ruth T; Pearson, Carla; Lam, Brian Y; Ma, Marcella; Pitfield, Deborah; Yeo, Giles S H; Godfrey, Edmund; Cheow, Heok K; Chatterjee, V Krishna; Carroll, Nicholas R; Shaw, Ashley; Buscombe, John R; Simpson, Helen L

    2017-10-01

    In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period. Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed. Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I-IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 ( YY1 ) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden. Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease. © 2017 The authors.

  20. Behandling af insulinom med alkoholsklerosering

    DEFF Research Database (Denmark)

    Schnack, Christina; Christensen, Carina Ørts; Beck-Nielsen, Henning

    2012-01-01

    The efficacy and safety of endoscopic ultrasound (EUS)-guided alcohol ablation of an insulinoma in a patient not candidate for surgery is being evaluated. A 89 year-old male patient with insulinoma and serious cardiac disease was treated with EUS-guided alcohol ablation. The only complication...... was a slight degree of pancreatitis. Two months after the ablation values of plasma glucose and serum pro-insulin were normalized. EUS-guided alcohol ablation is a safe and efficient alternative to surgical resection of insulinomas in poor surgical candidates....

  1. Laser Tissue Welding - Distal Pancreatectomy Sealing Study

    Science.gov (United States)

    2018-04-20

    Pancreatic Tumor, Benign; Pancreatic Neoplasms; Pancreatic Adenocarcinoma; Pancreatic Pseudocyst; Pancreatic Neuroendocrine Tumor; Pancreas; Insulinoma; Pancreatic Cyst; Pancreatic Teratoma; Pancreatic Polypeptide Tumor; Pancreatic Vipoma; Pancreatic Cystadenoma; Pancreas Injury; Pancreatic Gastrinoma; Pancreatic Glucagonoma

  2. In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic ?-Cells

    OpenAIRE

    Velasquez, Claudia; Vasquez, Juan Sebastian; Balcazar, Norman

    2017-01-01

    Background The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic ?-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). Methods From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic ...

  3. Role of 68Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study

    International Nuclear Information System (INIS)

    Prasad, Vikas; Sainz-Esteban, Aurora; Arsenic, Ruza; Ploeckinger, Ursula; Denecke, Timm; Pape, Ulrich-Frank; Pavel, Marianne; Pascher, Andreas; Kuehnen, Peter; Blankenstein, Oliver

    2016-01-01

    To explore the role of 68 Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. This explorative study suggests that SR PET in combination with CT may play a significant role in the detection

  4. Mechanisms of pancreatic beta-cell growth and regeneration

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1989-01-01

    Information about the mechanism of beta-cell growth and regeneration may be obtained by studies of insulinoma cells. In the present study the growth and function of the rat insulinoma cell lines RINm5F and 5AH were evaluated by addition of serum, hormones, and growth factors. It was found...... of insulin mRNA content showed that the insulinoma cells only contained about 2% of that of normal rat beta-cells. These results are discussed in relation to the role of growth factors, oncogenes, and differentiation in the growth and regeneration of beta-cells....... that transferrin is the only obligatory factor whereas growth hormone, epidermal growth factor, fibroblast growth factor, and TRH had modulating effects. A heat-labile heparin binding serum factor which stimulated thymidine incorporation but not cell proliferation was demonstrated in human serum. Measurements...

  5. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2011-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist 125 I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic β-cells and mouse insulinomas, but it does not label human pancreatic β-cells and insulinomas. High affinity displacement (IC 50 approximately 2 nM) is observed in mouse β-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist 125 I-GLP-1(7-36)amide intensively labels mouse pancreatic β-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  6. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Bern (Switzerland)

    2011-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist {sup 125}I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic {beta}-cells and mouse insulinomas, but it does not label human pancreatic {beta}-cells and insulinomas. High affinity displacement (IC{sub 50} approximately 2 nM) is observed in mouse {beta}-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist {sup 125}I-GLP-1(7-36)amide intensively labels mouse pancreatic {beta}-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  7. Anti-diabetic effects of rice hull smoke extract in alloxan-induced diabetic mice

    Science.gov (United States)

    We investigated the protective effect of a liquid rice hull smoke extract (RHSE) against diabetes in alloxan-induced diabetic mice. Anti-diabetic effects of RHSE were evaluated in both the rat insulinoma-1 cell line (INS-1) and diabetic ICR mice induced by inraperitoneal (ip) injection of alloxan. ...

  8. Expression of the growth hormone receptor gene in insulin producing cells

    DEFF Research Database (Denmark)

    Møldrup, Annette; Billestrup, N; Nielsen, Jens Høiriis

    1990-01-01

    Growth hormone (GH) plays a dual role in glucose homeostasis. On the one hand, it exerts an insulin antagonistic effect on the peripheral tissue, on the other hand, it stimulates insulin biosynthesis and beta-cell proliferation. The expression of GH-receptors on the rat insulinoma cell line RIN-5...

  9. CT study of pancreatic diseases with modified dynamic scanning

    International Nuclear Information System (INIS)

    Qian Minghui; Zhu Guangying

    1990-01-01

    Experience of 20 cases modified dynamic CT scanning is presented. With a slight increased X-ray tube burden, it is possible to investigate tumor blood supply and find small pancreatic insulinoma with this method. The capsular sign typical for chronic traumatic pancreatic hematoma on CT is presented

  10. Single agent- and combination treatment with two targeted suicide gene therapy systems is effective in chemoresistant small cell lung cancer cells

    DEFF Research Database (Denmark)

    Michaelsen, Signe R; Christensen, Camilla L; Sehested, Maxwell

    2012-01-01

    Transcriptional targeted suicide gene (SG) therapy driven by the insulinoma-associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to small cell lung cancer (SCLC) cells and tumors. It remains to be determined whether acquired chemoresistance......, as observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter-driven SG therapy....

  11. Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection

    DEFF Research Database (Denmark)

    Rønn, S G; Börjesson, A; Bruun, C

    2008-01-01

    The pro-inflammatory cytokines IL-1 and IFNgamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS...

  12. Immature transformed rat islet beta-cells differentially express C-peptides derived from the genes coding for insulin I and II as well as a transfected human insulin gene

    DEFF Research Database (Denmark)

    Blume, N; Petersen, J S; Andersen, L C

    1992-01-01

    is induced in the transformed heterogeneous rat islet cell clone, NHI-6F, by transient in vivo passage. During this process a transfected human insulin gene is coactivated with the endogenous nonallelic rat insulin I and II genes. Newly established cultures from NHI-6F insulinomas having a high frequency...

  13. Differential expression of glutamic acid decarboxylase in rat and human islets

    DEFF Research Database (Denmark)

    Petersen, J S; Russel, S; Marshall, M O

    1993-01-01

    catabolism or GAD enzyme activity. In a rat insulinoma cell line (NHI-6F) producing both glucagon and insulin depending on the culture conditions, GAD64 expression was detected only in cultures in which the insulin producing phenotype dominated. In conclusion, these data demonstrate that the two GAD isoforms...

  14. Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications

    Directory of Open Access Journals (Sweden)

    Meike eKörner

    2012-12-01

    Full Text Available Peptide hormones of the glucagon-like peptide (GLP family play an increasing clinical role, such as GLP-1 in diabetes therapy. Moreover, GLP receptors are over-expressed in various human tumor types and therefore represent molecular targets for important clinical applications. In particular, virtually all benign insulinomas highly over-express GLP-1 receptors (GLP-1R. Targeting GLP-1R with the stable GLP-1 analogs 111In-DOTA/ DPTA-exendin-4 offers a new approach to successfully localize these small tumors. This non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. Malignant insulinomas, in contrast to their benign counterparts, express GLP-1R in only one third of the cases, while they more often express the somatostatin type 2 receptors. Importantly, one of the two receptors appears to be always expressed in malignant insulinomas. The GLP-1R overexpression in selected cancers is worth to be kept in mind with regard to the increasing use of GLP-1 analogs for diabetes therapy. While the functional role of GLP-1R in neoplasia is not known yet, it may be safe to monitore patients undergoing GLP-1 therapy carefully.

  15. Endocrine diseases in ferrets

    NARCIS (Netherlands)

    Schoemaker, N.J.; van Zeeland, Y.R.A.

    2013-01-01

    SUMMARY Endocrine diseases are among the most commonly seen conditions in ferrets. Tumours of the islet cells in the pancreas, referred to as insulinomas, and tumours of the adrenal glands, referred to as hyperadrenocorticism, are more commonly described in this species than in any other species.

  16. Is a dynamic MRI examination of the pancreas still necessary?

    International Nuclear Information System (INIS)

    Morakkabati-Spitz, N.; Willinek, W.A.; Falkenhausen, M. von; Flacke, S.; Schild, H.; Kreft, B.

    2002-01-01

    Purpose: Evaluation of the diagnostic potential of a dynamic MR examination of the pancreas. Material and Methods: Retrospective study on 49 patients who underwent MRI of the pancreas (2 insulinomas, 2 cystadenomas, 19 pancreatic carcinomas, 26 patients with chronic pancreatitis). Interpretation was done in two steps: Initial evaluation of T 2 -weighted TSE-sequences, T 1 -weighted gradient echo sequences before and after injection of Gadolinium-DTPA i.v. Afterwards, additional evaluation of a dynamic contrast-enhanced MRI series of the pancreas with four dynamic scans. Result: Dynamic MR examination of the pancreas is useful in case of insulinomas. However, in case of pancreatic cancer an additional dynamic MR examination of the pancreas does not provide further clinically relevant information. Conclusion: In patients with a suspicion of pancreatic cancer, the injection of contrast material should preferably be used for the performance of a contrast-enhanced MR angiography at the expense of a dynamic MR examination. (orig.) [de

  17. Symptomatic Hypoglycemia Related to Inappropriately High IGF-II Serum Levels in a Patient with Desmoplastic Small Round Cell Tumor

    Directory of Open Access Journals (Sweden)

    Williams Fernandes Barra

    2010-01-01

    Full Text Available A 45-year old man was diagnosed with desmoplastic small round cell tumor (DSRCT with involvement of the peritoneum and pelvis. Disease progression was observed despite systemic chemotherapy. Six months after diagnosis, he developed severe hypoglycemia presented with seizures. He received intravenous glucose infusion and hydrocortisone with poor glycemic control, but with seizures resolution. The investigation excluded insulinoma, adrenal, liver and GH deficiencies. Laboratory showed slight rise of IGF-II and significant increase of the ratio IGF-II : IGF-I, which is pathognomonic of non-islet cell tumor hypoglycemia (NICTH. He received the diagnoses of NICTH related to IGF-II inappropriate production by DSRCT. Despite the attempt to control tumor mass and hypoglycemia, the patient died 9 months after diagnosis. NICTH related to inappropriate IGF-II secretion should be investigated in all cancer patients with refractory hypoglycemia whom insulinoma and other metabolic abnormalities were excluded from.

  18. The uncovering and characterization of a CCKoma syndrome in enteropancreatic neuroendocrine tumor patients

    DEFF Research Database (Denmark)

    Rehfeld, Jens F; Federspiel, Birgitte; Agersnap, Mikkel

    2016-01-01

    OBJECTIVE: Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma...... disease and diarrhea with permanently low gastrin in plasma suggest that CCKomas may mimic gastrinoma-like symptoms, because CCK peptides are full agonists of the gastrin/CCK-B receptor....

  19. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future

    International Nuclear Information System (INIS)

    Hubalewska-Dydejczyk, A.; Sowa-Staszczak, A.; Tomaszuk, M.; Stefańska, A.

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) receptors expression has been found on many types of cancer cells. In case of benign insulinoma the density of those receptors is even higher than the density of somatostatin receptors. This article presents the results of clinical trials proving the utility of GLP-1 receptors imaging. Scintigraphy or positron emission tomography with the use of GLP-1 analogues labelled with appropriate radioisotopes ( 111I n, 99m Tc, 68 Ga, 18 F or 64 Cu) seem to be superior compared with other available techniques in diagnosis of hardly detectable benign insulinoma. While surgery is the only effective therapy for insulinoma patients, therefore proper preoperative localization of the tumor allows sparing operation. Glucagon-like peptide 1 receptors might become also a target for imaging of other tumors such as gastrinoma, pheochromocytoma and medullary thyroid cancer (MTC), which also were shown to over express this type of receptors. However, studies with larger groups of patients are required to prove the clinical usefulness of this indication. Moreover GLP-1 receptor imaging seems to be a potential tool to evaluate pancreatic beta cell mass (BCM). It may be useful in the early diagnosis of beta cell loss in preclinical phases of diabetes. The panceratic beta cells imaging may influence the prophylaxis of diabetes and management of diabetic patients. Presented results of clinical trials prove that glucagon-like peptide 1 receptor imaging might become helpful diagnostic strategy particularly in case of patients with benign insulinoma tumors, but also patients with gastrinoma, pheochromocytoma, medullary thyroid cancer and diabetes.

  20. TiSH - a robust and sensitive global phosphoproteomics strategy employing a combination of TiO(2), SIMAC, and HILIC

    DEFF Research Database (Denmark)

    Engholm-Keller, Kasper; Birck, Pernille; Størling, Joachim

    2012-01-01

    losses. We demonstrate the capability of this strategy by quantitative investigation of early interferon-γ signaling in low quantities of insulinoma cells. We identified ~6600 unique phosphopeptides from 300μg of peptides/condition (22 unique phosphopeptides/μg) in a duplex dimethyl labeling experiment....... This strategy thus shows great potential for interrogating signaling networks from low amounts of sample with high sensitivity and specificity....

  1. Characterization of pancreatic transcription factor Pdx-1 binding sites using promoter microarray and serial analysis of chromatin occupancy

    OpenAIRE

    Keller, David M; McWeeney, Shannon; Arsenlis, Athanasios; Drouin, Jacques; Wright, Christopher V E; Wang, Haiyan; Wollheim, Claes; White, Peter; Kaestner, Klaus H; Goodman, Richard H

    2007-01-01

    The homeobox transcription factor Pdx-1 is necessary for pancreas organogenesis and beta cell function, however, most Pdx-1-regulated genes are unknown. To further the understanding of Pdx-1 in beta cell biology, we have characterized its genomic targets in NIT-1 cells, a mouse insulinoma cell line. To identify novel targets, we developed a microarray that includes traditional promoters as well as non-coding conserved elements, micro-RNAs, and elements identified through an unbiased approach ...

  2. Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene

    DEFF Research Database (Denmark)

    Efrat, S; Linde, S; Kofod, Hans

    1988-01-01

    Three pancreatic beta-cell lines have been established from insulinomas derived from transgenic mice carrying a hybrid insulin-promoted simian virus 40 tumor antigen gene. The beta tumor cell (beta TC) lines maintain the features of differentiated beta cells for about 50 passages in culture. The ...... both to immortalize a rare cell type and to provide a selection for the maintenance of its differentiated phenotype....

  3. Clinical Features and Causes of Endogenous Hyperinsulinemic Hypoglycemia in Korea

    Directory of Open Access Journals (Sweden)

    Chang-Yun Woo

    2015-04-01

    Full Text Available BackgroundEndogenous hyperinsulinemic hypoglycemia (EHH is characterized by an inappropriately high plasma insulin level, despite a low plasma glucose level. Most of the EHH cases are caused by insulinoma, whereas nesidioblastosis and insulin autoimmune syndrome (IAS are relatively rare.MethodsTo evaluate the relative frequencies of various causes of EHH in Korea, we retrospectively analyzed 84 patients who were diagnosed with EHH from 1998 to 2012 in a university hospital.ResultsAmong the 84 EHH patients, 74 patients (88%, five (6%, and five (6% were diagnosed with insulinoma, nesidioblastosis or IAS, respectively. The most common clinical manifestation of EHH was neuroglycopenic symptoms. Symptom duration before diagnosis was 14.5 months (range, 1 to 120 months for insulinoma, 1.0 months (range, 6 days to 7 months for nesidioblastosis, and 2.0 months (range, 1 to 12 months for IAS. One patient, who was diagnosed with nesidioblastosis in 2006, underwent distal pancreatectomy but was later determined to be positive for insulin autoantibodies. Except for one patient who was diagnosed in 2007, the remaining three patients with nesidioblastosis demonstrated severe hyperinsulinemia (157 to 2,719 µIU/mL, which suggests that these patients might have had IAS, rather than nesidioblastosis.ConclusionThe results of this study suggest that the prevalence of IAS may be higher in Korea than previously thought. Therefore, measurement of insulin autoantibody levels is warranted for EHH patients, especially in patients with very high plasma insulin levels.

  4. The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans.

    Science.gov (United States)

    Jensen, P B; Kristensen, P; Clausen, J T; Judge, M E; Hastrup, S; Thim, L; Wulff, B S; Foged, C; Jensen, J; Holst, J J; Madsen, O D

    1999-03-26

    The hypothalamic satiety peptide CART (cocaine and amphetamine regulated transcript) is expressed at high levels in anorectic rat glucagonomas but not in hypoglycemic insulinomas. However, a non-anorectic metastasis derived from the glucagonoma retained high CART expression levels and produced circulating CART levels comparable to that of the anorectic tumors. Moreover, distinct glucagonoma lines derived by stable HES-1 transfection of the insulinoma caused severe anorexia but retained low circulating levels of CART comparable to that of insulinoma bearing or control rats. Islet tumor associated anorexia and circulating CART levels are thus not correlated, and in line with this peripheral administration of CART (5-50 mg/kg) produced no effect on feeding behavior. In the rat two alternatively spliced forms of CART mRNA exist and quantitative PCR revealed expression of both forms in the hypothalamus, in the different islet tumors, and in the islets of Langerhans. Immunocytochemistry as well as in situ hybridization localized CART expression to the somatostatin producing islet D cell. A potential endocrine/paracrine role of islet CART remains to be clarified.

  5. Anestesia para paciente portadora de múltiplas afecções endócrinas: relato de caso Anestesia para paciente portadora de múltiples afecciones endocrinas: relato de caso Anesthesia in a patient with multiple endocrine abnormalities: case report

    Directory of Open Access Journals (Sweden)

    Renato Toledo Maciel

    2008-04-01

    Full Text Available JUSTIFICATIVA E OBJETIVOS: O insulinoma é o tumor endócrino pancreático mais comum. Pode estar associado a neoplasias endócrinas múltiplas (NEM. Relatou-se o caso de paciente com distúrbios endócrinos múltiplos que, no entanto, não se enquadram em síndromes (NEM já conhecidas e com particularidades clínico-anestésicas que influenciaram no manuseio de sua anestesia. RELATO DO CASO: Paciente feminina, 23 anos, apresentando hipoglicemias de difícil controle associadas à doença de Cushing e prolactinoma, sem sintomas compressivos hipofisários e com estudos de tireóide e de paratireóides sem alterações. A investigação laboratorial encontrou massa retroperitoneal de etiologia desconhecida que, relacionada à situação clínica, levou a hipótese de insulinoma. Relatava ainda ser testemunha de Jeová. A proposta terapêutica era biópsia da massa por videolaparoscopia e enucleação do insulinoma. Ao exame: obesa, dentes protrusos, Mallampati 3 e sintomas de apnéia obstrutiva do sono. Nos exames laboratoriais, o resultado relevante foi o hematócrito de 58%. Recebeu midazolam (7,5 mg e clonidina (200 µg via oral como medicação pré-anestésica. A indução anestésica foi realizada com fentanil (150 µg, clonidina (90 µg, propofol (150 mg e pancurônio (8 mg, sendo realizada a intubação traqueal sem problemas. Foram estabelecidos acesso venoso central e monitoração invasiva da pressão. Mantida infusão de glicose 5% com eletrólitos e monitorada a glicemia capilar a cada 30 minutos, que não acusou episódios de hipoglicemia durante a intervenção cirúrgica. Manteve-se hemodinamicamente estável mesmo durante o pneumoperitônio. No pós-operatório apresentou episódios de hipoglicemia que motivaram sua reoperação. CONCLUSÕES: A singularidade do caso está na conjunção de múltiplas endocrinopatias e de particularidades do manuseio cirúrgico-anestésico. A exérese do insulinoma deve ser monitorada no intra

  6. [Usefulness of arterial calcium stimulation with hepatic venous sampling in the localization diagnosis of endogenous hyperinsulinism].

    Science.gov (United States)

    Moreno Moreno, Paloma; Gutiérrez Alcántara, Carmen; Muñoz-Villanueva, María Del Carmen; Ortega, Rafael Palomares; Corpas Jiménez, María del Sierra; Zurera Tendero, Luis; Benito López, Pedro

    2010-03-01

    The aim of this study was to assess the utility of arterial calcium stimulation with hepatic venous sampling (ASVS) in the localization of tumors in patients with endogenous hyperinsulinism not detected with other methods. We performed a retrospective study of 26 patients admitted to our hospital for hypoglycemia who underwent ASVS because the source of hyperinsulinism was not clearly identified by other imaging techniques. The histopathological result in patients who underwent a surgical procedure was considered the reference for statistical study of the accuracy of this technique. Statistical analysis was performed by comparing proportions with the chi-squared test with Yates' correction for contingency tables, and Cohen's kappa coefficient as a measure of interrater agreement between two observations. Surgery was performed in 17 patients, 13 with positive ASVS and the remaining four with negative results. An insulinoma was removed in 12 patients, and 10 of these were detected in the ASVS. A total of 76.9 % of positive ASVS tests corresponded to a histological diagnosis of insulinoma, and 83% of these insulinomas were positive in ASVS. This association was statistically significant (chi cuadrado=7.340; p=0.012). Two of three patients with nesidioblastosis had a positive response in the ASVS. A good and statistically significant agreement was obtained between histopathologic diagnosis and ASVS results (kappa=0.556, p = 0.007). ASVS is a useful procedure in the localization diagnosis of endogenous hyperinsulinism not detected by other imaging tests. This technique allows tumors in the pancreatic gland to be identified and may be useful in the choice of the surgical technique to be used. Copyright 2009 SEEN. Published by Elsevier Espana. All rights reserved.

  7. Isolation and characterization of the human homologue of rig and its pseudogenes: The functional gene has features characteristic of housekeeping genes

    International Nuclear Information System (INIS)

    Shiga, Kiyoto; Yamamoto, Hiroshi; Okamoto, Hiroshi

    1990-01-01

    Rig (rat insulinoma gene) was first isolated from a cDNA library of rat insulinomas and has been found to be activated in various human tumors such as insulinomas, esophageal cancers, and colon cancers. Here the authors isolated the human homologue of rig from a genomic DNA library constructed from a human esophageal carcinoma and determined its complete nucleotide sequence. The gene is composed of about 3,000 nucleotides and divided into four exons separated by three introns: exon 3 encodes the nuclear location signal and the DNA-binding domain of the RIG protein. The transcription initiation site was located at -46 base pairs upstream from the first ATG codon. The 5'-flanking region of the gene has no apparent TATA-box or CAAT-box sequence. However, two GC boxes are found at -189 and -30 base pairs upstream from the transcription initiation site and five GC boxes are also found in introns 1 and 2. The gene is bounded in the 5' region by CpG islands, regions of DNA with a high GC content and a high frequency of CpG dinucleotides relative to the bulk genome. Furthermore, the human genome contains at least six copies of RIG pseudogenes, and four of them have the characteristics of processed pseudogenes. From these results together with the finding that RIG is expressed in a wide variety of tissues and cells, they speculate that RIG belongs to the class of housekeeping genes, whose products are necessary for the growth of all cell types

  8. Prolactin-secreting adenoma as part of the multiple endocrine neoplasia--type I (MEN-I) syndrome.

    Science.gov (United States)

    Levine, J H; Sagel, J; Rosebrock, G; Gonzalez, J J; Nair, R; Rawe, S; Powers, J M

    1979-06-01

    Two patients presented with the galactorrhea-amenorrhea syndrome. One patient had previously had parathyroid hyperplasia and the other an insulinoma. Preoperative evaluation of each patient revealed hyperprolactinemia and radiological evidence of an abnormal sella turcica. Pituitary adenomas were identified and removed at surgery. Immunostaining techniques confirmed the presence of prolactin-containing cells in both tumors. We propose that prolactin-secreting tumors be considered as part of the MEN-I syndrome, and that patients presenting with the galactorrhea-amenorrhea syndrome be screened and followed sequentially for evidence of other endocrine neoplasia.

  9. CT-arteriography of pancreas

    International Nuclear Information System (INIS)

    Yoshikawa, Jun; Matsui, Osamu; Kitagawa, Kiyohide; Kamimura, Ryoichi; Kadoya, Masumi; Suzuki, Masayuki; Takashima, Tutomu

    1985-01-01

    To evaluate diagnostic effectiveness of CT-arteriography (CTA) in pancreatic disease, the pictures of pancreatic CTA were analysed in 50 cases without pancreatic disease. In the pancreatic body, irregular spotty stain was seen in 15 out of 50 cases(30%). Especially, in patients who had dorsal pancreatic artery arising from superior mesenteric artery, this stain was seen in 9 out of 13 cases(69%) and its mechanism was considered to be double blood supply both from celiac artery and superior mesenteric artery. As a consequence, we think that CTA of pancreas is unusefull in diagnosis of pancreatic insulinomas or carcinomas. (author)

  10. No Contribution of GAD-65 and IA-2 Autoantibodies around Time of Diagnosis to the Increasing Incidence of Juvenile Type 1 Diabetes

    DEFF Research Database (Denmark)

    Thorsen, Steffen U.; Pipper, Christian B.; Mortensen, Henrik B.

    2016-01-01

    Aims. A new perspective on autoantibodies as pivotal players in the pathogenesis of type 1 diabetes (T1D) has recently emerged. Our key objective was to examine whether increased levels of autoantibodies against the β-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma...... associated antigen-2A (IA-2A) mirrored the 3.4% annual increase in incidence of T1D. Methods. From the Danish Childhood Diabetes Register, we randomly selected 500 patients and 500 siblings for GADA and IA-2A analysis (1997 through 2005). Blood samples were taken within three months after onset. A robust log...

  11. Vestibular syndrome due to a choroid plexus papilloma in a ferret.

    Science.gov (United States)

    van Zeeland, Yvonne; Schoemaker, Nico; Passon-Vastenburg, Maartje; Kik, Marja

    2009-01-01

    A 6-year-old, castrated male ferret (Mustela putorius furo) was presented with progressive neurological signs consisting of a right-sided head tilt and ataxia. Neurological examination revealed hemiparesis and absence of proprioception on the right side, consistent with central vestibular syndrome. Measurement of blood glucose excluded hypoglycemia due to insulinoma. Contrast-enhanced computed tomography revealed the presence of an intracranial mass, consistent with either granuloma or neoplasia. Palliative treatment with prednisolone yielded no improvement. At postmortem examination, a final diagnosis of a choroid plexus papilloma originating from the fourth ventricle was made. This is the first report of such a tumor in a ferret.

  12. Localization of sources of the hyperinsulinism through the image methods

    International Nuclear Information System (INIS)

    Abath, C.G.A.

    1990-01-01

    Pancreatic insulinomas are small tumours, manifested early by the high hormonal production. Microscopic changes, like islet cell hyperplasia or nesidioblastosis, are also sources of hyperinsulinism. The pre-operative localization of the lesions is important, avoiding unnecessary or insufficient blind pancreatectomies. It is presented the experience with 26 patients with hyperinsulinism, of whom six were examined by ultrasound, nine by computed tomography, 25 by angiography and 16 by pancreatic venous sampling for hormone assay, in order to localize the lesions. Percutaneous transhepatic portal and pancreatic vein catheterization with measurement of insuline concentrations was the most reliable and sensitive method for detecting the lesions, including those non-palpable during the surgical exploration (author)

  13. Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

    DEFF Research Database (Denmark)

    Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

    2010-01-01

    Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine...... deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1...

  14. CT-arteriography of pancreas

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Jun; Matsui, Osamu; Kitagawa, Kiyohide; Kamimura, Ryoichi; Kadoya, Masumi; Suzuki, Masayuki; Takashima, Tutomu

    1985-01-01

    To evaluate diagnostic effectiveness of CT-arteriography (CTA) in pancreatic disease, the pictures of pancreatic CTA were analysed in 50 cases without pancreatic disease. In the pancreatic body, irregular spotty stain was seen in 15 out of 50 cases(30%). Especially, in patients who had dorsal pancreatic artery arising from superior mesenteric artery, this stain was seen in 9 out of 13 cases(69%) and its mechanism was considered to be double blood supply both from celiac artery and superior mesenteric artery. As a consequence, we think that CTA of pancreas is unusefull in diagnosis of pancreatic insulinomas or carcinomas. (author).

