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Sample records for avascular pancreatic islets

  1. FEM-based oxygen consumption and cell viability models for avascular pancreatic islets.

    Science.gov (United States)

    Buchwald, Peter

    2009-04-16

    The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans) are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM) based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media. Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration. Partial differential equation (PDE) based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 microm diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations. Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for non-vascularised islet and can lead to considerable cell

  2. FEM-based oxygen consumption and cell viability models for avascular pancreatic islets

    Directory of Open Access Journals (Sweden)

    Buchwald Peter

    2009-04-01

    Full Text Available Abstract Background The function and viability of cultured, transplanted, or encapsulated pancreatic islets is often limited by hypoxia because these islets have lost their vasculature during the isolation process and have to rely on gradient-driven passive diffusion, which cannot provide adequate oxygen transport. Pancreatic islets (islets of Langerhans are particularly susceptible due to their relatively large size, large metabolic demand, and increased sensitivity to hypoxia. Here, finite element method (FEM based multiphysics models are explored to describe oxygen transport and cell viability in avascular islets both in static and in moving culture media. Methods Two- and three-dimensional models were built in COMSOL Multiphysics using the convection and diffusion as well as the incompressible Navier-Stokes fluid dynamics application modes. Oxygen consumption was assumed to follow Michaelis-Menten-type kinetics and to cease when local concentrations fell below a critical threshold; in a dynamic model, it was also allowed to increase with increasing glucose concentration. Results Partial differential equation (PDE based exploratory cellular-level oxygen consumption and cell viability models incorporating physiologically realistic assumptions have been implemented for fully scaled cell culture geometries with 100, 150, and 200 μm diameter islets as representative. Calculated oxygen concentrations and intra-islet regions likely to suffer from hypoxia-related necrosis obtained for traditional flask-type cultures, oxygen-permeable silicone-rubber membrane bottom cultures, and perifusion chambers with flowing media and varying incoming glucose levels are presented in detail illustrated with corresponding colour-coded figures and animations. Conclusion Results of the computational models are, as a first estimate, in good quantitative agreement with existing experimental evidence, and they confirm that during culture, hypoxia is often a problem for

  3. Pancreatic islet transplantation

    Directory of Open Access Journals (Sweden)

    Corrêa-Giannella Maria

    2009-09-01

    Full Text Available Abstract Background No formulation of exogenous insulin available to date has yet been able to mimic the physiological nictemeral rhythms of this hormone, and despite all engineering advancements, the theoretical proposal of developing a mechanical replacement for pancreatic β cell still has not been reached. Thus, the replacement of β cells through pancreas and pancreatic islet transplantation are the only concrete alternatives for re-establishing the endogenous insulin secretion in type 1 diabetic patients. Since only 1 to 1.5% of the pancreatic mass corresponds to endocrine tissue, pancreatic islets transplantation arises as a natural alternative. Data from the International Islet Transplant Registry (ITR from 1983 to December 2000 document a total of 493 transplants performed around the world, with progressively worse rates of post-transplant insulin independence. In 2000, the "Edmonton Protocol" introduced several modifications to the transplantation procedure, such as the use of a steroid-free immunosuppression regimen and transplantation of a mean islet mass of 11,000 islet equivalents per kilogram, which significantly improved 1-year outcomes. Although the results of a 5-year follow-up in 65 patients demonstrated improvement in glycemic instability in a significant portion of them, only 7.5% of the patients have reached insulin independence, indicating the need of further advances in the preservation of the function of transplanted islet. In addition to the scarcity of organs available for transplantation, islets transplantation still faces major challenges, specially those related to cell loss during the process of islet isolation and the losses related to the graft site, apoptosis, allorejection, autoimmunity, and immunosuppression. The main strategies to optimize islet transplantation aim at improving all these aspects. Conclusion Human islet transplantation should be regarded as an intervention that can decrease the frequency of

  4. Unraveling pancreatic islet biology by quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Jianying; Dann, Geoffrey P.; Liew, Chong W.; Smith, Richard D.; Kulkarni, Rohit N.; Qian, Weijun

    2011-08-01

    The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases.

  5. Human pancreatic islet progenitor cells demonstrate phenotypic ...

    Indian Academy of Sciences (India)

    Prakash

    The increasing scarcity in number of human pancreatic islets available for transplantation in type 1 diabetes (Shapiro et al. 2005, 2006), has accentuated the need for research in exploring alternative sources of insulin-producing cells for cell based therapy in diabetes. Since in vitro culture of islet β-cells demonstrates loss in ...

  6. Cyclic AMP in rat pancreatic islets

    International Nuclear Information System (INIS)

    Grill, V.; Borglund, E.; Cerasi, E.; Uppsala Univ.

    1977-01-01

    The incorporation of [ 3 H]adenine into cyclic AMP was studied in rat pancreatic islets under varying conditions of labeling. Prolonging the exposure to [ 3 H]adenine progressively augmented the islet cyclic [ 3 H]AMP level. Islets labeled for different periods of time and subsequently incubated (without adenine) in the presence of D-glucose or cholera toxin showed stimulations of intra-islet cyclic [ 3 H]AMP that were proportionate to the levels of radioactive nucleotide present under non-stimulatory conditions. Labeling the islets in a high glucose concentration (27.7 mM) did not modify the nucleotide responses to glucose or cholera toxin. The specific activity of cyclic [ 3 H]AMP, determined by simultaneous assay of cyclic [ 3 H]AMP and total cyclic AMP, was not influenced by glucose or cholera toxin. Glucose had no effect on the specific activity of labeled ATP

  7. Human pancreatic islet progenitor cells demonstrate phenotypic ...

    Indian Academy of Sciences (India)

    2009-04-24

    Apr 24, 2009 ... Phenotypic plasticity is a phenomenon that describes the occurrence of 2 or more distinct phenotypes under diverse conditions. This article discusses the work carried out over the past few years in understanding the potential of human pancreatic islet-derived progenitors for cell replacement therapy in ...

  8. Pancreatic islet transplantation. Experimental and clinical aspects

    DEFF Research Database (Denmark)

    Yderstræde, Knud Bonnet

    1987-01-01

    The deteriorating complications of diabetes mellitus (i.e. nephropathy, neuropathy, and retinopathy) have encouraged several attempts of causal therapy apart from a diversity of insulin therapies. These attempts include whole organ or segmental pancreas transplantation. In recent years, increasing...... interest has been shown in transplantation of isolated islets either directly, introduced intraportally, intramuscularly, inter alia, or encapsulated in artificial devices providing an immuno-isolation. Clinical application has revealed promising results concerning the immunological aspects. However......, quantitative assessment points to a difficulty in achieving satisfactory amounts of islets to attain normoglycaemia. Work with fetal pancreata has shown these to possess a growth potential in vitro thus, possibly, aiding the quantification of islets in transplantation models. In the field of pancreatic islet...

  9. Fission of pancreatic islets during postnatal growth of the mouse.

    Science.gov (United States)

    Seymour, Philip A; Bennett, William R; Slack, Jonathan M W

    2004-02-01

    A cell composition analysis was made of the pancreatic islets in postnatal H253 mice. This line has a lacZ insertion on the X chromosome so that in female hemizygotes 50% of cells should be positive for beta-galactosidase and 50% negative. Immediately after birth, the islets were of a heterogeneous cell composition. However, by 4 weeks some islets have become homogeneous. This suggests that islets progress towards monoclonality in a similar way to the intestinal crypts and stomach gastric glands. Pancreatic islets may therefore represent 'structural proliferative units' in the overall histological organization of the pancreas. Reduction of genetic heterogeneity might arise from cell turnover, fission of islets or both. Analysis of the cell composition of the X-inactivation mosaic mice also provides the first clear evidence for islet fission in pancreatic development. Irregularly shaped islets resembling dumb-bells, with a characteristic neck of alpha-cells, were observed with decreasing frequency with increasing age. Three-dimensional reconstruction confirmed their resemblance to conjoined islets. The cell composition analysis showed: (1) the relatedness of the two sides of a dumb-bell islet is significantly higher than between two non-dumb-bell islets and (2) the relatedness of two randomly selected islets decreases as the distance between them increases. This suggests that dumb-bell islets are in a state of fission rather than fusion, and that islet fission is a mode of islet production in the postnatal pancreas.

  10. Inhibition of carbachol-induced formation of inositolphosphates in isolated pancreatic islets

    DEFF Research Database (Denmark)

    Kardasz, A.M.J.; Capito, Kirsten; Hansen, Svend Erik

    1991-01-01

    Medicinsk biokemi, feed-back inhibition, phospholipase C, pancreatic islets, Calcium, proteinkinase C......Medicinsk biokemi, feed-back inhibition, phospholipase C, pancreatic islets, Calcium, proteinkinase C...

  11. Impact of islet size on pancreatic islet transplantation and potential interventions to improve outcome.

    Science.gov (United States)

    Zorzi, Daria; Phan, Tammy; Sequi, Marco; Lin, Yong; Freeman, Daniel H; Cicalese, Luca; Rastellini, Cristiana

    2015-01-01

    Better results have been recently reported in clinical pancreatic islet transplantation (ITX) due mostly to improved isolation techniques and immunosuppression; however, some limitations still exist. It is known that following transplantation, 30% to 60% of the islets are lost. In our study, we have investigated 1) the role of size as a factor affecting islet engraftment and 2) potential procedural manipulations to increase the number of smaller functional islets that can be transplanted. C57/BL10 mice were used as donors and recipients in a syngeneic islet transplant model. Isolated islets were divided by size (large, >300 μm; medium 150-300 μm; small, <150 μm). Each size was transplanted in chemically induced diabetic mice as full (600 IEQ), suboptimal (400 IEQ), and marginal mass (200 IEQ). Control animals received all size islets. Engraftment was defined as reversal of diabetes by day 7 posttransplantation. When the superiority of smaller islets was observed, strategies of overdigestion and fragmentation were adopted during islet isolation in the attempt to reduce islet size and improve engraftment. Smaller islets were significantly superior in engraftment compared to medium, large, and control (all sizes) groups. This was more evident when marginal mass data were compared. In all masses, success decreased as islet size increased. Once islets were engrafted, functionality was not affected by size. When larger islets were fragmented, a significant decrease in islet functionality was observed. On the contrary, if pancreata were slightly overdigested, although not as successful as small naive islets, an increase in engraftment was observed when compared to the control group. In conclusion, smaller islets are superior in engraftment following islet transplantation. Fragmentation has a deleterious effect on islet engraftment. Islet isolations can be performed by reducing islet size with slight overdigestion, and it can be safely adopted to improve clinical

  12. Postnatally disturbed pancreatic islet cell distribution in human islet amyloid polypeptide transgenic mice

    NARCIS (Netherlands)

    Wong, HY; Ahren, B; Lips, CJM; Hoppener, JWM; Sundler, F

    2003-01-01

    Objective: Islet amyloid polypeptide (IAPP)/amylin is produced by the pancreatic islet beta-cells, which also produce insulin. To study potential functions of IAPP, we have generated transgenic mice overexpressing human IAPP (hIAPP) in the beta-cells. These mice show a diabetic phenotype when

  13. Pancreatic islet regeneration: Therapeutic potential, unknowns and controversy

    Directory of Open Access Journals (Sweden)

    Ingrid L. Cockburn

    2015-07-01

    Full Text Available Glucose homeostasis in mammals is primarily maintained by the insulin-secreting β-cells contained within pancreas-resident islets of Langerhans. Gross disruption of this glucose regulation as a result of pancreatic dysfunction frequently results in diabetes, which is currently a major health concern in South Africa, as well as globally. For many years, researchers have realised that the pancreas, and specifically the islets of Langerhans, have a regenerative capacity, as islet mass has frequently been shown to increase following induced pancreatic injury. Given that gross β-cell loss contributes significantly to the pathogenesis of both type 1 and type 2 diabetes, endogenous pancreatic islet regeneration has been investigated extensively as a potential β-cell replacement therapy for diabetes. From the extensive research conducted on pancreatic regeneration, opposing findings and opinions have arisen as to how, and more recently even if, pancreatic regeneration occurs following induced injury. In this review, we outline and discuss the three primary mechanisms by which pancreatic regeneration is proposed to occur: neogenesis, β-cell replication and transdifferentiation. We further explain some of the advanced techniques used in pancreatic regeneration research, and conclude that despite the technologically advanced research tools available to researchers today, the mechanisms governing pancreatic regeneration may remain elusive until more powerful techniques are developed to allow for real-time, live-cell assessment of morphology and gene expression within the pancreas.

  14. File list: Oth.Pan.50.AllAg.Pancreatic_islets [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Pan.50.AllAg.Pancreatic_islets hg19 TFs and others Pancreas Pancreatic islets S...RX026719,SRX026702,SRX026720,SRX026706,SRX026721,SRX026714 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Pan.50.AllAg.Pancreatic_islets.bed ...

  15. File list: InP.Pan.10.AllAg.Pancreatic_islets [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Pan.10.AllAg.Pancreatic_islets hg19 Input control Pancreas Pancreatic islets SR...3,SRX340803,SRX375327,SRX340794,SRX026707,SRX375320 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Pan.10.AllAg.Pancreatic_islets.bed ...

  16. File list: ALL.Pan.50.AllAg.Pancreatic_islets [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Pan.50.AllAg.Pancreatic_islets hg19 All antigens Pancreas Pancreatic islets ERX...SRX026707,SRX375320,SRX026708,SRX026713 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Pan.50.AllAg.Pancreatic_islets.bed ...

  17. File list: Oth.Pan.05.AllAg.Pancreatic_islets [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Pan.05.AllAg.Pancreatic_islets hg19 TFs and others Pancreas Pancreatic islets S...RX026714,SRX026702,SRX026720,SRX026719,SRX026721,SRX026706 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Pan.05.AllAg.Pancreatic_islets.bed ...

  18. Controlled aggregation of primary human pancreatic islet cells leads to glucose-responsive pseudoislets comparable to native islets

    NARCIS (Netherlands)

    Hilderink, Janneke; Spijker, Siebe; Carlotti, Françoise; Lange, Lydia; Engelse, Marten; van Blitterswijk, Clemens; de Koning, Eelco; Karperien, Marcel; van Apeldoorn, Aart

    2015-01-01

    Clinical islet transplantation is a promising treatment for patients with type 1 diabetes. However, pancreatic islets vary in size and shape affecting their survival and function after transplantation because of mass transport limitations. To reduce diffusion restrictions and improve islet cell

  19. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture.

    Science.gov (United States)

    Malenczyk, Katarzyna; Keimpema, Erik; Piscitelli, Fabiana; Calvigioni, Daniela; Björklund, Peyman; Mackie, Kenneth; Di Marzo, Vincenzo; Hökfelt, Tomas G M; Dobrzyn, Agnieszka; Harkany, Tibor

    2015-11-10

    Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R(-/-) islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.

  20. Considerations for successful transplantation of encapsulated pancreatic islets

    NARCIS (Netherlands)

    de Vos, P; Hamel, AF; Tatarkiewicz, K

    Encapsulation of pancreatic islets allows for transplantion in the absence of immunosuppression. The technology is based on the principle that transplanted tissue is protected for the host immune system by an artificial membrane. Encapsulation offers a solution to the shortage of donors in clinical

  1. Human pancreatic islet progenitor cells demonstrate phenotypic ...

    Indian Academy of Sciences (India)

    Prakash

    exploring alternative sources of insulin-producing cells for cell based therapy in diabetes. Since in vitro culture of islet β-cells demonstrates loss in insulin (Beattie et al. 1999), several attempts have been made to identify stem / progenitor cells capable of differentiation into insulin-producing cells. Embryonic stem cells, which ...

  2. Pancreatic islet transplantation. Experimental and clinical aspects

    DEFF Research Database (Denmark)

    Yderstræde, Knud Bonnet

    1987-01-01

    transplantation, future models include microencapsulation and hybrid artificial devices, both of which provide immuno-isolation - thus the ability of allo- as well as xeno-transplantation. The obvious advantage of immuno-isolated islet transplant, as opposed to segmentally engrafted pancreas, is stressed...

  3. Regulation of Pancreatic Islet Gene Expression in Mouse Islets by Pregnancy

    DEFF Research Database (Denmark)

    Layden, Brian Thomas; Durai, Vivek; Newman, Marsha V

    2010-01-01

    Pancreatic beta cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in beta cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased......-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of G protein-coupled receptors which are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using real time RT-PCR assays......, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13.5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy....

  4. Sensing and Sensibility: Single-Islet-based Quality Control Assay of Cryopreserved Pancreatic Islets with Functionalized Hydrogel Microcapsules.

    Science.gov (United States)

    Chen, Wanyu; Shu, Zhiquan; Gao, Dayong; Shen, Amy Q

    2016-01-21

    Despite decades of research and clinical studies of islet transplantations, finding simple yet reliable islet quality assays that correlate accurately with in vivo potency is still a major challenge, especially for real-time and single-islet-based quality assessment. Herein, proof-of-concept studies of a cryopreserved microcapsule-based quality control assays are presented for single islets. Individual rat pancreatic islets and fluorescent oxygen-sensitive dye (FOSD) are encapsulated in alginate hydrogel microcapsules via a microfluidic device. To test the susceptibility of the microcapsules and the FOSD to cryopreservation, the islet microcapsules containing FOSD are cryopreserved and the islet functionalities (adenosine triphosphate, static insulin release measurement, and oxygen consumption rate) are assessed after freezing and thawing steps. The cryopreserved islet capsules with FOSD remain functional after encapsulation and freezing/thawing procedures, validating a simple yet reliable individual-islet-based quality control method for the entire islet processing procedure prior to transplantation. This work also demonstrates that the functionality of cryopreserved islets can be improved by introducing trehalose into the routinely used cryoprotectant dimethyl sulfoxide. The functionalized alginate hydrogel microcapsules with embedded FOSD and optimized cryopreservation protocol presented in this work serve as a versatile islet quality assay and offer tremendous promise for tackling existing challenges in islet transplantation procedures. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. RNA-sequencing of WFS1-deficient pancreatic islets.

    Science.gov (United States)

    Ivask, Marilin; Hugill, Alison; Kõks, Sulev

    2016-04-01

    Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in theWFS1gene.WFS1encodes an endoplasmic reticulum resident transmembrane protein. TheWfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of this study was to describe the insulin secretion and transcriptome of pancreatic islets inWFS1-deficient mice.WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KOpancreatic islets secreted less insulin after incubation in 2 and 10 mmol/L glucose and with tolbutamide solution compared toWTand Wfs1HZislets, but not after stimulation with 20 mmol/L glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KOhad an increased level of proinsulin. After incubation in 2 mmol/L glucose solution the proinsulin/insulin ratio in Wfs1KOwas significantly higher than that ofWTand Wfs1HZRNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated inWFS1-deficient mice. Functional annotation ofRNAsequencing results showed thatWFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  6. Novel Fusion Protein Targeting Mitochondrial DNA Improves Pancreatic Islet Functional Potency and Islet Transplantation Outcomes.

    Science.gov (United States)

    Danobeitia, Juan S; Chlebeck, Peter J; Shokolenko, Inna; Ma, Xiaobo; Wilson, Glenn; Fernandez, Luis A

    2017-11-01

    Long-term graft survival is an ongoing challenge in the field of islet transplantation. With the growing demand for transplantable organs, therapies to improve organ quality and reduce the incidence of graft dysfunction are of paramount importance. We evaluated the protective role of a recombinant DNA repair protein targeted to mitochondria (Exscien I-III), as a therapeutic agent using a rodent model of pancreatic islet transplantation. We first investigated the effect of therapy on isolated rat islets cultured with pro-inflammatory cytokines (interleukin-1 β, interferon γ, and tumor necrosis factor α) for 48 h and documented a significant reduction in apoptosis by flow cytometry, improved viability by immunofluorescence, and conserved functional potency in vitro and in vivo in Exscien I-III-treated islets. We then tested the effect of therapy in systemic inflammation using a rat model of donor brain death (BD) sustained for a 6-h period. Donor rats were allocated to 4 groups: (non-BD + vehicle, non-BD + Exscien I-III, BD + vehicle, and BD + Exscien I-III) and treated with Exscien I-III (4 mg/kg) or vehicle 30 min after BD induction. Sham (non-BD)-operated animals receiving either Exscien I-III or vehicle served as controls. Islets purified from BD + Exscien I-III-treated donors showed a significant increase in glucose-stimulated insulin release in vitro when compared to islets from vehicle-treated counterparts. In addition, donor treatment with Exscien I-III attenuated the effects of BD and significantly improved the functional potency of transplanted islets in vivo. Our data indicate that mitochondrially targeted antioxidant therapy is a novel strategy to protect pancreas and islet quality from the deleterious effects of cytokines in culture and during the inflammatory response associated with donation after BD. The potential for rapid translation into clinical practice makes Exscien I-III an attractive therapeutic option for the management of brain

  7. CT anglographic evaluation of pancreatic islet cell tumors

    International Nuclear Information System (INIS)

    Merine, D.S.; Fishman, E.K.; Kuhlman, J.E.; Siegelman, S.S.; Widlus, D.M.; Cameron, J.L.

    1989-01-01

    To increase the accuracy of CT staging of pancreatic cancer, the authors modified the standard techniques for CT angiography (CTA). Six patients with known or suspected pancreatic islet cell tumors were examined by CTA. The catheter was placed in the superior mesenteric artery, and a sequence of dynamic CT scans were obtained while 150 mL of Hypaque-30 was injected at a rate of 2 mL/sec. In addition to clear identification of the pancreatic tumor mass, CTA proved valuable in evaluating liver metastasis (n = 3) and venous thrombosis (n = 2. In one case, a 1-cm functioning insulinoma was demonstrated by CTA after unsuccessful angiographic detection. In all cases, correlation with surgical or biopsy results showed the CTA to be accurate

  8. Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life

    DEFF Research Database (Denmark)

    Barbosa, Francisco B; Capito, Kirsten; Kofod, Hans

    2002-01-01

    Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.7% protein group was reduced 50%. The islet insulin and DNA content were similar...