  15. The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes

    DEFF Research Database (Denmark)

    Madsen, O D; Karlsen, C; Nielsen, E

    1993-01-01

    that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene...... in animals carrying tumor necrosis factor-producing experimental tumors....... markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (

  16. Noninsulinoma pancreatogenous hypoglycemia syndrome in a Saudi male

    International Nuclear Information System (INIS)

    Karawagh, Abullah M.; Gasim, Abdelhamid M.; Abdelaziz, Muntasir M.; Abdullah, Layla S.

    2008-01-01

    Nesidioblastosis is focal or diffuse islet hyperplasia leading tohyperinsulinism with subsequent hypoglycemia in the absence of insulinoma,usually described in neonates and infancy. We described the first adult caseof nesidioblastosis in Saudi Arabia and the Gulf region. The diagnosis andtreatment of the condition can be very difficult and challenging. Despite thefact that our patient responded initially to surgical treatment, hishypoglycemic symptoms occasionally recurred and needed adjunctive medicaltreatment. Although initially thought to affect only infants and children,cases of nesidioblastosis can effect adults and pose a diagnostic andtherapeutic challenge to the clinicians. (author)

  17. Oncology of the ferret (Mustela putorius furo)

    International Nuclear Information System (INIS)

    Bunel Le Coz, Bertrand Jacques Thierry

    2006-01-01

    Ferret oncology is in full evolution. Many types of tumors are mentioned. They affect all the systems of the organism: the endocrine, hemo-lymphatic, integument, digestive, reproductive, musculoskeletal, cardiovascular, nervous, urinary or respiratory systems. Insulinoma, adrenocortical tumors and lymphoma are the three mostly seen tumors. Complementary examination have been developed too. CBC, biochemistry, radiography and ultrasonography can now be completed by cytology, immunohistochemistry, endoscopies, scan, I.R.M. or scintigraphy. Treatments such as surgery, chemotherapy or radiotherapy can be associated. They allow recovery or, if not a palliative solution. (author) [fr

  18. Benzbromarone, Quercetin, and Folic Acid Inhibit Amylin Aggregation

    Directory of Open Access Journals (Sweden)

    Laura C. López

    2016-06-01

    Full Text Available Human Amylin, or islet amyloid polypeptide (hIAPP, is a small hormone secreted by pancreatic β-cells that forms aggregates under insulin deficiency metabolic conditions, and it constitutes a pathological hallmark of type II diabetes mellitus. In type II diabetes patients, amylin is abnormally increased, self-assembled into amyloid aggregates, and ultimately contributes to the apoptotic death of β-cells by mechanisms that are not completely understood. We have screened a library of approved drugs in order to identify inhibitors of amylin aggregation that could be used as tools to investigate the role of amylin aggregation in type II diabetes or as therapeutics in order to reduce β-cell damage. Interestingly, three of the compounds analyzed—benzbromarone, quercetin, and folic acid—are able to slow down amylin fiber formation according to Thioflavin T binding, turbidimetry, and Transmission Electron Microscopy assays. In addition to the in vitro assays, we have tested the effect of these compounds in an amyloid toxicity cell culture model and we have found that one of them, quercetin, has the ability to partly protect cultured pancreatic insulinoma cells from the cytotoxic effect of amylin. Our data suggests that quercetin can contribute to reduce oxidative damage in pancreatic insulinoma β cells by modulating the aggregation propensity of amylin.

  19. In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic β-Cells

    Directory of Open Access Journals (Sweden)

    Claudia Velasquez

    2017-05-01

    Full Text Available BackgroundThe increase in circulating free fatty acid (FFA levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6].MethodsFrom fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated.ResultsThe high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion.ConclusionThese results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.

  20. Percutaneous transhepatic portal vein catheterisation in the diagnosis of hormone-producing tumors in the splanchnic area

    International Nuclear Information System (INIS)

    Luska, G.; Zick, R.; Otten, G.; Mitzkat, H.J.; Medizinische Hochschule Hannover; Medizinische Hochschule Hannover

    1981-01-01

    During 1980, percutaneous transhepatic portal vein catheterisation was carried out in eight patients with suspected hormone-producing tumours in an attempt to localise these. Seven patients with hyperinsulinism were suspected of having an insulinoma and one a gastrinoma. There were no complications following the catheterisation, and difficulties were reduced by the use of a special catheter. The blood samples were examined by radio-immunological methods for insulin or gastrin. On the basis of localised rise in hormone level, it was possible to diagnose three insulinomas and one gastrinoma in the pancreas. The betacell tumours were removed by enucleation or segmental resection, the gastrinoma by a Whipple's operation. Three patients showed an insulin gradient and sub-total pancreatectomies were performed. In one patient there was no definite abnormality in the insulin level and an operation has so far not been performed. Our experience indicates that this technique is difficult, but is nevertheless a reliable method for localising hormone-producing tumours and surgery should not be carried out without it. (orig.) [de

  1. The Destructive Action of IL-1α and IL-1β in IDDM is a Multistage Process: Evidence and Confirmation by Apoptotic Studies, Induction of Intermediates and Electron Microscopy

    Directory of Open Access Journals (Sweden)

    S. Vassiliadis

    1999-01-01

    Full Text Available Using the rat β-cell RIN-5AH insulinoma line as a means for studying insulin-dependent diabetes mellitus (IDDM, it is shown that interleukin-1 (IL-1 induces β-cell damage initiated by early apoptotic signals. This action is demonstrated by DNA fragmentation, as assessed by specific BrdU labeling, surface expression of Fas and nitric oxide (NO production. In addition, the interplay between NO and Fas is shown, while scanning electron microscopy (SEM confirms apoptosis by revealing the degree and type of cellular damage which, in the case of IL-1α, can be reversed by an inhibitor to NO synthesis. Apoptosis is also reconfirmed by transmission electron microscopy (TEM by observing condensed nuclear chromatin after IL-1 exposure. Thus, treatment of insulinoma cells with IL-1α and IL-1β seems to initiate a number of signals, including PKC activation as published previously, that ultimately lead to β-cell destruction. Each IL-1 isoform, however, definitely follows a different pathway of action.

  2. [Mechanisms of spontaneous hypoglycaemia in the adult (author's transl)].

    Science.gov (United States)

    Lubetzki, J; Duprey, J; Guillausseau, P J

    1979-06-01

    Hypoglycaemia increases hepatic glucose output; insulin release is suppressed and the secretion of counter regulatory hormones enhanced. Catecholamines and glucagon seem to play a major role. The brain energy content is initially preserved, but the neuronal activity exhibits a 40-60 % decrease. Neither cerebral blood flow, nor oxygen consumption are altered. In addition to glucose, other substrates are metabolized. Cerebral edema may occur. An insulin-storage defect seems to be the main abnormality in insulinoma beta cell function. The most accurate biological tests are the insulin/glucose ratio, stimulation tests and suppression tests such as fasting and insulin-induced hypoglycaemia. Ectopic release of ACTH, HCG, HLP, glucagon or gastrin, is observed in some malignant insulinomas. When inconclusive, classic localising procedures may be effected by selective venous-blood sampling. Hypoglycaemia of extra-pancreatic tumors results from glucose hyperconsumption and decreases in glucose hepatic output, lipolysis and ketogenesis, related to secretion of insulin-like peptides NSILAs or NSILAp. Rare cases of hypoglycaemia related to insulin auto-antibodies of unknown origin have been reported. Alcoholic hypoglycemia results from diminished hepatic glycogen content, alcohol dehydrogenase pathway blockade, reduction of gluconeogenesis defect in the alcohol catabolic catalase pathway and enhancement of peripheral glucose consumption.

  3. 99mTc-exendin(9-39)/octreotide: biokinetics and radiation dosimetry in healthy individuals.

    Science.gov (United States)

    Ocampo-García, Blanca E; Santos-Cuevas, Clara L; Luna-Gutiérrez, Myrna A; Ignacio-Alvarez, Eleazar; Pedraza-López, Martha; Manzano-Mayoral, Cesar

    2017-11-01

    About 90% of insulinomas are benign and 5-15% are malignant. Benign insulinomas express the glucagon-like peptide-1 receptor (GLP-1R, which recognizes exendin-4 and low levels of the somatostatin receptor (SSTR, which recognizes octreotide), whereas malignant insulinomas overexpress SSTR and low levels of GLP-1R. Recently, Lys(Tc-EDDA/HYNIC)-exendin(9-39)/Tc-EDDA/HYNIC-Tyr-octreotide was formulated to detect 100% of insulinomas. The aim of this study was to estimate the biokinetics and dosimetry of Tc-exendin(9-39)/octreotide in four healthy individuals. Tc-exendin(9-39)/octreotide was obtained from a lyophilized formulation with radiochemical purities of more than 97%, determined by reversed-phase high-performance liquid chromatography. Whole-body images from four healthy individuals were acquired at 20 min, 2, 6, and 24 h after Tc-exendin(9-39)/octreotide administration. Regions of interest were drawn around the source organs on each time frame. Each region of interest was corrected by background, attenuation, scattered radiation, and physical decay. The image sequence was used to extrapolate the Tc-exendin(9-39)/octreotide time-activity curves of each organ to adjust the biokinetic model and calculate the total number of disintegrations (N) that occurred in the source regions. N data were the input for the OLINDA/EXM code to calculate internal radiation doses. Furthermore, in a patient suspicious of harboring an insulinoma, whole-body single-photon emission computed tomography/computed tomography images were obtained at 3 h. For four healthy individuals, the blood activity showed a half-life value of 1.20 min for the fast component (T1/2 α=ln 2/34.71), 8.7 min for the first slow component (T1/2 β=ln 2/4.76), and 1.7 h for the second slow component (T1/2 γ=ln 2/0.401). The average equivalent doses calculated for a study using 555 MBq were 15.10, 4.13, 3.08, 2.61, and 1.90 mSv for the kidneys, upper large intestinal wall, lower large

  4. Man's best friend: How humans can develop Dirofilaria immitis infections

    Directory of Open Access Journals (Sweden)

    Devin Malik

    2016-01-01

    Full Text Available Canine heartworm, Dirofilaria immitis, is a nematode parasite that infects dogs by way of mosquito bite. Rarely, humans play accidental hosts to this parasite and are not a suitable environment for the nematode to live. As the parasite dies in the pulmonary vessels it embolizes the vessels causing infarction and eventual nodule formation in the lungs. In the right clinical context, a nodule can be considered malignant prompting invasive tissue sampling. We describe a case of a 48-year-old man who was found to have multiple asymptomatic scattered pulmonary nodules during imaging workup for an insulinoma. Fine needle biopsy of the largest nodule revealed a necrotic granuloma, lab testing and culture ruled out fungal and bacterial causes. Clinically, this picture was consistent with D. immitis infection.

  5. Neuroendocrine tumors of the pancreas.

    LENUS (Irish Health Repository)

    Davies, Karen

    2009-04-01

    Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.

  6. Neuroendocrine tumors of the pancreas.

    LENUS (Irish Health Repository)

    Davies, Karen

    2012-02-01

    Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.

  7. Benign neuroendocrine and other rare benign tumors of the pancreas; Benigne neuroendokrine und andere seltene benigne Tumoren des Pankreas

    Energy Technology Data Exchange (ETDEWEB)

    Happel, B.; Ba-Ssalamah, A. [Medizinische Universitaet Wien, Universitaetsklinik fuer Radiodiagnostik, Wien (Austria); Niederle, B. [Medizinische Universitaet Wien, Universitaetsklinik fuer Chirurgie, Wien (Austria); Puespoek, A. [Medizinische Universitaet Wien, Klinische Abteilung fuer Gastroenterologie und Hepatologie, Universitaetsklinik fuer Innere Medizin 3, Wien (Austria); Schima, W. [KH Goettlicher Heiland, Abteilung fuer Radiologie und Bildgebende Diagnostik, Wien (Austria)

    2008-08-15

    Neuroendocrine tumors (NET) of the pancreas are rare neoplasms, which arise from cells of the islets of Langerhans. The most common NET are the insulinoma, gastrinoma and hormone inactive NET. Very rare entities are the schwannoma, leiomyoma, teratoma, intrapancreatic lipoma, hemangioma and the intrapancreatic accessory spleen. Essential for therapy, which in most cases is difficult, are an exact localization and various modalities of imaging diagnostics. (orig.) [German] Neuroendokrine Tumoren (NET) des Pankreas sind seltene Neoplasien, die aus Zellen der Langerhans-Inseln entstehen. Zu den haeufigsten NET zaehlen Insulinome, Gastrinome und hormoninaktive NET. Als sehr selten auftretende Entitaeten sind das Schwannom, Leiomyom, Teratom, intrapankreatische Lipom, Haemangiom sowie die intrapankreatische Nebenmilz zu nennen. Fuer die Therapie sind die exakte Lokalisation und verschiedene Modalitaeten der bildgebenden Diagnostik, die sich in aller Regel schwierig gestaltet, essenziell. (orig.)

  8. Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

    International Nuclear Information System (INIS)

    Kwekkeboom, D.J.; Krenning, E.P.

    1997-01-01

    [ 111 In-DTPA-D-Phe 1 [-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [ 111 In-DTPA-D-Phe 1 [-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established. (orig.). With 4 figs., 1 tab

  9. Gluten-free diet increases beta-cell volume and improves glucose tolerance in an animal model of type 2 diabetes

    DEFF Research Database (Denmark)

    Haupt-Jørgensen, Martin; Buschard, Karsten; Hansen, Axel Kornerup

    2016-01-01

    Background Gluten-free (GF) diet alleviates type 1 diabetes in animal models and possibly in humans. We recently showed that fatty acid-induced insulin secretion is enhanced by enzymatically digested gluten (gliadin) stimulation in INS-1E insulinoma cells. We therefore hypothesized that GF diet...... would induce beta-cell rest and ameliorate type 2 diabetes. Methods C57BL/6JBomTac (B6) mice were fed a high-fat (HF), gluten-free high-fat (GF–HF), standard (STD) or gluten-free (GF) diet for 42 weeks. Results Short-term (6–24 weeks) GF–HF versus HF feeding impaired glucose tolerance and increased...... capacity controls pancreas volume. Thus, long-term GF diets may be beneficial for obese type 2 diabetes patients and trials should be performed....

  10. Compartmentalization of GABA synthesis by GAD67 differs between pancreatic beta cells and neurons

    DEFF Research Database (Denmark)

    Kanaani, Jamil; Cianciaruso, Chiara; Phelps, Edward A

    2015-01-01

    of the two non-allelic isoforms GAD65 and GAD67 to vesicular membranes is important for rapid delivery and accumulation of GABA for regulated secretion. While the membrane anchoring and trafficking of GAD65 are mediated by intrinsic hydrophobic modifications, GAD67 remains hydrophilic, and yet is targeted...... to vesicular membrane pathways and synaptic clusters in neurons by both a GAD65-dependent and a distinct GAD65-independent mechanism. Herein we have investigated the membrane association and targeting of GAD67 and GAD65 in monolayer cultures of primary rat, human, and mouse islets and in insulinoma cells. GAD......65 is primarily detected in Golgi membranes and in peripheral vesicles distinct from insulin vesicles in β-cells. In the absence of GAD65, GAD67 is in contrast primarily cytosolic in β-cells; its co-expression with GAD65 is necessary for targeting to Golgi membranes and vesicular compartments. Thus...

  11. Endocrine tumours in the guinea pig.

    Science.gov (United States)

    Künzel, Frank; Mayer, Jörg

    2015-12-01

    Functional endocrine tumours have long been thought to be rare in guinea pigs, although conditions such as hyperthyroidism and hyperadrenocorticism have been documented with increasing frequency so the prevalence of hormonal disorders may have been underestimated. Both the clinical signs and diagnosis of hyperthyroidism in guinea pigs appear to be very similar to those described in feline hyperthyroidism, and methimazole has been proven to be a practical therapy option. Hyperadrenocorticism has been confirmed in several guinea pigs with an adrenocorticotropic hormone stimulation test using saliva as a non-invasive sample matrix; trilostane has been successfully used to treat a guinea pig with hyperadrenocorticism. Insulinomas have only rarely been documented in guinea pigs and one animal was effectively treated with diazoxide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Clinical application of radioimmunoassays

    International Nuclear Information System (INIS)

    Dolecek, R.

    1974-01-01

    The normal average values of immunoreactive insulin (IRI) in the course of the glycemic curve and in glycemia in patients suffering from diabetes, acromegaly and in diagnostics of insulinomas are given. Changes of IRI values after peroral loading with glucose in obese patients and in patients suffering from burns are given. The values of the growth hormone (STH) are given: normal, in patients suffering from obesity, children of small growth, patients with severe burns and in patients suffering from pneumoconiosis with quick progression. The conditions are also stated for the determination of the levels of the luteinizing hormone and the follicle-stimulating hormone, the human placental lactogen and values of renin activity and angiotensin in patients suffering from burns, the values of the adrenocorticotropic hormone and the thyreotropic hormone. (J.P.)

  13. Transfer plate radioassay using adsorbed anti-insulin antibody to detect insulin secreted by islet cell cultures

    International Nuclear Information System (INIS)

    Scearce, R.M.; Oie, H.K.; Gazdar, A.F.; Chick, W.L.; Eisenbarth, G.S.

    1981-01-01

    A solid-phase radioimmunoassay for detection of insulin synthesized by islet cell clones is described. This assay employs anti-insulin antibody adsorbed onto fenestrated polyvinyl chloride 96-well plates ('transfer plates'). The calibrated aperture in the bottom of each transfer plate well permits fluid to enter the wells when transfer plates are lowered into microculture wells containing insulin. With this assay it is possible to rapidly screen hundreds of islet cell cultures for insulin production. The authors have used this assay to facilitate cloning of the RIN rat insulinoma cell line. The assay readily detects insulin synthesis by RIN cells and [ 125 I]insulin is not displaced by culture medium from cells which do not produce insulin. The transfer plate format should be applicable to semiautomate other radioimmunoassays. (Auth.)

  14. PPARd IS A LIPID SENSOR AND A REGULATOR OF FATTY ACID OXIDATION IN PANCREATIC β-CELLS

    DEFF Research Database (Denmark)

    Ravnskjær, Kim; Nielsen, Tina; Børgesen, Michael

    to stimulate fatty acid oxidation when activated by agonists in myocytes, cardiomycytes and adipo-cytes. A role for PPARd as regulator of basal fatty acid catabolism and energy expenditure was therefore suggested. Here we show that PPARd is the most abundantly expressed PPAR subtype in both primary pancreatic...... islets and in the insulinoma cell line INS-1E. This is reflected at the functional level in activity assays using a PPRE-driven luciferase reporter construct. The fatty acids oleic, arachidonic and linolenic acid are able to acivate this construct synergistically with the synthetic RXR agonist LG100268....... Selective activation of PPARd in INS-1E cells with the PPARd agonist L165041 in the presence or absence of the RXRa agonist LG100268 induces luciferase activity 3- and 7-fold respectively and mimics the effect of the fatty acids. The same subset genes involved in fatty acid uptake and oxidation...

  15. 25-hydroxyvitamin D, autoantigenic and total antibody concentrations

    DEFF Research Database (Denmark)

    Thorsen, Steffen Ullitz; Pipper, Christian B; Johannesen, Jesper

    2018-01-01

    conducted within this field. OBJECTIVE: Our objective was to investigate if higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with β-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma associated antigen-2A (IA-2A). Further, we also wanted to examine......BACKGROUND: B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been...... the relationship between 25(OH)D and total antibody concentrations. METHODS: We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean...

  16. Hydrolyzed infant formula and early β-cell autoimmunity

    DEFF Research Database (Denmark)

    Knip, Mikael; Åkerblom, Hans K; Becker, Dorothy

    2014-01-01

    -associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS......IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain...... intact proteins. OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA...

  17. Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Urban, Christian; Grundmann, Manuel

    2011-01-01

    The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic ß-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived...... from free fatty acids (FFAs) or glitazones, and are relatively lipophilic. Aiming at the development of potent, selective and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37......, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity and excellent in vitro permeability and metabolic stability....

  18. In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469

    DEFF Research Database (Denmark)

    Urban, C; Hamacher, A; Partke, H J

    2013-01-01

    in vitro potency of TUG-469 compared to the reference FFA1 agonist GW9508 and to prove in vivo activity in a pre-diabetic mouse model. The in vitro pharmacology of TUG-469 was studied using Ca(2+)-, cAMP-, and impedance-based assays at recombinant FFA1 and free fatty acid receptor 4, formerly known as GPR......120 (FFA4) expressing 1321N1 cells and the rat insulinoma cell line INS-1. Furthermore, we investigated the systemic effect of TUG-469 on glucose tolerance in pre-diabetic New Zealand obese (NZO) mice performing a glucose tolerance test after intraperitoneal administration of 5 mg/kg TUG-469...... significantly improved glucose tolerance in pre-diabetic NZO mice. TUG-469 turned out as a promising candidate for further drug development of FFA1 agonists for treatment of type 2 diabetes mellitus....

  19. The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes

    DEFF Research Database (Denmark)

    Madsen, O D; Karlsen, C; Nielsen, E

    1993-01-01

    in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal...... markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (loss parallels...... a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported...

  20. Identification of a growth hormone-responsive STAT5-binding element in the rat insulin 1 gene

    DEFF Research Database (Denmark)

    Galsgaard, E D; Gouilleux, F; Groner, B

    1996-01-01

    promoter activity 2-fold, and this stimulation was abolished by introduction of a block mutation in a gamma-interferon-activated sequence (GAS)-like element (GLE) with the sequence 5'-TTCTGGGAA-3' located in the rat insulin 1 enhancer at position -330 to -322. This element, termed Ins-GLE, was able...... transfected with STAT5 and GH receptor cDNAs, it was found that expression of STAT5 was necessary for GH induction of these two DNA-binding complexes. These results suggest that GH stimulates insulin 1 promoter activity by inducing the binding of STAT5 to Ins-GLE.......GH and PRL stimulate both proliferation and insulin production in pancreatic beta-cells as well as in the rat insulinoma cell line RIN-5AH, We report here that human GH increases insulin mRNA levels in RIN-5AH cells via both somatogenic and lactogenic receptors. GH stimulated the rat insulin 1...

  1. Celiac artery stenosis/occlusion treated by interventional radiology

    International Nuclear Information System (INIS)

    Ikeda, Osamu; Tamura, Yoshitaka; Nakasone, Yutaka; Yamashita, Yasuyuki

    2009-01-01

    Severe stenosis/occlusion of the proximal celiac trunk due to median arcuate ligament compression (MALC), arteriosclerosis, pancreatitis, tumor invasion, and celiac axis agenesis has been reported. However, clinically significant ischemic bowel disease attributable to celiac axis stenosis/occlusion appears to be rare because the superior mesenteric artery (SMA) provides for rich collateral circulation. In patients with celiac axis stenosis/occlusion, the most important and frequently encountered collateral vessels from the SMA are the pancreaticoduodenal arcades. Patients with celiac artery stenosis/occlusion are treated by interventional radiology (IR) via dilation of the pancreaticoduodenal arcade. In patients with dilation of the pancreaticoduodenal arcade on SMA angiograms, IR through this artery may be successful. Here we provide several tips on surmounting these difficulties in IR including transcatheter arterial chemoembolization for hepatocellular carcinoma, an implantable port system for hepatic arterial infusion chemotherapy to treat metastatic liver tumors, coil embolization of pancreaticoduodenal artery aneurysms, and arterial stimulation test with venous sampling for insulinomas.

  2. Celiac artery stenosis/occlusion treated by interventional radiology

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, Osamu [Department of Diagnostic Radiology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 1-1-1, Honjo Kumamoto 860-8505 (Japan)], E-mail: osamu-3643ik@do9.enjoy.ne.jp; Tamura, Yoshitaka; Nakasone, Yutaka; Yamashita, Yasuyuki [Department of Diagnostic Radiology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, 1-1-1, Honjo Kumamoto 860-8505 (Japan)

    2009-08-15

    Severe stenosis/occlusion of the proximal celiac trunk due to median arcuate ligament compression (MALC), arteriosclerosis, pancreatitis, tumor invasion, and celiac axis agenesis has been reported. However, clinically significant ischemic bowel disease attributable to celiac axis stenosis/occlusion appears to be rare because the superior mesenteric artery (SMA) provides for rich collateral circulation. In patients with celiac axis stenosis/occlusion, the most important and frequently encountered collateral vessels from the SMA are the pancreaticoduodenal arcades. Patients with celiac artery stenosis/occlusion are treated by interventional radiology (IR) via dilation of the pancreaticoduodenal arcade. In patients with dilation of the pancreaticoduodenal arcade on SMA angiograms, IR through this artery may be successful. Here we provide several tips on surmounting these difficulties in IR including transcatheter arterial chemoembolization for hepatocellular carcinoma, an implantable port system for hepatic arterial infusion chemotherapy to treat metastatic liver tumors, coil embolization of pancreaticoduodenal artery aneurysms, and arterial stimulation test with venous sampling for insulinomas.

  3. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    DEFF Research Database (Denmark)

    Pörksen, Sven; Laborie, Lene Bjerke; Nielsen, Lotte

    2010-01-01

    BACKGROUND: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA......-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. MATERIALS AND METHODS: In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months...... of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea...

  4. High Intensity Focused Ultrasound Ablation of Pancreatic Neuroendocrine Tumours: Report of Two Cases

    International Nuclear Information System (INIS)

    Orgera, Gianluigi; Krokidis, Miltiadis; Monfardini, Lorenzo; Bonomo, Guido; Della Vigna, Paolo; Fazio, Nicola; Orsi, Franco

    2011-01-01

    We describe the use of ultrasound-guided high-intensity focused ultrasound (HIFU) for ablation of two pancreatic neuroendocrine tumours (NETs; insulinomas) in two inoperable young female patients. Both suffered from episodes of severe nightly hypoglycemia that was not efficiently controlled by medical treatment. After HIFU ablation, local disease control and symptom relief were achieved without postinterventional complications. The patients remained free of symptoms during 9-month follow-up. The lesions appeared to be decreased in volume, and there was decreased enhancing pattern in the multidetector computed tomography control (MDCT). HIFU is likely to be a valid alternative for symptoms control in patients with pancreatic NETs. However, currently the procedure should be reserved for inoperable patients for whom symptoms cannot be controlled by medical therapy.

  5. Purification of alpha-toxin from Staphylococcus aureus and application to cell permeabilization

    International Nuclear Information System (INIS)

    Lind, I.; Ahnert-Hilger, G.; Fuchs, G.; Gratzl, M.

    1987-01-01

    Crude alpha-toxin was produced by Staphylococcus aureus, strain Wood 46. The amount of exotoxin was monitored during growth and all subsequent purification steps by determination of its hemolytic activity against rabbit erythrocytes. The culture supernatant was treated with ammonium sulfate (75% saturation). The resulting precipitate was dialyzed and subjected to cation-exchange chromatography. The fractions containing the hemolytic activity were further purified by gel chromatography. The final product was enriched by a factor of 8.5 compared to the crude toxin. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis the purified toxin exhibited one major band. It caused the release of 86 Rb+ and ATP from rat insulinoma (RIN A2) as well as pheochromocytoma cells (PC12) in culture, indicating efficient permeabilization of their plasma membranes for small molecules

  6. Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

    Science.gov (United States)

    2017-09-26

    Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

  7. Hipoglicemia endógena. estudio y manejo

    Directory of Open Access Journals (Sweden)

    B. Pedro Pineda, Dr.

    2013-09-01

    Full Text Available La hipoglicemia endógena (no asociada a Diabetes Mellitus es una enfermedad en general poco frecuente, pero que presenta desafíos diagnósticos y terapéuticos muy relevantes. Las manifestaciones clínicas son variables y el nivel de glicemia diagnóstico es controversial. En el diagnóstico diferencial deben considerarse el uso de fármacos, patologías médicas graves que alteren severamente el metabolismo de la glucosa y la presencia de una secreción endógena anormal de insulina (hipoglicemia hiperinsulinémica, cuya etiología principal es el insulinoma. Se describen los métodos diagnósticos utilizados, con especial énfasis en el test de ayuno prolongado y las alternativas terapéuticas principales de las diferentes etiologías señaladas.

  8. Hypoglycaemia related to inherited metabolic diseases in adults

    Directory of Open Access Journals (Sweden)

    Douillard Claire

    2012-05-01

    Full Text Available Abstract In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family. Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD, ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency].

  9. Endoscopic Ultrasound in Endocrinology: Imaging of the Adrenals and the Endocrine Pancreas.

    Science.gov (United States)

    Kann, Peter Herbert

    2016-01-01

    Endoscopic ultrasound (EUS) imaging of adrenal glands and its application to diagnostic procedures of adrenal diseases has been reported since 1998. It can be considered a relevant advantage in the field of adrenal diseases. Indeed, EUS allows the detection of adrenal lesions (even very small ones) and their characterization, the assessment of malignancy criteria, the early detection of neoplastic recurrences, the preoperative identification of morphologically healthy parts of the glands, the differentiation of extra-adrenal from adrenal tumors, and of the pathological entities associated with adrenal insufficiency, and the fine-needle aspiration biopsy (EUS-FNA) of suspicious lesions. At the same time, its clinical relevance depends on the experience of the endosonographer. Moreover, EUS is also by far the best and most sensitive imaging technique to detect and assess the follow-up of pancreatic manifestation of MEN1 disease. It furthermore enables the preoperatively localization of insulinomas and critical structures in their neighborhood, and may be relevant in planning surgical strategy. A positive EUS in a case of insulinoma furthermore confirms the endocrine diagnosis, especially considering the differential diagnosis of hypoglycemia factitia by oral antidiabetics. It can be supplemented by EUS-FNA. Again, it has to be considered that EUS may reveal false positive and false negative results, and the quality of the findings largely depends on the endosonographer's skills and experience. The most important technical details together with the advantages and limitations of EUS, and the pathognomonic characteristic of benign and malignant disorders of the adrenals and pancreas are presented here. © 2016 S. Karger AG, Basel.

  10. Preparation and characterization of hydroxyapatite/gelatin composite membranes for immunoisolation

    Science.gov (United States)

    Chen, Jyh-Ping; Chang, Feng-Nian

    2012-12-01

    Composite membranes are fabricated from hydroxyapatite (HAP) and gelatin for immunoisolation of cells. The films were fabricated by crosslinking 5 wt%, 10 wt%, and 20 wt% gelatin with 1 wt% glutaraldehyde (GA) in the presence of HAP. Fourier transform infrared spectroscopy analysis confirms imide bond formation between GA and gelatin, while the crystal structure of HAP powder remains unchanged from X-ray diffraction analysis. The degree of crosslinking depends on crosslinking time and gelatin concentration. For 5% and 10% gelatin, the degree of crosslinking levels off at 90% within 48 h. From scanning electron microscopy micrographs, the microstructure of the composite membrane depends on the amount of gelatin used in the crosslinking reaction. The mechanical strength of the composite membrane could be enhanced by increasing the gelatin concentration. BET analysis indicates that pore size of the micropores on the surface HAP/gelatin agglomerates decreases with increasing gelatin concentration. However, the macropore, through which diffusion of molecules occurs, is larger at higher gelatin concentrations. The permeability coefficients of different molecules through a HAP/gelatin composite membrane increase with increasing gelatin concentration and is inversely correlated with the molecular weight of the molecule. For immunoisolation of cells, the diffusion of large molecules stimulated by the immune system can be rejected by a chamber constructed from the HAP/gelatin membrane. Insulinoma cells were encapsulated in alginate-poly-L-lysine-alginate microcapsules and enclosed in a HAP/gelatin chamber. The chamber did not impair the viability and function of insulinoma cells and cells can secrete insulin in response to glucose concentration change. The chamber is therefore useful for the physiologically controlled secretion of insulin in response to the blood glucose level. Intraperitoneal transplantation of the chamber into streptozotocin-induced diabetic SD rats could

  11. The F-actin modifier villin regulates insulin granule dynamics and exocytosis downstream of islet cell autoantigen 512

    Directory of Open Access Journals (Sweden)

    Hassan Mziaut

    2016-08-01

    Full Text Available Objective: Insulin release from pancreatic islet β cells should be tightly controlled to avoid hypoglycemia and insulin resistance. The cortical actin cytoskeleton is a gate for regulated exocytosis of insulin secretory granules (SGs by restricting their mobility and access to the plasma membrane. Prior studies suggest that SGs interact with F-actin through their transmembrane cargo islet cell autoantigen 512 (Ica512 (also known as islet antigen 2/Ptprn. Here we investigated how Ica512 modulates SG trafficking and exocytosis. Methods: Transcriptomic changes in Ica512−/− mouse islets were analyzed. Imaging as well as biophysical and biochemical methods were used to validate if and how the Ica512-regulated gene villin modulates insulin secretion in mouse islets and insulinoma cells. Results: The F-actin modifier villin was consistently downregulated in Ica512−/− mouse islets and in Ica512-depleted insulinoma cells. Villin was enriched at the cell cortex of β cells and dispersed villin−/− islet cells were less round and less deformable. Basal mobility of SGs in villin-depleted cells was enhanced. Moreover, in cells depleted either of villin or Ica512 F-actin cages restraining cortical SGs were enlarged, basal secretion was increased while glucose-stimulated insulin release was blunted. The latter changes were reverted by overexpressing villin in Ica512-depleted cells, but not vice versa. Conclusion: Our findings show that villin controls the size of the F-actin cages restricting SGs and, thus, regulates their dynamics and availability for exocytosis. Evidence that villin acts downstream of Ica512 also indicates that SGs directly influence the remodeling properties of the cortical actin cytoskeleton for tight control of insulin secretion. Keywords: F-actin, Granules, Ica512, Insulin, Secretion, Villin

  12. Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

    Directory of Open Access Journals (Sweden)

    Marcel Cerqueira Cesar Machado

    Full Text Available Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and

  13. IMMUNOHISTOCHEMICAL DETERMINATION OF EXPRESSION OF SOMATOSTATIN RECEPTORS TYPES 1, 2A, 3 AND 5 IN NEUROENDOCRINE TUMORS OF VARIOUS LOCALIZATION AND GRADE

    Directory of Open Access Journals (Sweden)

    L. E. Gurevich

    2016-01-01

    Full Text Available Background: Prediction of clinical benefits of somatostatin analogues in patients with neuroendocrine tumors (NET is very important prior to their administration. Data on immunohistochemical assessment of the expression of somatostatin receptors (SSR of various types, obtained from large samples of NET with various localization, functional activity and degree of malignancy, are scarce; therefore, the study was aimed at assessment of the latter.Materials and methods: We performed an immunohistochemical study with antibodies to SSR1, 2A, 3 and 5  types on tissue samples obtained during diagnostic and intra-operative biopsies from 399 NETs: 168 from pancreas, 120 from gastrointestinal tract (stomach, 48, from small intestine, 39, 14 of which being from duodenum; appendix, 6, colon and the rectum, 15 and 12, respectively, 84 from lung, 6 from thymus/mediastinum, and 21 from NET metastases of unknown primary localization.Results: Very high levels expression of receptors SSR2A preferentially binding to somatostatin analogues, which are currently used in clinical practice, were detected in the small intestine NETs (22/25, 88%, appendix (5/6, 83.3%, colon (10/15, 66.7%, thymus (4/6, 66.7%, atypical carcinoids of the lung (10/15, 66.7%, stomach (27/41, 65.8% and pancreas (105/165, 63.6%. The lowest expression was found in rectal NETs (5/12, 41.7% and small and large cell neuroendocrine lung carcinomas (20, 11.1%. Among functioning NETs, the highest level of SSR2A was found in gastrinomas (18/19, 94.7%, glucagonomas (15/16, 93.8%, small intestine carcinoids (31/35, 88.6%, and somatostatinomas (2/3, 66.7%. The lowest expression was detected in ACTH secreting tumors with Cushing's syndrome (11/12, 50%, and in insulinomas (34/69, 49.3%. SSR2A expression in functionally inactive pancreatic NETs was significantly higher than in insulinomas (57/82, 34/69 vs 69.5 and 49.3%, respectively. SSR2A expression was associated with the degree of malignancy and is

  14. Hipoglicemias de Ayuno en el Adulto

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    Alfredo Jácome Roca

    1987-08-01

    Full Text Available

    Las hipoglicemias espontáneas (o no inducidas por medicamentos pueden presentarse bien en ayunas o en estados postprandiales (como reacción a la ingesta por lo que se han llamado también reactivas o funcionales. Las hipoglicemias que se observan en estado de ayuno se han denominado en su mayoría “orgánicas”, pues usualmente tienen relación con alguna lesión tisular (tumor, necrosis, atrofia en donde además puede haber exceso o deficiencia de una o varias hormonas (1.

    La hipoglicemia orgánica más común es la asociada con los insulinomas (tumores productores de insulina, tema que he revisado previamente con algún detalle (2; igual he hecho con las reactivas y las farmacotóxicas (3. En este artículo me ocuparé de las hipoglicemias de ayuno (observadas en el adulto distintas a las del insulinoma. Son éstas las asociadas a hipofunción endocrina, con deficiencia de las hormonas contrarreguladoras de la insulina (hipopituitarismos, insuficiencia suprarrenal crónica, supresión del eje hipófisis-suprarrenales postadministración de esteroides, hiperplasia suprarrenal congénita; cuando hay producción excesiva de factores insulinosímiles de crecimiento, consumo excesivo de glucosa o lesiones que interfieren con la gluconeogénesis (como en la neoplasia masiva; trastorno de la producción hepática de glucosa (como en la enfermedad hepato celular severa; falla en la producción de glucosa, aumento de la vida media de la insulina (insuficiencia renal crónica; falla relativa de producción, consumo o pérdidas excesivas de glucosa (como se observa en el ejercicio severo, glicosuria renal, embarazo y ayuno prolongado, donde los descensos de la glicemia son usualmente asintomáticos.

    No existe una cifra específica por debajo de la cual se produzcan siempre síntomas, pero un nivel que podría servir de referencia es el de 45 mgrs/dl. Algunos pacientes acostumbrados a hipoglicemia crónica (insulinomas, síndrome de

  15. Preparation and characterization of hydroxyapatite/gelatin composite membranes for immunoisolation

    International Nuclear Information System (INIS)

    Chen, Jyh-Ping; Chang, Feng-Nian

    2012-01-01

    Highlights: ► Cross-linking gelatin in the presence of hydroxyapatite forms composite membranes. ► The membrane was used for immunoisolation and encapsulation of cells. ► Encapsulated islet cells secrete insulin in response to glucose concentrations. ► The membrane is a good candidate for bioartificial pancreas development. - Abstract: Composite membranes are fabricated from hydroxyapatite (HAP) and gelatin for immunoisolation of cells. The films were fabricated by crosslinking 5 wt%, 10 wt%, and 20 wt% gelatin with 1 wt% glutaraldehyde (GA) in the presence of HAP. Fourier transform infrared spectroscopy analysis confirms imide bond formation between GA and gelatin, while the crystal structure of HAP powder remains unchanged from X-ray diffraction analysis. The degree of crosslinking depends on crosslinking time and gelatin concentration. For 5% and 10% gelatin, the degree of crosslinking levels off at 90% within 48 h. From scanning electron microscopy micrographs, the microstructure of the composite membrane depends on the amount of gelatin used in the crosslinking reaction. The mechanical strength of the composite membrane could be enhanced by increasing the gelatin concentration. BET analysis indicates that pore size of the micropores on the surface HAP/gelatin agglomerates decreases with increasing gelatin concentration. However, the macropore, through which diffusion of molecules occurs, is larger at higher gelatin concentrations. The permeability coefficients of different molecules through a HAP/gelatin composite membrane increase with increasing gelatin concentration and is inversely correlated with the molecular weight of the molecule. For immunoisolation of cells, the diffusion of large molecules stimulated by the immune system can be rejected by a chamber constructed from the HAP/gelatin membrane. Insulinoma cells were encapsulated in alginate-poly-L-lysine-alginate microcapsules and enclosed in a HAP/gelatin chamber. The chamber did not impair

  16. Preparation and characterization of hydroxyapatite/gelatin composite membranes for immunoisolation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jyh-Ping, E-mail: jpchen@mail.cgu.edu.tw [Department of Chemical and Materials Engineering, Chang Gung University, 259 Wen Hwa 1st Rd., Kwei-San, Taoyuan 333, Taiwan (China); Chang, Feng-Nian [Department of Chemical and Materials Engineering, Chang Gung University, 259 Wen Hwa 1st Rd., Kwei-San, Taoyuan 333, Taiwan (China)

    2012-12-01

    Highlights: Black-Right-Pointing-Pointer Cross-linking gelatin in the presence of hydroxyapatite forms composite membranes. Black-Right-Pointing-Pointer The membrane was used for immunoisolation and encapsulation of cells. Black-Right-Pointing-Pointer Encapsulated islet cells secrete insulin in response to glucose concentrations. Black-Right-Pointing-Pointer The membrane is a good candidate for bioartificial pancreas development. - Abstract: Composite membranes are fabricated from hydroxyapatite (HAP) and gelatin for immunoisolation of cells. The films were fabricated by crosslinking 5 wt%, 10 wt%, and 20 wt% gelatin with 1 wt% glutaraldehyde (GA) in the presence of HAP. Fourier transform infrared spectroscopy analysis confirms imide bond formation between GA and gelatin, while the crystal structure of HAP powder remains unchanged from X-ray diffraction analysis. The degree of crosslinking depends on crosslinking time and gelatin concentration. For 5% and 10% gelatin, the degree of crosslinking levels off at 90% within 48 h. From scanning electron microscopy micrographs, the microstructure of the composite membrane depends on the amount of gelatin used in the crosslinking reaction. The mechanical strength of the composite membrane could be enhanced by increasing the gelatin concentration. BET analysis indicates that pore size of the micropores on the surface HAP/gelatin agglomerates decreases with increasing gelatin concentration. However, the macropore, through which diffusion of molecules occurs, is larger at higher gelatin concentrations. The permeability coefficients of different molecules through a HAP/gelatin composite membrane increase with increasing gelatin concentration and is inversely correlated with the molecular weight of the molecule. For immunoisolation of cells, the diffusion of large molecules stimulated by the immune system can be rejected by a chamber constructed from the HAP/gelatin membrane. Insulinoma cells were encapsulated in alginate

  17. Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo.

    Science.gov (United States)

    Trindade, Alexandre; Djokovic, Dusan; Gigante, Joana; Mendonça, Liliana; Duarte, António

    2017-03-14

    The inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models. We used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas. We found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy. By reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control.

  18. Stimulation of pancreatic beta-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways

    DEFF Research Database (Denmark)

    Friedrichsen, Birgitte N; Neubauer, Nicole; Lee, Ying C

    2006-01-01

    pathways leading to mitosis by incretins and cytokines, respectively. The response to both GLP-1 and GIP was completely blocked by the protein kinase A (PKA) inhibitor, H89. In addition, the phosphoinositol 3-kinase (PI3K) inhibitor wortmannin and the mitogen-activated protein kinase kinase (MEK) inhibitor...... and we have previously demonstrated hGH-induced cyclin D2 expression in the insulinoma cell line, INS-1. GLP-1 time-dependently induced the cyclin D1 mRNA and protein levels in INS-1E, whereas the cyclin D2 levels were unaffected. However, minor effect of GLP-1 stimulation was observed on the cyclin D3 m......RNA levels. Transient transfection of a cyclin D1 promoter-luciferase reporter construct into islet monolayer cells or INS-1 cells revealed approximately a 2-3 fold increase of transcriptional activity in response to GLP-1 and GIP, and a 4-7 fold increase in response to forskolin. However, treatment...

  19. Detection of chromogranins A and B in endocrine tissues with radioactive and biotinylated oligonucleotide probes

    International Nuclear Information System (INIS)

    Lloyd, R.V.; Jin, L.; Fields, K.

    1990-01-01

    We analyzed the distribution of chromogranins A and B in normal and neoplastic endocrine tissues with secretory granules using 35 S-labeled and biotin-labeled oligonucleotide probes by in situ hybridization (ISH). Both radioactive and nonradioactive probes detected messenger RNAs (mRNAs) in frozen and paraffin tissue sections. Endocrine tissues with variable immunoreactivities for chromogranin A protein, such as small-cell lung carcinomas, neuroblastomas, insulinomas, and parathyroid adenomas, expressed the mRNA for chromogranins A and B in most cells. Some technical problems with the biotinylated probes included nonspecific nuclear staining and endogenous alkaline phosphatase, which was not completely abolished by levamisole pretreatment. A differential distribution of chromogranins A and B was seen in pituitary prolactinomas, which expressed abundant chromogranin B but not chromogranin A mRNAs, and in parathyroid adenomas, which expressed abundant chromogranin A but only small amounts of chromogranin B mRNAs. These results indicate that ISH can be used to detect chromogranins A and B in endocrine tissues with radioactive and biotinylated oligonucleotide probes and that the mRNAs for chromogranin A and B are demonstrable in some tumors even when the chromogranin proteins cannot be detected by immunohistochemistry

  20. In vivo imaging of chromogranin A-positive endocrine tumours by three-step monoclonal antibody targeting

    International Nuclear Information System (INIS)

    Siccardi, A.G.; Paganelli, G.; Pontiroli, A.E.; Pelagi, M.; Magnani, P.; Viale, G.; Faglia, G.; Fazio, F.

    1996-01-01

    The detection of chromogranins (Cg) by immunohistochemistry and serology represents a new in vitro diagnostic tool for endocrine tumours. We have recently reported on the feasibility of targeting chromogranin A (CgA) for in vivo detection of pituitary adenomas by immunoscintigraphy (ISG). The scintigraphic procedure, based on an anti-CgA monoclonal antibody and on the avidin-biotin three-step method (Cg-3S-ISG), was evaluated on a group of 29 consecutive patients with known or suspected endocrine tumours other than pituitary adenomas, i.e. medullary thyroid carcinoma, carcinoid, insulinoma and parathormone- or ACTH-producing tumours. Primary tumours (10) and recurrences (16) were visualised in 26 patients, whereas conventional imaging techniques (planar radiography, computerised tomography, magnetic resonance imaging and ultrasonography) failed to detect the tumour sites in ten of the same (Cg-3S-ISG-positive) patients. Therefore, these preliminary results indicate that Cg-3S-ISG, the first immunological method able to detect endocrine tumours in vivo, has a higher diagnostic accuracy than conventional imaging techniques (93.1% compared with 65.5%). (orig.). With 3 figs., 1 tab

  1. Diagnosis of pancreatic tumors by spiral angio CT

    International Nuclear Information System (INIS)

    Miura, Kohi; Nakao, Norio; Takayasu, Yukio; Okawa, Tomohisa

    1995-01-01

    Spiral angio were performed with injection of 30 ml of contrast material at a rate of 1 ml/sec with a scan delay of 6 sec through catheter into the celiac artery while the blood flow of the superior mesenteric artery (SMA) was occluded by the inflated balloon catheter. Spiral CT scans were obtained using Somatom Plus (Siemens). Parameter for spiral CT were 24-sec acquisition time, 5 mm collimation, 5 mm/sec table incrementation. Reconstructions were performed every 5 mm. Pancreatic cancers were characteristically depicted with spiral angio CT as hypodensity relative to normal enhanced pancreatic parenchyma. On dynamic angio CT studies performed in pancreatic cancers, the area of cancer and normal parenchyma had maximum level of enhancement at 10-15 sec after injection of contrast material via catheter into the celiac, and there was no difference in enhancement between tumor and normal parenchyma. On the other hand, the lesions of cancer were revealed as hypodensity with spiral angio CT. In case of chronic pancreatitis, the enhancement of the entire pancreas obtained with spiral angio CT was homogeneous. Insulinoma in the tail of pancreas was detected by spiral angio CT but was not detected by both selective angiography and conventional CT. Three-dimensional (3-D) rendering spiral angio CT data shows the extent of vascular involvement by pancreatic cancer and provides useful information for surgical planning. Spiral angio CT is the most useful procedure for diagnosis of pancreatic tumor. (author)

  2. Radionuclide therapy of endocrine-related cancer

    International Nuclear Information System (INIS)

    Kratochwil, C.; Giesel, F.L.

    2014-01-01

    This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [de

  3. Concurrent endocrine neoplasias in dogs and cats: a retrospective study (2004-2014).

    Science.gov (United States)

    Beatrice, Laura; Boretti, Felicitas Schär; Sieber-Ruckstuhl, Nadja S; Mueller, Claudia; Kümmerle-Fraune, Claudia; Hilbe, Monika; Grest, Paula; Reusch, Claudia E

    2018-03-17

    Multiple endocrine neoplasia (MEN) is a well-known syndrome in human medicine, whereas only a few cases of concurrent endocrine neoplasias have been reported in dogs and cats. The aim of this study was to evaluate the prevalence of concurrent endocrine neoplasias in dogs and cats at our clinic, identify possible breed and sex predispositions and investigate similarities with MEN syndromes in humans. Postmortem reports of 951 dogs and 1155 cats that died or were euthanased at the Clinic for Small Animal Internal Medicine, University of Zurich, between 2004 and 2014 were reviewed, and animals with at least two concurrent endocrine neoplasias and/or hyperplasias were included. Twenty dogs and 15 cats met the inclusion criteria. In dogs, the adrenal glands were most commonly affected. Multiple tumours affecting the adrenal glands and the association of these tumours with pituitary adenomas were the most common tumour combinations. Only one dog had a combination resembling human MEN type 1 syndrome (pituitary adenoma and insulinoma). In cats, the thyroid glands were most commonly affected and there were no similarities to human MEN syndromes. The prevalence of concurrent endocrine neoplasia was 2.1 per cent in dogs and 1.3 per cent in cats and MEN-like syndromes are very rare in these species. © British Veterinary Association (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  4. Autoimmunity in type 1 diabetes mellitus: a rat model

    International Nuclear Information System (INIS)

    Liu, Z.

    1987-01-01

    In this study, we have sought to isolate in vitro, from acutely diabetic BB rats, cytotoxic T lymphocytes, which exhibit specific cytotoxicity toward islet cells. Thoracic duct lymphocytes (TDL) from acutely diabetic BB rats cultured with irradiated MHC matched (RT1.u) islet cells and dendritic cells in vitro were shown to be specifically cytotoxic to MHC matched and mismatched allogeneic (RT1.1) and xenogeneic (hamster) islet target cells in a 3 H-leucine release assay. Two cell lines (V1A8 and V1D11) derived from the TDL culture showed similar patterns of non-MHC restricted islet cell killing which could be blocked by islet cells and cultured rat insulinoma cells (RIN5mF) but not by non-islet cells of various tissue origins. Both V1A8 and V1D11 were not cytotoxic to Natural Killer (NK) sensitive target cells, G1TC and YAC-1. Conventional surface markers for rat helper and suppressor/cytotoxic T cells were not detectable on either cell lines. The V1D11 cell line was positive for W 3/13 (rat T/NK marker) on OX-19 (rat T/macrophage marker), whereas the V1A8 cell line was only positive for W 3/13

  5. Roscoe Reid Graham (1890 to 1948): a Canadian pioneer in general surgery.

    Science.gov (United States)

    Piper, Christine C; Yeo, Charles J; Cowan, Scott W

    2014-05-01

    Roscoe Reid Graham, a Canadian surgeon trained at the University of Toronto, was a true pioneer in the field of general surgery. Although he may be best known for his omental patch repair of perforated duodenal ulcers-often referred to as the "Graham patch"-he had a number of other significant accomplishments that decorated his surgical career. Dr. Graham is credited with being the first surgeon to successfully enucleate an insulinoma. He ventured to do an essentially brand new operation based solely on his patient's symptoms and physical findings, a courageous move that even some of the most talented surgeons would shy away from. He also spent a large portion of his career dedicated to the study of rectal prolapse, working tirelessly to rid his patients of this awful affliction. He was recognized by a number of different surgical associations for his operative successes and was awarded membership to those both in Canada and the United States. Despite all of these accolades, Dr. Graham remained grounded and always fervent in his dedication to the patient and their presenting symptom(s), reminding us that to do anything more would be "meddlesome." In an age when medical professionals are often all too eager to make unnecessary interventions, it is imperative that we look back at our predecessors such as Roscoe Reid Graham, for they will continually redirect us toward our one and only obligation: the patient.

  6. Calcium Co-regulates Oxidative Metabolism and ATP Synthase-dependent Respiration in Pancreatic Beta Cells

    Science.gov (United States)

    De Marchi, Umberto; Thevenet, Jonathan; Hermant, Aurelie; Dioum, Elhadji; Wiederkehr, Andreas

    2014-01-01

    Mitochondrial energy metabolism is essential for glucose-induced calcium signaling and, therefore, insulin granule exocytosis in pancreatic beta cells. Calcium signals are sensed by mitochondria acting in concert with mitochondrial substrates for the full activation of the organelle. Here we have studied glucose-induced calcium signaling and energy metabolism in INS-1E insulinoma cells and human islet beta cells. In insulin secreting cells a surprisingly large fraction of total respiration under resting conditions is ATP synthase-independent. We observe that ATP synthase-dependent respiration is markedly increased after glucose stimulation. Glucose also causes a very rapid elevation of oxidative metabolism as was followed by NAD(P)H autofluorescence. However, neither the rate of the glucose-induced increase nor the new steady-state NAD(P)H levels are significantly affected by calcium. Our findings challenge the current view, which has focused mainly on calcium-sensitive dehydrogenases as the target for the activation of mitochondrial energy metabolism. We propose a model of tight calcium-dependent regulation of oxidative metabolism and ATP synthase-dependent respiration in beta cell mitochondria. Coordinated activation of matrix dehydrogenases and respiratory chain activity by calcium allows the respiratory rate to change severalfold with only small or no alterations of the NAD(P)H/NAD(P)+ ratio. PMID:24554722

  7. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

    Directory of Open Access Journals (Sweden)

    Kyle S. McCommis

    2016-08-01

    Full Text Available Objective: Transport of pyruvate into the mitochondrial matrix by the Mitochondrial Pyruvate Carrier (MPC is an important and rate-limiting step in its metabolism. In pancreatic β-cells, mitochondrial pyruvate metabolism is thought to be important for glucose sensing and glucose-stimulated insulin secretion. Methods: To evaluate the role that the MPC plays in maintaining systemic glucose homeostasis, we used genetically-engineered Drosophila and mice with loss of MPC activity in insulin-producing cells. Results: In both species, MPC deficiency results in elevated blood sugar concentrations and glucose intolerance accompanied by impaired glucose-stimulated insulin secretion. In mouse islets, β-cell MPC-deficiency resulted in decreased respiration with glucose, ATP-sensitive potassium (KATP channel hyperactivity, and impaired insulin release. Moreover, treatment of pancreas-specific MPC knockout mice with glibenclamide, a sulfonylurea KATP channel inhibitor, improved defects in islet insulin secretion and abnormalities in glucose homeostasis in vivo. Finally, using a recently-developed biosensor for MPC activity, we show that the MPC is rapidly stimulated by glucose treatment in INS-1 insulinoma cells suggesting that glucose sensing is coupled to mitochondrial pyruvate carrier activity. Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia. Keywords: Stimulus-coupled secretion, Insulin, β-Cell, Diabetes, Pyruvate, Mitochondria, Drosophila

  8. Herpes simplex virus induces the marked up-regulation of the zinc finger transcriptional factor INSM1, which modulates the expression and localization of the immediate early protein ICP0

    Directory of Open Access Journals (Sweden)

    Kimura Hiroshi

    2011-05-01

    Full Text Available Abstract Background Herpes simplex viruses (HSVs rapidly shut off macromolecular synthesis in host cells. In contrast, global microarray analyses have shown that HSV infection markedly up-regulates a number of host cell genes that may play important roles in HSV-host cell interactions. To understand the regulatory mechanisms involved, we initiated studies focusing on the zinc finger transcription factor insulinoma-associated 1 (INSM1, a host cell protein markedly up-regulated by HSV infection. Results INSM1 gene expression in HSV-1-infected normal human epidermal keratinocytes increased at least 400-fold 9 h after infection; INSM1 promoter activity was also markedly stimulated. Expression and subcellular localization of the immediate early HSV protein ICP0 was affected by INSM1 expression, and chromatin immunoprecipitation (ChIP assays revealed binding of INSM1 to the ICP0 promoter. Moreover, the role of INSM1 in HSV-1 infection was further clarified by inhibition of HSV-1 replication by INSM1-specific siRNA. Conclusions The results suggest that INSM1 up-regulation plays a positive role in HSV-1 replication, probably by binding to the ICP0 promoter.

  9. Targets and probes for non-invasive imaging of β-cells

    Energy Technology Data Exchange (ETDEWEB)

    Jodal, Andreas; Behe, Martin [Paul Scherrer Institut, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); Schibli, Roger [Paul Scherrer Institut, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Villigen (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Zurich (Switzerland)

    2017-04-15

    β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications. (orig.)

  10. Role of immune system in type 1 diabetes mellitus pathogenesis.

    Science.gov (United States)

    Szablewski, Leszek

    2014-09-01

    The immune system is the body's natural defense system against invading pathogens. It protects the body from infection and works to communicate an individual's well-being through a complex network of interconnected cells and cytokines. This system is an associated host defense. An uncontrolled immune system has the potential to trigger negative complications in the host. Type 1 diabetes results from the destruction of pancreatic β-cells by a β-cell-specific autoimmune process. Examples of β-cell autoantigens are insulin, glutamic acid decarboxylase, tyrosine phosphatase, and insulinoma antigen. There are many autoimmune diseases, but type 1 diabetes mellitus is one of the well-characterized autoimmune diseases. The mechanisms involved in the β-cell destruction are still not clear; it is generally believed that β-cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes are involved in the β-cell-specific autoimmune process. It is necessary to determine what exact factors are causing the immune system to become unregulated in such a manner as to promote an autoimmune response. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. IA-2 autoantibody affinity in children at risk for type 1 diabetes.