  9. A double mechanism for the mesenchymal stem cells' positive effect on pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Arianna Scuteri

    Full Text Available The clinical usability of pancreatic islet transplantation for the treatment of type I diabetes, despite some encouraging results, is currently hampered by the short lifespan of the transplanted tissue. In vivo studies have demonstrated that co-transplantation of Mesenchymal Stem Cells (MSCs with transplanted pancreatic islets is more effective with respect to pancreatic islets alone in ensuring glycemia control in diabetic rats, but the molecular mechanisms of this action are still unclear. The aim of this study was to elucidate the molecular mechanisms of the positive effect of MSCs on pancreatic islet functionality by setting up direct, indirect and mixed co-cultures. MSCs were both able to prolong the survival of pancreatic islets, and to directly differentiate into an "insulin-releasing" phenotype. Two distinct mechanisms mediated these effects: i the survival increase was observed in pancreatic islets indirectly co-cultured with MSCs, probably mediated by the trophic factors released by MSCs; ii MSCs in direct contact with pancreatic islets started to express Pdx1, a pivotal gene of insulin production, and then differentiated into insulin releasing cells. These results demonstrate that MSCs may be useful for potentiating pancreatic islets' functionality and feasibility.

  10. Rat pancreatic islet function during prolonged glucose stimulation in vitro : Effect of sex and reproductive state

    NARCIS (Netherlands)

    Moes, H; Koiter, TR

    Prolonged stimulation with glucose may induce desensitisation of pancreatic beta-cell function in male rats. The effects of such a treatment on pancreatic islets of pregnant (P) rats, in which beta-cell function is enhanced, were studied in a perifusion design and compared with the effects on islets

  11. Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis

    DEFF Research Database (Denmark)

    Størling, Joachim; Pociot, Flemming

    2017-01-01

    Type 1 diabetes (T1D) is a chronic immune-mediated disease resulting from the selective destruction of the insulin-producing pancreatic islet β-cells. Susceptibility to the disease is the result of complex interactions between environmental and genetic risk factors. Genome-wide association studie...... with focus on pancreatic islet cell inflammation and β-cell apoptosis....

  12. Diffusion weighted MR imaging of pancreatic islet cell tumors

    International Nuclear Information System (INIS)

    Bakir, Baris; Salmaslioglu, Artur; Poyanli, Arzu; Rozanes, Izzet; Acunas, Bulent

    2010-01-01

    Purpose: The aim of our study is to demonstrate the feasibility of body diffusion weighted (DW) MR imaging in the evaluation of pancreatic islet cell tumors (ICTs) and to define apparent diffusion coefficient (ADC) values for these tumors. Materials and methods: 12 normal volunteers and 12 patients with histopathologically proven pancreatic ICT by surgery were included in the study. DW MR images were obtained by a body-phased array coil using a multisection single-shot echo planar sequence on the axial plane without breath holding. In addition, the routine abdominal imaging protocol for pancreas was applied in the patient group. We measured the ADC value within the normal pancreas in control group, pancreatic ICT, and surrounding pancreas parenchyma. Mann-Whitney U-test has been used to compare ADC values between tumoral tissues and normal pancreatic tissues of the volunteers. Wilcoxon Signed Ranks Test was preferred to compare ADC values between tumoral tissues and surrounding pancreatic parenchyma of the patients. Results: In 11 patients out of 12, conventional MR sequences were able to demonstrate ICTs successfully. In 1 patient an indistinct suspicious lesion was noted at the pancreatic tail. DW sequence was able to demonstrate the lesions in all of the 12 patients. On the DW images, all ICTs demonstrated high signal intensity relative to the surrounding pancreatic parenchyma. The mean and standard deviations of the ADC values (x10 -3 mm 2 /s) were as follows: ICT (n = 12), 1.51 ± 0.35 (0.91-2.11), surrounding parenchyma (n = 11) 0.76 ± 0.15 (0.51-1.01) and normal pancreas in normal volunteers (n = 12), 0.80 ± 0.06 (0.72-0.90). ADC values of the ICT were significantly higher compared with those of surrounding parenchyma (p < 0.01) and normal pancreas (p < 0.001). Conclusion: DW MR imaging does not appear to provide significant contribution to routine MR imaging protocol in the evaluation of pancreatic islet cell tumors. But it can be added to MR imaging

  13. Diffusion weighted MR imaging of pancreatic islet cell tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bakir, Baris [Department of Radiology, Istanbul University, Istanbul Medical School, Capa 34390, Istanbul (Turkey)], E-mail: drbarisbakir@yahoo.com; Salmaslioglu, Artur; Poyanli, Arzu; Rozanes, Izzet; Acunas, Bulent [Department of Radiology, Istanbul University, Istanbul Medical School, Capa 34390, Istanbul (Turkey)

    2010-04-15

    Purpose: The aim of our study is to demonstrate the feasibility of body diffusion weighted (DW) MR imaging in the evaluation of pancreatic islet cell tumors (ICTs) and to define apparent diffusion coefficient (ADC) values for these tumors. Materials and methods: 12 normal volunteers and 12 patients with histopathologically proven pancreatic ICT by surgery were included in the study. DW MR images were obtained by a body-phased array coil using a multisection single-shot echo planar sequence on the axial plane without breath holding. In addition, the routine abdominal imaging protocol for pancreas was applied in the patient group. We measured the ADC value within the normal pancreas in control group, pancreatic ICT, and surrounding pancreas parenchyma. Mann-Whitney U-test has been used to compare ADC values between tumoral tissues and normal pancreatic tissues of the volunteers. Wilcoxon Signed Ranks Test was preferred to compare ADC values between tumoral tissues and surrounding pancreatic parenchyma of the patients. Results: In 11 patients out of 12, conventional MR sequences were able to demonstrate ICTs successfully. In 1 patient an indistinct suspicious lesion was noted at the pancreatic tail. DW sequence was able to demonstrate the lesions in all of the 12 patients. On the DW images, all ICTs demonstrated high signal intensity relative to the surrounding pancreatic parenchyma. The mean and standard deviations of the ADC values (x10{sup -3} mm{sup 2}/s) were as follows: ICT (n = 12), 1.51 {+-} 0.35 (0.91-2.11), surrounding parenchyma (n = 11) 0.76 {+-} 0.15 (0.51-1.01) and normal pancreas in normal volunteers (n = 12), 0.80 {+-} 0.06 (0.72-0.90). ADC values of the ICT were significantly higher compared with those of surrounding parenchyma (p < 0.01) and normal pancreas (p < 0.001). Conclusion: DW MR imaging does not appear to provide significant contribution to routine MR imaging protocol in the evaluation of pancreatic islet cell tumors. But it can be added to

  14. Functional implications of long non-coding RNAs in the pancreatic islets of Langerhans

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    Lena eEliasson

    2014-07-01

    Full Text Available Type-2 diabetes (T2D is a complex disease characterized by insulin resistance in target tissues and impaired insulin release from pancreatic beta cells. As central tissue of glucose homeostasis, the pancreatic islet continues to be an important focus of research to understand the pathophysiology of the disease. The increased access to human pancreatic islets has resulted in improved knowledge of islet function, and together with advances in RNA sequencing and related technologies, revealed the transcriptional and epigenetic landscape of human islet cells. The discovery of thousands of long non-coding RNA (lncRNA transcripts highly enriched in the pancreatic islet and/or specifically-expressed in the beta-cells, points to yet another layer of gene regulation of many hitherto unknown mechanistic principles governing islet cell functions. Here we review fundamental islet physiology and propose functional implications of the lncRNAs in islet development and endocrine cell functions. We also take into account important differences between rodent and human islets in terms of morphology and function, and suggest how species-specific lncRNAs may partly influence gene regulation to define the unique phenotypic identity of an organism and the functions of its constituent cells. The implication of primate-specific lncRNAs in diabetes will be far-reaching in all aspects of diabetes research, but most importantly in the identification and development of novel targets to improve pancreatic islet cell functions as a therapeutic approach to treat T2D.

  15. [Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].

    Science.gov (United States)

    Godehardt, Antonia W; Schilling-Leiß, Dagmar; Sanzenbacher, Ralf; Tönjes, Ralf R

    2015-11-01

    In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.

  16. Can pancreatic duct-derived progenitors be a source of islet regeneration?

    International Nuclear Information System (INIS)

    Xia, Bing; Zhan, Xiao-Rong; Yi, Ran; Yang, Baofeng

    2009-01-01

    The regenerative process of the pancreas is of interest because the main pathogenesis of diabetes mellitus is an inadequate number of insulin-producing β-cells. The functional mass of β-cells is decreased in type 1 diabetes, so replacing missing β-cells or triggering their regeneration may allow for improved type 1 diabetes treatment. Therefore, expansion of the β-cell mass from endogenous sources, either in vivo or in vitro, represents an area of increasing interest. The mechanism of islet regeneration remains poorly understood, but the identification of islet progenitor sources is critical for understanding β-cell regeneration. One potential source is the islet proper, via the dedifferentiation, proliferation, and redifferentiation of facultative progenitors residing within the islet. Neogenesis, or that the new pancreatic islets can derive from progenitor cells present within the ducts has been reported, but the existence and identity of the progenitor cells have been debated. In this review, we focus on pancreatic ductal cells, which are islet progenitors capable of differentiating into islet β-cells. Islet neogenesis, seen as budding of hormone-positive cells from the ductal epithelium, is considered to be one mechanism for normal islet growth after birth and in regeneration, and has suggested the presence of pancreatic stem cells. Numerous results support the neogenesis hypothesis, the evidence for the hypothesis in the adult comes primarily from morphological studies that have in common the production of damage to all or part of the pancreas, with consequent inflammation and repair. Although numerous studies support a ductal origin for new islets after birth, lineage-tracing experiments are considered the 'gold standard' of proof. Lineage-tracing experiments show that pancreatic duct cells act as progenitors, giving rise to new islets after birth and after injury. The identification of differentiated pancreatic ductal cells as an in vivo progenitor for

  17. Can pancreatic duct-derived progenitors be a source of islet regeneration?

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Bing [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Zhan, Xiao-Rong, E-mail: xiaorongzhan@sina.com [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Yi, Ran [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Yang, Baofeng [Department of Pharmacology, State Key Laboratory of Biomedicine and Pharmacology, Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China)

    2009-06-12

    The regenerative process of the pancreas is of interest because the main pathogenesis of diabetes mellitus is an inadequate number of insulin-producing {beta}-cells. The functional mass of {beta}-cells is decreased in type 1 diabetes, so replacing missing {beta}-cells or triggering their regeneration may allow for improved type 1 diabetes treatment. Therefore, expansion of the {beta}-cell mass from endogenous sources, either in vivo or in vitro, represents an area of increasing interest. The mechanism of islet regeneration remains poorly understood, but the identification of islet progenitor sources is critical for understanding {beta}-cell regeneration. One potential source is the islet proper, via the dedifferentiation, proliferation, and redifferentiation of facultative progenitors residing within the islet. Neogenesis, or that the new pancreatic islets can derive from progenitor cells present within the ducts has been reported, but the existence and identity of the progenitor cells have been debated. In this review, we focus on pancreatic ductal cells, which are islet progenitors capable of differentiating into islet {beta}-cells. Islet neogenesis, seen as budding of hormone-positive cells from the ductal epithelium, is considered to be one mechanism for normal islet growth after birth and in regeneration, and has suggested the presence of pancreatic stem cells. Numerous results support the neogenesis hypothesis, the evidence for the hypothesis in the adult comes primarily from morphological studies that have in common the production of damage to all or part of the pancreas, with consequent inflammation and repair. Although numerous studies support a ductal origin for new islets after birth, lineage-tracing experiments are considered the 'gold standard' of proof. Lineage-tracing experiments show that pancreatic duct cells act as progenitors, giving rise to new islets after birth and after injury. The identification of differentiated pancreatic ductal

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

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    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.

  19. Immunohistochemical analysis of pancreatic islets of platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus ssp.).

    Science.gov (United States)

    He, Chuan; Myers, Mark A; Forbes, Briony E; Grützner, Frank

    2015-04-01

    Monotremes have undergone remarkable changes to their digestive and metabolic control system; however, the monotreme pancreas remains poorly characterized. Previous work in echidna demonstrated the presence of pancreatic islets, but no information is available for platypus and the fine structure has not been described for either monotreme. Based on our recent finding that monotremes lack the ghrelin gene, which is expressed in mouse and human pancreatic islets, we investigated the structure of monotreme islets in more detail. Generally, as in birds, the islets of monotremes were smaller but greater in number compared with mouse. β-cells were the most abundant endocrine cell population in platypus islets and were located peripherally, while α-cells were observed both in the interior and periphery of the islets. δ-cells and pancreatic polypeptide (PP)-cells were mainly found in the islet periphery. Distinct PP-rich (PP-lobe) and PP-poor areas (non-PP-lobe) are present in therian mammals, and we identified these areas in echidna but not platypus pancreas. Interestingly, in some of the echidna islets, α- and β-cells tended to form two poles within the islets, which to our knowledge is the first time this has been observed in any species. Overall, monotreme pancreata share the feature of consisting of distinct PP-poor and PP-rich islets with other mammals. A higher number of islets and α- or β-cell only islets are shared between monotremes and birds. The islets of monotremes were larger than those of birds but smaller compared with therian mammals. This may indicate a trend of having fewer larger islets comprising several endocrine cell types during mammalian evolution. © 2015 Anatomical Society.

  20. A VERSATILE ALGINATE DROPLET GENERATOR APPLICABLE FOR MICROENCAPSULATION OF PANCREATIC-ISLETS

    NARCIS (Netherlands)

    WOLTERS, GHJ; FRITSCHY, WM; GERRITS, D; VANSCHILFAGAARDE, R

    1992-01-01

    Alginate beads for immunoisolation of pancreatic islets by microencapsulation should be small, smooth, and spherical in order to ensure that around the islets a strong alginate-polylysine-alginate capsule will be formed with optimal biocompatibility and diffusion of nutrients and hormones. However,

  1. A Retrievable, Efficacious Polymeric Scaffold for Subcutaneous Transplantation of Rat Pancreatic Islets

    NARCIS (Netherlands)

    Smink, Alexandra M; Hertsig, Don T; Schwab, Leendert; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Haan, Bart J; de Vos, Paul

    2016-01-01

    OBJECTIVE: We aim on developing a polymeric ectopic scaffold in a readily accessible site under the skin. SUMMARY BACKGROUND DATA: The liver as transplantation site for pancreatic islets is associated with significant loss of islets. Several extrahepatic sites were tested in experimental animals,

  2. A Retrievable, Efficacious Polymeric Scaffold for Subcutaneous Transplantation of Rat Pancreatic Islets

    NARCIS (Netherlands)

    Smink, Alexandra M; Hertsig, Don T; Schwab, Leendert; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Haan, Bart J; de Vos, Paul

    OBJECTIVE: We aim on developing a polymeric ectopic scaffold in a readily accessible site under the skin. SUMMARY BACKGROUND DATA: The liver as transplantation site for pancreatic islets is associated with significant loss of islets. Several extrahepatic sites were tested in experimental animals,

  3. Microfabricated biocapsules for the immunoisolation of pancreatic islets of Langerhans

    Science.gov (United States)

    Desai, Tejal Ashwin

    1998-08-01

    A silicon-based microfabricated biocapsule was developed and evaluated for use in the immunoisolation of transplanted cells, specifically pancreatic islets of Langerhans for the treatment of Type I diabetes. The transplantation of cells with specific functions is a promising therapy for a wide variety of pathologies including diabetes, Parkinson's, and hemophilia. Such transplanted cells, however, are sensitive to both cellular and humoral immune rejection as well as damage by autoimmune activity, without chronic immunosuppression. The research presented in this dissertation investigated whether microfabricated silicon-based biocapsules, with uniform membrane pore sizes in the tens of nanometer range, could provide an immunoprotective environment for pancreatic islets and other insulin-secreting cell lines, while maintaining cell viability and functionality. By utilizing fabrication techniques commonly employed in the microelectronics industry (MEMS), membranes were fabricated with precisely controlled and uniform pore sizes, allowing the optimization of biocapsule membrane parameters for the encapsulation of specific hormone-secreting cell types. The biocapsule-forming process employed bulk micromachining to define cell-containing chambers within single crystalline silicon wafers. These chambers interface with the surrounding biological environment through polycrystalline silicon filter membranes, which were surface micromachined to present a high density of uniform pores to allow sufficient permeability to oxygen, glucose, and insulin. Both in vitro and in vivo experiments established the biocompatibility of the microfabricated biocapsule, and demonstrated that encapsulated cells could live and function normally in terms of insulin-secretion within microfabricated environments for extended periods of time. This novel research shows the potential of using microfabricated biocapsules for the encapsulation of several different cell xenografts. The semipermeability

  4. Carbon monoxide and pancreatic islet blood flow in the rat: inhibition of haem oxygenase does not affect islet blood perfusion.

    Science.gov (United States)

    Carlsson, P-O; Bodin, B; Andersson, A; Jansson, L

    2006-01-01

    To determine whether carbon monoxide, a known gaseous vasorelaxator, affects pancreatic islet blood flow in rats. Sprague-Dawley rats were anaesthetized with thiobutabarbital and injected intravenously with the haem oxygenase inhibitor tin-protoporphyrin IX dichloride (SnPP; 4, 10 or 20 mg/kg body-weight). After 15 min, blood flow measurements were performed using a microsphere technique. There was a slight increase in mean arterial blood pressure with the highest dose of SnPP. No effects on total pancreatic, islet, duodenal, colonic, renal or adrenal blood flow were seen with any of the applied doses. The findings of this study suggest that the haem oxygenase-carbon monoxide system is likely to be of limited importance in the regulation of blood perfusion to the pancreas, the islets of Langerhans or any of the other studied organs.

  5. A Combinatorial Protein Microarray for Probing Materials Interaction with Pancreatic Islet Cell Populations

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    Bahman Delalat

    2016-08-01

    Full Text Available Pancreatic islet transplantation has become a recognized therapy for insulin-dependent diabetes mellitus. During isolation from pancreatic tissue, the islet microenvironment is disrupted. The extracellular matrix (ECM within this space not only provides structural support, but also actively signals to regulate islet survival and function. In addition, the ECM is responsible for growth factor presentation and sequestration. By designing biomaterials that recapture elements of the native islet environment, losses in islet function and number can potentially be reduced. Cell microarrays are a high throughput screening tool able to recreate a multitude of cellular niches on a single chip. Here, we present a screening methodology for identifying components that might promote islet survival. Automated fluorescence microscopy is used to rapidly identify islet derived cell interaction with ECM proteins and immobilized growth factors printed on arrays. MIN6 mouse insulinoma cells, mouse islets and, finally, human islets are progressively screened. We demonstrate the capability of the platform to identify ECM and growth factor protein candidates that support islet viability and function and reveal synergies in cell response.

  6. Pancreatic islets of variable size - insulin secretion and glucose utilization

    International Nuclear Information System (INIS)

    Colella, R.M.; Bonner-Weir, S.; Braunstein, L.P.; Schwalke, M.; Weir, G.C.

    1985-01-01

    Glucose metabolism and insulin secretion were studied in isolated rat pacreatic islets of different sizes and the amount of tissue was quantitated by the measurement of DNA. It was found that larger islets (140-210 ng DNA/islet) utilized more glucose (based on the conversion of 3 H-5-glucose to 3 H 2 O) per ng of DNA than islets containing less DNA (60-120 ng/islet). However, the insulin secreted per ng of DNA in response to a given glucose concentration was the same in islets of all sizes. Also, the islet insulin and glucagon content when expressed in terms of DNA did not depend upon islet size. Thus, although glucose utilization rates expressed as a function of islet DNA content were greater in larger islets, no such relationship was found for glucose-induced insulin release or insulin and glucagon content. 17 reference, 1 figure, 3 tables

  7. Data on morphometric analysis of the pancreatic islets from C57BL/6 and BALB/c mice

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    Thiago Aparecido da Silva

    2016-09-01

    Full Text Available The endocrine portion of the pancreas, which is characterized by pancreatic islets, has been widely investigated among different species. The BALB/c and C57BL/6 mice are extensively used in experimental research, and the morphometric differences in the pancreatic islets of these animals have not been evaluated so far. Thus, our data have a comparative perspective related to the morphometric analysis of area, diameters, circularity, and density of pancreatic islets from BALB/c and C57BL/6 mice. The data presented here are focused to evaluate the differences in morphology of pancreatic islets of two common laboratory mouse strains.

  8. Chronically decreased oxygen tension in rat pancreatic islets transplanted under the kidney capsule.

    Science.gov (United States)

    Carlsson, P O; Palm, F; Andersson, A; Liss, P

    2000-03-15

    A factor of potential importance in the failure of islet grafts is poor or inadequate engraftment of the islets in the implantation organ. This study measured the oxygen tension and blood perfusion in 1-, 2-, and 9-month-old islet grafts. The partial pressure of oxygen was measured in pancreatic islets transplanted beneath the renal capsule of diabetic and nondiabetic recipient rats with a modified Clark electrode (outer tip diameter 2-6 microm). The size of the graft (250 islets) was by purpose not large enough to cure the diabetic recipients. The oxygen tension in islets within the pancreas was also recorded. Blood perfusion was measured with the laser-Doppler technique. Within native pancreatic islets, the partial pressure of oxygen was approximately 40 mm Hg (n=8). In islets transplanted to nondiabetic animals, the oxygen tension was approximately 6-7 mm Hg 1, 2, and 9 months posttransplantation. No differences could be seen between the different time points after transplantation. In the diabetic recipients, an even more pronounced decrease in graft tissue oxygen tension was recorded. The mean oxygen tension in the superficial renal cortex surrounding the implanted islets was similar in all groups (approximately 15 mm Hg). Intravenous administration of glucose (0.1 gxkg(-1)x min(-1)) did not affect the oxygen tension in any of the investigated tissues. The islet graft blood flow was similar in all groups, measuring approximately 50% of the blood flow in the kidney cortex. The oxygen tension in islets implanted beneath the kidney capsule is markedly lower than in native islets up to 9 months after transplantation. Moreover, persistent hyperglycemia in the recipient causes an even further decrease in graft oxygen tension, despite similar blood perfusion. To what extent this may contribute to islet graft failure remains to be determined.