    Science.gov (United States)

    Krause, Stephanie; Chmiel, Ruth; Bonifacio, Ezio; Scholz, Marlon; Powell, Michael; Furmaniak, Jadwiga; Rees Smith, Bernard; Ziegler, Anette-G; Achenbach, Peter

    2012-12-01

    Autoantibodies to insulinoma-associated protein 2 (IA-2A) are associated with increased risk for type 1 diabetes. Here we examined IA-2A affinity and epitope specificity to assess heterogeneity in response intensity in relation to pathogenesis and diabetes risk in 50 children who were prospectively followed from birth. At first IA-2A appearance, affinity ranged from 10(7) to 10(11)L/mol and was high (>1.0×10(9)L/mol) in 41 (82%) children. IA-2A affinity was not associated with epitope specificity or HLA class II haplotype. On follow-up, affinity increased or remained high, and IA-2A were commonly against epitopes within the protein tyrosine phosphatase-like IA-2 domain and the homologue protein IA-2β. IA-2A were preceded or accompanied by other islet autoantibodies in 49 (98%) children, of which 34 progressed to diabetes. IA-2A affinity did not stratify diabetes risk. In conclusion, the IA-2A response in children is intense with rapid maturation against immunogenic epitopes and a strong association with diabetes development. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Radiation carcinogenesis. Comprehensive final report, 16 May 1979-31 December 1980

    International Nuclear Information System (INIS)

    Warren, S.; Brown, C.E.; Gates, O.

    1981-03-01

    This abstract covers three main areas of investigation: mesothelioma induction by asbestos, radiation tumorigenesis and transplantable tumors. Canadian and Rhodesian asbestos fibers have been administered under anesthesia to rats by intratracheal, intrapleural and intraperitoneal injection. Additional groups were given 3-methylcholanthrene or x-radiation along with asbestos. A large series of mice also treated as above have displayed mesotheliomas. In addition, glass fiber injections and feeding of asbestos were done and have produced negative results to date. The carcinogenic effect of whole-body radiation on hemi-irradiated parabiont partners exposed to a single 1000 R dose of x-ray was evidenced by a significant increase in the incidence of malignant tumors in only six tissues: skin, supporting soft tissue, kidney, bone, pancreatic islets and ovary. In the male adrenal medulla and in the female breast genetic and parabiotic hormonal factors were judged to exert a significant effect. The occurrence of incisional (anastomotic) sarcomas in significant numbers in hemi-irradiated and parabiont control pairs suggests the operation of mechanical factors complicating the healing process, only slightly enhanced by radiation. One of the very valuable but unanticipated developments of the rat radiation program was the isolation of two transplantable endocrine tumors with strong hormonal potentials: an insulinoma of the pancreas and a pheochromocytoma of the adrenal medulla

  13. Targets and probes for non-invasive imaging of β-cells

    International Nuclear Information System (INIS)

    Jodal, Andreas; Behe, Martin; Schibli, Roger

    2017-01-01

    β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications. (orig.)

  14. Tissue strands as "bioink" for scale-up organ printing.

    Science.gov (United States)

    Yu, Yin; Ozbolat, Ibrahim T

    2014-01-01

    Organ printing, takes tissue spheroids as building blocks together with additive manufacturing technique to engineer tissue or organ replacement parts. Although a wide array of cell aggregation techniques has been investigated, and gained noticeable success, the application of tissue spheroids for scale-up tissue fabrication is still worth investigation. In this paper, we introduce a new micro-fabrication technique to create tissue strands at the scale of 500-700μm as a "bioink" for future robotic tissue printing. Printable alginate micro-conduits are used as semi-permeable capsules for tissue strand fabrication. Mouse insulinoma beta TC3 cell tissue strands were formed upon 4 days post fabrication with reasonable mechanical strength, high cell viability close to 90%, and tissue specific markers expression. Fusion was readily observed between strands when placing them together as early as 24h. Also, tissue strands were deposited with human umbilical vein smooth muscle cells (HUVSMCs) vascular conduits together to fabricated miniature pancreatic tissue analog. Our study provided a novel technique using tissue strands as "bioink" for scale-up bioprinting of tissues or organs.

  15. A microwell cell culture platform for the aggregation of pancreatic β-cells.

    Science.gov (United States)

    Bernard, Abigail B; Lin, Chien-Chi; Anseth, Kristi S

    2012-08-01

    Cell-cell contact between pancreatic β-cells is important for maintaining survival and normal insulin secretion. Various techniques have been developed to promote cell-cell contact between β-cells, but a simple yet robust method that affords precise control over three-dimensional (3D) β-cell cluster size has not been demonstrated. To address this need, we developed a poly(ethylene glycol) (PEG) hydrogel microwell platform using photolithography. This microwell cell-culture platform promotes the formation of 3D β-cell aggregates of defined sizes from 25 to 210 μm in diameter. Using this platform, mouse insulinoma 6 (MIN6) β-cells formed aggregates with cell-cell adherin junctions. These naturally formed cell aggregates with controllable sizes can be removed from the microwells for macroencapsulation, implantation, or other biological assays. When removed and subsequently encapsulated in PEG hydrogels, the aggregated cell clusters demonstrated improved cellular viability (>90%) over 7 days in culture, while the β-cells encapsulated as single cells maintained only 20% viability. Aggregated MIN6 cells also exhibited more than fourfold higher insulin secretion in response to a glucose challenge compared with encapsulated single β-cells. Further, the cell aggregates stained positively for E-cadherin, indicative of the formation of cell junctions. Using this hydrogel microwell cell-culture method, viable and functional β-cell aggregates of specific sizes were created, providing a platform from which other biologically relevant questions may be answered.

  16. Detection of chromogranins A and B in endocrine tissues with radioactive and biotinylated oligonucleotide probes

    Energy Technology Data Exchange (ETDEWEB)

    Lloyd, R.V.; Jin, L.; Fields, K. (Univ. of Michigan, Ann Arbor (USA))

    1990-01-01

    We analyzed the distribution of chromogranins A and B in normal and neoplastic endocrine tissues with secretory granules using {sup 35}S-labeled and biotin-labeled oligonucleotide probes by in situ hybridization (ISH). Both radioactive and nonradioactive probes detected messenger RNAs (mRNAs) in frozen and paraffin tissue sections. Endocrine tissues with variable immunoreactivities for chromogranin A protein, such as small-cell lung carcinomas, neuroblastomas, insulinomas, and parathyroid adenomas, expressed the mRNA for chromogranins A and B in most cells. Some technical problems with the biotinylated probes included nonspecific nuclear staining and endogenous alkaline phosphatase, which was not completely abolished by levamisole pretreatment. A differential distribution of chromogranins A and B was seen in pituitary prolactinomas, which expressed abundant chromogranin B but not chromogranin A mRNAs, and in parathyroid adenomas, which expressed abundant chromogranin A but only small amounts of chromogranin B mRNAs. These results indicate that ISH can be used to detect chromogranins A and B in endocrine tissues with radioactive and biotinylated oligonucleotide probes and that the mRNAs for chromogranin A and B are demonstrable in some tumors even when the chromogranin proteins cannot be detected by immunohistochemistry.

  17. Endoplasmic reticulum redox state is not perturbed by pharmacological or pathological endoplasmic reticulum stress in live pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Irmgard Schuiki

    Full Text Available Accumulation of unfolded, misfolded and aggregated proteins in the endoplasmic reticulum (ER causes ER stress. ER stress can result from physiological situations such as acute increases in secretory protein biosynthesis or pathological conditions that perturb ER homeostasis such as alterations in the ER redox state. Here we monitored ER redox together with transcriptional output of the Unfolded Protein Response (UPR in INS-1 insulinoma cells stably expressing eroGFP (ER-redox-sensor and mCherry protein driven by a GRP78 promoter (UPR-sensor. Live cell imaging, flow cytometry and biochemical characterization were used to examine these parameters in response to various conditions known to induce ER stress. As expected, treatment of the cells with the reducing agent dithiothreitol caused a decrease in the oxidation state of the ER accompanied by an increase in XBP-1 splicing. Unexpectedly however, other treatments including tunicamycin, thapsigargin, DL-homocysteine, elevated free fatty acids or high glucose had essentially no influence on the ER redox state, despite inducing ER stress. Comparable results were obtained with dispersed rat islet cells expressing eroGFP. Thus, unlike in yeast cells, ER stress in pancreatic β-cells is not associated with a more reducing ER environment.

  18. Geometric effect of the hydrogel grid structure on in vitro formation of homogeneous MIN6 cell clusters.

    Science.gov (United States)

    Bae, Chae Yun; Min, Mun-kyeong; Kim, Hail; Park, Je-Kyun

    2014-07-07

    A microstructure-based hydrogel was employed to study the relationship between spatial specificity and cellular behavior, including cell fate, proliferation, morphology, and insulin secretion in pancreatic β-cells. To effectively form homogeneous cell clusters in vitro, we made cell-containing hydrogel membrane constructs with an adapted grid structure based on a hexagonal micropattern. Homogeneous cell clusters (average diameter: 83.6 ± 14.2 μm) of pancreatic insulinoma (MIN6) cells were spontaneously generated in the floating hydrogel membrane constructs, including a hexagonal grid structure (size of cavity: 100 μm, interval between cavities: 30 μm). Interestingly, 3D clustering of MIN6 cells mimicking the structure of pancreatic islets was coalesced into a merged aggregate attaching to each hexagonal cavity of the hydrogel grid structure. The fate and insulin secretion of homogeneous cell clusters in the hydrogel grid structure were also assessed. The results of these designable hydrogel-cell membrane constructs suggest that facultative in vitro β-cell proliferation and maintenance can be applied to biofunctional assessments.

  19. Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.

    Directory of Open Access Journals (Sweden)

    Yukina Kawada

    Full Text Available Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2 expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.

  20. Noninvasive assessment of tissue-engineered graft viability by oxygen-17 magnetic resonance spectroscopy.

    Science.gov (United States)

    Einstein, Samuel A; Weegman, Bradley P; Kitzmann, Jennifer P; Papas, Klearchos K; Garwood, Michael

    2017-05-01

    Transplantation of macroencapsulated tissue-engineered grafts (TEGs) is being investigated as a treatment for type 1 diabetes, but there is a critical need to measure TEG viability both in vitro and in vivo. Oxygen deficiency is the most critical issue preventing widespread implementation of TEG transplantation and delivery of supplemental oxygen (DSO) has been shown to enhance TEG survival and function in vivo. In this study, we demonstrate the first use of oxygen-17 magnetic resonance spectroscopy ( 17 O-MRS) to measure the oxygen consumption rate (OCR) of TEGs and show that in addition to providing therapeutic benefits to TEGs, DSO with 17 O 2 can also enable measurements of TEG viability. Macroencapsulated TEGs containing βTC3 murine insulinoma cells were prepared with three fractional viabilities and provided with 17 O 2 . Cellular metabolism of 17 O 2 into nascent mitochondrial water (H 2 17 O) was monitored by 17 O-MRS and, from the measured data, OCR was calculated. For comparison, OCR was simultaneously measured on a separate, but equivalent sample of cells with a well-established stirred microchamber technique. OCR measured by 17 O-MRS agreed well with measurements made in the stirred microchamber device. These studies confirm that 17 O-MRS can quantify TEG viability noninvasively. Biotechnol. Bioeng. 2017;114: 1118-1121. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

    Directory of Open Access Journals (Sweden)

    Chih-Ting Su

    2016-11-01

    Full Text Available Insulin antibodies (IA associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA found in insulin autoimmune syndrome (IAS, which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%, high insulin concentration (111.9 IU/mL and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly.

  2. The ATP/DNA Ratio Is a Better Indicator of Islet Cell Viability Than the ADP/ATP Ratio

    Science.gov (United States)

    Suszynski, T.M.; Wildey, G.M.; Falde, E.J.; Cline, G.W.; Maynard, K. Stewart; Ko, N.; Sotiris, J.; Naji, A.; Hering, B.J.; Papas, K.K.

    2009-01-01

    Real-time, accurate assessment of islet viability is critical for avoiding transplantation of nontherapeutic preparations. Measurements of the intracellular ADP/ATP ratio have been recently proposed as useful prospective estimates of islet cell viability and potency. However, dead cells may be rapidly depleted of both ATP and ADP, which would render the ratio incapable of accounting for dead cells. Since the DNA of dead cells is expected to remain stable over prolonged periods of time (days), we hypothesized that use of the ATP/DNA ratio would take into account dead cells and may be a better indicator of islet cell viability than the ADP/ATP ratio. We tested this hypothesis using mixtures of healthy and lethally heat-treated (HT) rat insulinoma cells and human islets. Measurements of ATP/DNA and ADP/ATP from the known mixtures of healthy and HT cells and islets were used to evaluate how well these parameters correlated with viability. The results indicated that ATP and ADP were rapidly (within 1 hour) depleted in HT cells. The fraction of HT cells in a mixture correlated linearly with the ATP/DNA ratio, whereas the ADP/ADP ratio was highly scattered, remaining effectively unchanged. Despite similar limitations in both ADP/ADP and ATP/DNA ratios, in that ATP levels may fluctuate significantly and reversibly with metabolic stress, the results indicated that ATP/DNA was a better measure of islet viability than the ADP/ATP ratio. PMID:18374063

  3. No Contribution of GAD-65 and IA-2 Autoantibodies around Time of Diagnosis to the Increasing Incidence of Juvenile Type 1 Diabetes: A 9-Year Nationwide Danish Study

    Directory of Open Access Journals (Sweden)

    Steffen U. Thorsen

    2016-01-01

    Full Text Available Aims. A new perspective on autoantibodies as pivotal players in the pathogenesis of type 1 diabetes (T1D has recently emerged. Our key objective was to examine whether increased levels of autoantibodies against the β-cell autoantigens glutamic acid decarboxylase (isoform 65 (GADA and insulinoma associated antigen-2A (IA-2A mirrored the 3.4% annual increase in incidence of T1D. Methods. From the Danish Childhood Diabetes Register, we randomly selected 500 patients and 500 siblings for GADA and IA-2A analysis (1997 through 2005. Blood samples were taken within three months after onset. A robust log-normal regression model was used. Nine hundred children and adolescents had complete records and were included in the analysis. Cochran-Armitage test for trend was used to evaluate changes in prevalence of autoantibody positivity by period. Results. No significant changes in levels of GADA and IA-2A were found over our 9-year study period. No trends in autoantibody positivity—in either patients or siblings—were found. Levels of GADA and IA-2A were significantly associated with HLA risk groups and GADA with age. Conclusion. The prevalence of positivity and the levels of GADA and IA-2A have not changed between 1997 and 2005 in newly diagnosed patients with T1D and their siblings without T1D.

  4. Insulin-secretagogue activity and cytoprotective role of the traditional antidiabetic plant Scoparia dulcis (Sweet Broomweed).

    Science.gov (United States)

    Latha, Muniappan; Pari, Leelavinothan; Sitasawad, Sandhya; Bhonde, Ramesh

    2004-09-03

    Scoparia dulcis (Sweet Broomweed) has been documented as a traditional treatment of diabetes. The administration of an aqueous extract of Scoparia dulcis at a dose of 200 mg/kg body weight significantly decreased the blood glucose with significant increase in plasma insulin level in streptozotocin diabetic rats at the end of 15 days treatment. The insulin secretagogue action of Scoparia dulcis plant extract (SPEt) was further investigated using isolated pancreatic islets from mice. SPEt at a dose of 10 microg/ml evoked 6.0 fold stimulation of insulin secretion from isolated islets indicating its insulin secretagogue activity. In addition the effect of SPEt on streptozotocin induced cell death and nitric oxide (NO) in terms of nitrite production were also examined. SPEt protected against streptozotocin- mediated cytotoxicity (88%) and NO production in rat insulinoma cell line (RINm5F). Above results suggest the glucose lowering effect of SPEt to be associated with potentiation of insulin release from pancreatic islets. Our results revealed the possible therapeutic value of Scoparia dulcis for the better control, management and prevention of diabetes mellitus progression.

  5. Antidiabetic effects of scoparic acid D isolated from Scoparia dulcis in rats with streptozotocin-induced diabetes.

    Science.gov (United States)

    Latha, Muniappan; Pari, Leelavinothan; Ramkumar, Kunga Mohan; Rajaguru, Palanisamy; Suresh, Thangaraj; Dhanabal, Thangavel; Sitasawad, Sandhya; Bhonde, Ramesh

    2009-01-01

    We evaluated the antihyperglycaemic effect of scoparic acid D (SAD), a diterpenoid isolated from the ethanol extract of Scoparia dulcis in streptozotocin (STZ)-induced diabetic male Wistar rats. SAD was administered orally at a dose of 10, 20 and 40 mg kg(-1) bodyweight for 15 days. At the end of the experimental period, the SAD-treated STZ diabetic rats showed decreased levels of glucose as compared with diabetic control rats. The improvement in blood glucose levels of SAD-treated rats was associated with a significant increase in plasma insulin levels. SAD at a dose of 20 mg kg(-1) bodyweight exhibited a significant effect when compared with other doses. Further, the effect of SAD was tested on STZ-treated rat insulinoma cell lines (RINm5F cells) and isolated islets in vitro. SAD at a dose of 20 microg mL(-1) evoked two-fold stimulation of insulin secretion from isolated islets, indicating its insulin secretagogue activity. Further, SAD protected STZ-mediated cytotoxicity and nitric oxide (NO) production in RINm5F cells. The present study thus confirms the antihyperglycaemic effect of SAD and also demonstrated the consistently strong cytoprotective properties of SAD.

  6. Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors.

    Science.gov (United States)

    Choi, Jun-Ho; Seo, Dong-Wan; Song, Tae Jun; Park, Do Hyun; Lee, Sang Soo; Lee, Sung Koo; Kim, Myung-Hwan

    2018-05-04

     Radiofrequency ablation (RFA) has been increasingly employed in experimental and clinical settings for the management of pancreatic lesions. This study aimed to assess the safety and efficacy of endoscopic ultrasound (EUS)-guided RFA for benign solid pancreatic tumors.  In a single-center, prospective study, 10 patients with benign solid pancreatic tumors underwent EUS-RFA. After the RFA electrode had been inserted into the pancreatic mass, the radiofrequency generator was activated to deliver 50 W of ablation power.  Among the 10 patients, 16 sessions of EUS-RFA were successfully performed. Diagnoses included nonfunctioning neuroendocrine tumor (n = 7), solid pseudopapillary neoplasm (n = 2), and insulinoma (n = 1); the median largest diameter of the tumors was 20 mm (range 8 - 28 mm). During follow-up (median 13 months), radiologic complete response was achieved in seven patients. Two adverse events (12.4 %; 1 moderate and 1 mild) occurred.  EUS-RFA may be a safe and potentially effective treatment option in selected patients with benign solid pancreatic tumors. Multiple sessions may be required if there is a remnant tumor, and adverse events must be carefully monitored. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Essential role of the small GTPase Ran in postnatal pancreatic islet development.

    Directory of Open Access Journals (Sweden)

    Fang Xia

    Full Text Available The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin(+ β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo.

  8. Radiation carcinogenesis. Progress report VI, 16 May 1978--15 May 1979

    International Nuclear Information System (INIS)

    Warren, S.; Gates, O.

    1979-01-01

    Asbestos fibers, Canadian and Rhodesian chrysotile, have induced mesotheliomas and pleural plaques in mice and rats. The pathogenesis of the lesions is being studied. Proliferation of the adrenal cortical A cells is accelerated in time and enhanced in extent by ionizing radiation in female RAP mice. The development of cortical tumors was significantly correlated with extensive A cell proliferation. Whole-body protracted doses, above 500 rads, were followed by a 9% tumor incidence. Endocrine neoplasia in mice appears related to functional ties between several endocrines particularly adrenal, ovary, and pituitary. A study of the spontaneous benign and malignant tumors ocurring in control NEDH rats has provided background for the tumorigenic effects of radiation and also of altered hormonal internal milieu. Begin tumors have been produced by radiation in a wide variety of tissues for the first time, providing data as to the relative responsiveness in benign tumor production of various tissues to a dose of 1000 rads. The hormonal changes secondary to parabiosis and hemi-irradiation of the pair are important. A radiation-induced functioning pheochromocytoma causing hypertension and death has been found widely useful by investigators. A radiation-induced malignant insulinoma has also been widely used, and insulin-producing DNA from it has served in the hands of others through genetic engineering to provide an insulin-producing strain of the bacillus E. coli

  9. Radiation carcinogenesis. Progress report V, 16 May 1977--15 May 1978

    International Nuclear Information System (INIS)

    Warren, S.; Gates, O.

    1978-01-01

    Experiments are underway on the cocarcinogenic effects of asbestos and carcinogenic hydrocarbons using rats and mice as test objects. None of the protocols of these experiments have as yet been completed. The study of tumorigenesis in irradiated parabiont rats has been completed. Study of the benign tumors indicates that radiation is an effective neoplastic stimulus for only a limited number of organs and tissues, chiefly ovary, adrenal, mammary tissue, islands of Langerhans, and liver. In general the benign tumors did not seriously affect health, and in only a very few animals did they become malignant. The incidence of malignant tumors in the parabiont series has been tabulated and analyzed. Parabiosis alone appears to increase the incidence of leukemia and solid lymphoid tumors in NEDH rats. Our study of radiation tumorigenesis in the adrenal cortest in the mouse has been completed. The cortex is highly resistant to tumor induction by irradiation. Cortical tumorigenesis is strongly influenced by changes in pituitary and ovarian hormones. Proliferation of capsular ''A'' cells appears to be an important early factor in carcinogenesis. Hormonal imbalance continues to be an important factor in tumorigenesis in the parabiont pairs. If each of a pair of parabiont rats is irradiated sequentially at intervals, 30 days after a lethal dose of radiation is enough to permit the irradiated rat to support its partner through a like dose as effectively as would an unirradiated animal. The transplantable radiation-induced functioning pheochromocytoma and insulinoma of rats continue to be valuable research tools

  10. Sulforaphane protects against cytokine- and streptozotocin-induced β-cell damage by suppressing the NF-κB pathway

    International Nuclear Information System (INIS)

    Song, Mi-Young; Kim, Eun-Kyung; Moon, Woo-Sung; Park, Jin-Woo; Kim, Hyung-Jin; So, Hong-Seob; Park, Raekil; Kwon, Kang-Beom; Park, Byung-Hyun

    2009-01-01

    Sulforaphane (SFN) is an indirect antioxidant that protects animal tissues from chemical or biological insults by stimulating the expression of several NF-E2-related factor-2 (Nrf2)-regulated phase 2 enzymes. Treatment of RINm5F insulinoma cells with SFN increases Nrf2 nuclear translocation and expression of phase 2 enzymes. In this study, we investigated whether the activation of Nrf2 by SFN treatment or ectopic overexpression of Nrf2 inhibited cytokine-induced β-cell damage. Treatment of RIN cells with IL-1β and IFN-γ induced β-cell damage through a NF-κB-dependent signaling pathway. Activation of Nrf2 by treatment with SFN and induction of Nrf2 overexpression by transfection with Nrf2 prevented cytokine toxicity. The mechanism by which Nrf2 activation inhibited NF-κB-dependent cell death signals appeared to involve the reduction of oxidative stress, as demonstrated by the inhibition of cytokine-induced H 2 O 2 production. The protective effect of SFN was further demonstrated by the restoration of normal insulin secreting responses to glucose in cytokine-treated rat pancreatic islets. Furthermore, pretreatment with SFN blocked the development of type 1 diabetes in streptozotocin-treated mice

  11. Cystic pancreatic neuroendocrine tumors (cPNETs: a systematic review and meta-analysis of case series

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    Luis Hurtado-Pardo

    Full Text Available Cystic pancreatic neuroendocrine tumors represent 13% of all neuroendocrine tumors. The aim of this study is to analyze the phenotype and biologic behavior of resected cystic neuroendocrine tumors. A systematic review and meta-analysis were conducted until September 2016 using a search in Medline, Scopus, and EMBASE with the terms "cystic pancreatic endocrine neoplasm", "cystic islets tumors" and "cystic islets neoplasms". From the 795 citations recovered 80 studies reporting on 431 patients were selected. 87.1% (n = 387 were sporadic tumors and 10.3% (n = 40 corresponded to multiple endocrine neoplasia type 1. Were diagnosed incidentally 44.6% (n = 135. Cytology was found to have a sensitivity of 78.5%. Were non-functional tumors 85% (n = 338, and among the functional tumors, insulinoma was the most frequent. According to the European Neuroendocrine Tumor Society staging, 87.8% were limited to the pancreas (I-IIb, and 12.2% were advanced (III-IV. Disease-free survival at 5 years in stages (I-IIIa and (IIIb-IV was 91.5% and 54.2%, respectively; and was significantly lower (p = 0.0001 in functional tumors. In patients with multiple endocrine neoplasia there was a higher incidence of functional (62.5% and multifocal (28.1% tumors. Disease-free survival at 5 and 10 years was 60%. Cystic pancreatic neuroendocrine tumors exhibit phenotypical characteristics which are different to those of solid neuroendocrine tumors.

  12. Severe hypoglycemia secondary to methimazole-induced insulin autoimmune syndrome in a 16 year old African-American male.

    Science.gov (United States)

    Gomez Cruz, Michelle J; Jabbar, Muhammad; Saini, Natinder; Eng, Donna; Crawford, Brandon; Vazquez, Delia M; Menon, Ram; Chen, Ming

    2012-12-01

    Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African-American adolescent. A 16-yr-old healthy African-American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio-ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia. © 2012 John Wiley & Sons A/S.

  13. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

    Science.gov (United States)

    Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

    2016-01-01

    Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

  14. Zinc as a paracrine effector in pancreatic islet cell death.

    Science.gov (United States)

    Kim, B J; Kim, Y H; Kim, S; Kim, J W; Koh, J Y; Oh, S H; Lee, M K; Kim, K W; Lee, M S

    2000-03-01

    Because of a huge amount of Zn2+ in secretory granules of pancreatic islet beta-cells, Zn2+ released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn2+ on beta-cell death. Zn2+ induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn2+ by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Zn2+ chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-(6-methoxy-quinolyl)-para-toluene-sulfonamide staining revealed that Zn2+ was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn2+ is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people.

  15. Re-exposure to beta cell autoantigens in pancreatic allograft recipients with preexisting beta cell autoantibodies.

    Science.gov (United States)

    Mujtaba, Muhammad Ahmad; Fridell, Jonathan; Book, Benita; Faiz, Sara; Sharfuddin, Asif; Wiebke, Eric; Rigby, Mark; Taber, Tim

    2015-11-01

    Re-exposure to beta cell autoantigens and its relevance in the presence of donor-specific antibodies (DSA) in pancreatic allograft recipients is not well known. Thirty-three patients requiring a pancreas transplant were enrolled in an IRB approved study. They underwent prospective monitoring for DSA and beta cell autoantibody (BCAA) levels to GAD65, insulinoma-associated antigen 2 (IA-2), insulin (micro-IAA [mIAA]), and islet-specific zinc transporter isoform-8 (ZnT8). Twenty-five (75.7%) had pre-transplant BCAA. Twenty had a single antibody (mIAA n = 15, GAD65 n = 5); five had two or more BCAA (GAD65 + mIAA n = 2, GAD65 + mIAA+IA-2 n = 2, GA65 + mIAA+IA-2 + ZnT8 = 1). No changes in GAD65 (p > 0.29), IA-2 (>0.16), and ZnT8 (p > 0.07) were observed between pre-transplant and post-transplant at 6 or 12 months. A decrease in mIAA from pre- to post-6 months (p BCAA was observed at one yr. Seven (21.0%) developed de novo DSA. The incidence of DSA was 24% in patients with BCAA vs. 25% in patients without BCAA (p = 0.69). Pancreatic allograft function of patients with vs. without BCAA, and with and without BCAA + DSA was comparable until last follow-up (three yr). Re-exposure to beta cell autoantigens by pancreas transplant may not lead to increased levels or development of new BCAA or pancreatic allograft dysfunction. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Rituximab selectively suppresses specific islet antibodies.

    Science.gov (United States)

    Yu, Liping; Herold, Kevan; Krause-Steinrauf, Heidi; McGee, Paula L; Bundy, Brian; Pugliese, Alberto; Krischer, Jeff; Eisenbarth, George S

    2011-10-01

    The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients (P 1 year in insulin-treated patients. For the patients receiving insulin for >2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific effects of rituximab on levels of IAAs.