  9. In Vitro Proliferation of Porcine Pancreatic Islet Cells for β-Cell Therapy Applications

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    Guoguang Niu

    2016-01-01

    Full Text Available β-Cell replacement through transplantation is the only curative treatment to establish a long-term stable euglycemia in diabetic patients. Owing to the shortage of donor tissue, attempts are being made to develop alternative sources of insulin-secreting cells. Stem cells differentiation and reprograming as well as isolating pancreatic progenitors from different sources are some examples; however, no approach has yet yielded a clinically relevant solution. Dissociated islet cells that are cultured in cell numbers by in vitro proliferation provide a promising platform for redifferentiation towards β-cells phenotype. In this study, we cultured islet-derived cells in vitro and examined the expression of β-cell genes during the proliferation. Islets were isolated from porcine pancreases and enzymatically digested to dissociate the component cells. The cells proliferated well in tissue culture plates and were subcultured for no more than 5 passages. Only 10% of insulin expression, as measured by PCR, was preserved in each passage. High glucose media enhanced insulin expression by about 4–18 fold, suggesting a glucose-dependent effect in the proliferated islet-derived cells. The islet-derived cells also expressed other pancreatic genes such as Pdx1, NeuroD, glucagon, and somatostatin. Taken together, these results indicate that pancreatic islet-derived cells, proliferated in vitro, retained the expression capacity for key pancreatic genes, thus suggesting that the cells may be redifferentiated into insulin-secreting β-like cells.

  10. Microencapsulated 3-Dimensional Sensor for the Measurement of Oxygen in Single Isolated Pancreatic Islets

    Science.gov (United States)

    Khalil, Gamal; Sweet, Ian R.; Shen, Amy Q.

    2012-01-01

    Background Oxygen consumption reflects multiple processes in pancreatic islets including mechanisms contributing to insulin secretion, oxidative stress and viability, providing an important readout in studies of islet function, islet viability and drug testing. Due to the scarcity, heterogeneity, and intrinsic kinetic properties of individual islets, it would be of great benefit to detect oxygen consumption by single islets. We present a novel method we have developed to image oxygen in single islets. Methodology/Principal Findings Using a microfluidics system, individual islets and a fluorescent oxygen-sensitive dye were encased within a thin alginate polymer layer. Insulin secretion by the encapsulated islets was normal. Fluorescent signal from the encased dye, detected using a standard inverted fluorescence microscope and digital camera, was stable and proportional to the amount of oxygen in the media. When integrated into a perifusion system, the sensing system detected changes in response to metabolic substrates, mitochondrial poisons, and induced-oscillations. Glucose responses averaged 30.1±7.1% of the response to a metabolic inhibitor (cyanide), increases were observed in all cases (n = 6), and the system was able to resolve changes in oxygen consumption that had a period greater than 0.5 minutes. The sensing system operated similarly from 2–48 hours following encapsulation, and viability and function of the islets were not significantly affected by the encapsulation process. Conclusions/Significance An oxygen-dependent dye situated around and within a pancreatic islet encapsulated by a thin layer of alginate was sensitive to changes in oxygen consumption, and was not harmful to the function or viability of islets over the course of two days. The microcapsule-based sensing method is particularly suited to assessing the effects of compounds (dose responses and time courses) and chronic changes occurring over the course of days. The approach should be

  11. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue

    International Nuclear Information System (INIS)

    Lechner, Andreas; Nolan, Anna L.; Blacken, Robyn A.; Habener, Joel F.

    2005-01-01

    Cellular replacement therapy holds promise for the treatment of diabetes mellitus but donor tissue is severely limited. Therefore, we investigated whether insulin-secreting cells could be differentiated in vitro from a monolayer of cells expanded from human donor pancreatic islets. We describe a three-step culture protocol that allows for the efficient generation of insulin-producing cell clusters from in vitro expanded, hormone-negative cells. These clusters express insulin at levels of up to 34% that of average freshly isolated human islets and secrete C-peptide upon membrane depolarization. They also contain cells expressing the other major islet hormones (glucagon, somatostatin, and pancreatic polypeptide). The source of the newly differentiated endocrine cells could either be indigenous stem/progenitor cells or the proliferation-associated dedifferentiation and subsequent redifferentiation of mature endocrine cells. The in vitro generated cell clusters may be efficacious in providing islet-like tissue for transplantation into diabetic recipients

  12. Dimethyl fumarate protects pancreatic islet cells and non-endocrine tissue in L-arginine-induced chronic pancreatitis.

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    Lourdes Robles

    Full Text Available Chronic pancreatitis (CP is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP.Male Wistar rats fed daily DMF (25 mg/kg or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g × 2, 1 hr apart. Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg. Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO, and lipid peroxidation level (MDA. In vitro assessments included determination of heme oxygenase (HO-1 protein expression by Western blot.Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P <0.05. Untreated CP rats had pancreatic atrophy, severe acinar architectural damage, edema, and fatty infiltration as well as elevated MDA and MPO levels, which were significantly improved by DMF treatment. After islet isolation, the volume of non-endocrine tissue was significantly smaller in untreated CP group. Although islet counts were similar in the two groups, islet viability was significantly reduced in untreated CP group and improved with DMF treatment. In vitro incubation of human pancreatic tissue with DMF significantly increased HO-1 expression.Administration of DMF attenuated L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical

  13. Hypothyroidism Affects Vascularization and Promotes Immune Cells Infiltration into Pancreatic Islets of Female Rabbits

    Science.gov (United States)

    Rodríguez-Castelán, Julia; Martínez-Gómez, Margarita; Castelán, Francisco; Cuevas, Estela

    2015-01-01

    Thyroidectomy induces pancreatic edema and immune cells infiltration similarly to that observed in pancreatitis. In spite of the controverted effects of hypothyroidism on serum glucose and insulin concentrations, the number and proliferation of Langerhans islet cells as well as the presence of extracellular matrix are affected depending on the islet size. In this study, we evaluated the effect of methimazole-induced hypothyroidism on the vascularization and immune cells infiltration into islets. A general observation of pancreas was also done. Twelve Chinchilla-breed female adult rabbits were divided into control (n = 6) and hypothyroid groups (n = 6, methimazole, 0.02% in drinking water for 30 days). After the treatment, rabbits were sacrificed and their pancreas was excised, histologically processed, and stained with Periodic Acid-Schiff (PAS) or Masson's Trichrome techniques. Islets were arbitrarily classified into large, medium, and small ones. The external and internal portions of each islet were also identified. Student-t-test and Mann-Whitney-U test or two-way ANOVAs were used to compare variables between groups. In comparison with control rabbits, hypothyroidism induced a strong infiltration of immune cells and a major presence of collagen and proteoglycans in the interlobular septa. Large islets showed a high vascularization and immune cells infiltration. The present results show that hypothyroidism induces pancreatitis and insulitis. PMID:26175757

  14. Targeting pancreatic islets with phage display assisted by laser pressure catapult microdissection.

    Science.gov (United States)

    Yao, Virginia J; Ozawa, Michael G; Trepel, Martin; Arap, Wadih; McDonald, Donald M; Pasqualini, Renata

    2005-02-01

    Heterogeneity of the microvasculature in different organs has been well documented by multiple methods including in vivo phage display. However, less is known about the diversity of blood vessels within functionally distinct regions of organs. Here, we combined in vivo phage display with laser pressure catapult microdissection to identify peptide ligands for vascular receptors in the islets of Langerhans in the murine pancreas. Protein database analyses of the peptides, CVSNPRWKC and CHVLWSTRC, showed sequence identity to two ephrin A-type ligand homologues, A2 and A4. Confocal microscopy confirmed that most immunoreactivity of CVSNPRWKC and CHVLWSTRC phage was associated with blood vessels in pancreatic islets. Antibodies recognizing EphA4, a receptor for ephrin-A ligands, were similarly associated with islet blood vessels. Importantly, binding of both islet-homing phage and anti-EphA4 antibody was strikingly increased in blood vessels of pancreatic islet tumors in RIP-Tag2 transgenic mice. These results indicate that endothelial cells of blood vessels in pancreatic islets preferentially express EphA4 receptors, and this expression is increased in tumors. Our findings show in vivo phage display and laser pressure catapult microdissection can be combined to reveal endothelial cell specialization within focal regions of the microvasculature.

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

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    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.

  16. Pancreatic islet blood flow during euglycaemic, hyperinsulinaemic clamp in anaesthetized rats.

    Science.gov (United States)

    Jansson, L; Andersson, A; Bodin, B; Källskog, O

    2007-04-01

    Previous studies have demonstrated that pancreatic islet blood flow is crucially dependent on blood glucose concentration. Thus, hyperglycaemia increases and hypoglycaemia decreases islet blood perfusion, by a combination of nervous and metabolic signals. The aim of the present study was to evaluate if hyperinsulinaemia, without associated hypoglycaemia, affects islet blood flow. Thiobutabarbital-anaesthetized Wistar-Furth rats were subjected to an euglycaemic, hyperinsulinaemic clamp, that is they were infused for 60 min with either saline, insulin (18 mU kg(-1) min(-1)), glucose (27 mg kg(-1) min(-1)) or both glucose and insulin. This was followed by islet blood flow measurements with a microsphere technique. Animals receiving only glucose doubled their blood glucose and serum insulin concentrations, whereas rats receiving only insulin had blood glucose concentrations <2 mmol L(-1) and a 10-fold increase in serum insulin concentrations. Animals given simultaneous glucose and insulin had normal blood glucose concentrations but a 10-fold increase in serum insulin concentrations. Total pancreatic blood flow was unaffected in all animals. Islet blood flow was increased in hyperglycaemic and decreased in hypoglycaemic rats compared with control rats. Islet blood flow did not differ between clamped and control rats. Serum insulin concentration per se does not affect islet blood flow, whereas the ambient blood glucose concentration is of major importance in this context.

  17. Human omentum fat-derived mesenchymal stem cells transdifferentiates into pancreatic islet-like cluster.

    Science.gov (United States)

    Dhanasekaran, M; Indumathi, S; Harikrishnan, R; Mishra, Rashmi; Lissa, R P; Rajkumar, J S; Sudarsanam, D

    2013-10-01

    Current protocols of islet cell transplantation for the treatment of diabetes mellitus have been hampered by islet availability and allograft rejection. Although bone marrow and subcutaneous adipose tissue stem cells feature their tissue repair efficacy, applicability of stem cells from various sources is being researched to develop a promising therapy for diabetes mellitus. Although omentum fat has emerged as an innovative source of stem cells, the dearth of researches confirming its transdifferentiation potential limits its applicability as a regenerative tool in diabetic therapy. Thus, this work is a maiden attempt to explore the colossal potency of omentum fat-derived stem cells on its lucrative differentiation ability. The plasticity of omentum fat stem cells was substantiated by transdifferentiation into pancreatic islet-like clusters, which was confirmed by dithizone staining and immunocytochemistry for insulin. It was also confirmed by the expression of pancreatic endocrine markers nestin and pancreatic duodenal homeobox 1 (Pdx 1) using Fluorescence-activated cell sorting (FACS), neurogenic 3, islet-1 transcription factor, paired box gene 4, Pdx 1 and insulin using quantitative real-time polymerase chain reaction and through insulin secretion assay. This study revealed the in vitro differentiation potency of omentum fat stem cells into pancreatic islet-like clusters. However, further research pursuits exploring its in vivo endocrine efficacy would make omentum fat stem cells a superior source for β-cell replacement therapy. Copyright © 2013 John Wiley & Sons, Ltd.

  18. Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Fabienne Billiard

    2018-01-01

    Full Text Available Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.

  19. Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA

    International Nuclear Information System (INIS)

    Permutt, M.A.; Koranyi, L.; Keller, K.; Lacy, P.E.; Scharp, D.W.; Mueckler, M.

    1989-01-01

    Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-K m , low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. The authors isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus

  20. The morphology of islets within the porcine donor pancreas determines the isolation result: successful isolation of pancreatic islets can now be achieved from young market pigs.

    Science.gov (United States)

    Krickhahn, Mareike; Bühler, Christoph; Meyer, Thomas; Thiede, Arnulf; Ulrichs, Karin

    2002-01-01

    Clinical islet allotransplantation has become an increasingly efficient "routine" therapy in recent years. Shortage of human donor organs leads to porcine pancreatic islets as a potential source for islet xenotransplantation. Yet it is still very difficult to isolate sufficient numbers of intact porcine islets, particularly from young market pigs. In the following study islets were successfully isolated from retired breeders [4806 +/- 720 islet equivalents per gram organ (IEQ/g); n = 25; 2-3 years old; RB] and also from young hybrid pigs [2868 +/- 260 IEQ/g; n = 65; 4-6 months old; HY] using LiberasePI and a modified version of Ricordi's digestion-filtration technique. As expected, isolations from RB showed significantly better results (p organs from RB (80%) contained mainly large islets (diameter > 200 microm), in contrast to only 35% of all pancreases from HY. Remarkably, the islet size in situ, regardless whether detected in RB or HY, strongly determined the isolation result. A donor organ with predominantly large islets resulted in significantly higher numbers of IEQs compared with a donor organ with predominantly small islets [RB(Large Islets): 5680 +/- 3,318 IEQ/g (n= 20); RB(Small Islets): 1353 +/- 427 IEQ/g (n = 5); p organ prior to the isolation process. Under these conditions highly successful isolations can reliably be performed even from young market pigs.

  1. Transplanted human pancreatic islets after long-term insulin independence

    DEFF Research Database (Denmark)

    Muller, Y D; Gupta, Shashank; Morel, P

    2013-01-01

    Long-term insulin independence after islets of Langerhans transplantation is rarely achieved. The aims of this study were to identify the histological and immunological features of islets transplanted in a type 1 diabetic patient who died of a cerebral hemorrhage after >13 years insulin independe......Long-term insulin independence after islets of Langerhans transplantation is rarely achieved. The aims of this study were to identify the histological and immunological features of islets transplanted in a type 1 diabetic patient who died of a cerebral hemorrhage after >13 years insulin...... independence. Islets were pooled from two donors with respectively one and five HLA mismatches. Insulin-positive islets were found throughout the right and left liver, and absent in the pancreas. Two- and three-dimensional analysis showed that islets lost their initial rounded and compact morphology, had...... microdissection samples, compared to 1/23 for the least matched donor. This case report demonstrates that allogeneic islets can survive over 13 years while maintaining insulin independence. Allogeneic islets had unique morphologic features and implanted in the liver regardless of their size. Finally, our results...

  2. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors.

    Science.gov (United States)

    Erlic, Zoran; Ploeckinger, Ursula; Cascon, Alberto; Hoffmann, Michael M; von Duecker, Laura; Winter, Aurelia; Kammel, Gerit; Bacher, Janina; Sullivan, Maren; Isermann, Berend; Fischer, Lars; Raffel, Andreas; Knoefel, Wolfram Trudo; Schott, Matthias; Baumann, Tobias; Schaefer, Oliver; Keck, Tobias; Baum, Richard P; Milos, Ioana; Muresan, Mihaela; Peczkowska, Mariola; Januszewicz, Andrzej; Cupisti, Kenko; Tönjes, Anke; Fasshauer, Mathias; Langrehr, Jan; von Wussow, Peter; Agaimy, Abbas; Schlimok, Günter; Lamberts, Regina; Wiech, Thorsten; Schmid, Kurt Werner; Weber, Alexander; Nunez, Mercedes; Robledo, Mercedes; Eng, Charis; Neumann, Hartmut P H

    2010-12-01

    Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (PICTs compared to sporadic cases. VHL was prevalent in ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

  3. Immunohistochemical and morphometric study of the development of fetal and newborn rat pancreatic islets

    International Nuclear Information System (INIS)

    Badawoud, Mohammed H.

    2003-01-01

    Aim of this study is to perform a detailed morphometric immunohistochemichal study of develpment of fetal and newborn rat pancreatic islets. 24 pancreas were obtained from 19 and 21-day-old fetal rats,1 and 4-day-old newborn rats. They were fixed in a buffered neutral formalin ,dehydrated and embedded in paraplast. Sections were stained with anti-insulin antibodies. Study was performed at Department of Anatomy, King Abdul-Aziz University, Jeddah,Kingdom of Saudi Arabia, between 2001 and 2002. The volume density of B cells showed a grdual increase during the last days of gestation and a slight increase during the first 4 days after birth. All the other morphometric parameters showed a gradual increase during the last days of gestation and during the first days after birth.The B cell nuclear diameter and volume showed a slight increase after birth. B cells were stained and present in the central part of of fetal and new born islets,while the other islet cells were present in the periphery of the islets. The size of endocrine tissue, which was represented by the islet diameter, islet volume, islet volume density, total number of islet cells,number of B cells and volume density of B cells showed a progressive increase during the prenatal period. (author)

  4. Selection of polymers for application in scaffolds applicable for human pancreatic islet transplantation.

    Science.gov (United States)

    Smink, Alexandra M; de Haan, Bart J; Paredes-Juarez, Genaro A; Wolters, Anouk H G; Kuipers, Jeroen; Giepmans, Ben N G; Schwab, Leendert; Engelse, Marten A; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Vos, Paul

    2016-05-13

    The liver is currently the site for transplantation of islets in humans. This is not optimal for islets, but alternative sites in humans are not available. Polymeric scaffolds in surgically accessible areas are a solution. As human donors are rare, the polymers should not interfere with functional survival of human-islets. We applied a novel platform to test the adequacy of polymers for application in scaffolds for human-islet transplantation. Viability, functionality, and immune parameters were included to test poly(D,L-lactide-co-ε-caprolactone) (PDLLCL), poly(ethylene oxide terephthalate)/polybutylene terephthalate (PEOT/PBT) block copolymer, and polysulfone. The type of polymer influenced the functional survival of human islets. In islets cultured on PDLLCL the glucagon-producing α-cells and insulin-producing β-cells contained more hormone granules than in islets in contact with PEOT/PBT or polysulfone. This was studied with ultrastructural analysis by electron microscopy (nanotomy) during 7 d of culture. PDLLCL was also associated with statistically significant lower release of double-stranded DNA (dsDNA, a so called danger-associate molecular pattern (DAMP)) from islets on PDLLCL when compared to the other polymers. DAMPs support undesired immune responses. Hydrophilicity of the polymers did not influence dsDNA release. Islets on PDLLCL also showed less cellular outgrowth. These outgrowing cells were mainly fibroblast and some β-cells undergoing epithelial to mesenchymal cell transition. None of the polymers influenced the glucose-stimulated insulin secretion. As PDLLCL was associated with less release of DAMPs, it is a promising candidate for creating a scaffold for human islets. Our study demonstrates that for sensitive, rare cadaveric donor tissue such as pancreatic islets it might be necessary to first select materials that do not influence functionality before proposing the biomaterial for in vivo application. Our presented platform may facilitate

  5. A Retrievable, Efficacious Polymeric Scaffold for Subcutaneous Transplantation of Rat Pancreatic Islets.

    Science.gov (United States)

    Smink, Alexandra M; Hertsig, Don T; Schwab, Leendert; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Haan, Bart J; de Vos, Paul

    2017-07-01

    We aim on developing a polymeric ectopic scaffold in a readily accessible site under the skin. The liver as transplantation site for pancreatic islets is associated with significant loss of islets. Several extrahepatic sites were tested in experimental animals, but many have practical limitations in the clinical setting and do not have the benefit of easy accessibility. Functional survival of rat islets was tested during 7 days of culture in the presence of poly(D,L-lactide-co-ε-caprolactone) (PDLLCL), poly(ethylene oxide terephthalate)/polybutylene terephthalate (PEOT/PBT) block copolymer, and polysulfone. Tissue responses were studied in vivo after subcutaneous implantation in rats. Culture on PEOT/PBT and polysulfone profoundly disturbed function of islets, and induced severe tissue responses in vivo. Modification of their hydrophilicity did not change the suitability of the polymers. PDLLCL was the only polymer that promoted functional survival of rat islets in vitro and was associated with minor tissue reactions after 28 days. Rat islets were transplanted in the PDLLCL scaffold in a diabetic rat model. Before islet seeding, the scaffold was allowed to engraft for 28 days to allow the tissue response to dampen and to allow blood vessel growth into the device. Islet transplantation into the scaffold resulted in normoglycemia within 3 days and for the duration of the study period of 16 weeks. In conclusion, we found that some polymers such as PEOT/PBT and polysulfone interfere with islet function. PDLLCL is a suitable polymer to create an artificial islet transplantation site under the skin and supports islet survival.

  6. Fluorescent protein vectors for pancreatic islet cell identification in live-cell imaging.

    Science.gov (United States)

    Shuai, Hongyan; Xu, Yunjian; Yu, Qian; Gylfe, Erik; Tengholm, Anders

    2016-10-01

    The islets of Langerhans contain different types of endocrine cells, which are crucial for glucose homeostasis. β- and α-cells that release insulin and glucagon, respectively, are most abundant, whereas somatostatin-producing δ-cells and particularly pancreatic polypeptide-releasing PP-cells are more scarce. Studies of islet cell function are hampered by difficulties to identify the different cell types, especially in live-cell imaging experiments when immunostaining is unsuitable. The aim of the present study was to create a set of vectors for fluorescent protein expression with cell-type-specific promoters and evaluate their applicability in functional islet imaging. We constructed six adenoviral vectors for expression of red and green fluorescent proteins controlled by the insulin, preproglucagon, somatostatin, or pancreatic polypeptide promoters. After transduction of mouse and human islets or dispersed islet cells, a majority of the fluorescent cells also immunostained for the appropriate hormone. Recordings of the sub-plasma membrane Ca(2+) and cAMP concentrations with a fluorescent indicator and a protein biosensor, respectively, showed that labeled cells respond to glucose and other modulators of secretion and revealed a striking variability in Ca(2+) signaling among α-cells. The measurements allowed comparison of the phase relationship of Ca(2+) oscillations between different types of cells within intact islets. We conclude that the fluorescent protein vectors allow easy identification of specific islet cell types and can be used in live-cell imaging together with organic dyes and genetically encoded biosensors. This approach will facilitate studies of normal islet physiology and help to clarify molecular defects and disturbed cell interactions in diabetic islets.

  7. Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Eva Ludvigsen

    2011-01-01

    Full Text Available Somatostatin acts via five receptors (sst1-5. We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

  8. The fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model

    International Nuclear Information System (INIS)

    Jo, Junghyo; Periwal, Vipul; Hörnblad, Andreas; Ahlgren, Ulf; Kilimnik, German; Hara, Manami

    2013-01-01

    The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas. (paper)

  9. Loss of end-differentiated β-cell phenotype following pancreatic islet transplantation.

    Science.gov (United States)

    Anderson, S J; White, M G; Armour, S L; Maheshwari, R; Tiniakos, D; Muller, Y D; Berishvili, E; Berney, T; Shaw, J A M

    2018-03-01

    Replacement of pancreatic β-cells through deceased donor islet transplantation is a proven therapy for preventing recurrent life-threatening hypoglycemia in type 1 diabetes. Although near-normal glucose levels and insulin independence can be maintained for many years following successful islet transplantation, restoration of normal functional β-cell mass has remained elusive. It has recently been proposed that dedifferentiation/plasticity towards other endocrine phenotypes may play an important role in stress-induced β-cell dysfunction in type 2 diabetes. Here we report loss of end-differentiated β-cell phenotype in 2 intraportal islet allotransplant recipients. Despite excellent graft function and sustained insulin independence, all examined insulin-positive cells had lost expression of the end-differentiation marker, urocortin-3, or appeared to co-express the α-cell marker, glucagon. In contrast, no insulin + /urocortin-3 - cells were seen in nondiabetic deceased donor control pancreatic islets. Loss of end-differentiated phenotype may facilitate β-cell survival during the stresses associated with islet isolation and culture, in addition to sustained hypoxia following engraftment. As further refinements in islet isolation and culture are made in parallel with exploration of alternative β-cell sources, graft sites, and ultimately fully vascularized bioengineered insulin-secreting microtissues, differentiation status immunostaining provides a novel tool to assess whether fully mature β-cell phenotype has been maintained. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  10. Fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model

    Science.gov (United States)

    Jo, Junghyo; Hörnblad, Andreas; Kilimnik, German; Hara, Manami; Ahlgren, Ulf; Periwal, Vipul

    2013-01-01

    The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, have not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension, 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with fractal dimension 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas. PMID:23629025

  11. Construction of functional pancreatic artificial islet tissue composed of fibroblast-modified polylactic- co-glycolic acid membrane and pancreatic stem cells.

    Science.gov (United States)

    Liu, Liping; Tan, Jing; Li, Baoyuan; Xie, Qian; Sun, Junwen; Pu, Hongli; Zhang, Li

    2017-09-01

    Objective To improve the biocompatibility between polylactic- co-glycolic acid membrane and pancreatic stem cells, rat fibroblasts were used to modify the polylactic- co-glycolic acid membrane. Meanwhile, we constructed artificial islet tissue by compound culturing the pancreatic stem cells and the fibroblast-modified polylactic- co-glycolic acid membrane and explored the function of artificial islets in diabetic nude mice. Methods Pancreatic stem cells were cultured on the fibroblast-modified polylactic- co-glycolic acid membrane in dulbecco's modified eagle medium containing activin-A, β-catenin, and exendin-4. The differentiated pancreatic stem cells combined with modified polylactic- co-glycolic acid membrane were implanted subcutaneously in diabetic nude mice. The function of artificial islet tissue was explored by detecting blood levels of glucose and insulin in diabetic nude mice. Moreover, the proliferation and differentiation of pancreatic stem cells on modified polylactic- co-glycolic acid membrane as well as the changes on the tissue structure of artificial islets were investigated by immunofluorescence and haematoxylin and eosin staining. Results The pancreatic stem cells differentiated into islet-like cells and secreted insulin when cultured on fibroblast-modified polylactic- co-glycolic acid membrane. Furthermore, when the artificial islet tissues were implanted into diabetic nude mice, the pancreatic stem cells combined with polylactic- co-glycolic acid membrane modified by fibroblasts proliferated, differentiated, and secreted insulin to reduce blood glucose levels in diabetic nude mice. Conclusion Pancreatic stem cells can be induced to differentiate into islet-like cells in vitro. In vivo, the artificial islet tissue can effectively regulate the blood glucose level in nude mice within a short period. However, as time increased, the structure of the artificial islets was destroyed due to the erosion of blood cells that resulted in the gradual

  12. Microencapsulation of Pancreatic Islets for Use in a Bioartificial Pancreas

    Science.gov (United States)

    Opara, Emmanuel C.; McQuilling, John P.; Farney, Alan C.

    2013-01-01

    Islet transplantation is the most exciting treatment option for individuals afflicted with Type 1 diabetes. However, the severe shortage of human pancreas and the need to use risky immunosuppressive drugs to prevent transplant rejection remain two major obstacles for the routine use of islet transplantation in diabetic patients. Successful development of a bioartificial pancreas using the approach of microencapsulation with perm-selective coating of islets with biopolymers for graft immunoisolation holds tremendous promise for diabetic patients because it has great potential to overcome these two barriers. In this chapter, we provide a detailed description of the microencapsulation process. PMID:23494435

  13. Pre-Microporation Improves Outcome of Pancreatic Islet Labelling for Optical and F-19 MR Imaging

    Czech Academy of Sciences Publication Activity Database

    Herynek, V.; Gálisová, A.; Srinivas, M.; van Dinther, E.A.W.; Kosinová, E.; Růžička, Jiří; Jirátová, K.; Kříž, J.; Jirák, D.

    2017-01-01

    Roč. 19, jun (2017), s. 6 ISSN 1480-9222 R&D Projects: GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : pancreatic islets * cell labelling * microporation Subject RIV: FP - Other Medical Disciplines Impact factor: 2.042, year: 2016

  14. UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Dalgaard, Louise T., E-mail: ltd@ruc.dk [Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (United States); Department of Science, Systems and Models, Roskilde University (Denmark)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer UCP2 mRNA levels are decreased in islets of Langerhans from glucokinase deficient mice. Black-Right-Pointing-Pointer UCP2 mRNA up-regulation by glucose is dependent on glucokinase. Black-Right-Pointing-Pointer Absence of UCP2 increases GSIS of glucokinase heterozygous pancreatic islets. Black-Right-Pointing-Pointer This may protect glucokinase deficient mice from hyperglycemic damages. -- Abstract: Uncoupling Protein 2 (UCP2) is expressed in the pancreatic {beta}-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

  15. Automated Analysis of Microscopic Images of Isolated Pancreatic Islets

    Czech Academy of Sciences Publication Activity Database

    Habart, D.; Švihlík, J.; Schier, Jan; Cahová, M.; Girman, P.; Zacharovová, K.; Berková, Z.; Kříž, J.; Fabryová, E.; Kosinová, L.; Papáčková, Z.; Kybic, J.; Saudek, F.

    2016-01-01

    Roč. 25, č. 12 (2016), s. 2145-2156 ISSN 0963-6897 Grant - others:GA ČR(CZ) GA14-10440S Institutional support: RVO:67985556 Keywords : enumeration of islets * image processing * image segmentation * islet transplantation * machine-learning * quality control Subject RIV: IN - Informatics, Computer Science Impact factor: 3.006, year: 2016 http://library.utia.cas.cz/separaty/2016/ZOI/schier-0465945.pdf

  16. Human pancreatic islet-derived extracellular vesicles modulate insulin expression in 3D-differentiating iPSC clusters.

    Directory of Open Access Journals (Sweden)

    Diana Ribeiro

    Full Text Available It has been suggested that extracellular vesicles (EVs can mediate crosstalk between hormones and metabolites within pancreatic tissue. However, the possible effect of pancreatic EVs on stem cell differentiation into pancreatic lineages remains unknown. Herein, human islet-derived EVs (h-Islet-EVs were isolated, characterized and subsequently added to human induced pluripotent stem cell (iPSC clusters during pancreatic differentiation. The h-islet-EVs had a mean size of 117±7 nm and showed positive expression of CD63 and CD81 EV markers as measured by ELISA. The presence of key pancreatic transcription factor mRNA, such as NGN3, MAFA and PDX1, and pancreatic hormone proteins such as C-peptide and glucagon, were confirmed in h-Islet-EVs. iPSC clusters were differentiated in suspension and at the end stages of the differentiation protocol, the mRNA expression of the main pancreatic transcription factors and pancreatic hormones was increased. H-Islet-EVs were supplemented to the iPSC clusters in the later stages of differentiation. It was observed that h-Islet-EVs were able to up-regulate the intracellular levels of C-peptide in iPSC clusters in a concentration-dependent manner. The effect of h-Islet-EVs on the differentiation of iPSC clusters cultured in 3D-collagen hydrogels was also assessed. Although increased mRNA expression for pancreatic markers was observed when culturing the iPSC clusters in 3D-collagen hydrogels, delivery of EVs did not affect the insulin or C-peptide intracellular content. Our results provide new information on the role of h-Islet-EVs in the regulation of insulin expression in differentiating iPSC clusters, and are highly relevant for pancreatic tissue engineering applications.

  17. Human pancreatic islet-derived extracellular vesicles modulate insulin expression in 3D-differentiating iPSC clusters.

    Science.gov (United States)

    Ribeiro, Diana; Andersson, Eva-Marie; Heath, Nikki; Persson-Kry, Anette; Collins, Richard; Hicks, Ryan; Dekker, Niek; Forslöw, Anna

    2017-01-01

    It has been suggested that extracellular vesicles (EVs) can mediate crosstalk between hormones and metabolites within pancreatic tissue. However, the possible effect of pancreatic EVs on stem cell differentiation into pancreatic lineages remains unknown. Herein, human islet-derived EVs (h-Islet-EVs) were isolated, characterized and subsequently added to human induced pluripotent stem cell (iPSC) clusters during pancreatic differentiation. The h-islet-EVs had a mean size of 117±7 nm and showed positive expression of CD63 and CD81 EV markers as measured by ELISA. The presence of key pancreatic transcription factor mRNA, such as NGN3, MAFA and PDX1, and pancreatic hormone proteins such as C-peptide and glucagon, were confirmed in h-Islet-EVs. iPSC clusters were differentiated in suspension and at the end stages of the differentiation protocol, the mRNA expression of the main pancreatic transcription factors and pancreatic hormones was increased. H-Islet-EVs were supplemented to the iPSC clusters in the later stages of differentiation. It was observed that h-Islet-EVs were able to up-regulate the intracellular levels of C-peptide in iPSC clusters in a concentration-dependent manner. The effect of h-Islet-EVs on the differentiation of iPSC clusters cultured in 3D-collagen hydrogels was also assessed. Although increased mRNA expression for pancreatic markers was observed when culturing the iPSC clusters in 3D-collagen hydrogels, delivery of EVs did not affect the insulin or C-peptide intracellular content. Our results provide new information on the role of h-Islet-EVs in the regulation of insulin expression in differentiating iPSC clusters, and are highly relevant for pancreatic tissue engineering applications.

  18. The effect of Nrf2 pathway activation on human pancreatic islet cells.

    Directory of Open Access Journals (Sweden)

    Yuichi Masuda

    Full Text Available Pancreatic islets are known to contain low level of antioxidants that renders them vulnerable to oxidative stress. Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Activation of Nrf2 pathway induces up-regulation of numerous genes encoding antioxidant and phase II detoxifying enzymes and related proteins. However, little is known regarding the role of this pathway in human islet cells. The aim was to investigate the effect of Nrf2 activator (dh404, CDDO-9,11-dihydro-trifluoroethyl amide on human islet cells.Human islets were obtained from cadaveric donors. After dh404 treatment, Nrf2 translocation, mRNA expression, and protein abundance of its key target gene products were examined. The proportion of dh404-treated or non-treated viable islet beta cells was analyzed using flowcytemetry. The cytoprotective effects against oxidative stress and production of inflammatory mediators, and in vivo islet function after transplantation were determined.Nrf2 nuclear translocation was confirmed by con-focal microscope within 2 hours after treatment, which was associated with a dose-dependent increase in mRNA expression of anti-oxidants, including NQO1, HO-1, and GCLC. Enhanced HO-1 expression in dh404 treated islets was confirmed by Western Blot assay. Islet function after transplantation (2000 IEQ/mouse to diabetic nude mice was not affected with or without dh404 treatment. After induction of oxidative stress with hydrogen peroxide (200 μM the proportion of dh404-treated viable islet cells was significantly higher in the dh404-treated than untreated islets (74% vs.57%; P<0.05. Dh404 significantly decreased production of cytokines/chemokines including IL-1β, IL-6, IFN-γ and MCP-1.Treatment of human pancreatic islets with the potent synthetic Nrf2 activator, dh404, significantly increased expression of the key anti-oxidants enzymes, decreased inflammatory mediators in islets and conferred

  19. Glycolytic and Mitochondrial Metabolism in Pancreatic Islets from MSG-Treated Obese Rats Subjected to Swimming Training

    Directory of Open Access Journals (Sweden)

    Nayara de Carvalho Leite

    2013-02-01

    Full Text Available Backgrounds/Aims: Obese rats obtained by neonatal monosodium glutamate (MSG administration present insulin hypersecretion. The metabolic mechanism by which glucose catabolism is coupled to insulin secretion in the pancreatic β-cells from MSG-treated rats is understood. The purpose of this study was to evaluate glucose metabolism in pancreatic islets from MSG-treated rats subjected to swimming training. Methods: MSG-treated and control (CON rats swam for 30 minutes (3 times/week over a period of 10 weeks. Pancreatic islets were isolated and incubated with glucose in the presence of glycolytic or mitochondrial inhibitors. Results: Swimming training attenuated fat pad accumulation, avoiding changes in the plasma levels of lipids, glucose and insulin in MSG-treated rats. Adipocyte and islet hypertrophy observed in MSG-treated rats were attenuated by exercise. Pancreatic islets from MSG-treated obese rats also showed insulin hypersecretion, greater glucose transporter 2 (GLUT2 expression, increased glycolytic flux and reduced mitochondrial complex III activity. Conclusion: Swimming training attenuated islet hypertrophy and normalised GLUT2 expression, contributing to a reduction in the glucose responsiveness of pancreatic islets from MSG-treated rats without altering glycolytic flux. However, physical training increased the activity of mitochondrial complex III in pancreatic islets from MSG-treated rats without a subsequent increase in glucose-induced insulin secretion.

  20. G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction

    DEFF Research Database (Denmark)

    Holst, Birgitte; Egerod, Kristoffer L; Jin, Chunyu

    2009-01-01

    G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn(++) sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1alpha and HNF-4......alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect...... of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up...

  1. Immunohistochemical localization of glucagon and pancreatic polypeptide on rat endocrine pancreas: coexistence in rat islet cells

    Directory of Open Access Journals (Sweden)

    YH Huang

    2009-08-01

    Full Text Available We used immunofluorescence double staining method to investigate the cellular localization of glucagon and pancreatic polypeptide (PP in rat pancreatic islets. The results showed that both A-cells (glucagon-secreting cells and PP-cells (PPsecreting cells were located in the periphery of the islets. However, A-cells and PP-cells had a different regional distribution. Most of A-cells were located in the splenic lobe but a few of them were in the duodenal lobe of the pancreas. In contrast, the majority of PP-cells were found in the duodenal lobe and a few of them were in the splenic lobe of the pancreas. Furthermore, we found that 67.74% A-cells had PP immunoreactivity, 70.92% PP-cells contained glucagon immunoreactivity with immunofluorescence double staining. Our data support the concept of a common precursor stem cell for pancreatic hormone-producing cells.

  2. Culturing pancreatic islets in microfluidic flow enhances morphology of the associated endothelial cells.

    Directory of Open Access Journals (Sweden)

    Krishana S Sankar

    Full Text Available Pancreatic islets are heavily vascularized in vivo with each insulin secreting beta-cell associated with at least one endothelial cell (EC. This structure is maintained immediately post-isolation; however, in culture the ECs slowly deteriorate, losing density and branched morphology. We postulate that this deterioration occurs in the absence of blood flow due to limited diffusion of media inside the tissue. To improve exchange of media inside the tissue, we created a microfluidic device to culture islets in a range of flow-rates. Culturing the islets from C57BL6 mice in this device with media flowing between 1 and 7 ml/24 hr resulted in twice the EC-density and -connected length compared to classically cultured islets. Media containing fluorescent dextran reached the center of islets in the device in a flow-rate-dependant manner consistent with improved penetration. We also observed deterioration of EC morphology using serum free media that was rescued by addition of bovine serum albumin, a known anti-apoptotic signal with limited diffusion in tissue. We further examined the effect of flow on beta-cells showing dampened glucose-stimulated Ca(2+-response from cells at the periphery of the islet where fluid shear-stress is greatest. However, we observed normal two-photon NAD(PH response and insulin secretion from the remainder of the islet. These data reveal the deterioration of islet EC-morphology is in part due to restricted diffusion of serum albumin within the tissue. These data further reveal microfluidic devices as unique platforms to optimize islet culture by introducing intercellular flow to overcome the restricted diffusion of media components.

  3. Vitality of pancreatic islets labeled for magnetic resonance imaging with iron particles.

    Science.gov (United States)

    Berkova, Z; Kriz, J; Girman, P; Zacharovova, K; Koblas, T; Dovolilova, E; Saudek, F

    2005-10-01

    We previously described an in vivo method for pancreatic islet visualization using magnetic resonance imaging with the aid of superparamagnetic nanoparticles of iron oxide (Resovist) or by magnetic beads precoated with antibodies (Dynabeads). The aim of this study was to investigate the in vitro effect of islet labeling on their quality. Isolated rat islets were cultivated for 48 hours with a contrast agent or, in the case of magnetic antibody-coated beads, for only 2 hours. The ability to secrete insulin was tested by a static insulin release assay and the results were expressed as a stimulation index. Staining with propidium iodide and acridine orange was performed to determine the ratio of live to dead cells. Stimulation indices in the Resovist islets (n = 23) vs controls (n = 14) were 15.3 and 15.0, respectively, and in the Dynabeads islets (n = 15) vs controls (n = 12) 21.3 and 19.9, respectively. The vitality of the Resovist islets vs controls determined by live/dead cells ratio was 90.8% and 91.1%, respectively (n = 20), and in the Dynabeads islets vs controls was 89.4% and 91.8%, respectively (n = 11). Islet labeling with the contrast agent as well as with specific antibodies with iron beads did not change the vitality and insulin-secreting capacity assessed in vitro (P > .05). Magnetic resonance using iron nanoparticles represents the only method for in-vivo visualization of transplanted islets so far. Our data represent an important contribution for its clinical use.

  4. Assessment of Toxicological Perturbations and Variants of Pancreatic Islet Development in the Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Karilyn E. Sant

    2016-09-01

    Full Text Available The pancreatic islets, largely comprised of insulin-producing beta cells, play a critical role in endocrine signaling and glucose homeostasis. Because they have low levels of antioxidant defenses and a high perfusion rate, the endocrine islets may be a highly susceptible target tissue of chemical exposures. However, this endpoint, as well as the integrity of the surrounding exocrine pancreas, is often overlooked in studies of developmental toxicology. Disruption of development by toxicants can alter cell fate and migration, resulting in structural alterations that are difficult to detect in mammalian embryo systems, but that are easily observed in the zebrafish embryo model (Danio rerio. Using endogenously expressed fluorescent protein markers for developing zebrafish beta cells and exocrine pancreas tissue, we documented differences in islet area and incidence rates of islet morphological variants in zebrafish embryos between 48 and 96 h post fertilization (hpf, raised under control conditions commonly used in embryotoxicity assays. We identified critical windows for chemical exposures during which increased incidences of endocrine pancreas abnormalities were observed following exposure to cyclopamine (2–12 hpf, Mono-2-ethylhexyl phthalate (MEHP (3–48 hpf, and Perfluorooctanesulfonic acid (PFOS (3–48 hpf. Both islet area and length of the exocrine pancreas were sensitive to oxidative stress from exposure to the oxidant tert-butyl hydroperoxide during a highly proliferative critical window (72 hpf. Finally, pancreatic dysmorphogenesis following developmental exposures is discussed with respect to human disease.

  5. Ionic and secretory response of pancreatic islet cells to minoxidil sulfate

    Energy Technology Data Exchange (ETDEWEB)

    Antoine, M.H.; Hermann, M.; Herchuelz, A.; Lebrun, P. (Laboratory of Pharmacology, Brussels Free University School of Medicine (Belgium))

    1991-07-01

    Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the K+ channel openers. The present study was undertaken to characterize the effects of minoxidil sulfate on ionic and secretory events in rat pancreatic islets. The drug unexpectedly provoked a concentration-dependent decrease in 86Rb outflow. This inhibitory effect was reduced in a concentration-dependent manner by glucose and tolbutamide. Minoxidil sulfate did not affect 45Ca outflow from islets perfused in the presence of extracellular Ca++ and absence or presence of glucose. However, in islets exposed to a medium deprived of extracellular Ca++, the drug provoked a rise in 45Ca outflow. Whether in the absence or presence of extracellular Ca++, minoxidil sulfate increased the cytosolic free Ca++ concentration of islet cells. Lastly, minoxidil sulfate increased the release of insulin from glucose-stimulated pancreatic islets. These results suggest that minoxidil sulfate reduces the activity of the ATP-sensitive K+ channels and promotes an intracellular translocation of Ca++. The latter change might account for the effect of the drug on the insulin-releasing process. However, the secretory response to minoxidil sulfate could also be mediated, at least in part, by a modest Ca++ entry.

  6. Characterization of a pancreatic islet cell tumor in a polar bear (Ursus maritimus).

    Science.gov (United States)

    Fortin, Jessica S; Benoit-Biancamano, Marie-Odile

    2014-01-01

    Herein, we report a 25-year-old male polar bear suffering from a pancreatic islet cell tumor. The aim of this report is to present a case of this rare tumor in a captive polar bear. The implication of potential risk factors such as high carbohydrate diet or the presence of amyloid fibril deposits was assessed. Necropsy examination revealed several other changes, including nodules observed in the liver, spleen, pancreas, intestine, and thyroid glands that were submitted for histopathologic analysis. Interestingly, the multiple neoplastic nodules were unrelated and included a pancreatic islet cell tumor. Immunohistochemistry of the pancreas confirmed the presence of insulin and islet amyloid polypeptide (IAPP) within the pancreatic islet cells. The IAPP gene was extracted from the paraffin-embedded liver tissue and sequenced. IAPP cDNA from the polar bear exhibits some differences as compared to the sequence published for several other species. Different factors responsible for neoplasms in bears such as diet, infectious agents, and industrial chemical exposure are reviewed. This case report raised several issues that further studies may address by evaluating the prevalence of cancers in captive or wild animals. © 2014 Wiley Periodicals, Inc.