  17. Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives.

    Science.gov (United States)

    Bosi, Emanuele; Boulware, David C; Becker, Dorothy J; Buckner, Jane H; Geyer, Susan; Gottlieb, Peter A; Henderson, Courtney; Kinderman, Amanda; Sosenko, Jay M; Steck, Andrea K; Bingley, Polly J

    2017-08-01

    Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease. To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated antigen 2, and zinc transporter 8 and islet cell antibodies were tested every 6 to 12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8 years, 8 to 11 years, 12 to 17 years, and ≥18 years, and optimal age breakpoints were identified by recursive partitioning analysis. After median follow-up of 2 years, 141 relatives had developed at least one additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: Relatives with GADA showed a gradual decrease in risk over the four age groups, whereas relatives with IAA showed a sharp decrease above age 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA. In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, whereas immune responses initially directed at glutamic acid decarboxylase can mature over a longer period. These differences have important implications for monitoring these patients and for designing prevention trials. Copyright © 2017 Endocrine Society

  18. Development of autoantibodies in the TrialNet Natural History Study.

    Science.gov (United States)

    Vehik, Kendra; Beam, Craig A; Mahon, Jeffrey L; Schatz, Desmond A; Haller, Michael J; Sosenko, Jay M; Skyler, Jay S; Krischer, Jeffrey P

    2011-09-01

    Understanding the relationship between age and islet autoantibody (Ab) seroconversion can establish the optimal screening interval(s) to assess risk for type 1 diabetes, identify subjects who can participate in prevention trials, and determine associated costs. This study assessed the rates of seroconversion to glutamic acid decarboxylase positive (GAD65(+)), insulin positive (mIAA(+)), and insulinoma-associated protein 2 positive (ICA512(+)) in a large cohort of relatives of type 1 diabetes probands undergoing Ab rescreening in the TrialNet Natural History Study. Of 32,845 children aged <18 years screened for Abs, 1,287 (3.9%) were GAD65(+), 778 (2.4%) were mIAA(+), 677 (2.1%) were ICA512(+), and 31,038 were Ab-negative. Ab-negative children were offered annual rescreening up to 18 years of age. Cox regression was used to estimate the risk for GAD65, mIAA, and ICA512 seroconversion. RESULTS There were 205 children who seroconverted to GAD65(+), 155 who seroconverted to mIAA(+), and 53 who seroconverted to ICA512(+) over 5.8 years of follow-up. The risk of mIAA (hazard ratio 0.89 [95% CI 0.85-0.92]) and GAD65 (0.96 [0.93-0.99]) seroconversion significantly decreased with increasing age (i.e., for each 1-year increase in age, the risk of seroconversion decreased by 11% [P < 0.0001] for mIAA and 4% [P = 0.04] for GAD65) across all ages. The cumulative Ab seroconversion was 2% for those <10 years of age versus 0.7% for those ≥10 years of age. The risk of development of islet Abs declines with increasing age in type 1 diabetes relatives. These data support annual screening for children <10 years of age and one additional screening in adolescence.

  19. The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes.

    Science.gov (United States)

    Bingley, Polly J; Boulware, David C; Krischer, Jeffrey P

    2016-03-01

    Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention. The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies. Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry. Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention.

  20. Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shan-Shan [Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing (China); Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing (China); Jiang, Teng [Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing (China); Wang, Yi; Gu, Li-Ze [Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing (China); Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing (China); Wu, Hui-Wen [Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing (China); Tan, Lan [Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing (China); Guo, Jun, E-mail: Guoj@njmu.edu.cn [Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing (China); Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing (China)

    2014-01-17

    Highlights: •PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in β-cells. •Activated PKR inhibited β-cell proliferation by arresting cell cycle at G1 phase. •Activated PKR fully abrogated the pro-proliferative effects of IGF-I on β-cells. -- Abstract: Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic β-cells. Here, we adopted insulinoma cell lines and mice islet β-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic β-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic β-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic β-cells may contribute to the pathogenesis of T2DM.

  1. A case of insulin and ACTH co-secretion by a neuroendocrine tumour.

    Science.gov (United States)

    Solomou, S; Khan, R; Propper, D; Berney, D; Druce, M

    2014-01-01

    A 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment. The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.

  2. Identification of circulating microRNAs in HNF1A-MODY carriers.

    Science.gov (United States)

    Bonner, C; Nyhan, K C; Bacon, S; Kyithar, M P; Schmid, J; Concannon, C G; Bray, I M; Stallings, R L; Prehn, J H M; Byrne, M M

    2013-08-01

    HNF1A-MODY is a monogenic form of diabetes caused by mutations in the HNF1A gene. Here we identify, for the first time, HNF1A-MODY-associated microRNAs (miRNAs) that can be detected in the serum of HNF1A-MODY carriers. An miRNA array was carried out in rat INS-1 insulinoma cells inducibly expressing the common human Pro291fsinsC-HNF1A frame shift mutation. Differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of miRNAs in the serum of HNF1A-MODY carriers (n = 31), MODY-negative family members (n = 10) and individuals with type 2 diabetes mellitus (n = 17) was quantified by absolute real-time PCR analysis. Inducible expression of Pro291fsinsC-HNF1A in INS-1 cells caused a significant upregulation of three miRNAs (miR-103, miR-224, miR-292-3p). The differential expression of two miRNAs (miR-103 and miR-224) was validated in vitro. Strongly elevated levels of miR-103 and miR-224 could be detected in the serum of HNF1A-MODY carriers compared with MODY-negative family controls. Serum levels of miR-103 distinguished HNF1A-MODY carriers from HbA1c-matched individuals with type 2 diabetes mellitus. Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers.

  3. Antibiotics induce mitonuclear protein imbalance but fail to inhibit respiration and nutrient activation in pancreatic β-cells.

    Science.gov (United States)

    Santo-Domingo, Jaime; Chareyron, Isabelle; Broenimann, Charlotte; Lassueur, Steve; Wiederkehr, Andreas

    2017-08-15

    Chloramphenicol and several other antibiotics targeting bacterial ribosomes inhibit mitochondrial protein translation. Inhibition of mitochondrial protein synthesis leads to mitonuclear protein imbalance and reduced respiratory rates as confirmed here in HeLa and PC12 cells. Unexpectedly, respiration in INS-1E insulinoma cells and primary human islets was unaltered in the presence of chloramphenicol. Resting respiratory rates and glucose stimulated acceleration of respiration were also not lowered when a range of antibiotics including, thiamphenicol, streptomycin, gentamycin and doxycycline known to interfere with bacterial protein synthesis were tested. However, chloramphenicol efficiently reduced mitochondrial protein synthesis in INS-1E cells, lowering expression of the mtDNA encoded COX1 subunit of the respiratory chain but not the nuclear encoded ATP-synthase subunit ATP5A. Despite a marked reduction of the essential respiratory chain subunit COX1, normal respiratory rates were maintained in INS-1E cells. ATP-synthase dependent respiration was even elevated in chloramphenicol treated INS-1E cells. Consistent with these findings, glucose-dependent calcium signaling reflecting metabolism-secretion coupling in beta-cells, was augmented. We conclude that antibiotics targeting mitochondria are able to cause mitonuclear protein imbalance in insulin secreting cells. We hypothesize that in contrast to other cell types, compensatory mechanisms are sufficiently strong to maintain normal respiratory rates and surprisingly even result in augmented ATP-synthase dependent respiration and calcium signaling following glucose stimulation. The result suggests that in insulin secreting cells only lowering COX1 below a threshold level may result in a measurable impairment of respiration. When focusing on mitochondrial function, care should be taken when including antibiotics targeting translation for long-term cell culture as depending on the sensitivity of the cell type analyzed

  4. SAD-A kinase controls islet β-cell size and function as a mediator of mTORC1 signaling.

    Science.gov (United States)

    Nie, Jia; Liu, Xiaolei; Lilley, Brendan N; Zhang, Hai; Pan, Y Albert; Kimball, Scot R; Zhang, Jun; Zhang, Weiping; Wang, Li; Jefferson, Leonard S; Sanes, Joshua R; Han, Xiao; Shi, Yuguang

    2013-08-20

    The mammalian target of rapamycin (mTOR) plays an important role in controlling islet β-cell function. However, the underlying molecular mechanisms remain poorly elucidated. Synapses of amphids defective kinase-A (SAD-A) is a 5' adenosine monophosphate-activated protein kinase-related protein kinase that is exclusively expressed in pancreas and brain. In this study, we investigated a role of the kinase in regulating pancreatic β-cell morphology and function as a mediator of mTOR complex 1 (mTORC1) signaling. We show that global SAD-A deletion leads to defective glucose-stimulated insulin secretion and petite islets, which are reminiscent of the defects in mice with global deletion of ribosomal protein S6 kinase 1, a downstream target of mTORC1. Consistent with these findings, selective deletion of SAD-A in pancreas decreased islet β-cell size, whereas SAD-A overexpression significantly increased the size of mouse insulinomas cell lines β-cells. In direct support of SAD-A as a unique mediator of mTORC1 signaling in islet β-cells, we demonstrate that glucose dramatically stimulated SAD-A protein translation in isolated mouse islets, which was potently inhibited by rapamycin, an inhibitor of mTORC1. Moreover, the 5'-untranslated region of SAD-A mRNA is highly structured and requires mTORC1 signaling for its translation initiation. Together, these findings identified SAD-A as a unique pancreas-specific effector protein of mTORC1 signaling.

  5. Microcystin-LR Induces Apoptosis via NF-κB /iNOS Pathway in INS-1 Cells

    Directory of Open Access Journals (Sweden)

    Kai Shen

    2011-07-01

    Full Text Available Cyanobacterial toxins, especially the microcystins, are found in eutrophied waters throughout the world, and their potential to impact on human and animal health is a cause for concern. Microcystin-LR (MC-LR is one of the common toxic microcystin congeners and occurs frequently in diverse water systems. Recent work suggested that apoptosis plays a major role in the toxic effects induced by MC-LR in hepatocytes. However, the roles of MC-LR in pancreatic beta cells have not been fully established. The aim of the present study was to assess possible in vitro effects of MC-LR on cell apoptosis in the rat insulinoma cell line, INS-1. Our results demonstrated that MC-LR promoted selectively activation of NF-κB (increasing nuclear p50/p65 translocation and increased the mRNA and protein levels of induced nitric oxide synthase (iNOS. The chronic treatment with MC-LR stimulated nitric oxide (NO production derived from iNOS and induced apoptosis in a dose dependent manner in INS-1 cells. Meanwhile, this effect was inhibited by the NF-κB inhibitor PDTC, which reversed the apoptosis induced by MC-LR. Our observations indicate that MC-LR induced cell apoptosis via an iNOS-dependent pathway. A well-known nuclear transcription factor, NF-κB, is activated and mediates intracellular nitric oxide synthesis. We suggest that the apoptosis induced by chronic MC-LR in vivo presents a possible cause of β-cell dysfunction, as a key environmental factor in the development of diabetes mellitus.

  6. Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo.

    Science.gov (United States)

    Gundala, Naveen K V; Naidu, Vegi G M; Das, Undurti N

    2017-03-01

    We studied whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5F) cells against alloxan-induced apoptosis in vitro and type 1 diabetes mellitus (type 1 DM) in vivo and if so, mechanism of this beneficial action. In vitro study was conducted using RIN5F cells while in vivo study was performed in Wistar rats. The effect of PUFAs, cyclo-oxygenase and lipoxygenase inhibitors, various eicosanoids and PUFAs metabolites: lipoxin A4 (LXA4), resolvin D2 and protectin against alloxan-induced cytotoxicity to RIN5F cells and type 1 DM was studied. Expression of PDX1, P65 NF-kB and IKB in RIN5F cells and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue and plasma glucose, insulin and tumor necrosis factor-α and antioxidants, lipid peroxides and nitric oxide were measured. Of all, arachidonic acid (AA) was found to be the most effective against alloxan-induced cytotoxicity to RIN5F cells and preventing type 1 DM. Both cyclo-oxygenase and lipoxygenase inhibitors did not block the beneficial actions of AA in vitro and in vivo. Alloxan inhibited LXA4 production by RIN5F cells and in alloxan-induced type 1 DM Wistar rats. AA-treatment restored LXA4 levels to normal both in vitro and in vivo. LXA4 protected RIN5F cells against alloxan-induced cytotoxicity and prevented type 1 DM and restored expression of Nrf2, Glut2, COX2, and iNOS genes and abnormal antioxidants to near normal. AA seems to bring about its beneficial actions against alloxan-induced cytotoxicity and type 1 DM by enhancing the production of LXA4. © 2016 BioFactors, 43(2):251-271, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  7. Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus.

    Directory of Open Access Journals (Sweden)

    Marie P Fogarty

    2014-09-01

    Full Text Available Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3'UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.

  8. Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells.

    Science.gov (United States)

    Song, Jia-Le; Zhao, Xin; Wang, Qiang; Zhang, Ting

    2013-05-01

    Reactive oxygen species (ROS)-induced pancreatic β cell death affects insulin secretion and is important in the pathogenesis of diabetes. Lagerstroemia speciosa, a traditional folk medicine, has been used for t he prevention and treatment of diabetes. However, whether Lagerstroemia speciosa has a cytoprotective effect on pancreatic β cells remains to be elucidated. The present study aimed to investigate the cytoprotective effects of hot water extracts from Lagerstroemia speciosa leaves (LWE) on 3-morpholinosydnonimine (SIN-1)-induced oxidative damage in Syrian hamster pancreatic insulinoma HIT-T15 cells. The HIT-T15 cells were first treated with SIN-1 (50 µM) for 24 h and then co-incubated with LWE for 48 h. SIN-1 significantly decreased HIT-T15 cell viability (PHIT-T15 cells in a dose‑dependent manner. To further investigate the protective effects of LWE on SIN-1‑induced oxidative stress in HIT-T15 cells, the cellular levels of ROS, lipid peroxidation and endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px), were determined. LWE decreased the intracellular levels of ROS and lipid peroxidation, and increased the activities of antioxidant enzymes. These results suggest that LWE has a cytoprotective effect against SIN-1‑induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, a decrease in ROS levels and an increase in antioxidant enzyme activity. In addition, LWE increased insulin secretion in SIN-1-treated HIT-T15 cells. Our results suggested that LWE were effective in the treatment of diabetes. Further studies are required to study the anti-diabetic molecular mechanism in a cell model.

  9. Amelioration of streptozotocin‑induced pancreatic β cell damage by morin: Involvement of the AMPK‑FOXO3‑catalase signaling pathway.

    Science.gov (United States)

    Wang, Ning; Zhang, Jiahui; Qin, Mengting; Yi, Wenjing; Yu, Shuang; Chen, Yi; Guan, Jing; Zhang, Rui

    2018-03-01

    Pancreatic β cells are sensitive to oxidative stress, which is one of the predominant causes of cell damage and the emergence of diabetes. The identification of effective therapeutic strategies to protect pancreatic cells from oxidative stress has increased interest in the screening of antioxidants from natural products. The present study aimed to investigate the protective effects of morin against streptozotocin (STZ)‑induced cell damage in a rat insulinoma cell line (RINm5F pancreatic β cells) and to identify the underlying mechanisms. The results indicated that morin inhibited the increase in intracellular reactive oxygen species, attenuated the activity of poly (ADP‑ribose) polymerase, restored intracellular nicotinamide adenine dinucleotide levels and reduced the apoptotic cell death of STZ‑treated pancreatic β cells. Treatment with morin significantly upregulated catalase in pancreatic β cells, and ameliorated the STZ‑induced loss of catalase at the genetic, protein and enzymatic level. In further experiments, morin induced the phosphorylation of 5' adenosine monophosphate‑activated protein kinase (AMPK), which subsequently promoted the translocation of forkhead box O3 (FOXO3) to the nucleus. Specific small interfering RNAs (siRNAs) against AMPK and FOXO3 suppressed morin‑induced catalase expression. Furthermore, catalase‑specific siRNA abolished the protective effects of morin against STZ‑stimulated cell death. Taken together, these results indicated that morin protected RINm5F cells from STZ‑induced cell damage by triggering the phosphorylation of AMPK, thus resulting in subsequent activation of FOXO3 and induction of catalase.

  10. Gestational diabetes mellitus is associated with TCF7L2 gene polymorphisms independent of HLA-DQB1*0602 genotypes and islet cell autoantibodies

    Science.gov (United States)

    Papadopoulou, A.; Lynch, K. F.; Shaat, N.; Håkansson, R.; Ivarsson, S. A.; Berntorp, K.; Agardh, C. D.; Lernmark, Å

    2011-01-01

    Aims To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. Methods We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. Results The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P gestational diabetes in mothers born in Sweden (P = 0.010). Conclusions The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden. PMID:21672010

  11. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: role of NADH and consequences for insulin secretion.

    Science.gov (United States)

    Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J S; Gray, Joshua P

    2012-01-15

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H(2)O(2)), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H(2)O(2) inhibit insulin secretion. Menadione, which produces H(2)O(2) via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H(2)O(2) production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H(2)O(2) formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H(2)O(2) and menadione on insulin secretion. Published by Elsevier Inc.

  12. The serological and biochemical markers of adrenal cortex and endocrine pancreas dysfunction in patients with Hashimoto's thyroiditis: A hospital-based pilot study

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    Jaya Prakash Sahoo

    2017-01-01

    Full Text Available Background: The prevalence of both islet cell and adrenal autoimmunity among Asian Indian hypothyroidism patients with Hashimoto's thyroiditis (HT is lacking in literature. Objectives: The objective of this study was to assess the proportion of Addison's disease (AD and type 1 diabetes mellitus (T1DM in patients with HT. Materials and Methods: The patients with hypothyroidism due to HT were included in this study over 2 years. Primary hypothyroidism was defined as high serum thyroid-stimulating hormone (>5.5 mIU/L with or without low thyroxine level. HT was defined by the presence of high thyroid peroxidase antibody (Ab titer (>35 IU/ml. Autoimmune markers of AD and T1DM, i.e., adrenal (21-hydroxylase Ab, glutamic acid decarboxylase (GAD Ab, and insulinoma-associated antigen-2 (IA-2 Ab were measured among them. In addition, 250 μg adrenocorticotropic hormone (ACTH stimulation test was done in patients with adrenal Ab. Similarly, beta cell function was assessed in patients with GAD and/or IA-2 Ab. Results: Out of 150 patients screened, 136 patients were included in this study. Seven patients had adrenal Ab while 15 had IA-2 Ab. The GAD Ab was not present in any of the patients in the study. ACTH stimulation test was done in four of seven patients with adrenal Ab and beta cell function was assessed in 8 of 15 patients with islet cell Ab. All patients with adrenal Ab had normal adrenal function and 1 out of 15 with IA-2 Ab developed diabetes mellitus during follow-up. Conclusions: Either adrenal or islet cell Ab was found in 16% Asian Indian hypothyroidism patients with HT.

  13. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.

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    Vincent Plagnol

    2011-08-01

    Full Text Available The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC human leukocyte antigen (HLA region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP data in type 1 diabetes (T1D patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506, insulinoma-associated antigen 2 (IA-2A, n = 2,498, antibodies to the autoimmune thyroid (Graves' disease (AITD autoantigen thyroid peroxidase (TPOA, n = 8,300, and antibodies against gastric parietal cells (PCA, n = 4,328 that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10: 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A.

  14. Radiofrequency ablation of neuroendocrine liver metastases: the Middlesex experience.

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    Gillams, A; Cassoni, A; Conway, G; Lees, W

    2005-01-01

    Current treatment options for neuroendocrine liver metastases are not widely applicable or not that effective. Image-guided thermal ablation offers the possibility of a minimally invasive, albeit palliative, treatment that decreases tumor volume, preserves most of the normal liver, and can be repeated several times. We report our experience with image-guided thermal ablation in 25 patients with unresectable liver metastases. Since 1990 we have treated 189 tumors at 66 treatment sessions in 25 patients (12 female, 13 male; median age, 56 years; age range, 26--78 years). Thirty treatments were performed with a solid-state laser, and 36 treatments were performed with radiofrequency ablation. All but one treatment was performed percutaneously under image guidance. Sixteen patients had metastases from carcinoid primaries, three from gastrinoma, two from insulinoma, and four from miscellaneous causes. Fourteen of 25 had symptoms from hormone secretion. Imaging follow-up was available in 19 patients at a median of 21 months (range, 4--75 months). There was a complete response in six patients, a partial response in seven, and stable disease in one; hence, tumor load was controlled in 14 of 19 patients (74%). Relief of hormone-related symptoms was achieved in nine of 14 patients (69%). The median survival period from the diagnosis of liver metastases was 53 months. One patient with end-stage cardiac disease died after a carcinoid crisis. There were eight (12%) complications: five local and three distant, four major and four minor. As a minimally invasive, readily repeatable procedure that can be used to ablate small tumors, preferably before patients become severely symptomatic, radiofrequency ablation can provide effective control of liver tumor volume in most patients over many years.

  15. Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity

    International Nuclear Information System (INIS)

    Seo, Daniele; Faintuch, Bluma Linkowski; Aparecida de Oliveira, Erica; Faintuch, Joel

    2017-01-01

    Introduction: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. Methods: GLP-1-βAla-HYNIC and HYNIC-βAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. Results: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2 ± 8.2 mg/dl in C, 590.4 ± 23.3 mg/dl in ADC, 234.3 ± 66.7 mg/dl in DIO, and 96.6 ± 9.3 in DRO (p = 0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. 99m Tc-HYNIC-βAla-Exendin-4 demonstrated better results than GLP-1-βAla-HYNIC- 99m Tc. Conclusions: 1) Diet-induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-βAla-Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery.

  16. Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population.

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    Kubo, Atsushi; Stull, Robert; Takeuchi, Mitsuaki; Bonham, Kristina; Gouon-Evans, Valerie; Sho, Masayuki; Iwano, Masayuki; Saito, Yoshihiko; Keller, Gordon; Snodgrass, Ralph

    2011-01-01

    In order to define the molecular mechanisms regulating the specification and differentiation of pancreatic β-islet cells, we investigated the effect of upregulating Pdx1 and Ngn3 during the differentiation of the β-islet-like cells from murine embryonic stem (ES) cell-derived activin induced-endoderm. Induced overexpression of Pdx1 resulted in a significant upregulation of insulin (Ins1 and Ins2), and other pancreas-related genes. To enhance the developmental progression from the pancreatic bud to the formation of the endocrine lineages, we induced the overexpression express of Ngn3 together with Pdx1. This combination dramatically increased the level and timing of maximal Ins1 mRNA expression to approximately 100% of that found in the βTC6 insulinoma cell line. Insulin protein and C-peptide expression was confirmed by immunohistochemistry staining. These inductive effects were restricted to c-kit(+) endoderm enriched EB-derived populations suggesting that Pdx1/Ngn3 functions after the specification of pancreatic endoderm. Although insulin secretion was stimulated by various insulin secretagogues, these cells had only limited glucose response. Microarray analysis was used to evaluate the expression of a broad spectrum of pancreatic endocrine cell-related genes as well as genes associated with glucose responses. Taken together, these findings demonstrate the utility of manipulating Pdx1 and Ngn3 expression in a stage-specific manner as an important new strategy for the efficient generation of functionally immature insulin-producing β-islet cells from ES cells.

  17. Pdx1 and Ngn3 overexpression enhances pancreatic differentiation of mouse ES cell-derived endoderm population.

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    Atsushi Kubo

    Full Text Available In order to define the molecular mechanisms regulating the specification and differentiation of pancreatic β-islet cells, we investigated the effect of upregulating Pdx1 and Ngn3 during the differentiation of the β-islet-like cells from murine embryonic stem (ES cell-derived activin induced-endoderm. Induced overexpression of Pdx1 resulted in a significant upregulation of insulin (Ins1 and Ins2, and other pancreas-related genes. To enhance the developmental progression from the pancreatic bud to the formation of the endocrine lineages, we induced the overexpression express of Ngn3 together with Pdx1. This combination dramatically increased the level and timing of maximal Ins1 mRNA expression to approximately 100% of that found in the βTC6 insulinoma cell line. Insulin protein and C-peptide expression was confirmed by immunohistochemistry staining. These inductive effects were restricted to c-kit(+ endoderm enriched EB-derived populations suggesting that Pdx1/Ngn3 functions after the specification of pancreatic endoderm. Although insulin secretion was stimulated by various insulin secretagogues, these cells had only limited glucose response. Microarray analysis was used to evaluate the expression of a broad spectrum of pancreatic endocrine cell-related genes as well as genes associated with glucose responses. Taken together, these findings demonstrate the utility of manipulating Pdx1 and Ngn3 expression in a stage-specific manner as an important new strategy for the efficient generation of functionally immature insulin-producing β-islet cells from ES cells.

  18. Physiologic basics and clinical experience with somatostatin-receptor-scintigraphy

    International Nuclear Information System (INIS)

    Henze, E.; Eberhardt, J.U.; Bohuslavizki, K.H.

    1994-01-01

    The introduction of radiolabelled octreotide, an analogon to the receptor binding hormone Somatostatin, has markedly increased the ability to detect structures and tumours carrying somatostatin receptors by nuclear medicine imaging with high sensitivity and specificity. It has been shown that in vitro receptor density and in vivo scintigraphic results correlate well in particular in tumours of neuroendocrine origin of the GI tract such as insulinomas, gastrinomas, glucagonomas, carcionoids, but also in paragangliomas, small cell lung cancer and meningiomas. As receptors were also shown to be present on so called activated leucocytes granulomas, lymphomas and autoimmune disease have been imaged with octreotide successfully. The specific tracer (In-111-DTPA-D-PHE-Octreotide, Octreoscan R ) is rapidly cleared from the blood pool by the kidneys and, partially, via the liver providing a high target to background ratio. Physiologic uptake is usually observed in the pituitary and thyroid glands, in spleen and liver. Optimum tracer accumulation for tumour scintigraphy is seen on the 24-h-images with the best target to background ratios. Additional SPECT-imaging is recommended in particular in the abdominal regions. The sensitivity in imaging the above named tumours ranges from 70 up to 100%. In-111 octreotide imaging is of diagnostic impact both for the primary diagnostic evaluation as well as for detecting or excluding secondary manifestations in known tumour sites. Of specific value is the information on relative receptor density in the tumour to be treated as may be obtained by quantitative In-111 octreotide imaging for decision making whether or not to use cold octreotide (Sandostatin R ) as a receptor blocking drug for therapy as well as for treatment follow-up studies. (author)

  19. L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2.

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    Nakatsu, Daiki; Horiuchi, Yuta; Kano, Fumi; Noguchi, Yoshiyuki; Sugawara, Taichi; Takamoto, Iseki; Kubota, Naoto; Kadowaki, Takashi; Murata, Masayuki

    2015-03-10

    Increase in the concentration of plasma L-cysteine is closely associated with defective insulin secretion from pancreatic β-cells, which results in type 2 diabetes (T2D). In this study, we investigated the effects of prolonged L-cysteine treatment on glucose-stimulated insulin secretion (GSIS) from mouse insulinoma 6 (MIN6) cells and from mouse pancreatic islets, and found that the treatment reversibly inhibited glucose-induced ATP production and resulting GSIS without affecting proinsulin and insulin synthesis. Comprehensive metabolic analyses using capillary electrophoresis time-of-flight mass spectrometry showed that prolonged L-cysteine treatment decreased the levels of pyruvate and its downstream metabolites. In addition, methyl pyruvate, a membrane-permeable form of pyruvate, rescued L-cysteine-induced inhibition of GSIS. Based on these results, we found that both in vitro and in MIN6 cells, L-cysteine specifically inhibited the activity of pyruvate kinase muscle isoform 2 (PKM2), an isoform of pyruvate kinases that catalyze the conversion of phosphoenolpyruvate to pyruvate. L-cysteine also induced PKM2 subunit dissociation (tetramers to dimers/monomers) in cells, which resulted in impaired glucose-induced ATP production for GSIS. DASA-10 (NCGC00181061, a substituted N,N'-diarylsulfonamide), a specific activator for PKM2, restored the tetramer formation and the activity of PKM2, glucose-induced ATP production, and biphasic insulin secretion in L-cysteine-treated cells. Collectively, our results demonstrate that impaired insulin secretion due to exposure to L-cysteine resulted from its direct binding and inactivation of PKM2 and suggest that PKM2 is a potential therapeutic target for T2D.

  20. nas

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    Modesto Varas

    Full Text Available Introduction and objective: pancreatic endocrine tumors (PET are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. Patients and methods: the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010. A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. Results: a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y (14 males, 5 females, and tumor size was 5 to 80 mm (X: 20 mm. Metastatic disease was present in 37% (7/19. Most underwent the following imaging techniques: ultrasounds, computed tomography (CT and magnetic resonance imaging (MRI. Fine needle aspiration punction (FNA was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%, insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN], Zollinger-Ellison syndrome (ZES from gastrinoma: 5 (3 with MEN-1, glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%. Four (4/14: 28% has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4, somatostatin (3 and interferon (2 before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19. Conclusions: age was similar to that described in the literature. Males were predominant. Most cases were non-functioning (37%. Most patients underwent surgery (73% with little morbidity (28% and an actuarial survival of 73.6% at the time of the study.

  1. Nutrient regulation by continuous feeding removes limitations on cell yield in the large-scale expansion of Mammalian cell spheroids.

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    Bradley P Weegman

    Full Text Available Cellular therapies are emerging as a standard approach for the treatment of several diseases. However, realizing the promise of cellular therapies across the full range of treatable disorders will require large-scale, controlled, reproducible culture methods. Bioreactor systems offer the scale-up and monitoring needed, but standard stirred bioreactor cultures do not allow for the real-time regulation of key nutrients in the medium. In this study, β-TC6 insulinoma cells were aggregated and cultured for 3 weeks as a model of manufacturing a mammalian cell product. Cell expansion rates and medium nutrient levels were compared in static, stirred suspension bioreactors (SSB, and continuously fed (CF SSB. While SSB cultures facilitated increased culture volumes, no increase in cell yields were observed, partly due to limitations in key nutrients, which were consumed by the cultures between feedings, such as glucose. Even when glucose levels were increased to prevent depletion between feedings, dramatic fluctuations in glucose levels were observed. Continuous feeding eliminated fluctuations and improved cell expansion when compared with both static and SSB culture methods. Further improvements in growth rates were observed after adjusting the feed rate based on calculated nutrient depletion, which maintained physiological glucose levels for the duration of the expansion. Adjusting the feed rate in a continuous medium replacement system can maintain the consistent nutrient levels required for the large-scale application of many cell products. Continuously fed bioreactor systems combined with nutrient regulation can be used to improve the yield and reproducibility of mammalian cells for biological products and cellular therapies and will facilitate the translation of cell culture from the research lab to clinical applications.

  2. The EARP Complex and Its Interactor EIPR-1 Are Required for Cargo Sorting to Dense-Core Vesicles.

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    Irini Topalidou

    2016-05-01

    Full Text Available The dense-core vesicle is a secretory organelle that mediates the regulated release of peptide hormones, growth factors, and biogenic amines. Dense-core vesicles originate from the trans-Golgi of neurons and neuroendocrine cells, but it is unclear how this specialized organelle is formed and acquires its specific cargos. To identify proteins that act in dense-core vesicle biogenesis, we performed a forward genetic screen in Caenorhabditis elegans for mutants defective in dense-core vesicle function. We previously reported the identification of two conserved proteins that interact with the small GTPase RAB-2 to control normal dense-core vesicle cargo-sorting. Here we identify several additional conserved factors important for dense-core vesicle cargo sorting: the WD40 domain protein EIPR-1 and the endosome-associated recycling protein (EARP complex. By assaying behavior and the trafficking of dense-core vesicle cargos, we show that mutants that lack EIPR-1 or EARP have defects in dense-core vesicle cargo-sorting similar to those of mutants in the RAB-2 pathway. Genetic epistasis data indicate that RAB-2, EIPR-1 and EARP function in a common pathway. In addition, using a proteomic approach in rat insulinoma cells, we show that EIPR-1 physically interacts with the EARP complex. Our data suggest that EIPR-1 is a new interactor of the EARP complex and that dense-core vesicle cargo sorting depends on the EARP-dependent trafficking of cargo through an endosomal sorting compartment.

  3. Decreased 11β-Hydroxysteroid Dehydrogenase 1 Level and Activity in Murine Pancreatic Islets Caused by Insulin-Like Growth Factor I Overexpression.

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    Subrata Chowdhury

    Full Text Available We have reported a high expression of IGF-I in pancreatic islet β-cells of transgenic mice under the metallothionein promoter. cDNA microarray analysis of the islets revealed that the expression of 82 genes was significantly altered compared to wild-type mice. Of these, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1, which is responsible for the conversion of inert cortisone (11-dehydrocorticosterone, DHC in rodents to active cortisol (corticosterone in the liver and adipose tissues, has not been identified previously as an IGF-I target in pancreatic islets. We characterized the changes in its protein level, enzyme activity and glucose-stimulated insulin secretion. In freshly isolated islets, the level of 11β-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11β-HSD1 was observed exclusively in glucagon-producing, islet α-cells but at a lower level in transgenic vs. wild-type animals. MT-IGF islets also exhibited reduced enzymatic activities. Dexamethasone (DEX and DHC inhibited glucose-stimulated insulin secretion from freshly isolated islets of wild-type mice. In the islets of MT-IGF mice, 48-h pre-incubation of DEX caused a significant decrease in insulin release, while the effect of DHC was largely blunted consistent with diminished 11β-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11β-HSD1 cDNA in MIN6 insulinoma cells, which together with DHC caused apoptosis and a significant decrease in proliferation. Both effects were abolished with the treatment of an 11β-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11β-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion.

  4. Scoparia dulcis, a traditional antidiabetic plant, protects against streptozotocin induced oxidative stress and apoptosis in vitro and in vivo.

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    Latha, Muniappan; Pari, Leelavinothan; Sitasawad, Sandhya; Bhonde, Ramesh

    2004-01-01

    Oxidative stress is implicated in the pathogenesis of diabetic complications. The experiments were performed on normal and experimental male Wistar rats treated with Scoparia dulcis plant extract (SPEt). The effect of SPEt was tested on streptozotocin (STZ) treated Rat insulinoma cell lines (RINm5F cells) and isolated islets in vitro. Administration of an aqueous extract of Scoparia dulcis by intragastric intubation (po) at a dose of 200 mg/kg body weight significantly decreased the blood glucose and lipid peroxidative marker thiobarbituric acid reactive substances (TBARS) with significant increase in the activities of plasma insulin, pancreatic superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in streptozotocin diabetic rats at the end of 15 days treatment. Streptozotocin at a dose of 10 mug/mL evoked 6-fold stimulation of insulin secretion from isolated islets indicating its insulin secretagogue activity. The extract markedly reduced the STZ-induced lipidperoxidation in RINm5F cells. Further, SPEt protected STZ-mediated cytotoxicity and nitric oxide (NO) production in RINm5F cells. Treatment of RINm5F cells with 5 mM STZ and 10 mug of SPEt completely abrogated apoptosis induced by STZ, suggesting the involvement of oxidative stress. Flow cytometric assessment on the level of intracellular peroxides using fluorescent probe 2'7'-dichlorofluorescein diacetate (DCF-DA) confirmed that STZ (46%) induced an intracellular oxidative stress in RINm5F cells, which was suppressed by SPEt (21%). In addition, SPEt also reduced (33%) the STZ-induced apoptosis (72%) in RINm5F cells indicating the mode of protection of SPEt on RIN m5Fcells, islets, and pancreatic beta-cell mass (histopathological observations). Present study thus confirms antihyperglycemic effect of SPEt and also demonstrated the consistently strong antioxidant properties of Scoparia dulcis used in the traditional medicine. (c) 2004 Wiley Periodicals, Inc.

  5. Long-term survival of transplanted allogeneic cells engineered to express a T cell chemorepellent.

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    Papeta, Natalia; Chen, Tao; Vianello, Fabrizio; Gererty, Lyle; Malik, Ashish; Mok, Ying-Ting; Tharp, William G; Bagley, Jessamyn; Zhao, Guiling; Stevceva, Liljana; Yoon, Victor; Sykes, Megan; Sachs, David; Iacomini, John; Poznansky, Mark C

    2007-01-27

    Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected. Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy. Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue. This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.

  6. Central pancreatectomy for benign pancreatic pathology/trauma: is it a reasonable pancreas-preserving conservative surgical strategy alternative to standard major pancreatic resection?

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    Johnson, Maria A; Rajendran, Shanmugasundaram; Balachandar, Tirupporur G; Kannan, Devy G; Jeswanth, Satyanesan; Ravichandran, Palaniappan; Surendran, Rajagopal

    2006-11-01

    The aim of this study was to assess the technical feasibility, safety and outcome of central pancreatectomy (CP) with pancreaticogastrostomy or pancreaticojejunostomy in appropriately selected patients with benign central pancreatic pathology/trauma. Benign lesions/trauma of the pancreatic neck and proximal body pose an interesting surgical challenge. CP is an operation that allows resection of benign tumours located in the pancreatic isthmus that are not suitable for enucleation. Between January 2000 and December 2005, eight central pancreatectomies were carried out. There were six women and two men with a mean age of 35.7 years. The cephalic pancreatic stump is oversewn and the distal stump is anastomosed end-to-end with a Roux-en-Y jejunal loop in two and with the stomach in six patients. The indications for CP were: non-functional islet cell tumours in two patients, traumatic pancreatic neck transection in two and one each for insulinoma, solid pseudopapillary tumour, splenic artery pseudoaneurysm and pseudocyst. Pancreatic exocrine function was evaluated by a questionnaire method. Endocrine function was evaluated by blood glucose level. Morbidity rate was 37.5% with no operative mortality. Mean postoperative hospital stay was 10.5 days. Neither of the patients developed pancreatic fistula nor required reoperations or interventional radiological procedures. At a mean follow up of 26.4 months, no patient had evidence of endocrine or exocrine pancreatic insufficiency, all the patients were alive and well without clinical and imaging evidence of disease recurrence. When technically feasible, CP is a safe, pancreas-preserving pancreatectomy for non-enucleable benign pancreatic pathology/trauma confined to pancreatic isthmus that allows for cure of the disease without loss of substantial amount of normal pancreatic parenchyma with preservation of exocrine/endocrine function and without interruption of enteric continuity.

  7. 64,000-Mr autoantigen in type I diabetes. Evidence against its surface location on human islets

    International Nuclear Information System (INIS)

    Colman, P.G.; Campbell, I.L.; Kay, T.W.; Harrison, L.C.

    1987-01-01

    The sera of type I (insulin-dependent) diabetic subjects are reported to contain autoantibodies against a 64,000-Mr protein identified in [ 35 S]methionine biosynthetically labeled pancreatic islet cells. We have attempted to localize this autoantigen to the surface of the beta-cell and to define its properties. Sera from 10 newly diagnosed type I diabetic subjects, including five of the index sera originally used to identify the autoantigen, were shown to specifically precipitate a reduced protein of 67,000 Mr from Triton-solubilized, surface 125 I-labeled cultured adult human islet and rat insulinoma (RINm5F) cells but not from fresh rat spleen cells. Further characterization revealed that this protein was bovine serum albumin (BSA) adsorbed to cells from fetal calf serum (FCS)-supplemented culture medium and precipitated by BSA antibodies present in many diabetic sera. No labeled proteins were specifically precipitated when surface 125 I-labeled and solubilized human islet or RINm5F cells were precleared with anti-BSA immunoglobulins or when cells were first cultured in human serum. In contrast, a 64,000-Mr protein, clearly not BSA, was precipitated by diabetic globulins from human islets but not from RINm5F cells labeled with [ 35 S]methionine. In addition, a protein of the same size as well as proteins of approximately 35,000, 43,000, 140,000, and 200,000 Mr were specifically precipitated by diabetic globulins from freshly isolated human islets solubilized in Triton X-100 and then labeled with 125 I. These findings suggest that the 64,000-Mr antigen is not expressed on the surface of human islet cells, at least in culture, and therefore question its relevance as a target for islet cell surface antibodies in initiating beta-cell damage

  8. The comprehensive electrophysiological study of curcuminoids on delayed-rectifier K+ currents in insulin-secreting cells.

    Science.gov (United States)

    Kuo, Ping-Chung; Yang, Chia-Jung; Lee, Yu-Chi; Chen, Pei-Chun; Liu, Yen-Chin; Wu, Sheng-Nan

    2018-01-15

    Curcumin (CUR) has been demonstrated to induce insulin release from pancreatic β-cells; however, how curcuminoids (including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)) exert any possible effects on membrane ion currents inherently in insulin-secreting cells remains largely unclear. The effects of CUR and other structurally similar curcuminoids on ion currents in rat insulin-secreting (INS-1) insulinoma cells were therefore investigated in this study. The effects of these compounds on ionic currents and membrane potential were studied by patch-clamp technique. CUR suppressed the amplitude of delayed-rectifier K + current (I K(DR) ) in a time-, state- and concentration-dependent manner in these cells and the inhibition was not reversed by diazoxide, nicorandil or chlorotoxin. The value of dissociation constant for CUR-induced suppression of I K(DR) in INS-1 cells was 1.26μM. Despite the inability of CUR to alter the activation rate of I K(DR) , it accelerated current inactivation elicited by membrane depolarization. Increasing CUR concentrations shifted the inactivation curve of I K(DR) to hyperpolarized potential and slowed the recovery of I K(DR) inactivation. CUR, DMC, and BDMC all exerted depressant actions on I K(DR) amplitude to a similar magnitude, although DMC and BDMC did not increase current inactivation clearly. CUR slightly suppressed the peak amplitude of voltage-gated Na + current. CUR, DMC and BDMC depolarized the resting potential and increased firing frequency of action potentials. The CUR-mediated decrease of I K(DR) and the increase of current inactivation also occurred in βTC-6 INS-1 cells. Taken these results together, these effects may be one of the possible mechanisms contributing their insulin-releasing effect. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. iNOS+ macrophages: potential alternate and tool for effective tumor therapy

    International Nuclear Information System (INIS)

    Prakash, Hridayesh; KIug, Felix; Jäger, Dirk; Hammerling, Gunter; Beckhove, Philipp

    2014-01-01

    Inefficient migration of immune effector cells in the tumor is a major limitation of effective therapy against solid tumors. This is due to immunosuppressive micro environment and impermissive endothelium which protects tumors from immune attack which is attributed to massive infiltration of tumors by macrophages which are known as tumor associated macrophages which are INOS low , Arginase- 1+ , Ym- 1+ , CD206 + (known as M2 or alternatively activated or tumor associated macrophages). Accumulation of M2 has been associated with the poor prognosis in the majority of cancer patients. Radiotherapy has recently been introduced as a potential strategy to improve cancer immunotherapy and tumor immune rejection. This is the only clinically advanced approach for noninvasive, site-specific intervention in cancer patients. Majority of cancer patients are routinely irradiated with therapeutic and high doses of γ-radiations which frequently manifest severe local/systemic acute. Low dose radiation (LDR) on the other hand may provide good alternatives of HDR for avoiding such toxicities. In this line, our pioneer study demonstrated that local/systemic low dose irradiation of tumors (2 Gy) effectively modified tumor micro environment and facilitated infiltration of peripheral immune effectors cells (T-cells) in neuroendocrine tumor of pancreas called insulinoma in RIP1-Tag5 (RT5) mice and primary human pancreatic carcinoma. Such tumor infiltration of T cells remained strictly dependent on iNOS + peritumoral macrophages. Our study also explicitly revealed that adoptive transfer of iNOS expressing macrophages in unirradiated RIP1-Tag5 (RT5) also offer a promising intervention to establish those populations of macrophages in the tumor tissue that enable therapeutic efficacy of cancer immunotherapy. We here demonstrate the critical role of iNOS + macrophages in joint regulation of tumor micro environment (angiogenesis) as well as effector T cell recruitment into tumor tissue and

  10. Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification.

    Science.gov (United States)

    Gherardi, Samuele; Ripoche, Doriane; Mikaelian, Ivan; Chanal, Marie; Teinturier, Romain; Goehrig, Delphine; Cordier-Bussat, Martine; Zhang, Chang X; Hennino, Ana; Bertolino, Philippe

    2017-04-01

    Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters. However, lack of binding between Menin and Ezh2 suggests that another member of the PRC complex is mediating this indirect interaction. Having found that ActivinB - a TGFβ superfamily member encoded by the Inhbb gene - is upregulated in insulinoma tumours caused by Men1 invalidation, we hypothesize that Menin could directly participate in the epigenetic-repression of Inhbb gene expression. Using Animal model and cell lines, we report that loss of Menin is directly associated with ActivinB-induced expression both in vivo and in vitro. Our work further reveals that ActivinB expression is mediated through a direct modulation of H3K27me3 marks on the Inhbb locus in Menin-KO cell lines. More importantly, we show that Menin binds on the promoter of Inhbb gene where it favours the recruitment of Ezh2 via an indirect mechanism involving Akt-phosphorylation. Our data suggests therefore that Menin could take an important part to the Ezh2-epigenetic repressive landscape in many cells and tissues through its capacity to modulate Akt phosphorylation. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

    Science.gov (United States)

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

    2015-10-01

    The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  12. Detection of transketolase in bone marrow-derived insulin-producing cells: benfotiamine enhances insulin synthesis and glucose metabolism.

    Science.gov (United States)

    Oh, Seh-Hoon; Witek, Rafal P; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E

    2009-01-01

    Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus.

  13. Detection of Transketolase in Bone Marrow—Derived Insulin-Producing Cells: Benfotiamine Enhances Insulin Synthesis and Glucose Metabolism

    Science.gov (United States)

    Witek, Rafal P.; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E.

    2009-01-01

    Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus. PMID:18393672

  14. Synthesis and in vitro cytotoxicity of mPEG-SH modified gold nanorods

    Science.gov (United States)

    Didychuk, Candice L.; Ephrat, Pinhas; Belton, Michelle; Carson, Jeffrey J. L.

    2008-02-01

    Plasmon-resonant gold nanorods show great potential as an agent for contrast-enhanced biomedical imaging or for phototherapeutics. This is primarily due to the high molar extinction coefficient at the absorption maximum and the dependence of the wavelength of the absorption maximum on the aspect ratio, which is tunable in the near-infrared (NIR) during synthesis. Although gold nanorods can be produced in high-yield through the seed-mediated growth technique, the presence of residual cetyltrimethylammonium bromide (CTAB), a stabilizing surfactant required for nanorod growth, interferes with cell function and causes cytotoxicity. To overcome this potential obstacle to in vivo use, we synthesized gold nanorods and conjugated them to a methoxy (polyethylene glycol)-thiol (mPEG (5000)-SH). This approach yielded mPEG-SH modified gold nanorods with optical and morphometric properties that were similar to raw (CTAB) nanorods. Both the CTAB and mPEG-SH nanorods were tested for cytotoxicity against the HL-60 human leukemia cell line by trypan blue exclusion, and the mPEG-SH modified gold nanorods were also tested against a rat insulinoma (RIN-38) and squamous cell carcinoma (SCCVII) cell line. Cells incubated for 24 h with the mPEG-SH modified nanorods had little change in cell viability compared to cells incubated with vehicle alone. This was in contrast to cytotoxicity of CTAB nanorods on HL-60 cells. These results suggest that mPEG-SH modified gold nanorods are better suited for cell loading protocols and injection into animals and facilitate their use for imaging and phototherapeutic purposes.

  15. Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

    Science.gov (United States)

    Trikha, Saurabh; Jeremic, Aleksandar M.

    2013-01-01

    Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells. PMID:24019897

  16. PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.

    Directory of Open Access Journals (Sweden)

    Hyo-Sup Kim

    Full Text Available BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.

  17. Implications of the use of the labelled benzyl guanidine derivatives in nuclear medicine

    International Nuclear Information System (INIS)

    Zhagar, I.

    1994-01-01

    The development and synthesis of various labelled benzyl guanidine derivatives is described. After a brief outline of the tracer characteristics and the whole body imaging with 131- I -MIBG, 'pitfalls' of the visualization of sympathochromafine tissues and the possibilities of various pharmacological impacts on scintigraphy are discussed. Special emphasis is given to dosimetric and methodological aspects of MIBG scintigraphy in children, as well as to some new diagnostic applications of labelled benzyl guanidine in cardiology and pulmology. Whole body scintigraphy with 131-I-MIBG performed in groups of patients with pheochromocytoma, paraganglioma, neuroblastoma, medullary thyroid carcinoma, carcinoid and malignant insulinoma. Tumor, myocardial and salivary gland uptake of MIBG were estimated semi quantitatively, according to the method of Nakajo. The uptake of 131-I-MIBG was calculated from the activity measured prior and after the application and images acquired and was expressed as percent of dose administered.The results obtained confirm the high sensitivity and specificity of 131- I - MIBG in the scintigraphic evaluation of pheochromocytoma and euroblastoma. In medullary thyroid carcinoma it was found less sensitive than 99m Tc(V) -DMS A scan. The clinical evolution and uptake values were very well correlated. In patients developing bone marrow infiltration, uptake in primary tumor diminished. Good response to operative therapy in pheochromocytoma patients as well as to chemotherapy with neuroblastoma, was associated with an increase of myocardial MIBG uptake. There was highly significant negative correlation between myocardial uptake of MIBG and urinary catecholamine concentrations. Results obtained in determination 131- I -MIBG uptake in some neural crest tumors lead to the conclusion that the choice of background regions of interest can significantly influence the final results of quantification. (author)

  18. Development of biomarker specific of pancreatic beta cells (incretin radiolabelled) for image of beta functional mass in diabetic and obese: study in animal model; Desenvolvimento de biomarcador específico de células beta pancreáticas (incretina radiomarcada) para imagem da massa beta funcional em diabéticos e obesos: estudo em modelo animal

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Daniele

    2017-07-01

    Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with {sup 99m} Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was {sup 99m}Tc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations. (author)

  19. Characterization of the distal promoter of the human pyruvate carboxylase gene in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Ansaya Thonpho

    Full Text Available Pyruvate carboxylase (PC is an enzyme that plays a crucial role in many biosynthetic pathways in various tissues including glucose-stimulated insulin secretion. In the present study, we identify promoter usage of the human PC gene in pancreatic beta cells. The data show that in the human, two alternative promoters, proximal and distal, are responsible for the production of multiple mRNA isoforms as in the rat and mouse. RT-PCR analysis performed with cDNA prepared from human liver and islets showed that the distal promoter, but not the proximal promoter, of the human PC gene is active in pancreatic beta cells. A 1108 bp fragment of the human PC distal promoter was cloned and analyzed. It contains no TATA box but possesses two CCAAT boxes, and other putative transcription factor binding sites, similar to those of the distal promoter of rat PC gene. To localize the positive regulatory region in the human PC distal promoter, 5'-truncated and the 25-bp and 15-bp internal deletion mutants of the human PC distal promoter were generated and used in transient transfections in INS-1 832/13 insulinoma and HEK293T (kidney cell lines. The results indicated that positions -340 to -315 of the human PC distal promoter serve as (an activator element(s for cell-specific transcription factor, while the CCAAT box at -71/-67, a binding site for nuclear factor Y (NF-Y, as well as a GC box at -54/-39 of the human PC distal promoter act as activator sequences for basal transcription.

  20. Disorders of the pediatric pancreas: imaging features

    International Nuclear Information System (INIS)

    Nijs, Els; Callahan, Michael J.; Taylor, George A.

    2005-01-01

    The purpose of this manuscript is to provide an overview of the normal development of the pancreas as well as pancreatic pathology in children. Diagnostic imaging plays a major role in the evaluation of the pancreas in infants and children. Familiarity with the range of normal appearance and the diseases that commonly affect this gland is important for the accurate and timely diagnosis of pancreatic disorders in the pediatric population. Normal embryology is discussed, as are the most common congenital anomalies that occur as a result of aberrant development during embryology. These include pancreas divisum, annular pancreas, agenesis of the dorsal pancreatic anlagen and ectopic pancreatic tissue. Syndromes that can manifest pancreatic pathology include: Beckwith Wiedemann syndrome, von Hippel-Lindau disease and autosomal dominant polycystic kidney disease. Children and adults with cystic fibrosis and Shwachman-Diamond syndrome frequently present with pancreatic insufficiency. Trauma is the most common cause of pancreatitis in children. In younger children, unexplained pancreatic injury must always alert the radiologist to potential child abuse. Pancreatic pseudocysts are a complication of trauma, but can also be seen in the setting of acute or chronic pancreatitis from other causes. Primary pancreatic neoplasms are rare in children and are divided into exocrine tumors such as pancreatoblastoma and adenocarcinoma and into endocrine or islet cell tumors. Islet cell tumors are classified as functioning (insulinoma, gastrinoma, VIPoma and glucagonoma) and nonfunctioning tumors. Solid-cystic papillary tumor is probably the most common pancreatic tumor in Asian children. Although quite rare, secondary tumors of the pancreas can be associated with certain primary malignancies. (orig.)

  1. Pseudoislets as primary islet replacements for research: report on a symposium at King's College London, London UK.

    Science.gov (United States)

    Persaud, Shanta J; Arden, Catherine; Bergsten, Peter; Bone, Adrian J; Brown, James; Dunmore, Simon; Harrison, Moira; Hauge-Evans, Astrid; Kelly, Catriona; King, Aileen; Maffucci, Tania; Marriott, Claire E; McClenaghan, Neville; Morgan, Noel G; Reers, Christina; Russell, Mark A; Turner, Mark D; Willoughby, Emma; Younis, Mustafa Y G; Zhi, Z L; Jones, Peter M

    2010-01-01

    Laboratory-based research aimed at understanding processes regulating insulin secretion and mechanisms underlying β-cell dysfunction and loss in diabetes often makes use of rodents, as these processes are in many respects similar between rats/mice and humans. Indeed, a rough calculation suggests that islets have been isolated from as many as 150,000 rodents to generate the data contained within papers published in 2009 and the first four months of 2010. Rodent use for islet isolation has been mitigated, to a certain extent, by the availability of a variety of insulin-secreting cell lines that are used by researchers world-wide. However, when maintained as monolayers the cell lines do not replicate the robust, sustained secretory responses of primary islets which limits their usefulness as islet surrogates. On the other hand, there have been several reports that configuration of MIN6 β-cells, derived from a mouse insulinoma, as three-dimensional cell clusters termed ‘pseudoislets’ largely recapitulates the function of primary islet β-cells. The Diabetes Research Group at King’s College London has been using the MIN6 pseudoislet model for over a decade and they hosted a symposium on “Pseudoislets as primary islet replacements for research”, which was funded by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), in London on 15th and 16th April 2010. This small, focused meeting was conceived as an opportunity to consolidate information on experiences of working with pseudoislets between different UK labs, and to introduce the theory and practice of pseudoislet culture to laboratories working with islets and/or β-cell lines but who do not currently use pseudoislets. This short review summarizes the background to the development of the cell line-derived pseudoislet model, the key messages arising from the symposium and emerging themes for future pseudoislet research.

  2. Nutrient Regulation by Continuous Feeding Removes Limitations on Cell Yield in the Large-Scale Expansion of Mammalian Cell Spheroids

    Science.gov (United States)

    Weegman, Bradley P.; Nash, Peter; Carlson, Alexandra L.; Voltzke, Kristin J.; Geng, Zhaohui; Jahani, Marjan; Becker, Benjamin B.; Papas, Klearchos K.; Firpo, Meri T.

    2013-01-01

    Cellular therapies are emerging as a standard approach for the treatment of several diseases. However, realizing the promise of cellular therapies across the full range of treatable disorders will require large-scale, controlled, reproducible culture methods. Bioreactor systems offer the scale-up and monitoring needed, but standard stirred bioreactor cultures do not allow for the real-time regulation of key nutrients in the medium. In this study, β-TC6 insulinoma cells were aggregated and cultured for 3 weeks as a model of manufacturing a mammalian cell product. Cell expansion rates and medium nutrient levels were compared in static, stirred suspension bioreactors (SSB), and continuously fed (CF) SSB. While SSB cultures facilitated increased culture volumes, no increase in cell yields were observed, partly due to limitations in key nutrients, which were consumed by the cultures between feedings, such as glucose. Even when glucose levels were increased to prevent depletion between feedings, dramatic fluctuations in glucose levels were observed. Continuous feeding eliminated fluctuations and improved cell expansion when compared with both static and SSB culture methods. Further improvements in growth rates were observed after adjusting the feed rate based on calculated nutrient depletion, which maintained physiological glucose levels for the duration of the expansion. Adjusting the feed rate in a continuous medium replacement system can maintain the consistent nutrient levels required for the large-scale application of many cell products. Continuously fed bioreactor systems combined with nutrient regulation can be used to improve the yield and reproducibility of mammalian cells for biological products and cellular therapies and will facilitate the translation of cell culture from the research lab to clinical applications. PMID:24204645

  3. GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.

    Science.gov (United States)

    Danielpur, Liron; Sohn, Yang-Sung; Karmi, Ola; Fogel, Chen; Zinger, Adar; Abu-Libdeh, Abdulsalam; Israeli, Tal; Riahi, Yael; Pappo, Orit; Birk, Ruth; Zangen, David H; Mittler, Ron; Cabantchik, Zvi-Ioav; Cerasi, Erol; Nechushtai, Rachel; Leibowitz, Gil

    2016-10-01

    Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). A case report and in vitro mechanistic studies. We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of β-cell dysfunction and the effects of GLP-1-RA. Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

  4. An exploration of Glb1 Homologue AntibodyLevels in Children at Increased Risk for Type 1 Diabetes mellitus

    Science.gov (United States)

    Simpson, M.; Mojibian, M.; Barriga, K.; Scott, F.W.; Fasano, A.; Rewers, M.; Norris, J.M.