  7. Factors Influencing Quantification of in Vivo Bioluminescence Imaging: Application to Assessment of Pancreatic Islet Transplants

    Directory of Open Access Journals (Sweden)

    John Virostko

    2004-10-01

    Full Text Available The aim of this study is to determine and characterize factors influencing in vivo bioluminescence imaging (BLI and apply them to the specific application of imaging transplanted pancreatic islets. Noninvasive quantitative assessment of transplanted pancreatic islets poses a formidable challenge. Murine pancreatic islets expressing firefly luciferase were transplanted under the renal capsule or into the portal vein of nonobese diabetic–severe combined immunodeficiency mice and the bioluminescence was quantified with a cooled charge coupled device camera and digital photon image analysis. The important, but often neglected, effects of wound healing, mouse positioning, and transplantation site on bioluminescence measurements were investigated by imaging a constant emission, isotropic light-emitting bead (λ = 600 implanted at the renal or hepatic site. The renal beads emitted nearly four times more light than hepatic beads with a smaller spot size, indicating that light absorption and scatter are greatly influenced by the transplant site and must be accounted for in BLI measurements. Detected luminescence decreased with increasing angle between the mouse surface normal and optical axis. By defining imaging parameters such as postsurgical effects, animal positioning, and light attenuation as a function of transplant site, this study develops BLI as a useful imaging modality for quantitative assessment of islets post-transplantation.

  8. Obestatin enhances in vitro generation of pancreatic islets through regulation of developmental pathways.

    Directory of Open Access Journals (Sweden)

    Alessandra Baragli

    Full Text Available Availability of large amounts of in vitro generated β-cells may support replacement therapy in diabetes. However, methods to obtain β-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic β-cell survival and function. Obestatin prevents β-cell apoptosis, preserves β-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro β-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii increased cell survival and reduced apoptosis during precursor selection; (iii promoted the generation of islet-like cell clusters (ICCs with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs, Notch receptors and neurogenin 3 (Ngn3 during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional β-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration.

  9. Entrapment of dispersed pancreatic islet cells in CultiSpher-S macroporous gelatin microcarriers : Preparation, in vitro characterization, and microencapsulation

    NARCIS (Netherlands)

    Del Guerra, S; Bracci, C; Nilsson, K; Belcourt, A; Kessler, L; Lupi, R; Marselli, L; De Vos, P; Marchetti, P

    2001-01-01

    Immunoprotection of pancreatic islets for successful allo- or xenotransplantation without chronic immunosuppression is an attractive, but still elusive, approach for curing type 1 diabetes. It was recently shown that, even in the absence of fibrotic overgrowth, other factors, mainly insufficient

  10. Antidiabetic effects of Eucalyptus globulus on pancreatic islets: a stereological study.

    Science.gov (United States)

    Mahmoudzadeh-Sagheb, H; Heidari, Z; Bokaeian, M; Moudi, B

    2010-05-01

    The leaves of Eucalyptus globulus (eucalyptus) are used for the treatment of diabetes mellitus in traditional medicine. The aim of this study was to evaluate the effects of eucalyptus on streptozotocin (STZ)-induced damage in pancreatic islands by stereological methods. Fifty mature normoglycaemic male Wistar rats, weighing 200-250 g, were selected and randomly divided into 5 groups (n = 10): control; STZ-induced diabetic (D) - by intraperitoneal injection of 60 mg/kg streptozotocin; treated control (TC); and treated diabetic (TD1, 2), respectively, received 20 and 62.5 g/kg of eucalyptus in their diet, and 2.5 g/L aqueous extract of eucalyptus in their drinking water from one week after induction of diabetes. After four weeks of the experiment, stereological estimation of volume density and total volume of islets and beta cells, volume-weighted mean islet volume, mass of the islets and pancreas, and total number of islets were carried out. Administration of eucalyptus significantly decreased the weight loss and increase of water and food intake in the treated diabetic groups in comparison to the STZ-induced diabetic (D) group. Volume density and total volume of islets, volume-weighted mean islet volume, mass of islets, and mass of pancreas of both treated diabetic groups were higher than the D group. In TD2, these stereological parameters increased significantly compared to the D group (p 0.05). The results suggested that Eucalyptus globulus with a dose-dependent manner ameliorates diabetic states by partial restoration of pancreatic beta cells and repair of STZ-induced damage in rats. This study suggests a beneficial effect of eucalyptus in the treatment of diabetes.

  11. Autoimmunity against INS-IGF2 expressed in human pancreatic islets.

    OpenAIRE

    Kanatsuna, Norio; Taneera, Jalal; Vaziri Sani, Fariba; Wierup, Nils; Larsson, Helena; Delli, Ahmed; Skärstrand, Hanna; Balhuizen, Alexander; Bennet, Hedvig; Steiner, Donald F; Törn, Carina; Fex, Malin; Lernmark, Åke

    2013-01-01

    Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes chil...

  12. Dimethyl Fumarate Protects Pancreatic Islet Cells and Non-Endocrine Tissue in L-Arginine-Induced Chronic Pancreatitis

    Science.gov (United States)

    Robles, Lourdes; Vaziri, Nosratola D.; Li, Shiri; Masuda, Yuichi; Takasu, Chie; Takasu, Mizuki; Vo, Kelly; Farzaneh, Seyed H.; Stamos, Michael J.; Ichii, Hirohito

    2014-01-01

    Background Chronic pancreatitis (CP) is a progressive disorder resulting in the destruction and fibrosis of the pancreatic parenchyma which ultimately leads to impairment of the endocrine and exocrine functions. Dimethyl Fumarate (DMF) was recently approved by FDA for treatment of patients with multiple sclerosis. DMF's unique anti-oxidant and anti-inflammatory properties make it an interesting drug to test on other inflammatory conditions. This study was undertaken to determine the effects of DMF on islet cells and non-endocrine tissue in a rodent model of L-Arginine-induced CP. Methods Male Wistar rats fed daily DMF (25 mg/kg) or vehicle by oral gavage were given 5 IP injections of L-Arginine (250 mg/100 g×2, 1 hr apart). Rats were assessed with weights and intra-peritoneal glucose tolerance tests (IPGTT, 2 g/kg). Islets were isolated and assessed for islet mass and viability with flow cytometry. Non-endocrine tissue was assessed for histology, myeloperoxidase (MPO), and lipid peroxidation level (MDA). In vitro assessments included determination of heme oxygenase (HO-1) protein expression by Western blot. Results Weight gain was significantly reduced in untreated CP group at 6 weeks. IPGTT revealed significant impairment in untreated CP group and its restoration with DMF therapy (P L-Arginine-induced CP and islet function in rats. DMF treatment could be a possible strategy to improve clinical outcome in patients with CP. PMID:25198679

  13. PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet.

    Science.gov (United States)

    Lorenzo, Petra I; Fuente-Martín, Esther; Brun, Thierry; Cobo-Vuilleumier, Nadia; Jimenez-Moreno, Carmen María; G Herrera Gomez, Irene; López Noriega, Livia; Mellado-Gil, José Manuel; Martin-Montalvo, Alejandro; Soria, Bernat; Gauthier, Benoit R

    2015-10-27

    PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4(+) progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP(+) subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP(+) cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP(+) cells were more resistant to apoptosis than their GFP(-) counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets.

  14. Diabetes mellitus in the BB/W rat. Insulitis in pancreatic islet grafts after transplantation in diabetic recipients.

    OpenAIRE

    Weringer, E. J.; Like, A. A.

    1986-01-01

    Spontaneous diabetes mellitus in the BioBreeding/Worcester (BB/W) rat is preceded by lymphocytic insulitis which destroys pancreatic beta cells. Cultured major histocompatibility complex identical pancreatic islets and adrenal cortex derived from diabetes-resistant BB/W donors were transplanted into diabetic recipients with hyperglycemia of variable duration. Islet grafts were the targets of BB/W immune attack and revealed lymphocytic insulitis after transplantation into diabetic recipients e...

  15. Pancreatic islet-cell viability, functionality and oxidative status ...

    Indian Academy of Sciences (India)

    Unknown

    lar) in case of lean and obese mice (Dalpe-Scott et al. 1983). Antibiotics also show concentration dependant effect on the islet functionality. Injection of tetracycline hydrochloride at the dose of 25 mg/kg body weight in mice did not change the functional activity of the β-cells and the rate of insulin formation and secretion for ...

  16. A hybrid of cells and pancreatic islets toward a new bioartificial pancreas

    Directory of Open Access Journals (Sweden)

    Yuji Teramura

    2016-03-01

    Full Text Available Cell surface engineering using single-stranded DNA–poly(ethylene glycol-conjugated phospholipid (ssDNA–PEG-lipid is useful for inducing cell–cell attachment two and three dimensionally. In this review, we summarize our recent techniques for cell surface engineering and their applications to islet transplantation. Because any DNA sequence can be immobilized onto the cell surface by hydrophobic interactions between ssDNA–PEG-lipid and the cellular membrane without impairing cell function, a cell–cell hybrid can be formed through the DNA hybridization. With this technique, it would be possible to create three-dimensional hybrid structures of pancreatic islets coated with various accessory cells, such as patients’ own cells, mesenchymal and adipose-derived stem cells, endothelial progenitor cells, neural crest stem cells or regulatory T cells, which might significantly improve the outcome of islet transplantation in diabetic patients.

  17. Differentiation of mesenchymal stem cells derived from pancreatic islets and bone marrow into islet-like cell phenotype.

    Directory of Open Access Journals (Sweden)

    Cristina Zanini

    Full Text Available BACKGROUND: Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself. METHODOLOGY/PRINCIPAL FINDINGS: In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs. HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1, insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin. CONCLUSIONS/SIGNIFICANCE: Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of

  18. Glucose activates prenyltransferases in pancreatic islet {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Goalstone, Marc [Department of Medicine, University of Colorado, VA Medical Center, Denver, CO 80220 (United States); Kamath, Vasudeva [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States); Kowluru, Anjaneyulu, E-mail: akowluru@med.wayne.edu [Department of Pharmaceutical Sciences, Wayne State University, VA Medical Center, Detroit, MI 48201 (United States)

    2010-01-01

    A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet {beta}-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 {beta}-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20 mM] markedly stimulated the expression of the {alpha}-subunits of FTase/GGTase-1, but not the {beta}-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.

  19. Glucose activates prenyltransferases in pancreatic islet β-cells

    International Nuclear Information System (INIS)

    Goalstone, Marc; Kamath, Vasudeva; Kowluru, Anjaneyulu

    2010-01-01

    A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet β-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 β-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20 mM] markedly stimulated the expression of the α-subunits of FTase/GGTase-1, but not the β-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.

  20. General Information about Pancreatic Neuroendocrine Tumors (Islet Cell Tumors)

    Science.gov (United States)

    ... a non-functional pancreatic NET. Abdominal CT scan (CAT scan) : A procedure that makes a series of ... called octreotide scan and SRS. Insulinoma Fasting serum glucose and insulin test : A test in which a ...

  1. Causes of limited survival of microencapsulated pancreatic islet grafts

    NARCIS (Netherlands)

    de Groot, Martijn; Schuurs, T.A; van Schilfgaarde, Reinout

    Successful transplantation of pancreatic tissue has been demonstrated to be an efficacious method of restoring glycemic control in type 1 diabetic patients. To establish graft acceptance patients require lifelong immunosuppression, which in turn is associated with severe deleterious side effects.

  2. Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

    Science.gov (United States)

    Peschke, Elmar; Bähr, Ina; Mühlbauer, Eckhard

    2013-01-01

    The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes. PMID:23535335

  3. Protein disulfide isomerase ameliorates β-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide.

    Science.gov (United States)

    Montane, Joel; de Pablo, Sara; Obach, Mercè; Cadavez, Lisa; Castaño, Carlos; Alcarraz-Vizán, Gema; Visa, Montserrat; Rodríguez-Comas, Júlia; Parrizas, Marcelina; Servitja, Joan Marc; Novials, Anna

    2016-01-15

    Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits in islets of type 2 diabetic patients. hIAPP misfolding and aggregation is one of the factors that may lead to β-cell dysfunction and death. Endogenous chaperones are described to be important for the folding and functioning of proteins. Here, we examine the effect of the endoplasmic reticulum chaperone protein disulfide isomerase (PDI) on β-cell dysfunction. Among other chaperones, PDI was found to interact with hIAPP in human islet lysates. Furthermore, intrinsically recovered PDI levels were able to restore the effect of high glucose- and palmitate-induced β-cell dysfunction by increasing 3.9-fold the glucose-stimulated insulin secretion levels and restoring insulin content up to basal control values. Additionally, PDI transduction decreased induced apoptosis by glucolipotoxic conditions. This approach could reveal a new therapeutic target and aid in the development of strategies to improve β-cell dysfunction in type 2 diabetic patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Processing of superparamagnetic iron contrast agent ferucarbotran in transplanted pancreatic islets

    Czech Academy of Sciences Publication Activity Database

    Zacharovová, K.; Berková, Z.; Jirák, D.; Herynek, V.; Vancová, Marie; Dovolilová, E.; Saudek, F.

    2012-01-01

    Roč. 7, č. 6 (2012), s. 485-493 ISSN 1555-4309 Institutional research plan: CEZ:AV0Z60220518 Keywords : magnetic resonance imaging * pancreatic islets * transplantation * superparamagnetic iron oxide nanoparticles * ferucarbotran * β cells * diabetes * immunohistochemistry * transmission electron microscopy Subject RIV: CE - Biochemistry Impact factor: 2.872, year: 2012 http://onlinelibrary.wiley.com/doi/10.1002/cmmi.1477/full

  5. Differential diagnosis of non-functional islet cell tumor and pancreatic carcinoma with sonography

    Energy Technology Data Exchange (ETDEWEB)

    Yang Wei [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China); Chen Minhua [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China)]. E-mail: minhuachen@vip.sina.com; Yan Kun [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China); Wu Wei [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China); Dai Ying [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China); Zhang Hui [Department of Ultrasound, School of Oncology, Peking University, Beijing 100036 (China)

    2007-06-15

    Objective: To investigate the differential diagnosis of non-functional islet cell tumor (NFICT) and pancreatic ductal adenocarcinoma (pancreatic carcinoma) with clinical presentation and sonographic features. Materials and methods: Twenty cases of NFICT were investigated in the study, and 41 cases of pancreatic carcinoma were included as the control group. Among them, 5 NFICT and 32 pancreatic carcinomas underwent CEUS with SonoVue. Clinical presentation and sonographic characteristics were evaluated with Logistic regression analysis. Furthermore, the preliminary result of contrast enhanced ultrasound (CEUS) was analyzed. Results: Statistic analysis showed four significant factors in differential diagnosis for NFICT and pancreatic carcinoma, including age (P < 0.001), tumor size (P = 0.006), tumor margin (P < 0.001) and vascularity of tumor (P = 0.004). Combined these four factors, the sensitivity, specificity and accuracy are 95.0%, 95.1% and 95.1%, respectively. When the patient is younger than 60 years, and tumor is smaller than 5 cm with well-defined margin and hypervascular, it would be most likely a NFICT other than pancreatic carcinoma. NFICT often shows early enhancement and more homogeneous infusion than pancreatic carcinoma on CEUS (P = 0.005 and 0.008). Conclusions: Sonography is able to provide useful differential information for NFICT, which is often misdiagnosed as pancreatic carcinoma.

  6. The role of interventional radiology and imaging in pancreatic islet cell transplantation

    International Nuclear Information System (INIS)

    Dixon, S.; Tapping, C.R.; Walker, J.N.; Bratby, M.; Anthony, S.; Boardman, P.; Phillips-Hughes, J.; Uberoi, R.

    2012-01-01

    Pancreatic islet cell transplantation (PICT) is a novel treatment for patients with insulin-dependent diabetes who have inadequate glycaemic control or hypoglycaemic unawareness, and who suffer from the microvascular/macrovascular complications of diabetes despite aggressive medical management. Islet transplantation primarily aims to improve the quality of life for type 1 diabetic patients by achieving insulin independence, preventing hypoglycaemic episodes, and reversing hypoglycaemic unawareness. The islet cells for transplantation are extracted and purified from the pancreas of brain-stem dead, heart-beating donors. They are infused into the recipient's portal vein, where they engraft into the liver to release insulin in order to restore euglycaemia. Initial strategies using surgical access to the portal vein have been superseded by percutaneous access using interventional radiology techniques, which are relatively straightforward to perform. It is important to be vigilant during the procedure in order to prevent major complications, such as haemorrhage, which can be potentially life-threatening. In this article we review the history of islet cell transplantation, present an illustrated review of our experience with islet cell transplantation by describing the role of imaging and interventional radiology, and discuss current research into imaging techniques for monitoring graft function.

  7. Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial.

    Science.gov (United States)

    Coronel, Maria M; Geusz, Ryan; Stabler, Cherie L

    2017-06-01

    A major obstacle in the survival and efficacy of tissue engineered transplants is inadequate oxygenation, whereby unsupportive oxygen tensions result in significant cellular dysfunction and death within the implant. In a previous report, we developed an innovative oxygen generating biomaterial, termed OxySite, to provide supportive in situ oxygenation to cells and prevent hypoxia-induced damage. Herein, we explored the capacity of this biomaterial to mitigate hypoxic stress in both rat and nonhuman primate pancreatic islets by decreasing cell death, supporting metabolic activity, sustaining aerobic metabolism, preserving glucose responsiveness, and decreasing the generation of inflammatory cytokines. Further, the impact of supplemental oxygenation on in vivo cell function was explored by the transplantation of islets previously co-cultured with OxySite into a diabetic rat model. Transplant outcomes revealed significant improvement in graft efficacy for OxySite-treated islets, when transplanted within an extrahepatic site. These results demonstrate the potency of the OxySite material to mitigate activation of detrimental hypoxia-induced pathways in islets during culture and highlights the importance of in situ oxygenation on resulting islet transplant outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development.

    Science.gov (United States)

    Soyer, Josselin; Flasse, Lydie; Raffelsberger, Wolfgang; Beucher, Anthony; Orvain, Christophe; Peers, Bernard; Ravassard, Philippe; Vermot, Julien; Voz, Marianne L; Mellitzer, Georg; Gradwohl, Gérard

    2010-01-01

    The transcription factor neurogenin 3 (Neurog3 or Ngn3) controls islet cell fate specification in multipotent pancreatic progenitor cells in the mouse embryo. However, our knowledge of the genetic programs implemented by Ngn3, which control generic and islet subtype-specific properties, is still fragmentary. Gene expression profiling in isolated Ngn3-positive progenitor cells resulted in the identification of the uncharacterized winged helix transcription factor Rfx6. Rfx6 is initially expressed broadly in the gut endoderm, notably in Pdx1-positive cells in the developing pancreatic buds, and then becomes progressively restricted to the endocrine lineage, suggesting a dual function in both endoderm development and islet cell differentiation. Rfx6 is found in postmitotic islet progenitor cells in the embryo and is maintained in all developing and adult islet cell types. Rfx6 is dependent on Ngn3 and acts upstream of or in parallel with NeuroD, Pax4 and Arx transcription factors during islet cell differentiation. In zebrafish, the Rfx6 ortholog is similarly found in progenitors and hormone expressing cells of the islet lineage. Loss-of-function studies in zebrafish revealed that rfx6 is required for the differentiation of glucagon-, ghrelin- and somatostatin-expressing cells, which, in the absence of rfx6, are blocked at the progenitor stage. By contrast, beta cells, whose number is only slightly reduced, were no longer clustered in a compact islet. These data unveil Rfx6 as a novel regulator of islet cell development.

  9. Spontaneous Hypoglycemia After Islet Autotransplantation for Chronic Pancreatitis.

    Science.gov (United States)

    Lin, Yu Kuei; Faiman, Charles; Johnston, Philip C; Walsh, R Matthew; Stevens, Tyler; Bottino, Rita; Hatipoglu, Betul A

    2016-10-01

    Spontaneous hypoglycemia has been reported in patients after total pancreatectomy (TP) and islet autotransplantation (IAT) with maintained insulin independence. Details surrounding these events have not been well described. The objective of the study was to determine the frequency and characteristics of spontaneous hypoglycemia in patients undergoing TP-IAT and/or to ascertain predictive or protective factors of its development. This was an observational cohort study in 40 patients who underwent TP-IAT from August 2008 to May 2014, with a median follow-up of 34 months. The study was conducted at a single institution (Cleveland Clinic). Patients included recipients of TP-IAT. The intervention included small, frequent meals in those patients who developed spontaneous hypoglycemia. Incidence of spontaneous hypoglycemia development, characteristics of the patients developing hypoglycemia, and their response to small, frequent meals were measured. Six of 12 patients, who maintained insulin independence, developed spontaneous hypoglycemia. The episodes could be fasting, postprandial, and/or exercise associated, with the frequency ranging from two to three times daily to once every 1-2 weeks. All patients experienced at least one episode that required external assistance, glucagon administration, and/or emergent medical attention. Patients who developed hypoglycemia had a lower median age and tended to have a lower median islet equivalent/kg body weight but a higher median total islet equivalent, body mass index, and homeostatic model assessment for insulin resistance score. All patients who received small, frequent meal intervention had improvement in severity and/or frequency of the hypoglycemic episodes. Spontaneous hypoglycemia is prevalent after TP-IAT. Although the underlying pathophysiology responsible for these hypoglycemia events remains to be elucidated, small, frequent meal intervention is helpful in ameliorating this condition.

  10. Dynamics and Synchrony of Pancreatic beta-cells and Islets

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2006-01-01

    description of these processes and their interactions would provide important input in the search for a better treatment of the disease. The thesis describes several aspects of mathematical modeling of beta-cells relevant for the understanding of glucose stimulated insulin secretion. It consists...... and the synchronized behavior of many coupled beta-cells as well as to the synchrony of islets. Rather than developing new biophysical models, the thesis investigates existing models, their integration and simplifications, and analyzed the corresponding dynamics, in order to use these models for investigating...

  11. Pancreatic Islet Cell Amyloidosis Manifesting as a Large Pancreas

    International Nuclear Information System (INIS)

    Onur, Mehmet Ruhi; Yalniz, Mehmet; Poyraz, Ahmet Kursad; Oezercan, Ibrahim Hanifi; Ozkan, Yusuf

    2012-01-01

    A 39-year-old female patient presented to our hospital with epigastric pain lasting for two months. Laboratory results showed impaired glucose tolerance. Ultrasonography of the patient showed a hypoechoic, diffusely enlarged pancreas. CT revealed a large pancreas, with multiple calcifications. On MRI, a diffusely enlarged pancreas was seen hypointense on both T1- and T2-weighted images with heterogeneous enhancement after gadolinium administration. A biopsy of the pancreas revealed primary amyloidosis of islet cells. Decreased signal on T1-weighted images without inflammation findings on CT and MRI were clues for the diagnosis.

  12. Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans

    NARCIS (Netherlands)

    de Jong, V. Martijn; Abreu, Joana R. F.; Verrijn Stuart, Annemarie A.; van der Slik, Arno R.; Verhaeghen, Katrijn; Engelse, Marten A.; Blom, Bianca; Staal, Frank J. T.; Gorus, Frans K.; Roep, Bart O.

    2013-01-01

    Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), is differentially spliced between pancreatic

  13. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Douillet, Christelle [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Currier, Jenna [Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Saunders, Jesse [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Bodnar, Wanda M. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States); Matoušek, Tomáš [Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic); Stýblo, Miroslav, E-mail: styblo@med.unc.edu [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  14. Demonstration of pepsinogen C in human pancreatic islets

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier

    1987-01-01

    Pancreatic tissue from 16 post mortem kidney donors have been examined for the content of pepsinogens. A zymogen with electrophoretic mobility, isoelectric point and molecular weight equal to that of pepsinogen C of gastric origin was found in all specimens. A comparison between pepsinogen C extr...

  15. Effect of alcohol on insulin secretion and viability of human pancreatic islets

    Directory of Open Access Journals (Sweden)

    Nikolić Dragan

    2017-01-01

    Full Text Available Introduction/Objective. There are controversial data in the literature on the topic of effects of alcohol on insulin secretion, apoptosis, and necrosis of the endocrine and exocrine pancreas. The goal of this research was to determine how alcohol affects the insulin secretion and viability of human adult pancreatic islets in vitro during a seven-day incubation. Methods. Human pancreatic tissue was digested with Collagenase XI, using a non-automated method. Cultures were incubated in Roswell Park Memorial Institute (RPMI medium containing alcohol (10 μl of alcohol in 100 ml of medium. Insulin stimulation index (SI and viability of the islets were determined on the first, third, and seventh day of cultivation. Results. Analysis of the viability of the islets showed that there wasn’t significant difference between the control and the test group. In the test group, viability of the cultures declined with the time of incubation. SI of the test group was higher compared to the control group, by 50% and 25% on the first and third day of cultivation, respectively. On the seventh day, insulin secretion was reduced by 25%. The difference was not statistically significant (p > 0.05. In the test group, significant decline in insulin secretion was found on the third and seventh day of incubation (p ≤ 0.05. Conclusion. Alcohol can increase or decrease insulin secretion of islets cultures, which may result in an inadequate response of pancreatic β-cells to blood glucose, leading to insulin resistance, and increased risk of developing type 2 diabetes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41002

  16. Expression of Receptors for Tetanus Toxin and Monoclonal Antibody A2B5 by Pancreatic Islet Cells

    Science.gov (United States)

    Eisenbarth, G. S.; Shimizu, K.; Bowring, M. A.; Wells, S.

    1982-08-01

    Studies of the reaction of antibody A2B5 and tetanus toxin with pancreatic islet cells, islet cell tumors, and other human amine precursor uptake and decarboxylation (APUD) tumors are described. By indirect immunofluorescence, antibody A2B5 and tetanus toxin were shown to specifically bind to the plasma membrane of human, rat, chicken, and mouse islet cells. The binding of antibody A2B5 to the cell surface of living islet cells has allowed isolation of these cells from a suspension of pancreatic cells by using a fluorescence-activated cell sorter. In studies designed to determine whether tetanus toxin and antibody A2B5 bound to the same surface antigen, A2B5 and tetanus toxin did not compete for binding to normal islet cells, a human islet cell tumor, or a rat islet cell tumor. In addition to binding to islet cell tumors, antibody A2B5 reacts with frozen sections, isolated cells, and cell lines of neural, neural crest, and APUD origin.

  17. An 'alpha-beta' of pancreatic islet microribonucleotides

    DEFF Research Database (Denmark)

    Dalgaard, Louise Torp; Eliasson, Lena

    2017-01-01

    . Moreover, processing of miRNAs appears to be altered by obesity, diabetes, and aging. A number of miRNAs (such as miR-7, miR-21, miR-29, miR-34a, miR-212/miR-132, miR-184, miR-200 and miR-375) are involved in mediating beta cell dysfunction and/or compensation induced by hyperglycemia, oxidative stress......, cytotoxic cytokines, and in rodent models of fetal metabolic programming prediabetes and overt diabetes. Studies of human type 2 diabetic islets underline that these miRNA families could have important roles also in human type 2 diabetes. Furthermore, there is a genuine gap of knowledge regarding mi...

  18. Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

    International Nuclear Information System (INIS)

    Chow, S.A.; Falany, J.L.; Fischer, L.J.

    1989-01-01

    The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals

  19. Assessment of benzene induced oxidative impairment in rat isolated pancreatic islets and effect on insulin secretion.

    Science.gov (United States)

    Bahadar, Haji; Maqbool, Faheem; Mostafalou, Sara; Baeeri, Maryam; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Abdollahi, Mohammad

    2015-05-01

    Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. The Efficacy of a Prevascularized, Retrievable Poly(D,L,-lactide-co-epsilon-caprolactone) Subcutaneous Scaffold as Transplantation Site for Pancreatic Islets

    NARCIS (Netherlands)

    Smink, Alexandra M; Li, Shiri; Hertsig, Don T; de Haan, Bart J; Schwab, Leendert; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; Lakey, Jonathan R T; de Vos, Paul

    Background. The liver as transplantation site for human pancreatic islets is a harsh microenvironment for islets and it lacks the ability to retrieve the graft. A retrievable, extrahepatic transplantation site that mimics the pancreatic environment is desired. Ideally, this transplantation site

  1. Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat

    Directory of Open Access Journals (Sweden)

    Bhattacharjee Ankita

    2015-06-01

    Full Text Available Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/day with or without supplementation of folic acid (36 μg/kg body weight/day or vitamin B12 (0.63 μg/kg body weight/day alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat.

  2. Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase.

    Science.gov (United States)

    Vetterli, Laurène; Carobbio, Stefania; Pournourmohammadi, Shirin; Martin-Del-Rio, Rafael; Skytt, Dorte M; Waagepetersen, Helle S; Tamarit-Rodriguez, Jorge; Maechler, Pierre

    2012-10-01

    In pancreatic β-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a β-cell-specific GDH knockout mouse model, called βGlud1(-/-). The absence of GDH in islets isolated from βGlud1(-/-) mice resulted in abrogation of insulin release evoked by glutamine combined with 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or l-leucine. Reintroduction of GDH in βGlud1(-/-) islets fully restored the secretory response. Regarding glucose stimulation, insulin secretion in islets isolated from βGlud1(-/-) mice exhibited half of the response measured in control islets. The amplifying pathway, tested at stimulatory glucose concentrations in the presence of KCl and diazoxide, was markedly inhibited in βGlud1(-/-) islets. On glucose stimulation, net synthesis of glutamate from α-ketoglutarate was impaired in GDH-deficient islets. Accordingly, glucose-induced elevation of glutamate levels observed in control islets was absent in βGlud1(-/-) islets. Parallel biochemical pathways, namely alanine and aspartate aminotransferases, could not compensate for the lack of GDH. However, the secretory response to glucose was fully restored by the provision of cellular glutamate when βGlud1(-/-) islets were exposed to dimethyl glutamate. This shows that permissive levels of glutamate are required for the full development of glucose-stimulated insulin secretion and that GDH plays an indispensable role in this process.

  3. Direct Substrate Delivery Into Mitochondrial Fission-Deficient Pancreatic Islets Rescues Insulin Secretion.

    Science.gov (United States)

    Kabra, Uma D; Pfuhlmann, Katrin; Migliorini, Adriana; Keipert, Susanne; Lamp, Daniel; Korsgren, Olle; Gegg, Moritz; Woods, Stephen C; Pfluger, Paul T; Lickert, Heiko; Affourtit, Charles; Tschöp, Matthias H; Jastroch, Martin

    2017-05-01

    In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1 , we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria. © 2017 by the American Diabetes Association.

  4. Simultaneous determination of the content of serotonin, dopamine, noradrenaline and adrenaline in pancreatic islets isolated from fed and starved mice

    International Nuclear Information System (INIS)

    Hansen, S.E.; Hedeskov, C.J.

    1977-01-01

    A highly sensitive double isotope method for the simultaneous determination of serotonin, dopamine, noradrenaline and adrenaline has been developed. Advantages and limitations of the method are discussed. The mentioned biogenic amines are all present in isolated pancreatic islet tissue from albino mice in concentrations ranging from approximately 5-30 μmol per kg wet weight (0.8-5 x 10 -3 pmol/ng DNA). A somewhat higher content of these amines, especially dopamine, was found in pancreatic acinar tissue. The hypothesis that the impaired glucose-induced insulin secretion during starvation partly is caused by an increased content of biogenic amines in the pancreatic islets was not supported by our experiments which showed an unchanged islet content of these amines after 48 h starvation. (author)

  5. MiR-184 expression is regulated by AMPK in pancreatic islets.

    Science.gov (United States)

    Martinez-Sanchez, Aida; Nguyen-Tu, Marie-Sophie; Cebola, Ines; Yavari, Arash; Marchetti, Piero; Piemonti, Lorenzo; de Koning, Eelco; Shapiro, A M James; Johnson, Paul; Sakamoto, Kei; Smith, David M; Leclerc, Isabelle; Ashrafian, Houman; Ferrer, Jorge; Rutter, Guy A

    2018-01-08

    AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β-cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits (βAMPKdKO mice) impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human β-cells. We identified 14 down-regulated and 9 up-regulated miRNAs in βAMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for β-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of β-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in β-cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.

  6. Protective effect of ganoderma lucidum polysaccharides on pancreatic islet in type 2 diabetes mellitus rats

    International Nuclear Information System (INIS)

    Tang Zhigang; Xue Hua; Qiao Jin; Gu Jinhua; Xu Jiliang

    2010-01-01

    Objective: To investigate the protective effects of ganoderma lucidum polysaccharides (GLPs) on pancreatic islet in T2DM rats. Method: SD rats were fed high-fat diet for 4 weeks and then were injected STZ (30 mg/kg) to induce the type 2 diabetes mellitus(T2DM). Once the T2DM model were set successfully, rats were divided into six groups randomly: the normal group (NG), diabetes mellitus group (DMG), GPLs low dosage group (GLPs-LG), GPLs middle dosage group (GLPs-MG), GLPs high dosage group (GLPs-HG) and the berberine group (BerG). They received GLPs with different dosages (200, 400, or 800 mg/kg) and berberine (30 mg/kg) continually for 10 weeks. At 10th weekend, the following indexes of rats in each group were measured respectively: blood glucose, insulin sensivity index (ISI), the contents of NO, SOD, MDA, GSH-Px, CAT in pancreas tissue. At the same time pathological change of pancreas was evaluated by hematoxylin/eosin staining and immunohistochemistry of insulin. Result: As compared with the diabetic model, the decrease of blood glucose with GLPs treatment for 10 weeks were observed. There was also notably increased antioxidant enzyme activity such as superoxide dismutase (SOD), catalase (CAT) as well as decreased MDA content in the pancreatic homogenate. Under light microscope, GLPs-HG treated T2DM showed significantly ameliorated pathological changes, increased islet area and enhanced insulin staining intensity in islets. Conclusion: GLPs has protective effect on the STZ-induced islet injury in T2DM rats through increasing antioxidant enzyme activity and reducing oxidative stress. (authors)

  7. Delineation of glutamate pathways and secretory responses in pancreatic islets with β-cell-specific abrogation of the glutamate dehydrogenase

    DEFF Research Database (Denmark)

    Vetterli, Laurène; Carobbio, Stefania; Pournourmohammadi, Shirin

    2012-01-01

    In pancreatic β-cells, glutamate dehydrogenase (GDH) modulates insulin secretion, although its function regarding specific secretagogues is unclear. This study investigated the role of GDH using a β-cell-specific GDH knockout mouse model, called βGlud1(-/-). The absence of GDH in islets isolated...... from βGlud1(-/-) mice resulted in abrogation of insulin release evoked by glutamine combined with 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid or l-leucine. Reintroduction of GDH in βGlud1(-/-) islets fully restored the secretory response. Regarding glucose stimulation, insulin secretion in islets...... isolated from βGlud1(-/-) mice exhibited half of the response measured in control islets. The amplifying pathway, tested at stimulatory glucose concentrations in the presence of KCl and diazoxide, was markedly inhibited in βGlud1(-/-) islets. On glucose stimulation, net synthesis of glutamate from α...

  8. Excessive food intake, obesity and inflammation process in Zucker fa/fa rat pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Myriam Chentouf

    Full Text Available Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced β-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to ß-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro-inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and β-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1β, IL-6 and TNFα expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning β-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35 and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1β and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of β-cell function by IL-1β. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an

  9. PPAR-γ overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein

    International Nuclear Information System (INIS)

    Ito, Eisuke; Ozawa, Sachihiko; Takahashi, Kazuto; Tanaka, Toshiaki; Katsuta, Hidenori; Yamaguchi, Shinya; Maruyama, Masahiro; Takizawa, Makoto; Katahira, Hiroshi; Yoshimoto, Katsuhiko; Nagamatsu, Shinya; Ishida, Hitoshi

    2004-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) regulates several cellular functions, but its physiological role in pancreatic islet cells remains to be investigated. In this study, we confirmed the presence of PPAR-γ in rat isolated islets and examined its role on insulin and glucagon secretion by using PPAR-γ-overexpressed islets. PPAR-γ overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose (p < 0.05). In addition, insulin secretion evoked by high potassium depolarization also was significantly decreased from PPAR-γ-overexpressed islets (p < 0.05). On the other hand, no significant change in glucagon release was observed after high potassium depolarization between PPAR-γ-overexpressed and control islets. Insulin and glucagon content in islets was not statistically different between the two groups. In addition, the expression of uncoupling protein-2 (UCP-2) was found to be induced in PPAR-γ-overexpressed islets. This result clearly indicates that the deteriorative effect of PPAR-γ overexpression on the secretory machinery is selective for pancreatic β-cells. And it is possible that its site of action can be located in the energy-consuming exocytotic process of insulin secretory granules, and that the reduction of ATP production through increased UCP-2 reduces insulin exocytosis

  10. Microbial contamination of transplant solutions during pancreatic islet autotransplants is not associated with clinical infection in a pediatric population.

    Science.gov (United States)

    Berger, Megan G; Majumder, Kaustav; Hodges, James S; Bellin, Melena D; Schwarzenberg, Sarah Jane; Gupta, Sameer; Dunn, Ty B; Beilman, Gregory J; Pruett, Timothy L; Freeman, Martin L; Wilhelm, Joshua J; Sutherland, David E R; Chinnakotla, Srinath

    2016-01-01

    Total pancreatectomy and islet autotransplant (TP-IAT) is a potential treatment for children with severe refractory chronic pancreatitis. Cultures from the resected pancreas and final islet preparation are frequently positive for microbes. It is unknown whether positive cultures are associated with adverse outcomes in pediatric patients. We reviewed the medical records of children (n = 86) who underwent TP-IAT from May 2006-March 2015 with emphasis on demographics, previous pancreatic interventions, culture results, islet yield, hospital days, posttransplant islet function, and posttransplant infections. We compared outcomes in patients with positive (n = 57) and negative (n = 29) cultures. Patients with positive cultures had higher rates of previous pancreas surgery (P = 0.007) and endoscopic retrograde cholangiopancreatography (P < 0.0001). Positive cultures were not associated with posttransplant infections (P = 1.00) or prolonged hospital length of stay (P = 0.29). Patients with positive final islet preparation culture showed increased rates of graft failure at 2 years posttransplant (P = 0.041), but not when adjusted for islet mass transplanted (P = 0.39). Positive cultures during pediatric TP-IATs do not increase the risk of posttransplant infections or prolong hospital length of stay. Endocrine function depends on islet mass transplanted. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  11. A supervised learning framework for pancreatic islet segmentation with multi-scale color-texture features and rolling guidance filters.

    Science.gov (United States)

    Huang, Yue; Liu, Chi; Eisses, John F; Husain, Sohail Z; Rohde, Gustavo K

    2016-10-01

    Islet cell quantification and function is important for developing novel therapeutic interventions for diabetes. Existing methods of pancreatic islet segmentation in histopathological images depend strongly on cell/nuclei detection, and thus are limited due to a wide variance in the appearance of pancreatic islets. In this paper, we propose a supervised learning pipeline to segment pancreatic islets in histopathological images, which does not require cell detection. The proposed framework firstly partitions images into superpixels, and then extracts multi-scale color-texture features from each superpixel and processes these features using rolling guidance filters, in order to simultaneously reduce inter-class ambiguity and intra-class variation. Finally, a linear support vector machine (SVM) is trained and applied to segment the testing images. A total of 23 hematoxylin-and-eosin-stained histopathological images with pancreatic islets are used for verifying the framework. With an average accuracy of 95%, training time of 20 min and testing time of 1 min per image, the proposed framework outperforms existing approaches with better segmentation performance and lower computational cost. © 2016 International Society for Advancement of Cytometry. © 2016 International Society for Advancement of Cytometry.

  12. The effect of lesions of the sympathoadrenal system on training induced adaptations in adipocytes and pancreatic islets in rats

    DEFF Research Database (Denmark)

    Stallknecht, B; Roesdahl, M; Vinten, J

    1996-01-01

    Physical training increases insulin stimulated glucose uptake in adipocytes and decreases insulin secretion from pancreatic islets. The mechanism behind these adaptations is not known. Because in acute exercise adrenergic activity influences both adipocytes and pancreatic islets, the sympathetic...... nervous system was examined as the possible mediator. Rats were either adrenodemedullated or sham adrenodemedullated and underwent either unilateral abdominal sympathectomy or were sham sympathectomized. Resting plasma adrenaline concentration in adrenodemedullated rats was 32% of the concentration...... in sham adrenodemedullated rats (P muscle noradrenaline content in sympathectomized leg was 9% of content in sham sympathectomized leg (P

  13. Histomorphological and morphometric studies of the pancreatic islet cells of diabetic rats treated with extracts of Annona muricata.

    Science.gov (United States)

    Adeyemi, D O; Komolafe, O A; Adewole, O S; Obuotor, E M; Abiodun, A A; Adenowo, T K

    2010-05-01

    Microanatomical changes in the pancreatic islet cells of streptozotocin induced diabetic Wistar rats were studied after treatment with methanolic extracts of Annona muricata leaves. Thirty adult Wistar rats were randomly assigned into three groups (control, untreated diabetic group, and A. muricata-treated diabetic group) of ten rats each. Diabetes mellitus was experimentally induced in groups B and C by a single intra-peritoneal injection of 80 mg/kg streptozotocin dissolved in 0.1 M citrate buffer. The control rats were intraperitoneally injected with an equivalent volume of citrate buffer. Daily intra peritoneal injections of 100 mg/kg A. muricata were administered to group C rats for two weeks. Post sacrifice the pancreases of the rats were excised and fixed in Bouin's fluid. The tissues were processed for paraffin embedding and sections of 5 mum thickness were produced and stained with H & E, Gomori aldehyde fuchsin, and chrome alum haematoxylin-phloxine for demonstration of the beta-cells of islets of pancreatic islets. Histomorphological and morphometric examination of the stained pancreatic sections showed a significant increase in the number, diameter, and volume of the beta-cells of pancreatic islets of the A. muricata-treated group (5.67 +/- 0.184 N/1000 mum(2), 5.38 +/- 0.093 mum and 85.12 +/- 4.24 mum(3), respectively) when compared to that of the untreated diabetic group of rats (2.85 +/- 0.361 N/1000 mum(2), 2.85 +/- 0.362 mum and 69.56 +/- 5.216 mum(3), respectively). The results revealed regeneration of the beta-cells of islets of pancreatic islet of rats treated with extract of A. muricata.

  14. Use of additives, scaffolds and extracellular matrix components for improvement of human pancreatic islet outcomes in vitro: A systematic review.

    Science.gov (United States)

    Lemos, Natália Emerim; de Almeida Brondani, Letícia; Dieter, Cristine; Rheinheimer, Jakeline; Bouças, Ana Paula; Bauermann Leitão, Cristiane; Crispim, Daisy; Bauer, Andrea Carla

    2017-09-03

    Pancreatic islet transplantation is an established treatment to restore insulin independence in type 1 diabetic patients. Its success rates have increased lately based on improvements in immunosuppressive therapies and on islet isolation and culture. It is known that the quality and quantity of viable transplanted islets are crucial for the achievement of insulin independence and some studies have shown that a significant number of islets are lost during culture time. Thus, in an effort to improve islet yield during culture period, researchers have tested a variety of additives in culture media as well as alternative culture devices, such as scaffolds. However, due to the use of different categories of additives or devices, it is difficult to draw a conclusion on the benefits of these strategies. Therefore, the aim of this systematic review was to summarize the results of studies that described the use of medium additives, scaffolds or extracellular matrix (ECM) components during human pancreatic islets culture. PubMed and Embase repositories were searched. Of 5083 articles retrieved, a total of 37 articles fulfilled the eligibility criteria and were included in the review. After data extraction, articles were grouped as follows: 1) "antiapoptotic/anti-inflammatory/antioxidant," 2) "hormone," 3) "sulphonylureas," 4) "serum supplements," and 5) "scaffolds or ECM components." The effects of the reviewed additives, ECM or scaffolds on islet viability, apoptosis and function (glucose-stimulated insulin secretion - GSIS) were heterogeneous, making any major conclusion hard to sustain. Overall, some "antiapoptotic/anti-inflammatory/antioxidant" additives decreased apoptosis and improved GSIS. Moreover, islet culture with ECM components or scaffolds increased GSIS. More studies are needed to define the real impact of these strategies in improving islet transplantation outcomes.