    2010-01-01

    Aims To determine whether Glb1 homologue antibodies are associated with islet autoimmunity (IA) in children at increased risk for type 1 diabetes (T1D), and to investigate their relation with putative environmental correlates of T1D. Methods We selected a sample from the Diabetes Autoimmunity Study in the Young (DAISY), a prospective study of children at increased risk for T1D. Cases were those who were positive for insulin, glutamic acid decarboxylase (GAD), or insulinoma-associated antigen-2 (IA-2) autoantibodies on two consecutive visits and either diagnosed with diabetes mellitus or still autoantibody positive when selected. Controls were from the same increased risk group, of similar age as the cases but negative for autoantibodies. Sera from 91 IA cases and 82 controls were analyzed in a blinded manner for immunoglobulin G (IgG) antibodies to Glb1 homologue by ELISA. Results Adjusting for family history of T1D and HLA-DR4 positivity, Glb1 homologue antibodies were not associated with IA case status (OR: 1.01, 95% CI: 0.99 – 1.03). Adjusting for age, family history of T1D, and HLA-DR4 positivity, Glb1 homologue antibody levels were inversely associated with breast-feeding duration (beta = −0.08, p = 0.001) and directly associated with current intake of foods containing gluten (beta = 0.24, p = 0.007) in IA cases but not in controls. Zonulin, a biomarker of gut permeability, was directly associated with Glb1 homologue antibody levels in cases (beta = 0.73, p = 0.003) but not in controls. Conclusion Differences in correlates of Glb1 antibodies in IA cases and controls suggest an underlying difference in mucosal immune response. PMID:19622083

  5. Disorders of the pediatric pancreas: imaging features

    Energy Technology Data Exchange (ETDEWEB)

    Nijs, Els [University Hospital Gasthuisberg, Department of Radiology, Leuven (Belgium); Callahan, Michael J.; Taylor, George A. [Boston Children' s Hospital, Department of Radiology, Boston, MA (United States)

    2005-04-01

    The purpose of this manuscript is to provide an overview of the normal development of the pancreas as well as pancreatic pathology in children. Diagnostic imaging plays a major role in the evaluation of the pancreas in infants and children. Familiarity with the range of normal appearance and the diseases that commonly affect this gland is important for the accurate and timely diagnosis of pancreatic disorders in the pediatric population. Normal embryology is discussed, as are the most common congenital anomalies that occur as a result of aberrant development during embryology. These include pancreas divisum, annular pancreas, agenesis of the dorsal pancreatic anlagen and ectopic pancreatic tissue. Syndromes that can manifest pancreatic pathology include: Beckwith Wiedemann syndrome, von Hippel-Lindau disease and autosomal dominant polycystic kidney disease. Children and adults with cystic fibrosis and Shwachman-Diamond syndrome frequently present with pancreatic insufficiency. Trauma is the most common cause of pancreatitis in children. In younger children, unexplained pancreatic injury must always alert the radiologist to potential child abuse. Pancreatic pseudocysts are a complication of trauma, but can also be seen in the setting of acute or chronic pancreatitis from other causes. Primary pancreatic neoplasms are rare in children and are divided into exocrine tumors such as pancreatoblastoma and adenocarcinoma and into endocrine or islet cell tumors. Islet cell tumors are classified as functioning (insulinoma, gastrinoma, VIPoma and glucagonoma) and nonfunctioning tumors. Solid-cystic papillary tumor is probably the most common pancreatic tumor in Asian children. Although quite rare, secondary tumors of the pancreas can be associated with certain primary malignancies. (orig.)

  6. Development of biomarker specific of pancreatic beta cells (incretin radiolabelled) for image of beta functional mass in diabetic and obese: study in animal model

    International Nuclear Information System (INIS)

    Seo, Daniele

    2017-01-01

    Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with 99m Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was 99m Tc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations. (author)

  7. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  8. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2014-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  9. Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic β-cells

    International Nuclear Information System (INIS)

    Chen, Shan-Shan; Jiang, Teng; Wang, Yi; Gu, Li-Ze; Wu, Hui-Wen; Tan, Lan; Guo, Jun

    2014-01-01

    Highlights: •PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in β-cells. •Activated PKR inhibited β-cell proliferation by arresting cell cycle at G1 phase. •Activated PKR fully abrogated the pro-proliferative effects of IGF-I on β-cells. -- Abstract: Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic β-cells. Here, we adopted insulinoma cell lines and mice islet β-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic β-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic β-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic β-cells may contribute to the pathogenesis of T2DM

  10. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

    Energy Technology Data Exchange (ETDEWEB)

    Cline, Gary W., E-mail: gary.cline@yale.edu [Yale University School of Medicine (United States); Zhao, Xiaojian [Yale University School of Medicine (United States); Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L. [Pfizer Global Research and Development, Pfizer Inc., Groton CT (United States)

    2011-09-02

    Highlights: {yields} We screened G-protein coupled receptors for imaging pancreatic. {yields} Database mining and immunohistochemistry identified GPCRs enriched in {beta}-cells. {yields} In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. {yields} GPCR candidates for imaging of {beta}-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic {beta}-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet {beta}-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 {approx} GLP-1R > mGluR5. Favorable islet selectivity and biodistribution

  11. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic β-cell mass

    International Nuclear Information System (INIS)

    Cline, Gary W.; Zhao, Xiaojian; Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L.

    2011-01-01

    Highlights: → We screened G-protein coupled receptors for imaging pancreatic. → Database mining and immunohistochemistry identified GPCRs enriched in β-cells. → In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. → GPCR candidates for imaging of β-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic β-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet β-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 ∼ GLP-1R > mGluR5. Favorable islet selectivity and biodistribution characteristics suggest several GPCRs as potential

  12. Mapping Mammalian Cell-type-specific Transcriptional Regulatory Networks Using KD-CAGE and ChIP-seq Data in the TC-YIK Cell Line

    Science.gov (United States)

    Lizio, Marina; Ishizu, Yuri; Itoh, Masayoshi; Lassmann, Timo; Hasegawa, Akira; Kubosaki, Atsutaka; Severin, Jessica; Kawaji, Hideya; Nakamura, Yukio; Suzuki, Harukazu; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R. R.

    2015-01-01

    Mammals are composed of hundreds of different cell types with specialized functions. Each of these cellular phenotypes are controlled by different combinations of transcription factors. Using a human non islet cell insulinoma cell line (TC-YIK) which expresses insulin and the majority of known pancreatic beta cell specific genes as an example, we describe a general approach to identify key cell-type-specific transcription factors (TFs) and their direct and indirect targets. By ranking all human TFs by their level of enriched expression in TC-YIK relative to a broad collection of samples (FANTOM5), we confirmed known key regulators of pancreatic function and development. Systematic siRNA mediated perturbation of these TFs followed by qRT-PCR revealed their interconnections with NEUROD1 at the top of the regulation hierarchy and its depletion drastically reducing insulin levels. For 15 of the TF knock-downs (KD), we then used Cap Analysis of Gene Expression (CAGE) to identify thousands of their targets genome-wide (KD-CAGE). The data confirm NEUROD1 as a key positive regulator in the transcriptional regulatory network (TRN), and ISL1, and PROX1 as antagonists. As a complimentary approach we used ChIP-seq on four of these factors to identify NEUROD1, LMX1A, PAX6, and RFX6 binding sites in the human genome. Examining the overlap between genes perturbed in the KD-CAGE experiments and genes with a ChIP-seq peak within 50 kb of their promoter, we identified direct transcriptional targets of these TFs. Integration of KD-CAGE and ChIP-seq data shows that both NEUROD1 and LMX1A work as the main transcriptional activators. In the core TRN (i.e., TF-TF only), NEUROD1 directly transcriptionally activates the pancreatic TFs HSF4, INSM1, MLXIPL, MYT1, NKX6-3, ONECUT2, PAX4, PROX1, RFX6, ST18, DACH1, and SHOX2, while LMX1A directly transcriptionally activates DACH1, SHOX2, PAX6, and PDX1. Analysis of these complementary datasets suggests the need for caution in interpreting Ch

  13. Complete Biological Evaluation of Therapeutical Radiopharmaceuticals in Rodents, Laboratory Beagles and Veterinary Patients - Preclinical Distribution-, Kinetic-, Excretion-, Internal Dosimetry-, Radiotoxicological-, Radiation Safety- and Efficacy Data

    International Nuclear Information System (INIS)

    Balogh, L.; Domokos, M.; Polyak, A.; Thuroczy, J.; Janoki, G.

    2009-01-01

    the requirements of their owners, handling veterinarians and last but not least serve a very reliable model for (radio)pharmaceutical investigators. Canine osteosarcomas, metastatic bone tumors, insulinomas, multiple liver-, and splenic tumors, bladder carcinomas and chronic arthritis might be the best examples in that topic. (author)

  14. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Su Jin; Kang, Hyung Kyung [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Song, Dong Keun [Department of Pharmacology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Eum, Won Sik; Park, Jinseu [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Kwon, Hyeok Yil, E-mail: hykwon@hallym.ac.kr [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2015-06-05

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction.

  15. Positive autoantibodies to ZnT8 indicate elevated risk for additional autoimmune conditions in patients with Addison's disease.

    Science.gov (United States)

    Fichna, Marta; Rogowicz-Frontczak, Anita; Żurawek, Magdalena; Fichna, Piotr; Gryczyńska, Maria; Zozulińska-Ziółkiewicz, Dorota; Ruchała, Marek

    2016-07-01

    Autoimmune Addison's disease (AAD) associates with exceptional susceptibility to develop other autoimmune conditions, including type 1 diabetes (T1D), marked by positive serum autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated protein 2 (IA-2A). Zinc transporter 8 (ZnT8) is a new T1D autoantigen, encoded by the SLC30A8 gene. Its polymorphic variant rs13266634C/T seems associated with the occurrence of serum ZnT8 antibodies (ZnT8A). This study was designed to determine the prevalence of serum ZnT8A and their clinical implication in 140 AAD patients. Other beta cell and thyroid-specific autoantibodies were also investigated, and ZnT8A results were confronted with the rs13266634 genotype. ZnT8A were detectable in 8.5 %, GADA in 20.7 %, IA-2A in 5.7 %, IAA in 1.6 % and various anti-thyroid antibodies in 7.1-67.8 % individuals. Type 1 diabetes was found in 10 % AAD patients. ZnT8A were positive in 57.1 % of T1D patients and 3.4 % non-diabetic AAD. Analysis of ZnT8A enabled to identify autoimmunity in two (14.3 %) T1D individuals previously classified as autoantibody-negative. ZnT8A-positive patients revealed significantly higher number of autoimmune conditions (p < 0.001), increased prevalence of T1D (p < 0.001) and other beta cell-specific autoantibodies. Carriers of the rs13266634 T-allele displayed increased frequency (p = 0.006) and higher titres of ZnT8A (p = 0.002). Our study demonstrates high incidence of ZnT8A in AAD patients. ZnT8A are associated with coexisting T1D and predictive of T1D in non-diabetic subjects. Moreover, positive ZnT8A in AAD indicate elevated risk for additional autoimmune conditions. Autoantibodies to beta cell antigens, comprising ZnT8, could be included in routine screening panels in AAD.

  16. Oxidation of methionine - is it limiting the diagnostic properties of 99mTc-labeled Exendin-4, a Glucagon-Like Peptide-1 receptor agonist?

    Science.gov (United States)

    Janota, Barbara; Karczmarczyk, Urszula; Laszuk, Ewa; Garnuszek, Piotr; Mikołajczak, Renata

    2016-01-01

    Preliminary clinical evaluation of 99mTc-EDDA/HYNIC-Met14-Exendin-4 showed that the complex offers new diagnostic possibilities for insulinoma and MTC. Exendin-4 contains methionine at position 14 in the amino acid chain, which may be oxidized to methionine sulfoxide and, from the pharmaceutical point of view, the oxidized moiety becomes an undesired impurity in the final radioactive preparation. Therefore, the aim of this study was to investigate the influence of commonly used methods to eliminate the effect of methionine oxidation in peptides, i.e. the replacement of methionine by norleucine (Nle) and the addition of L-methionine, on the in vitro stability and the biodistribution. 99mTc-EDDA/HYNIC-Met14-Exendin-4, 99mTc-EDDA/HYNIC-Nle14-Exendin-4, 99mTc-EDDA/HYNIC-Met14-Ex-endin-4 with the addition of L-methionine and an oxidized form of Exendin-4, i.e. 99mTc-EDDA/HYNIC-Met14(ox)-Exendin-4 were compared in vivo with 68Ga-NODAGA-Nle14-Exendin-4 in normal Wistar rats. The stability and lipophilicity were determined in vitro. Biodistribution studies confirmed the specific uptake of all tested complexes in the GLP-1 positive organs: lungs, pancreas and stomach. The uptake of 99mTc-EDDA/HYNIC-Met14-Exendin-4 with the addition of L-methionine and for 68Ga-NODAGA-Nle14-Exendin-4 at 1h p.i. was around 2-fold higher than that of 99mTc-EDDA/HYNIC-Met14-Exendin-4 and 99mTc-EDDA/HYNIC-Nle14-Exendin-4. Although the substitution of methionine by norleucine in the HYNIC-Exendin-4 did not result in improved bio-distribution, the use of L-methionine, as the excipient that inhibits the oxidation of methionine in the peptide chain resulted in higher lung/blood and stomach/blood uptake ratios. Our results confirmed that methionine at position 14 of amino acid chain of Exendin-4 plays an important role in the interaction with GLP-1 receptor positive tissue.

  17. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Heart, Emma [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Palo, Meridith; Womack, Trayce [Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States); Smith, Peter J.S. [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Institute for Life Sciences, University of Southampton (United Kingdom); Gray, Joshua P., E-mail: Joshua.p.gray@uscga.edu [Cellular Dynamics Program, Marine Biological Laboratory, Woods Hole, MA, 02543 (United States); Department of Science, United States Coast Guard Academy, New London, CT, 06320 (United States)

    2012-01-15

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H{sub 2}O{sub 2}), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H{sub 2}O{sub 2} inhibit insulin secretion. Menadione, which produces H{sub 2}O{sub 2} via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H{sub 2}O{sub 2} production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H{sub 2}O{sub 2} formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H{sub 2}O{sub 2} and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H{sub 2}O{sub 2} production is proportional to applied glucose levels. ► Quinone-mediated redox cycling

  18. The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

    International Nuclear Information System (INIS)

    Heart, Emma; Palo, Meridith; Womack, Trayce; Smith, Peter J.S.; Gray, Joshua P.

    2012-01-01

    Pancreatic β-cells release insulin in response to elevation of glucose from basal (4–7 mM) to stimulatory (8–16 mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H 2 O 2 ), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H 2 O 2 inhibit insulin secretion. Menadione, which produces H 2 O 2 via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H 2 O 2 production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1–10 μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H 2 O 2 formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H 2 O 2 and menadione on insulin secretion. -- Highlights: ► Menadione stimulation or inhibition of insulin secretion is dependent upon applied glucose levels. ► Menadione-dependent H 2 O 2 production is proportional to applied glucose levels. ► Quinone-mediated redox cycling is dependent on glycolysis

  19. Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line.

    Directory of Open Access Journals (Sweden)

    Natasha Chandiramani

    2011-01-01

    Full Text Available Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types.Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI-G1-RS that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity. Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1 inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2 decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3 increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4 increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate; and (5 reconstitution of glucose-stimulated insulin secretion.The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and

  20. Zinc transporter-8 autoantibodies can replace IA-2 autoantibodies as a serological marker for juvenile onset type 1 diabetes in India

    Directory of Open Access Journals (Sweden)

    C Shivaprasad

    2014-01-01

    Full Text Available Introduction: Zinc transporter-8 (ZnT8 is an islet cell secretory granule membrane protein recently identified as an autoantigen in type 1 diabetes (T1D. The aim of this study was to estimate the prevalence of antibodies to ZnT8 (ZnT8A in juvenile onset T1D and to determine the utility of ZnT8A as an independent marker of autoimmunity either alone in antibody-negative subjects or in conjunction with glutamic acid decarboxylase (GAD and insulinoma-2 antigen antibodies (GADA and IA2A. Research Design: ZnT8A, GADA, and IA2A were measured in sera of consecutive T1D patients (n = 88, age range 2-18 years within 4 years of diagnosis and 88 sex-matched controls. Results: The prevalences of GADA, ZnT8a, and IA2A were 64.7%, 31.8% and 19.3%, respectively. In newly diagnosed patients, the frequency of ZnT8A was 45%. ZnT8A were positive in 26% of patients negative for both GADA and IA2A. IA2A were positive only in two patients who were negative for other two antibodies. Combined use of ZnT8A and GADA could detect 97% of antibody positive patients. In receiver operating characteristic (ROC analysis, the performances of GADA and ZnT8As were better than that of IA2A; and AUCs of GADA, ZnT8A, and IA2A for the prediction of T1D were 0.8, 0.65, and 0.59, respectively. Conclusions: ZnT8A complements GADA and increases the diagnostic sensitivity for detection of autoimmunity in juvenile-onset T1D. Inclusion of ZnT8A increases the proportion of patients with antibody positivity to nearly 80%. ZnT8A can replace IA2A as a serological marker for autoimmunity in Indian T1D patients without loss of sensitivity and specificity.

  1. Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

    Science.gov (United States)

    Fendrich, V; Lopez, C L; Manoharan, J; Maschuw, K; Wichmann, S; Baier, A; Holler, J P; Ramaswamy, A; Bartsch, D K; Waldmann, J

    2014-10-01

    Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs. © 2014 Society for Endocrinology.

  2. EX4 stabilizes and activates Nrf2 via PKCδ, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mi-Hwi; Kim, Eung-Hwi [College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Jung, Hye Seung [Department of Internal Medicine, Seoul National University College of Medicine, Seoul (Korea, Republic of); Yang, Dongki [Department of Physiology, Gachon University College of Medicine, Incheon (Korea, Republic of); Park, Eun-Young, E-mail: parkey@mokpo.ac.kr [College of Pharmacy, Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam (Korea, Republic of); Jun, Hee-Sook, E-mail: hsjun@gachon.ac.kr [College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Yeonsu-ku, Incheon (Korea, Republic of); Gachon Medical Research Institute, Gil Hospital, Incheon (Korea, Republic of)

    2017-01-15

    Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H{sub 2}O{sub 2}. Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cδ inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCδ attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCδ activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. - Highlights: • EX4 protects against oxidative stress-induced pancreatic beta cell dysfunction. • EX4 increases antioxidant gene expression. • Antioxidative effect of EX4 is

  3. Pancreatic enucleation using the da Vinci robotic surgical system: a report of 26 cases.

    Science.gov (United States)

    Shi, Yusheng; Peng, Chenghong; Shen, Baiyong; Deng, Xiaxing; Jin, Jiabin; Wu, Zhichong; Zhan, Qian; Li, Hongwei

    2016-12-01

    As a tissue-sparing procedure, pancreatic enucleation has become an alternative for benign or borderline pancreatic tumours; it has been proved to be safe and feasible. To date, a large sample size of robotic pancreatic enucleation has not been reported. This study aimed to discuss the clinical evaluation and postoperative complications after robotic pancreatic enucleation and compare it with open surgery. Patients who underwent robotic or open pancreatic enucleation during December 2010-December 2014 at Shanghai Ruijin Hospital, affiliated with the Shanghai Jiaotong University School of Medicine in China, were included. Clinical data were collected and analysed. Patients were divided into an open group and a robotic group: 26 patients underwent robotic pancreatic enucleation, of whom 13 patients were female. The mean age was 51.7 years, the operation time was 125.7 ± 58.8 min, blood loss was 49.4 ± 33.4 ml and mean tumour size was 18.8 ± 7.9 mm; 17 patients underwent open pancreatic enucleation, of whom 11 were female. The mean age was 54.6 ± 17.2 min, blood loss was 198.5 ± 70.7 ml and mean tumour size was 3.5 ± 1.9 cm. Pathology included insulinomas, intrapancreatic mucinous neoplasmas (IPMNs), pancreatic neuro-endocrine tumours (PNETs), solid pseudopapillary tumours (SPTs) and serous cystadenomas (SCAs). Robotic pancreatic enucleations were associated with less trauma, shorter operation time, less blood loss and faster wound recovery compared with open pancreatic enucleation. Pancreatic fistulas (PFs) were the main complication that occurred in the robotic group; infection also occurred in the open group. All patients recovered after effective drainage and the use of somatostatin. The mean follow-up time was 25 months. No recurrence was discovered, and one patient in the open group suffered endocrine insufficiency. Robotic pancreatic enucleation is a safe and effective surgical procedure for pancreatic benign and borderline tumours. It produces less

  4. Combination of cross-sectional and molecular imaging studies in the localization of gastroenteropancreatic neuroendocrine tumors.

    Science.gov (United States)

    Toumpanakis, Christos; Kim, Michelle K; Rinke, Anja; Bergestuen, Deidi S; Thirlwell, Christina; Khan, Mohid S; Salazar, Ramon; Oberg, Kjell

    2014-01-01

    Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 ((68)Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 ((11)C)-5-hydroxy-L-tryptophan (5-HTP) PET and (18)F-dihydroxyphenylalanine ((18)F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of (68)Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, (18)F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, (18)F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more

  5. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    Directory of Open Access Journals (Sweden)

    de Beaufort Carine

    2010-09-01

    Full Text Available Abstract Background To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative for pancreatic autoantibodies [islet cell autoantibodies(ICA, glutamic acid decarboxylase antibodies (GADA and insulinoma-associated antigen-2 antibodies (IA-2A]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. Materials and methods In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. Results Twenty-four patients (9.1% tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002, lower blood glucose (P = 0.004, received less insulin (P = 0.05 and had lower HbA1c (P = 0.02 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8 by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. Conclusion GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.

  6. EX4 stabilizes and activates Nrf2 via PKCδ, contributing to the prevention of oxidative stress-induced pancreatic beta cell damage

    International Nuclear Information System (INIS)

    Kim, Mi-Hwi; Kim, Eung-Hwi; Jung, Hye Seung; Yang, Dongki; Park, Eun-Young; Jun, Hee-Sook

    2017-01-01

    Oxidative stress in pancreatic beta cells can inhibit insulin secretion and promote apoptotic cell death. Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, can suppress beta cell apoptosis, improve beta cell function and protect against oxidative damage. In this study, we investigated the molecular mechanisms for antioxidative effects of EX4 in pancreatic beta cells. INS-1 cells, a rat insulinoma cell line, were pretreated with EX4 and exposed to palmitate or H 2 O 2 . Reactive oxygen species (ROS) production, and glutathione and insulin secretion were measured. The mRNA and protein expression levels of antioxidant genes were examined. The level of nuclear factor erythroid 2-related factor 2 (Nrf2), its binding to antioxidant response element (ARE), and its ubiquination in the presence of EX4 were determined. The Nrf2 signaling pathway was determined using rottlerin (protein kinase [PK]Cδ inhibitor), H89 (PKA inhibitor) and LY294002 (phosphatidylinositide 3-kinase [PI3K] inhibitor). EX4 treatment decreased ROS production, recovered cellular glutathione levels and insulin secretion in the presence of oxidative stress in INS-1 cells. The expression levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 were increased by EX4 treatment. EX4 promoted Nrf2 translocation, ARE binding activity and enhanced stabilization of Nrf2 by inhibition of ubiquitination. Knockdown of Nrf2 abolished the effect of EX4 on increased insulin secretion. Inhibition of PKCδ attenuated Nrf2 translocation and antioxidative gene expression by EX4 treatment. We suggest that EX4 activates and stabilizes Nrf2 through PKCδ activation, contributing to the increase of antioxidant gene expression and consequently improving beta cell function in the presence of oxidative stress. - Highlights: • EX4 protects against oxidative stress-induced pancreatic beta cell dysfunction. • EX4 increases antioxidant gene expression. • Antioxidative effect of EX4 is mediated by

  7. In vitro phenotypic, genomic and proteomic characterization of a cytokine-resistant murine β-TC3 cell line.

    Directory of Open Access Journals (Sweden)

    Antonina Coppola

    Full Text Available Type 1 diabetes mellitus (T1DM is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival.The aim of our study was to investigate possible mechanisms of resistance to cytokine-induced β-cell death. To this purpose, we created a cytokine-resistant β-cell line (β-TC3R by chronically treating the β-TC3 murine insulinoma cell line with IL-1β + IFN-γ. β-TC3R cells exhibited higher proliferation rate and resistance to cytokine-mediated cell death in comparison to the parental line. Interestingly, they maintained expression of β-cell specific markers, such as PDX1, NKX6.1, GLUT2 and insulin. The analysis of the secretory function showed that β-TC3R cells have impaired glucose-induced c-peptide release, which however was only moderately reduced after incubation with KCl and tolbutamide. Gene expression analysis showed that β-TC3R cells were characterized by downregulation of IL-1β and IFN-γ receptors and upregulation of SOCS3, the classical negative regulator of cytokines signaling. Comparative proteomic analysis showed specific upregulation of 35 proteins, mainly involved in cell death, stress response and folding. Among them, SUMO4, a negative feedback regulator in NF-kB and JAK/STAT signaling pathways, resulted hyper-expressed. Silencing of SUMO4 was able to restore sensitivity to cytokine-induced cell death in β-TC3R cells, suggesting it may play a key role in acquired cytokine resistance by blocking JAK/STAT and NF-kB lethal signaling.In conclusion, our study represents the first extensive proteomic characterization of a murine cytokine-resistant β-cell line, which might represent a useful tool for studying the mechanisms involved in resistance to

  8. [Multidisciplinary approach to surgical disorders of the pancreas in children].