  15. Restructuring of pancreatic islets and insulin secretion in a postnatal critical window.

    Directory of Open Access Journals (Sweden)

    Cristina Aguayo-Mazzucato

    Full Text Available Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20, insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions, and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism.

  16. MicroRNA expression in alpha and beta cells of human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Dagmar Klein

    Full Text Available microRNAs (miRNAs play an important role in pancreatic development and adult β-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in α-and β-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98% subsets of human α-and β-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in β-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in α-cells (α-miRNAs and 134 were expressed more in β-cells (β-miRNAs. Bioinformatic analysis identified potential targets of β-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D community. cMaf, a transcription factor regulating glucagon expression expressed selectively in α-cells (TFα is targeted by β-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line αTC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TFα that inhibits the PI3K signaling pathway, at both RNA and protein levels.In conclusion, we identified miRNAs differentially expressed in pancreatic α- and β-cells and their potential transcription factor targets that could add new insights into different

  17. Glucagon-Secreting Alpha Cell Selective Two-Photon Fluorescent Probe TP-α: For Live Pancreatic Islet Imaging.

    Science.gov (United States)

    Agrawalla, Bikram Keshari; Chandran, Yogeswari; Phue, Wut-Hmone; Lee, Sung-Chan; Jeong, Yun-Mi; Wan, Si Yan Diana; Kang, Nam-Young; Chang, Young-Tae

    2015-04-29

    Two-photon (TP) microscopy has an advantage for live tissue imaging which allows a deeper tissue penetration up to 1 mm comparing to one-photon (OP) microscopy. While there are several OP fluorescence probes in use for pancreatic islet imaging, TP imaging of selective cells in live islet still remains a challenge. Herein, we report the discovery of first TP live pancreatic islet imaging probe; TP-α (Two Photon-alpha) which can selectively stain glucagon secreting alpha cells. Through fluorescent image based screening using three pancreatic cell lines, we discovered TP-α from a TP fluorescent dye library TPG (TP-Green). In vitro fluorescence test showed that TP-α have direct interaction and appear glucagon with a significant fluorescence increase, but not with insulin or other hormones/analytes. Finally, TP-α was successfully applied for 3D imaging of live islets by staining alpha cell directly. The newly developed TP-α can be a practical tool to evaluate and identify live alpha cells in terms of localization, distribution and availability in the intact islets.

  18. The voltage-gated proton channel Hv1 is expressed in pancreatic islet β-cells and regulates insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Qing [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Che, Yongzhe [School of Medicine, Nankai University, Tianjin 300071 (China); Li, Qiang; Zhang, Shangrong [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Gao, Ying-Tang [Key Laboratory of Artificial Cell, Third Central Clinical College of Tianjin Medical University, Tianjin 300170 (China); Wang, Yifan; Wang, Xudong; Xi, Wang; Zuo, Weiyan [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China); Li, Shu Jie, E-mail: shujieli@nankai.edu.cn [Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071 (China)

    2015-12-25

    The voltage-gated proton channel Hv1 is a potent acid extruder that participates in the extrusion of the intracellular acid. Here, we showed for the first time, Hv1 is highly expressed in mouse and human pancreatic islet β-cells, as well as β-cell lines. Imaging studies demonstrated that Hv1 resides in insulin-containing granules in β-cells. Knockdown of Hv1 with RNA interference significantly reduces glucose- and K{sup +}-induced insulin secretion in isolated islets and INS-1 (832/13) β-cells and has an impairment on glucose- and K{sup +}-induced intracellular Ca{sup 2+} homeostasis. Our data demonstrated that the expression of Hv1 in pancreatic islet β-cells regulates insulin secretion through regulating Ca{sup 2+} homeostasis.

  19. Direct long-term effect of hydrocortisone on insulin and glucagon release from mouse pancreatic islets in tissue culture

    DEFF Research Database (Denmark)

    Brunstedt, J; Nielsen, Jens Høiriis

    1981-01-01

    The effects of glucocorticoids on the pancreatic endocrine function was studied in isolated mouse pancreatic islets maintained in tissue culture for 1 to 3 weeks. Following culture for 2 week without corticoid supplement acute experiments with hydrocortisone showed no significant effect...... on the glucose-induced insulin release at 10(-8) to 10(-5) mol/l hydrocortisone. When, however, the islets were cultured in the presence of hydrocortisone, there was an increased insulin release to the medium in a dose-dependent manner, with the maximal effect at 10(-7) mol/l hydrocortisone. The release...... of glucagon to the medium was not affected to the same degree, but showed a slight inhibition at increasing concentrations of hydrocortisone. Short-term experiments after the culture period showed that islets cultured for 3 weeks in the presence of 10(-7) to 10(-5) mol/l hydrocortisone had an enhanced insulin...

  20. Dipeptidyl peptidase-4 inhibitors and preservation of pancreatic islet-cell function: a critical appraisal of the evidence

    NARCIS (Netherlands)

    van Genugten, R.E.; van Raalte, D.H.; Diamant, M.

    2012-01-01

    Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently,

  1. Unraveling the effects of 1,25(OH)(2)D-3 on global gene expression in pancreatic islets

    DEFF Research Database (Denmark)

    Wolden-Kirk, H.; Overbergh, L.; Gysemans, C.

    2013-01-01

    trafficking...... any effects of 1,25(OH)(2)D-3 on glucose-stimulated insulin release from healthy pancreatic islets. Conclusion: The effects of 1,25(OH)(2)D-3 on the expression of cytoskeletal and intracellular trafficking genes along with genes involved in ion transport may influence insulin exocytosis. However...

  2. Cytokines inducing bone marrow SCA+ cells migration into pancreatic islet and conversion into insulin-positive cells in vivo.

    Directory of Open Access Journals (Sweden)

    LuGuang Luo

    Full Text Available We hypothesize that specific bone marrow lineages and cytokine treatment may facilitate bone marrow migration into islets, leading to a conversion into insulin producing cells in vivo. In this study we focused on identifying which bone marrow subpopulations and cytokine treatments play a role in bone marrow supporting islet function in vivo by evaluating whether bone marrow is capable of migrating into islets as well as converting into insulin positive cells. We approached this aim by utilizing several bone marrow lineages and cytokine-treated bone marrow from green fluorescent protein (GFP positive bone marrow donors. Sorted lineages of Mac-1(+, Mac-1(-, Sca(+, Sca(-, Sca(-/Mac-1(+ and Sca(+/Mac-1(- from GFP positive mice were transplanted to irradiated C57BL6 GFP negative mice. Bone marrow from transgenic human ubiquitin C promoter GFP (uGFP, with strong signal C57BL6 mice was transplanted into GFP negative C57BL6 recipients. After eight weeks, migration of GFP positive donor' bone marrow to the recipient's pancreatic islets was evaluated as the percentage of positive GFP islets/total islets. The results show that the most effective migration comes from the Sca(+/Mac(- lineage and these cells, treated with cytokines for 48 hours, were found to have converted into insulin positive cells in pancreatic islets in vivo. This study suggests that bone marrow lineage positive cells and cytokine treatments are critical factors in determining whether bone marrow is able to migrate and form insulin producing cells in vivo. The mechanisms causing this facilitation as well as bone marrow converting to pancreatic beta cells still need to be investigated.

  3. Morphological assessment of pancreatic islet hormone content following aerobic exercise training in rats with poorly controlled Type 1 diabetes mellitus.

    Science.gov (United States)

    McDonald, Matthew W; Murray, Michael R; Hall, Katharine E; Noble, Earl G; Melling, C W James

    2014-01-01

    Regular exercise has been shown to improve many complications of Type 1 diabetes mellitus (T1DM) including enhanced glucose tolerance and increased cardiac function. While exercise training has been shown to increase insulin content in pancreatic islets of rats with T1DM, experimental models were severely hyperglycemic and not undergoing insulin treatment. Further, research to date has yet to determine how exercise training alters glucagon content in pancreatic islets. The purpose of the present investigation was to determine the impact of a 10-week aerobic training program on pancreatic islet composition in insulin-treated rats with T1DM. Second, it was determined whether the acute, exercise-mediated reduction in blood glucose experienced in rats with T1DM would become larger in magnitude following aerobic exercise training. Diabetes was induced in male Sprague-Dawley rats by multiple low dose injections of streptozotocin (20mg/kg i.p.) and moderate intensity aerobic exercise training was performed on a motorized treadmill for one hour per day for a total of 10 weeks. Rats with T1DM demonstrated significantly less islet insulin, and significantly more islet glucagon hormone content compared with non-T1DM rats, which did not significantly change following aerobic training. The reduction in blood glucose in response to a single exercise bout was similar across 10 weeks of training. Results also support the view that different subpopulations of islets exist, as small islets (<50 μm diameter) had significantly more insulin and glucagon in rats with and without T1DM.

  4. Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats

    International Nuclear Information System (INIS)

    Rashid, Kahkashan; Sil, Parames C.

    2015-01-01

    The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-β and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. - Highlights: • STZ induced cellular stress plays a vital role in pancreatic dysfunction. • Cellular stress causes inflammation, pancreatic islet cell death and diabetes. • Deregulation of Nrf-2

  5. Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats

    Energy Technology Data Exchange (ETDEWEB)

    Rashid, Kahkashan; Sil, Parames C., E-mail: parames@jcbose.ac.in

    2015-02-01

    The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-β and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus. - Highlights: • STZ induced cellular stress plays a vital role in pancreatic dysfunction. • Cellular stress causes inflammation, pancreatic islet cell death and diabetes. • Deregulation of Nrf-2

  6. Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy

    Directory of Open Access Journals (Sweden)

    Jason M. Tonne

    2013-09-01

    Streptozotocin (STZ, a glucosamine-nitrosourea compound, has potent genotoxic effects on pancreatic β-cells and is frequently used to induce diabetes in experimental animals. Glucagon-like peptide-1 (GLP-1 has β-cell protective effects and is known to preserve β-cells from STZ treatment. In this study, we analyzed the mechanisms of STZ-induced diabetes and GLP-1-mediated β-cell protection in STZ-treated mice. At 1 week after multiple low-dose STZ administrations, pancreatic β-cells showed impaired insulin expression, while maintaining expression of nuclear Nkx6.1. This was accompanied by significant upregulation of p53-responsive genes in islets, including a mediator of cell cycle arrest, p21 (also known as Waf1 and Cip1. STZ treatment also suppressed expression of a wide range of genes linked with key β-cell functions or diabetes development, such as G6pc2, Slc2a2 (Glut2, Slc30a8, Neurod1, Ucn3, Gad1, Isl1, Foxa2, Vdr, Pdx1, Fkbp1b and Abcc8, suggesting global β-cell defects in STZ-treated islets. The Tmem229B, Prss53 and Ttc28 genes were highly expressed in untreated islets and strongly suppressed by STZ, suggesting their potential roles in β-cell function. When a pancreas-targeted adeno-associated virus (AAV vector was employed for long-term Glp-1 gene delivery, pancreatic GLP-1 expression protected mice from STZ-induced diabetes through preservation of the β-cell mass. Despite its potent β-cell protective effects, however, pancreatic GLP-1 overexpression showed limited effects on the global gene expression profiles in the islets. Network analysis identified the programmed-cell-death-associated pathways as the most relevant network in Glp-1 gene therapy. Upon pancreatic GLP-1 expression, upregulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given the pro-β-cell-survival effects of Cxcl12 (Sdf-1 in inducing GLP-1 production in α-cells, pancreatic GLP-1-mediated Cxcl13 induction might also play a

  7. Nutrient and hormone-neurotransmitter stimuli induce hydrolysis of polyphosphoinositides in rat pancreatic islets

    International Nuclear Information System (INIS)

    Best, L.; Malaisse, W.J.

    1984-01-01

    Preincubation of rat pancreatic islets with 3 H-inositol, and subsequent exposure, in the presence of LiCl, to either glucose or carbamylcholine resulted in a rapid stimulation of 3 H-inositol 1,4,5-triphosphate and 3 H-myo-inositol 1,4-bisphosphate formation, the level of which reached a plateau after about 5 min of stimulation. Both stimuli also caused an approximately linear accumulation of 3 H-myo-inositol 1-phosphate. The amounts of 3 H-inositol phosphates formed were dependent on the concentration of LiCl. Studies of 32 P-labeling of islet ATP, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol 4-phosphate revealed that these approached isotopic equilibrium after about 240-min incubation, whereas 32 P-labeling of phosphatidylinositol, phosphatidic acid, phosphatidylcholine, and phosphatidylethanolamine proceeded at a lower rate. Carbamylcholine provoked an immediate fall in 32 P-PtdIns(4,5)P2 and, to a lesser extent, 32 P-phosphatidylinositol 4-phosphate. Glucose caused a similar response although, in this case, the most marked decline was in a more polar 32 P-labeled lipid. Cholecystokinin-pancreozymin was also found to induce 32 P-PtdIns(4,5)P2 hydrolysis, although the ionophore A23187 was without effect. Both carbamylcholine and glucose induced an increase in 32 P-phosphatidic acid. The results provide two independent pieces of evidence suggesting that phospholipase C-mediated hydrolysis of polyphosphoinositides occurs as an early response in rat islets to either nutrient or neurotransmitter secretagogues

  8. 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

    (delta-cells), and pancreatic polypeptide (PP-cells) in a sequential order. The endocrine cells are believed to arise from a stem cell with neuronal traits. The developmental lineage from a common neuron-like progenitor is evidenced by: transient coexpression of more than one cell type-specific hormone......-cadherin in brain. Insulinoma cells express E-cadherin but differ from primary islet cells by expressing a second cadherin molecule, which is similar to N-cadherin. The expression of NCAM and cadherin isoforms in the glucagonoma suggest that this transformed alpha-cell type has converted to an immature phenotype......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...

  9. Protein phosphorylation in pancreatic islets induced by 3-phosphoglycerate and 2-phosphoglycerate

    International Nuclear Information System (INIS)

    Pek, S.B.; Usami, Masaru; Bilir, N.; Fischer-Bovenkerk, C.; Ueda, Tetsufumi

    1990-01-01

    The authors have shown previously that 3-phosphoglycerate, which is a glycolytic metabolite of glucose, induces protein phosphorylation in bovine and rat brain and in rat heart, kidney, liver, lung, and whole pancreas. Since glycolytic metabolism of glucose is of paramount importance in insulin release, they considered the possibility that 3-phosphoglycerate may act as a coupling factor, and they searched for evidence for the existence of 3-phosphoglycerate-dependent protein phosphorylation systems in freshly isolated normal rat pancreatic islets. Membrane and cytosol fractions were incubated with [γ- 32 P]ATP and appropriate test substances and were subjected to NaDodSO 4 /PAGE and autoradiography. As little as 0.005 mM 3-phosphoglycerate or 2-phosphoglycerate stimulated the phosphorylation of 65-kDa cytosol protein by as early as 0.25 min. The phosphate bond of the 65-kDa phosphoprotein was sufficiently stable to withstand dialysis; the radioactivity could not be chased out by subsequent exposure to ATP, ADP, 3-phosphoglycerate, or 2,3-bisphosphoglycerate. Moreover, cAMP, cGMP, phorbol 12-myristate 13-acetate, or calcium failed to stimulate the phosphorylation of the 65-kDa protein. Phosphoglycerate-dependent protein phosphorylation in islets may have relevance to stimulation of insulin secretion

  10. TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded In Vitro.

    Directory of Open Access Journals (Sweden)

    Ginat Toren-Haritan

    Full Text Available In-vitro expansion of insulin-producing cells from adult human pancreatic islets could provide an abundant cell source for diabetes therapy. However, proliferation of β-cell-derived (BCD cells is associated with loss of phenotype and epithelial-mesenchymal transition (EMT. Nevertheless, BCD cells maintain open chromatin structure at β-cell genes, suggesting that they could be readily redifferentiated. The transforming growth factor β (TGFβ pathway has been implicated in EMT in a range of cell types. Here we show that human islet cell expansion in vitro involves upregulation of the TGFβ pathway. Blocking TGFβ pathway activation using short hairpin RNA (shRNA against TGFβ Receptor 1 (TGFBR1, ALK5 transcripts inhibits BCD cell proliferation and dedifferentiation. Treatment of expanded BCD cells with ALK5 shRNA results in their redifferentiation, as judged by expression of β-cell genes and decreased cell proliferation. These effects, which are reproducible in cells from multiple human donors, are mediated, at least in part, by AKT-FOXO1 signaling. ALK5 inhibition synergizes with a soluble factor cocktail to promote BCD cell redifferentiation. The combined treatment may offer a therapeutically applicable way for generating an abundant source of functional insulin-producing cells following ex-vivo expansion.

  11. Regulation of pancreatic islet beta-cell mass by growth factor and hormone signaling.

    Science.gov (United States)

    Huang, Yao; Chang, Yongchang

    2014-01-01

    Dysfunction and destruction of pancreatic islet beta cells is a hallmark of diabetes. Better understanding of cellular signals in beta cells will allow development of therapeutic strategies for diabetes, such as preservation and expansion of beta-cell mass and improvement of beta-cell function. During the past several decades, the number of studies analyzing the molecular mechanisms, including growth factor/hormone signaling pathways that impact islet beta-cell mass and function, has increased exponentially. Notably, somatolactogenic hormones including growth hormone (GH), prolactin (PRL), and insulin-like growth factor-1 (IGF-1) and their receptors (GHR, PRLR, and IGF-1R) are critically involved in beta-cell growth, survival, differentiation, and insulin secretion. In this chapter, we focus more narrowly on GH, PRL, and IGF-1 signaling, and GH-IGF-1 cross talk. We also discuss how these signaling aspects contribute to the regulation of beta-cell proliferation and apoptosis. In particular, our novel findings of GH-induced formation of GHR-JAK2-IGF-1R protein complex and synergistic effects of GH and IGF-1 on beta-cell signaling, proliferation, and antiapoptosis lead to a new concept that IGF-1R may serve as a proximal component of GH/GHR signaling. © 2014 Elsevier Inc. All rights reserved.

  12. Effects of growth hormone, prolactin, and placental lactogen on insulin content and release, and deoxyribonucleic acid synthesis in cultured pancreatic islets

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1982-01-01

    The direct effects of human GH (hGH), ovine pituitary PRL (oPRL), and human chorionic somatomammotropin [placental lactogen (hPL)] on the endocrine pancreas were studied in isolated pancreatic islets maintained in tissue culture. Islets of Langerhans were isolated by collagenase treatment of panc...

  13. The pancreatic islet factor STF-1 binds cooperatively with Pbx to a regulatory element in the somatostatin promoter: Importance of the FPWMK motif and of the homeodomain

    Energy Technology Data Exchange (ETDEWEB)

    Peers, B.; Sharma, S.; Johnson, T.; Montminy, M. [The Salk Institute, La Jolla, CA (United States)] [and others

    1995-12-01

    This report explores the role of homeodomain proteins in the regulation of cellular development through stimulating the transcription of target genes. It was shown that the islet-specific element TSEII of the somatostatin promoter recognizes a heteromeric complex composed of the homeodomain protein STF-1 and the cofactor Pbx in pancreatic islet cells. 26 refs., 5 figs., 1 tab.

  14. A single amino acid substitution in viral VP1 protein alters the lytic potential of clone-derived variants of echovirus 9 DM strain in human pancreatic islets.

    NARCIS (Netherlands)

    Paananen, A.; Ylipaasto, P.; Smura, T.; Lempinen, M.; Galama, J.M.; Roivainen, M.

    2013-01-01

    In vitro studies with primary human pancreatic islets suggest that several enterovirus serotypes are able to infect and replicate in beta cells. Some enterovirus strains are highly cytolytic in vitro whereas others show virus replication with no apparent islet destruction. The capability to induce

  15. Two-Photon Dye Cocktail for Dual-Color 3D Imaging of Pancreatic Beta and Alpha Cells in Live Islets.

    Science.gov (United States)

    Agrawalla, Bikram Keshari; Lee, Hyo Won; Phue, Wut-Hmone; Raju, Anandhkumar; Kim, Jong-Jin; Kim, Hwan Myung; Kang, Nam-Young; Chang, Young-Tae

    2017-03-08

    Insulin-secreting beta cells together with glucagon-producing alpha cells play an essential role in maintaining the optimal blood glucose level in the body, so the development of selective probes for imaging of these cell types in live islets is highly desired. Herein we report the development of a 2-glucosamine-based two-photon fluorescent probe, TP-β, that is suitable for imaging of beta cells in live pancreatic islets from mice. Flow cytometry studies confirmed that TP-β is suitable for isolation of primary beta cells. Moreover, two-photon imaging of TP-β-stained pancreatic islets showed brightly stained beta cells in live islets. Insulin enzyme-linked immunosorbent assays revealed that TP-β has no effect on glucose-stimulated insulin secretion from the stained islet. Finally, to develop a more convenient islet imaging application, we combined our recently published alpha-cell-selective probe TP-α with TP-β to make a "TP islet cocktail". This unique dye cocktail enabled single excitation (820 nm) and simultaneous dual-color imaging of alpha cells (green) and beta cells (red) in live pancreatic islets. This robust TP islet cocktail may serve as a valuable tool for basic diabetic studies.

  16. A Historical Perspective on the Identification of Cell Types in Pancreatic Islets of Langerhans by Staining and Histochemical Techniques.