    Science.gov (United States)

    Šnajdauf, J; Rygl, M; Petrů, O; Frýbová, B; Náhlovský, J; Mixa, V; Keil, R; Bronský, J; Kynčl, M; Kodet, R

    2018-01-01

    Surgical diseases of the pancreas in children are not common and may be associated with significant morbidity and potential mortality. A multidisciplinary approach is essential for correct diagnosis, surgical strategy and postoperative as well as follow-up care. Retrospective analysis of patients operated on due to a pathological lesion of the pancreas focused on diagnostics, operating procedures, postoperative complications, and long-term results. Between 1991 and 2016, eighty-nine children were treated in our department for a pathologic lesion of the pancreas. 39 of them were boys and 50 were girls. Mean age of the patients was 9.3 years (1 month-18.4 years). Patients were followed from the operation to the age of 19, after which they were referred for follow-up to adult specialists. The indications for surgery were trauma in 34 children, solid pseudopapillary tumor in 23 children, biopsy in 10, hyperinsulinism in 8, chronic pancreatitis in 4, pancreatic cyst in 3, insulinoma in 3, carcinoma in 2, and serous cystadenoma and pancreas divisum in one patient. The most frequent procedures performed on the pancreas were distal pancreatectomy in 35 cases, the duodenum-preserving pancreatic head resection in 23 cases, pseudocystogastroanastomosis in 11 cases, 9095% pancreatic resection in 5 cases, Whipple operation in two cases, Puestow procedure in one case, tumor enucleation in one case, and tumor biopsy for cancer in one case. In 5 patients after major pancreatic injury, ERCP and papillotomy with insertion of a stent into the pancreatic duct was performed. 3 patients died, one after a polytrauma with severe pancreatic injury and two patients with pancreatic cancer. Pancreatic surgery in children is not a common operation, and individual as well as institutional experience remains limited. After more than 20 years of experience with pancreatic surgery, we believe that close cooperation with surgeons, pediatric gastroenterologists, radiologists, anesthesiologists

  9. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

    International Nuclear Information System (INIS)

    Lee, Su Jin; Kang, Hyung Kyung; Song, Dong Keun; Eum, Won Sik; Park, Jinseu; Choi, Soo Young; Kwon, Hyeok Yil

    2015-01-01

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction

  10. Radionuclide therapy of endocrine-related cancer; Nuklearmedizinische Therapie endokriner Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L. [Universitaetsklinikum Heidelberg, Abteilung Nuklearmedizin, Heidelberg (Germany)

    2014-10-15

    This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [German] Dieser Artikel gibt einen Ueberblick ueber die etablierten sowie weitere vielversprechende, aktuell im Rahmen von Studien eingesetzte nuklearmedizinische Therapiemoeglichkeiten diverser endokrinologischer Neoplasien. Die Radiojodtherapie ist unveraendert die Therapie der Wahl beim differenzierten, jodspeichernden Schilddruesenkarzinom. Im metastasierten Stadium sind in ca. 50 % der Faelle noch

  11. An adenovirus-derived protein: A novel candidate for anti-diabetic drug development.

    Science.gov (United States)

    Hegde, Vijay; Na, Ha-Na; Dubuisson, Olga; Burke, Susan J; Collier, J Jason; Burk, David; Mendoza, Tamra; Dhurandhar, Nikhil V

    2016-02-01

    Exposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell-based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet. 8-9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting. In multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4. This study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the

  12. Insulin Radioimmunoassay for Clinical Research in Psychiatric, Pancreatic, Cirrhotic and Irradiated Patients

    Energy Technology Data Exchange (ETDEWEB)

    Czerniak, P.; Chlebowski, J.; Kulcar, S.; Boruchowski, Sabina [Department Of Radiotherapy and Isotopes and Department of Psychiatry, Tel-Aviv University Medical School (Israel); Faculty for Continuing Medical Education, Tel-Hashomer Hospital, Tel-Hashomer (Israel)

    1970-02-15

    A modified Hales-Randle method for insulin radioimmunoassay is described. An insulin response curve was established in normal cases after glucose loading. Pathological changes were then investigated in patients and animals before and after therapeutic, operative and radiological procedures. Four representative groups of this material will be illustrated. (1) Psychotic patients (acute and chronic schizophrenics, neurotics and depressives) were examined with the aim of learning about the variable effects produced by insulin shock-therapy, as well as for biochemical diagnosis purposes in psychotics. Highest insulin response curves were found in chronic schizophrenics with improvement after insulin therapy. Schizophrenics without improvement presented different curves. Lowest insulin values were found in acute schizophrenia. Depressives and anxiety neurotics showed insulin tolerance curves similar to those of non-psychotic patients. (2) Pancreatic patients. Special attention was paid to pancreatic carcinoma (insulinoma excepted). In most cases of pancreatic carcinoma a very low and flat insulin tolerance curve was found. The above findings may be of a diagnostic importance in this condition, which is clinically hardly recognized. (3) Liver cirrhotic patients. A special group of shunt operated patients was investigated. The study was performed on eight liver cirrhotics before and after porto-caval or reno-splenal shunt operation. The plasma insulin level was examined in the vena cava, renal and cubital blood. The influence of tolbutamide was analysed. The normally occurring retention of insulin by normal hepatic tissue was found to be considerably disturbed. Other interesting changes were observed. (4) The plasma insulin level in the radiologically exposed. Experimental and clinical studies were performed, with insulin doses before and after radiation. Whole body X-ray exposure (300 rads) to rats resulted in a rapid lowering of insulin or its disappearance. Recovery was

  13. Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Jeanette Baran-Gale

    Full Text Available Next-generation deep sequencing of small RNAs has unveiled the complexity of the microRNA (miRNA transcriptome, which is in large part due to the diversity of miRNA sequence variants ("isomiRs". Changes to a miRNA's seed sequence (nucleotides 2-8, including shifted start positions, can redirect targeting to a dramatically different set of RNAs and alter biological function. We performed deep sequencing of small RNA from mouse insulinoma (MIN6 cells (widely used as a surrogate for the study of pancreatic beta cells and developed a bioinformatic analysis pipeline to profile isomiR diversity. Additionally, we applied the pipeline to recently published small RNA-seq data from primary human beta cells and whole islets and compared the miRNA profiles with that of MIN6. We found that: (1 the miRNA expression profile in MIN6 cells is highly correlated with those of primary human beta cells and whole islets; (2 miRNA loci can generate multiple highly expressed isomiRs with different 5'-start positions (5'-isomiRs; (3 isomiRs with shifted start positions (5'-shifted isomiRs are highly expressed, and can be as abundant as their unshifted counterparts (5'-reference miRNAs. Finally, we identified 10 beta cell miRNA families as candidate regulatory hubs in a type 2 diabetes (T2D gene network. The most significant candidate hub was miR-29, which we demonstrated regulates the mRNA levels of several genes critical to beta cell function and implicated in T2D. Three of the candidate miRNA hubs were novel 5'-shifted isomiRs: miR-375+1, miR-375-1 and miR-183-5p+1. We showed by in silico target prediction and in vitro transfection studies that both miR-375+1 and miR-375-1 are likely to target an overlapping, but distinct suite of beta cell genes compared to canonical miR-375. In summary, this study characterizes the isomiR profile in beta cells for the first time, and also highlights the potential functional relevance of 5'-shifted isomiRs to T2D.

  14. GAD2 on chromosome 10p12 is a candidate gene for human obesity.

    Directory of Open Access Journals (Sweden)

    Philippe Boutin

    2003-12-01

    Full Text Available The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65 is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA, which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049 and an at-risk SNP (-243 A>G for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014. Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2 = 7.637, p = 0.02. In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p G SNP was associated with higher hunger scores (p = 0.007 and disinhibition scores (p = 0.028, as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively. SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively. These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

  15. Hiperinsulinismo na infância: quando apenas uma dosagem de insulina não é suficiente Hyperinsulinism in infancy and childhood: when an insulin level is not always enough

    Directory of Open Access Journals (Sweden)

    Andrew A. Palladino

    2008-12-01

    Full Text Available INTRODUÇÃO: A hipoglicemia em bebês e crianças pode causar convulsões, atraso de desenvolvimento e dano cerebral permanente. O hiperinsulinismo (HI é a causa mais comum de hipoglicemia, seja transitória ou permanente. A HI é caracterizada pela secreção inadequada de insulina, o que resulta em hipoglicemia persistente, de leve a grave. As diferentes formas de HI representam um grupo de doenças clínica, genética e morfologicamente heterogêneo. CONTEÚDO: Hiperinsulinismo congênito está associado às mutações de SUR-1 e Kir6.2, glucoquinase, glutamato desidrogenase, 3-hidroxiacil-CoA desidrogenase de cadeia curta e expressão ectópica de SLC16A1 na membrana plasmática das células beta. O HI pode estar associado ao estresse perinatal, como asfixia do nascimento, toxemia materna, prematuridade ou retardo do crescimento intra-uterino, resultando em hipoglicemia neonatal prolongada. Mimetismo de HI neonatal inclui pan-hipopituitarismo, hipoglicemia induzida por fármaco, insulinoma, anticorpos antiinsulina e estimuladores do receptor de insulina, síndrome de Beckwith-Wiedemann e distúrbios congênitos de glicosilação. Exames laboratoriais para HI podem incluir quantificação de glicose, insulina, β-hidroxibutirato, ácidos graxos, amônia e perfil de acilcarnitinas plasmáticos, além de ácidos orgânicos urinários. Os exames genéticos estão disponíveis em laboratórios comerciais para os genes sabidamente associados à hiperinsulinemia. Testes de resposta insulínica aguda (RIA são úteis na caracterização fenotípica. Exames de imagem e histológicos também estão disponíveis para diagnosticar e classificar o HI. O objetivo do tratamento de crianças com HI é prevenir os danos cerebrais da hipoglicemia, mantendo níveis de glicose plasmática acima de 70mg/dl por terapia farmacológica ou cirúrgica. CONCLUSÃO:A terapêutica do HI requer abordagem multidisciplinar que inclui endocrinologistas pedi

  16. Pancreatic endocrine tumors or apudomas Tumores endocrinos o apudomas pancreáticos

    Directory of Open Access Journals (Sweden)

    Modesto Varas

    2011-04-01

    Full Text Available Introduction and objective: pancreatic endocrine tumors (PET are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. Patients and methods: the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010. A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. Results: a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y (14 males, 5 females, and tumor size was 5 to 80 mm (X: 20 mm. Metastatic disease was present in 37% (7/19. Most underwent the following imaging techniques: ultrasounds, computed tomography (CT and magnetic resonance imaging (MRI. Fine needle aspiration punction (FNA was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%, insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN], Zollinger-Ellison syndrome (ZES from gastrinoma: 5 (3 with MEN-1, glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%. Four (4/14: 28% has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4, somatostatin (3 and interferon (2 before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19. Conclusions: age was similar to that described in the literature. Males were predominant. Most cases were non-functioning (37%. Most patients underwent surgery (73% with little morbidity (28% and an actuarial survival of 73.6% at the time of the study.Introducción y objetivo: los tumores endocrinos pancre

  17. Morbidity and mortality of aggressive resection in patients with advanced neuroendocrine tumors.

    Science.gov (United States)

    Norton, Jeffrey A; Kivlen, Maryann; Li, Michelle; Schneider, Darren; Chuter, Timothy; Jensen, Robert T

    2003-08-01

    There is considerable controversy about the treatment of patients with malignant advanced neuroendocrine tumors of the pancreas and duodenum. Aggressive surgery remains a potentially efficacious antitumor therapy but is rarely performed because of its possible morbidity and mortality. Aggressive resection of advanced neuroendocrine tumors can be performed with acceptable morbidity and mortality rates and may lead to extended survival. The medical records of patients with advanced neuroendocrine tumors who underwent surgery between 1997 and 2002 by a single surgeon at the University of California, San Francisco, were reviewed in an institutional review board-approved protocol. Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates were recorded. Disease-free survival was defined as no tumor identified on radiological imaging studies and no detectable abnormal hormone levels. Proportions were compared statistically using the Fisher exact test. Kaplan-Meier curves were used to estimate survival rates. Twenty patients were identified (11 men and 9 women). Of these, 10 (50%) had gastrinoma, 1 had insulinoma, and the remainder had nonfunctional tumors; 2 had multiple endocrine neoplasia type 1, and 1 had von Hippel-Lindau disease. The mean age was 55 years (range, 34-72 years). In 10 patients (50%), tumors were thought to be unresectable according to radiological imaging studies because of multiple bilobar liver metastases (n = 6), superior mesenteric vein invasion (n = 3), and extensive nodal metastases (n = 1). Tumors were completely removed in 15 patients (75%). Surgical procedures included 8 proximal pancreatectomies (pancreatoduodenectomy or whipple procedure), 3 total pancreatectomies, 9 distal pancreatectomies, and 3 tumor enucleations from the pancreatic head. Superior mesenteric vein reconstruction was done in 3 patients. Liver resections were done in 6 patients, and an extended periaortic node

  18. Molecular mechanisms of macrophage activation induced by the synergistic effects of low dose irradiation and adoptive T cell therapy

    International Nuclear Information System (INIS)

    Bender, Noemi

    2016-01-01

    The detection of cancerous cells by the immune system elicits spontaneous antitumour immune responses. Still, during their progression, tumours acquire characteristics that enable them to escape immune surveillance. Cancer immunotherapy aims to reverse tumour immune evasion by activating and directing the immune system against transformed tumour cells. However, the tumours' intrinsic resistance mechanisms limit the success of many immunotherapeutic approaches. The functionally and morphologically abnormal tumour vasculature forms a physical barrier and prevents the entry of tumour-reactive immune effector cells, while the immunosuppressive tumour microenvironment impairs their function. To block tumour immune evasion, therapeutic strategies are being developed that combine cancer immunotherapy with treatment modalities, such as radiotherapy, that reprogram the tumour microenvironment to increase treatment efficacies and improve clinical outcome. In various preclinical models radiotherapy was shown to enhance the efficacy of adoptive T cell therapy. Our group showed that in the RIP1-TAg5 mouse model of spontaneous insulinoma, the transfer of in vitro-activated tumour-specific T cells induces T cell infiltration and promotes long-term survival only in combination with neoadjuvant local low dose irradiation (LDI). These treatment effects were mediated by iNOS+ macrophages. In this thesis, we investigated the mechanisms underlying the improved T cell infiltration and prolonged survival upon combination therapy with adoptive T cell transfer and local LDI. We demonstrate that combination therapy leads to a normalization of the aberrant tumour vasculature and endothelial activation, an increase in intratumoural macrophages, a reduction of intratumoural myeloid derived suppressor cells and, most importantly, to tumour regression. These findings suggest that this treatment inhibits tumour immune suppression but also facilitates immune effector cell infiltration through the

  19. Arachidonic acid and lipoxinA4 attenuate streptozotocin-induced cytotoxicity to RIN5 F cells in vitro and type 1 and type 2 diabetes mellitus in vivo.

    Science.gov (United States)

    Gundala, Naveen K V; Naidu, Vegi G M; Das, Undurti N

    2017-03-01

    The aim of this study was to observe whether polyunsaturated fatty acids (PUFAs) can protect rat insulinoma (RIN5 F) cells against streptozotocin (STZ)-induced apoptosis in vitro and type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) in vivo and if so, what would be the mechanism of this action. RIN5 F cells were used for the in vitro study, whereas the in vivo study was performed in Wistar rats. STZ was used to induce apoptosis of RIN5 F cells in vitro and T1- and T2DM in vivo. The effect of PUFAs: γ-linolenic acid (GLA), arachidonic acid (AA) of ω-6 series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) of ω-3 series; cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors and antiinflammatory metabolite of AA and DHA, lipoxin A4 (LXA4), and resolvin D2 and protectin, respectively against STZ-induced cytotoxicity to RIN5 F cells in vitro and LXA4 against T1- and T2DM in vivo was studied. Changes in the antioxidant content, lipid peroxides, nitric oxide, and expression of PDX1, P65, nuclear factor-κb (NF-κb), and IKB genes in STZ-treated RIN5 F cells in vitro and Nrf2, GLUT2, COX2, iNOS protein levels in the pancreatic tissue of T1- and T2DM and LPCLN2 (lipocalin 2), NF-κb, IKB I in adipose tissue of T2DM after LXA4 treatment were studied. Plasma glucose, insulin, and tumor necrosis factor (TNF)-α levels also were measured in STZ-induced T1- and T2DM Wistar rats. Among all PUFAs tested, AA and EPA are the most effective against STZ-induced cytotoxicity to RIN5 F cells in vitro. Neither COX nor LOX inhibitors blocked the cytoprotective action of AA in vitro and T1- and T2DM by STZ. LXA4 production by RIN5 F cells in vitro and plasma LXA4 levels in STZ-induced T1- and T2DM animals were decreased by STZ that reverted to normal after AA treatment. AA prevented both T1- and T2DM induced by STZ. Antiinflammatory metabolite of AA and LXA4 prevented both T1- and T2DM induced by STZ. The expression of Pdx1, NF-κb, IKB genes in the

  20. Improved quality of life in patients treated with Peptide radionuclides.

    Science.gov (United States)

    Traub-Weidinger, T; Raderer, M; Uffmann, M; Angelberger, P; Kurtaran, A; Leimer, M; Preitfellner, J; Dudczak, R; Virgolini, I

    2011-07-01

    Peptide receptor radionuclide therapy (PRRT) has recently been established as an important treatment modality for somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to evaluate the clinical response, side-effects as well as the quality of life following (90)Y-DOTA-lanreotide (DOTALAN) and/or (90)Y-DOTA-Tyr (3)-DPhe(1)-octreotide (DOTATOC) therapy in patients with progressive metastatic disease during a 6-year follow-up period. Following dosimetric evaluation with (111)In-DOTALAN and (111)In-DOTATOC, 13 patients with estimated absorbed tumor doses of >5 Gy/GBq (carcinoid, n = 5; radioiodine-negative thyroid cancer, n = 4; gastrinoma, n = 1; insulinoma, n = 1; glucagonoma, n = 1; glomus jugularis tumor, n = 1) were assigned for PRRT. A dose of 925 MBq of (90)Y-DOTALAN (four patients) or 1.85-3.7 GBq of (90)Y-DOTATOC (10 patients) was administered intravenously and repeated every 4-8 weeks. Tumor dosimetry was performed prior to and under therapy, re-staging every 2-3 months. Pain intensity, Karnofsky score and general symptoms were evaluated in order to determine quality of life. Patients were followed until death. Altogether, 53 infusions of PRRT (1.85-14.1 GBq) were administered. After the first follow-up of 3 months of (90)Y-DOTALAN therapy, stable disease (SD) was observed in one patient and progressive disease (PD) in three patients. With (90)Y-DOTATOC therapy, SD was found in all 10 patients. During the re-evaluation period (4-27 months), one patient had to be shifted from (90)Y-DOTALAN to (90)Y-DOTATOC therapy due to reduced (111)In-DOTALAN uptake after 5.5 GBq. In the first 6 months after PRRT with DOTATOC, SD was found in nine of 10 patients and PD in one patient. Thereafter, SD was observed in two patients and PD in eight patients. Nine of 13 patients after PRRT with either DOTALAN or DOTATOC died. None of the patients had experienced severe acute hematological side-effects. Transient thrombocytopenia or lymphocytopenia was seen in

  1. Improved Quality of Life in Patients Treated with Peptide Radionuclides

    International Nuclear Information System (INIS)

    Traub-Weidinger, T; Raderer, M.; Uffmann, M.; Angelberger, P.; Kurtaran, A.; Leimer, M.; Preitfellner, J.; Dudczak, R.; Virgolini, I.

    2011-01-01

    Peptide receptor radionuclide therapy (PRRT) has recently been established as an important treatment modality for somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to evaluate the clinical response, side-effects as well as the quality of life following 90 Y-DOTA-lanreotide (DOTALAN) and/or 90 Y-DOTA-Tyr 3 -DPhe 1 -octreotide (DOTATOC) therapy in patients with progressive metastatic disease during a 6-year follow-up period. Following dosimetric evaluation with 111 In-DOTALAN and 111 In-DOTATOC, 13 patients with estimated absorbed tumor doses of >5 Gy/GBq (carcinoid, n = 5; radioiodine-negative thyroid cancer, n = 4; gastrinoma, n = 1; insulinoma, n = 1; glucagonoma, n = 1; glomus jugularis tumor, n = 1) were assigned for PRRT. A dose of 925 MBq of 90 Y-DOTALAN (four patients) or 1.85–3.7 GBq of 90 Y-DOTATOC (10 patients) was administered intravenously and repeated every 4–8 weeks. Tumor dosimetry was performed prior to and under therapy, re-staging every 2–3 months. Pain intensity, Karnofsky score and general symptoms were evaluated in order to determine quality of life. Patients were followed until death. Altogether, 53 infusions of PRRT (1.85–14.1 GBq) were administered. After the first follow-up of 3 months of 90 Y-DOTALAN therapy, stable disease (SD) was observed in one patient and progressive disease (PD) in three patients. With 90 Y-DOTATOC therapy, SD was found in all 10 patients. During the re-evaluation period (4–27 months), one patient had to be shifted from 90 Y-DOTALAN to 90 Y-DOTATOC therapy due to reduced 111 In-DOTALAN uptake after 5.5 GBq. In the first 6 months after PRRT with DOTATOC, SD was found in nine of 10 patients and PD in one patient. Thereafter, SD was observed in two patients and PD in eight patients. Nine of 13 patients after PRRT with either DOTALAN or DOTATOC died. None of the patients had experienced severe acute hematological side-effects. Transient thrombocytopenia or lymphocytopenia was seen in 10

  2. Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs

    International Nuclear Information System (INIS)

    Rydén, Anneli; Nyman, Görel; Nalin, Lovisa; Andreasson, Susanne; Korsgren, Olle; Eriksson, Olof; Jensen-Waern, Marianne

    2016-01-01

    Introduction: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of β-cells and in experimental animal research. Exendin-4 can be radiolabeled with 68 Ga, 111 In or 99m Tc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic β-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D). The compound, which is administered subcutaneously (SC) may cause nausea, vomiting and a minor increase in the heart rate (HR). However, possible side-effects on cardiovascular functions after intravenous (IV) administration have not been reported. This study describes the Exendin-4 dose at which cardiovascular side-effects occur in pigs and cynomolgus monkeys. The IV effect of the tracer on insulin secretion is also investigated in pigs. Methods: Seven clinically healthy littermate pigs (40 days old) were used; three of them were made diabetic by streptozotocin (STZ). All pigs underwent PET imaging under general anesthesia to examine the glucagon-like peptide-1 receptor (GLP-1R) in β-cells with radiolabeled Exendin-4. A baseline tracer dose IV [ 68 Ga]Exendin-4 (0.025 ± 0.010 μg/kg) followed by a competition dose IV [ 68 Ga]Exendin-4 (3.98 ± 1.33 μg/kg) 60 min later were administered. Blood samples were taken and analyzed for insulin secretion by using ELISA. Cardiovascular and respiratory variables were monitored throughout the experiment. Results: Immediately after administration of the high dose [ 68 Ga]Exendin-4 the HR rose from 122 ± 14 to 227 ± 40 bpm (p < 0.01) and from 100 ± 5 to 181 ± 13 bpm (p < 0.01) in healthy non-diabetic and diabetes-induced pigs, respectively. The tachycardia was observed for > 2 h and one healthy non-diabetic pig suffered cardiac arrest 3 h after the IV [ 68 Ga]Exendin-4

  3. Molecular mechanisms of macrophage activation induced by the synergistic effects of low dose irradiation and adoptive T cell therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bender, Noemi

    2016-12-19

    The detection of cancerous cells by the immune system elicits spontaneous antitumour immune responses. Still, during their progression, tumours acquire characteristics that enable them to escape immune surveillance. Cancer immunotherapy aims to reverse tumour immune evasion by activating and directing the immune system against transformed tumour cells. However, the tumours' intrinsic resistance mechanisms limit the success of many immunotherapeutic approaches. The functionally and morphologically abnormal tumour vasculature forms a physical barrier and prevents the entry of tumour-reactive immune effector cells, while the immunosuppressive tumour microenvironment impairs their function. To block tumour immune evasion, therapeutic strategies are being developed that combine cancer immunotherapy with treatment modalities, such as radiotherapy, that reprogram the tumour microenvironment to increase treatment efficacies and improve clinical outcome. In various preclinical models radiotherapy was shown to enhance the efficacy of adoptive T cell therapy. Our group showed that in the RIP1-TAg5 mouse model of spontaneous insulinoma, the transfer of in vitro-activated tumour-specific T cells induces T cell infiltration and promotes long-term survival only in combination with neoadjuvant local low dose irradiation (LDI). These treatment effects were mediated by iNOS+ macrophages. In this thesis, we investigated the mechanisms underlying the improved T cell infiltration and prolonged survival upon combination therapy with adoptive T cell transfer and local LDI. We demonstrate that combination therapy leads to a normalization of the aberrant tumour vasculature and endothelial activation, an increase in intratumoural macrophages, a reduction of intratumoural myeloid derived suppressor cells and, most importantly, to tumour regression. These findings suggest that this treatment inhibits tumour immune suppression but also facilitates immune effector cell infiltration through

  4. Antidiabetic, antioxidant and anti inflammatory properties of water and n-butanol soluble extracts from Saharian Anvillea radiata in high-fat-diet fed mice.

    Science.gov (United States)

    Kandouli, Chouaib; Cassien, Mathieu; Mercier, Anne; Delehedde, Caroline; Ricquebourg, Emilie; Stocker, Pierre; Mekaouche, Mourad; Leulmi, Zineb; Mechakra, Aicha; Thétiot-Laurent, Sophie; Culcasi, Marcel; Pietri, Sylvia

    2017-07-31

    According to Saharian traditional medicine, Anvillea radiata Coss. & Dur. (Asteraceae) has been valued for treating a variety of ailments such as gastro-intestinal, liver and pulmonary diseases, and has gained awareness for its beneficial effect on postprandial hyperglycemia. However, to best of our knowledge, no detailed study of the antidiabetic curative effects of this plant has been conducted yet. To determine the hypoglycemic and antidiabetic effect of dietary supplementation with Anvillea radiata extracts on high-fat-diet (HFD)-induced obesity and insulin resistance in C57BL/6J mice in relation with antioxidant, anti-inflammatory, pancreatic beta-cells and skeletal muscle protection, and digestive enzyme inhibiting properties. Six extracts (water soluble and organic) from aerial parts of the plant were analyzed phytochemically (total phenolic and flavonoid content) and screened for in vitro superoxide (by chemiluminescence) and hydroxyl radical (by electron paramagnetic resonance spin-trapping) scavenging, antioxidant (DPPH, TRAP and ORAC assays), xanthine oxidase, metal chelating, α-amylase and α-glucosidase inhibitory property, and protective effects on copper-induced lipoprotein oxidation. Then selected hydroalcoholic and aqueous extracts were assessed for toxicity in normal human lung fibroblasts and A549 cancer cells using FMCA and MTT assays. Two water-soluble extracts having the best overall properties were assessed for their (i) protective effect at 1-15µg/mL on metabolic activity of rat insulinoma-derived INS-1 cells exposed to hyperglycemic medium, and (ii) acute hypoglycemic effect on 16-weeks HFD-induced diabetic mice. Then diabetic mice were administered HFD supplemented by extracts (up to 150mg/kg/day) for 12 additional weeks using standard diet as control and the antidiabetic drug, metformin (150mg/kg), as positive control. Then the antidiabetic, anti-inflammatory and antioxidant activity of extracts were determined. Of the highly efficient

  5. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Waser, Beatrice

    2003-01-01

    Peptide receptors have been found to represent excellent targets for in vivo cancer diagnosis and therapy. Recent in vitro studies have shown that many cancers can overexpress not only one but several peptide receptors concomitantly. One of the challenges for nuclear medicine in this field in the coming decade will be to take advantage of the co-expression of peptide receptors for multireceptor tumour targeting. In vitro receptor studies can reveal which peptide receptor is overexpressed in which tumour and which receptors are co-expressed in an individual tumour; such knowledge is a prerequisite for successful in vivo development. One group of tumours of particular interest in this respect is the neuroendocrine tumours, which have previously been shown often to express peptide receptors. This review summarises our investigations of the concomitant expression of 13 different peptide receptors, in more than 100 neuroendocrine tumours of the human intestine, pancreas and lung, using in vitro receptor autoradiography with subtype-selective ligands. The incidence and density of the somatostatin receptors sst 1 -sst 5 , the VIP receptors VPAC 1 and VPAC 2 , the CCK 1 and CCK 2 receptors, the three bombesin receptor subtypes BB 1 (NMB receptor), BB 2 (GRP receptor) and BB 3 , and GLP-1 receptors were evaluated. While the presence of VPAC 1 and sst 2 was detected in the majority of these neuroendocrine tumours, the other receptors, more differentially expressed, revealed a characteristic receptor pattern in several tumour types. Ileal carcinoids expressed sst 2 and VPAC 1 receptors in virtually all cases and had CCK 1 , CCK 2 , sst 1 or sst 5 in approximately half of the cases; they were the only tumours of this series to express NMB receptors. Insulinomas were characterised by a very high incidence of GLP-1, CCK 2 and VPAC 1 receptors, with the GLP-1 receptors expressed in a particularly high density; they expressed sst 2 in two-thirds and sst 1 in approximately half of

  6. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting

    Energy Technology Data Exchange (ETDEWEB)

    Reubi, Jean Claude; Waser, Beatrice [Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, PO Box 62, 3010, Berne (Switzerland)

    2003-05-01

    Peptide receptors have been found to represent excellent targets for in vivo cancer diagnosis and therapy. Recent in vitro studies have shown that many cancers can overexpress not only one but several peptide receptors concomitantly. One of the challenges for nuclear medicine in this field in the coming decade will be to take advantage of the co-expression of peptide receptors for multireceptor tumour targeting. In vitro receptor studies can reveal which peptide receptor is overexpressed in which tumour and which receptors are co-expressed in an individual tumour; such knowledge is a prerequisite for successful in vivo development. One group of tumours of particular interest in this respect is the neuroendocrine tumours, which have previously been shown often to express peptide receptors. This review summarises our investigations of the concomitant expression of 13 different peptide receptors, in more than 100 neuroendocrine tumours of the human intestine, pancreas and lung, using in vitro receptor autoradiography with subtype-selective ligands. The incidence and density of the somatostatin receptors sst{sub 1}-sst{sub 5}, the VIP receptors VPAC{sub 1} and VPAC{sub 2}, the CCK{sub 1} and CCK{sub 2} receptors, the three bombesin receptor subtypes BB{sub 1} (NMB receptor), BB{sub 2} (GRP receptor) and BB{sub 3}, and GLP-1 receptors were evaluated. While the presence of VPAC{sub 1} and sst{sub 2} was detected in the majority of these neuroendocrine tumours, the other receptors, more differentially expressed, revealed a characteristic receptor pattern in several tumour types. Ileal carcinoids expressed sst{sub 2} and VPAC{sub 1} receptors in virtually all cases and had CCK{sub 1}, CCK{sub 2}, sst{sub 1} or sst{sub 5} in approximately half of the cases; they were the only tumours of this series to express NMB receptors. Insulinomas were characterised by a very high incidence of GLP-1, CCK{sub 2} and VPAC{sub 1} receptors, with the GLP-1 receptors expressed in a