    Science.gov (United States)

    Baskin, Denis G

    2015-08-01

    Before the middle of the previous century, cell types of the pancreatic islets of Langerhans were identified primarily on the basis of their color reactions with histological dyes. At that time, the chemical basis for the staining properties of islet cells in relation to the identity, chemistry and structure of their hormones was not fully understood. Nevertheless, the definitive islet cell types that secrete glucagon, insulin, and somatostatin (A, B, and D cells, respectively) could reliably be differentiated from each other with staining protocols that involved variations of one or more tinctorial techniques, such as the Mallory-Heidenhain azan trichrome, chromium hematoxylin and phloxine, aldehyde fuchsin, and silver impregnation methods, which were popularly used until supplanted by immunohistochemical techniques. Before antibody-based staining methods, the most bona fide histochemical techniques for the identification of islet B cells were based on the detection of sulfhydryl and disulfide groups of insulin. The application of the classical islet tinctorial staining methods for pathophysiological studies and physiological experiments was fundamental to our understanding of islet architecture and the physiological roles of A and B cells in glucose regulation and diabetes. © The Author(s) 2015.

  17. Pancreatic islet cell reaggregation systems: efficiency of cell reassociation and endocrine cell topography of rat islet-like aggregates.

    Science.gov (United States)

    Matta, S G; Wobken, J D; Williams, F G; Bauer, G E

    1994-07-01

    Single cells isolated from rat islets of Langerhans were cultured under conditions that support reassociation into islet-like aggregates. Comparisons were made of enzymatic methods of islet dissociation, rotational or static culture conditions, and culture at basal or stimulatory glucose concentrations. Over a period of 4 days the aggregates progressed through three stages of organization: cell coalescence to cellular chains, rearrangement of chains into small spheroids, and growth of spheroids. The numerical yield of aggregates was optimum after islets were dissociated with dispase. Culture under rotation resulted in the production of more aggregates of significantly larger diameter than under static conditions. Medium glucose concentrations of 4 and 11 mM supported cell reassociation under rotator culture, but no aggregation occurred under static culture at the basal (4 mM) glucose level. Aggregates resulting from 4-day rotator culture exhibited endocrine cell distributions similar to intact islets. Islet aggregates released insulin in response to glucose, but nonaggregated cells, maintained in culture, did not. The present comparisons reveal significant variability in the cellular composition, rate of formation, and yield of aggregates, and suggest that the methodology for producing aggregates should be carefully considered in experimental design.

  18. A model for cell migration in non-isotropic fibrin networks with an application to pancreatic tumor islets.

    Science.gov (United States)

    Chen, Jiao; Weihs, Daphne; Vermolen, Fred J

    2018-04-01

    Cell migration, known as an orchestrated movement of cells, is crucially important for wound healing, tumor growth, immune response as well as other biomedical processes. This paper presents a cell-based model to describe cell migration in non-isotropic fibrin networks around pancreatic tumor islets. This migration is determined by the mechanical strain energy density as well as cytokines-driven chemotaxis. Cell displacement is modeled by solving a large system of ordinary stochastic differential equations where the stochastic parts result from random walk. The stochastic differential equations are solved by the use of the classical Euler-Maruyama method. In this paper, the influence of anisotropic stromal extracellular matrix in pancreatic tumor islets on T-lymphocytes migration in different immune systems is investigated. As a result, tumor peripheral stromal extracellular matrix impedes the immune response of T-lymphocytes through changing direction of their migration.

  19. Dietary polyherbal supplementation decreases CD3+ cell infiltration into pancreatic islets and prevents hyperglycemia in nonobese diabetic mice.

    Science.gov (United States)

    Burke, Susan J; Karlstad, Michael D; Conley, Caroline P; Reel, Danielle; Whelan, Jay; Collier, J Jason

    2015-04-01

    Type 1 diabetes mellitus results from autoimmune-mediated destruction of pancreatic islet β-cells, a process associated with inflammatory signals. We hypothesized that dietary supplementation with botanicals known to contain anti-inflammatory properties would prevent losses in functional β-cell mass in nonobese diabetic (NOD) mice, a rodent model of autoimmune-mediated islet inflammation that spontaneously develops diabetes. Female NOD mice, a model of spontaneous autoimmune diabetes, were fed a diet supplemented with herbal extracts (1.916 g total botanical extracts per 1 kg of diet) over a 12-week period. The mice consumed isocaloric matched diets without (controls) and with polyherbal supplementation (PHS) ad libitum starting at a prediabetic stage (age 6 weeks) for 12 weeks. Control mice developed hyperglycemia (>180 mg/dL) within 16 weeks (n = 9). By contrast, mice receiving the PHS diet did not develop hyperglycemia by 18 weeks (n = 8). Insulin-positive cell mass within pancreatic islets was 31.9% greater in PHS mice relative to controls. We also detected a 26% decrease in CD3(+) lymphocytic infiltration in PHS mice relative to mice consuming a control diet. In vitro assays revealed reduced β-cell expression of the chemokines CCL2 and CXCL10 after overnight PHS addition to the culture media. We conclude that dietary PHS delays initiation of autoimmune-mediated β-cell destruction and subsequent onset of diabetes mellitus by diminishing islet inflammatory responses. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. The Potential Protective Action of Vitamin D in Hepatic Insulin Resistance and Pancreatic Islet Dysfunction in Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Leung, Po Sing

    2016-03-05

    Vitamin D deficiency (i.e., hypovitaminosis D) is associated with increased insulin resistance, impaired insulin secretion, and poorly controlled glucose homeostasis, and thus is correlated with the risk of metabolic diseases, including type 2 diabetes mellitus (T2DM). The liver plays key roles in glucose and lipid metabolism, and its dysregulation leads to abnormalities in hepatic glucose output and triglyceride accumulation. Meanwhile, the pancreatic islets are constituted in large part by insulin-secreting β cells. Consequently, islet dysfunction, such as occurs in T2DM, produces hyperglycemia. In this review, we provide a critical appraisal of the modulatory actions of vitamin D in hepatic insulin sensitivity and islet insulin secretion, and we discuss the potential roles of a local vitamin D signaling in regulating hepatic and pancreatic islet functions. This information provides a scientific basis for establishing the benefits of the maintenance, or dietary manipulation, of adequate vitamin D status in the prevention and management of obesity-induced T2DM and non-alcoholic fatty liver disease.

  1. Biotin uptake by mouse and human pancreatic beta cells/islets: a regulated, lipopolysaccharide-sensitive carrier-mediated process

    Science.gov (United States)

    Ghosal, Abhisek; Sekar, Thillai V.

    2014-01-01

    Biotin is essential for the normal function of pancreatic beta cells. These cells obtain biotin from their surroundings via transport across their cell membrane. Little is known about the uptake mechanism involved, how it is regulated, and how it is affected by internal and external factors. We addressed these issues using the mouse-derived pancreatic beta-TC-6 cells and freshly isolated mouse and human primary pancreatic beta cells as models. The results showed biotin uptake by pancreatic beta-TC-6 cells occurs via a Na+-dependent, carrier-mediated process, that is sensitive to desthiobiotin, as well as to pantothenic acid and lipoate; the process is also saturable as a function of concentration (apparent Km = 22.24 ± 5.5 μM). These cells express the sodium-dependent multivitamin transporter (SMVT), whose knockdown (with doxycycline-inducible shRNA) led to a sever inhibition in biotin uptake. Similarly, uptake of biotin by mouse and human primary pancreatic islets is Na+-dependent and carrier-mediated, and both cell types express SMVT. Biotin uptake by pancreatic beta-TC-6 cells is also adaptively regulated (via transcriptional mechanism) by extracellular substrate level. Chronic treatment of pancreatic beta-TC-6 cells with bacterial lipopolysaccharides (LPS) leads to inhibition in biotin uptake. This inhibition is mediated via a Toll-Like receptor 4-mediated process and involves a decrease in membrane expression of SMVT. These findings show, for the first time, that pancreatic beta cells/islets take up biotin via a specific and regulated carrier-mediated process, and that the process is sensitive to the effect of LPS. PMID:24904078

  2. Biosynthesis and release of thyrotropin-releasing hormone immunoreactivity in rat pancreatic islets in organ culture. Effects of age, glucose, and streptozotocin

    DEFF Research Database (Denmark)

    Dolva, L O; Welinder, B S; Hanssen, K F

    1983-01-01

    Thyrotropin-releasing hormone immunoreactivity (TRH-IR) was measured in isolated islets and in medium from rat pancreatic islets maintained in organ culture. TRH-IR in methanol extracts of both islets and culture medium was eluted in the same position as synthetic TRH by ion-exchange and gel......-IR into the culture medium was observed from islets of both 5-d-old (newborn) and 30-d-old (adult) rats with a maximum on the second day of culture (28.7 +/- 7.0 and 13.3 +/- 3.6 fmol/islet per d, respectively). The content of TRH-IR was higher in freshly isolated islets from newborn rats (22.4 +/- 2.3 fmol....../islet) than in adult rat islets, which, however, increased their content from 1.3 +/- 0.5 to 7.0 +/- 0.5 fmol/islet during the first 3 d of culture. Adult rat islets maintained in medium with 20 mM glucose released significantly more TRH-IR than islets in 3.3 mM glucose medium (13.0 +/- 0.7 vs. 4.3 +/- 0...

  3. Insulin therapy improves islet functions by restoring pancreatic vasculature in high-fat diet-fed streptozotocin-diabetic rats.

    Science.gov (United States)

    Gu, Huimin; Xia, Xuan; Chen, Zonglan; Liang, Hua; Yan, Jinhua; Xu, Fen; Weng, Jianping

    2014-05-01

    In a previous study, we showed early insulin therapy could improve β-cell function in type 2 diabetic patients. However, the molecular mechanism was not clear. In the present study, we addressed this question by analyzing the pancreatic microvasculature in diabetic rats after insulin treatment. Diabetes was induced in rats by a combination of low dose streptozotocin (STZ; 40 mg/kg) and feeding of a high-fat diet. After the induction of diabetes, rats were treated with neutral protamine Hagedorn insulin (NPH; 6–8 U/day, s.c.) for 3 weeks. Three days after the end of treatment, rats were subjected to an intraperitoneal glucose tolerance test (IPGTT). The pancreatic microvasculature and the amount and size of the islets were evaluated by immunohistochemistry. Western blot analysis was used to determine levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGF-R2) protein. Treatment with NPH improved insulin secretion from β-cells during the IPGTT and increased pancreatic islet size. The density of the microvasculature in the pancreas was determined by quantification of CD31, a marker of endothelial cells. Insulin treatment increased CD31 protein levels, as well as the expression of VEGF and VEGFR2. The results suggest that insulin treatment improves islet recovery by increasing angiogenesis in the pancreas. The mechanism is related to the induction of VEGF and VEGFR2 expression in diabetic rats.

  4. Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

    Science.gov (United States)

    Cappelli, Ana Paula G; Zoppi, Claudio C; Silveira, Leonardo R; Batista, Thiago M; Paula, Flávia M; da Silva, Priscilla M R; Rafacho, Alex; Barbosa-Sampaio, Helena C; Boschero, Antonio C; Carneiro, Everardo M

    2018-01-01

    In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H 2 O 2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H 2 O 2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H 2 O 2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H 2 O 2 (100 μM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine. © 2017 Wiley Periodicals, Inc.

  5. Histochemical analysis of the role of class I and class II Clostridium histolyticum collagenase in the degradation of rat pancreatic extracellular matrix for islet isolation

    NARCIS (Netherlands)

    Vos-Scheperkeuter, Greetje H.; van Suylichem, Paul T.R.; Wolters, G. H. J.; van Schilfgaarde, Reinout

    1997-01-01

    To understand why class II Clostridium histolyticum collagenase is much more effective than class I in the isolation of rat pancreatic islets, we analyzed the role of these collagenases in pancreatic tissue dissociation. Crude collagenase was purified and then fractionated into class I and II with

  6. Effect of total lymphoid irradiation and pretransplant blood transfusion on pancreatic islet allograft survival

    International Nuclear Information System (INIS)

    Mendez-Picon, G.; McGeorge, M.

    1983-01-01

    Total lymphoid irradiation (TLI) has been shown to have a strong immunosuppressive effect both experimentally and clinically. Pretransplant blood transfusions have also been shown to have a strong beneficial effect in the outcome of organ transplantation. A study was made of the effect of TLI and pretransplant blood transfusions, alone and in combination, as an immunosuppressive modality in the isolated pancreatic islet transplant in the rat model. Donor rats (Fischer RT1v1) were kept on a 50% DL-ethionine supplemented diet for 4-6 weeks prior to pancreas removal. Recipient rats (Lewis RT1) were made diabetics prior to transplantation by iv injection of streptozotocin (45 mg/kg). Transfusion protocol consisted of a biweekly transfusion of 2 ml of either donor specific or third party transfusions. Total lymphoid irradiation was carried out by daily administration of 200 rads during one week prior to transplantation. Transplantation of the isolated islets was performed by intraportal injection. Syngeneic transplant of one and a half donor pancreata in each recipient reverted the diabetic condition indefinitely (greater than 100 days). Untreated allogenic grafts had a mean survival time (MST) of 5.2 days. Total lymphoid irradiation in dosages of 800, 1000, and 1200 rads, as the only immunosuppressive regimen, prolonged the MST of allografts to 15.3, 16.5, and 21.8 days, respectively (P less than .05). Pretransplant third party blood transfusion had no effect on allograft survival (MST 6.0). When donor specific blood transfusions were given, the MST was prolonged to 25.3 days (P less than .05). When TLI was administered to recipients of donor specific transfusions, the MST of the allografts did not show any statistical significant difference when compared with untreated animals. This abrogation of the beneficial effect of specific blood transfusion was observed in all dosages of TLI employed: 800 rad (MST 3.0), 1000 rad (MST 8.0), 1200 rad (MST 5.18)

  7. Effects of some vanadyl coordination compounds on the in vitro insulin release from rat pancreatic islets.

    Science.gov (United States)

    Conconi, M T; DeCarlo, E; Vigolo, S; Grandi, C; Bandoli, G; Sicolo, N; Tamagno, G; Parnigotto, P P; Nussdorfer, G G

    2003-07-01

    Many lines of evidence indicate that vanadium inorganic salts possess insulin-mimetic and insulinotropic properties. However, they are poorly absorbed, so high oral doses are required to achieve effective plasma concentrations with possible undesirable toxic side-effects ensuing. Various organically-chelated vanadium compounds have been synthesized that are more potent than inorganic vanadium salts in their insulin-like effects due to their greater bioavailability. Unfortunately, little is known about the possible insulin secretagogue action of organic vanadyl coordination compounds. Hence, we investigated the effect of [VO(metformin)2]H2O, [VO(salicylidene-ethylenedimmine)2] and [VO(pyrrolidine-N-dithiocarbamate)2](VODTC) on insulin release from isolated rat pancreatic islets, and compared it to that of vanadyl sulfate (VOSO4). Of the three coordination compounds, only VODTC was found to exert insulin secretagogue action. VODTC, within concentrations ranging from 0.1 to 1.0 mM, enhanced both basal and glucose (11 mM)-stimulated insulin release. The effect involves calcium channels, since it was not appreciable in Ca2+-free medium. The stimulating action of VODTC required the presence of the whole metal-chelator complex inasmuch as the chelator DTC alone was ineffective. VOSO4 was unable to bring about any significant rise in insulin release from isolated islets. Taken together, our findings indicate that VODTC may be considered a potential elective pharmaceutical tool in the therapy of diabetes, especially of type 2, through its concomitant stimulatory effect on insulin secretion and insulin-mimetic action.

  8. MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1.

    Science.gov (United States)

    Wei, Jie; Ding, Dongxiao; Wang, Tao; Liu, Qiong; Lin, Yi

    2017-12-01

    Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 ( Pdx1 ) expression in mice. Inhibition of Pdx1 reduced glucose-stimulated insulin secretion and ATP production in the islets of BPA-exposed mice. Based on primary pancreatic islets, we also confirmed that miR-338 regulated Pdx1 and thus contributed to BPA-induced insulin secretory dysfunction from compensation to decompensation. Short-term BPA exposure downregulated miR-338 through activation of G-protein-coupled estrogen receptor 1 (Gpr30), whereas long-term BPA exposure upregulated miR-338 through suppression of glucagon-like peptide 1 receptor (Glp1r). Taken together, our results reveal a molecular mechanism, whereby BPA regulates Gpr30/Glp1r to mediate the expression of miR-338, which acts to control Pdx1-dependent insulin secretion. The Gpr30/Glp1r-miR-338-Pdx1 axis should be represented as a novel mechanism by which BPA induces insulin secretory dysfunction in pancreatic islets.-Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1. © FASEB.

  9. Damage to pancreatic acinar cells and preservation of islets of Langerhans in a rat model of acute pancreatitis induced by Karwinskia humboldtiana (buckthorn).

    Science.gov (United States)

    Carcano-Diaz, Katya; Garcia-Garcia, Aracely; Segoviano-Ramirez, Juan Carlos; Rodriguez-Rocha, Humberto; Loera-Arias, Maria de Jesus; Garcia-Juarez, Jaime

    2016-09-01

    Karwinskia humboldtiana (Kh) is a poisonous plant that grows in some regions of the American continent. Consuming large amounts of Kh fruit results in acute intoxication leading to respiratory failure, culminating in death within days. There is evidence of histological damage to the lungs, liver, and kidneys following accidental and experimental Kh intoxication. To date, the microscopic effect of Kh consumption on the pancreas has not been described. We examined the early effects of Kh fruit on pancreatic tissue at different stages of acute intoxication in the Wistar rat. We found progressive damage confined to the exocrine pancreas, starting with a reduction in the number of zymogen granules, loss of acinar architecture, the presence of autophagy-like vesicles, apoptosis and inflammatory infiltrate. The pancreatic pathology culminated in damaged acini characterized by necrosis and edema, with a complete loss of lobular architecture. Interestingly, the morphology of the islets of Langerhans was conserved throughout our evaluations. Taken together, our results indicate the damage induced by a high dose of Kh fruit in the Wistar rat is consistent with an early acute necrotizing pancreatitis that exclusively affects the exocrine pancreas. Therefore, this system might be useful as an animal model to study the treatment of pancreatic diseases. More importantly, as the islets of Langerhans were preserved, the active compounds of Kh fruit could be utilized for the treatment of acinar pancreatic cancer. Further studies might provide insight into the severity of acute Kh intoxication in humans and influence the design of treatments for pancreatic diseases and acinar pancreatic cancer.

  10. Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Zhidong Tu

    Full Text Available Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6 and diabetes-susceptible (BTBR mouse strains made genetically obese by the Leptin(ob/ob mutation (Lep(ob. High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

  11. Abscisic acid is an endogenous stimulator of insulin release from human pancreatic islets with cyclic ADP ribose as second messenger.

    Science.gov (United States)

    Bruzzone, Santina; Bodrato, Nicoletta; Usai, Cesare; Guida, Lucrezia; Moreschi, Iliana; Nano, Rita; Antonioli, Barbara; Fruscione, Floriana; Magnone, Mirko; Scarfì, Sonia; De Flora, Antonio; Zocchi, Elena

    2008-11-21

    Abscisic acid (ABA) is a plant stress hormone recently identified as an endogenous pro-inflammatory cytokine in human granulocytes. Because paracrine signaling between pancreatic beta cells and inflammatory cells is increasingly recognized as a pathogenetic mechanism in the metabolic syndrome and type II diabetes, we investigated the effect of ABA on insulin secretion. Nanomolar ABA increases glucose-stimulated insulin secretion from RIN-m and INS-1 cells and from murine and human pancreatic islets. The signaling cascade triggered by ABA in insulin-releasing cells sequentially involves a pertussis toxin-sensitive G protein, cAMP overproduction, protein kinase A-mediated activation of the ADP-ribosyl cyclase CD38, and cyclic ADP-ribose overproduction. ABA is rapidly produced and released from human islets, RIN-m, and INS-1 cells stimulated with high glucose concentrations. In conclusion, ABA is an endogenous stimulator of insulin secretion in human and murine pancreatic beta cells. Autocrine release of ABA by glucose-stimulated pancreatic beta cells, and the paracrine production of the hormone by activated granulocytes and monocytes suggest that ABA may be involved in the physiology of insulin release as well as in its dysregulation under conditions of inflammation.

  12. Preservation of beta cell function in adult human pancreatic islets for several months in vitro

    DEFF Research Database (Denmark)

    Brunstedt, J; Andersson, A; Frimodt-Møller, C

    1979-01-01

    Islets of Langerhans were isolated from four human kidney donors, aged 16 to 21 years by the collagenase method described for isolation of rodent islets. So far the human islets have been kept in tissue culture, without attachment, in medium RPMI 1640 supplemented with 10% calf serum for more than...

  13. Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity.

    Science.gov (United States)

    Carchia, E; Porreca, I; Almeida, P J; D'Angelo, F; Cuomo, D; Ceccarelli, M; De Felice, M; Mallardo, M; Ambrosino, C

    2015-10-29

    Epidemiologic and experimental studies have associated changes of blood glucose homeostasis to Bisphenol A (BPA) exposure. We took a toxicogenomic approach to investigate the mechanisms of low-dose (1 × 10(-9 )M) BPA toxicity in ex vivo cultures of primary murine pancreatic islets and hepatocytes. Twenty-nine inhibited genes were identified in islets and none in exposed hepatocytes. Although their expression was slightly altered, their impaired cellular level, as a whole, resulted in specific phenotypic changes. Damage of mitochondrial function and metabolism, as predicted by bioinformatics analyses, was observed: BPA exposure led to a time-dependent decrease in mitochondrial membrane potential, to an increase of ROS cellular levels and, finally, to an induction of apoptosis, attributable to the bigger Bax/Bcl-2 ratio owing to activation of NF-κB pathway. Our data suggest a multifactorial mechanism for BPA toxicity in pancreatic islets with emphasis to mitochondria dysfunction and NF-κB activation. Finally, we assessed in vitro the viability of BPA-treated islets in stressing condition, as exposure to high glucose, evidencing a reduced ability of the exposed islets to respond to further damages. The result was confirmed in vivo evaluating the reduction of glycemia in hyperglycemic mice transplanted with control and BPA-treated pancreatic islets. The reported findings identify the pancreatic islet as the main target of BPA toxicity in impairing the glycemia. They suggest that the BPA exposure can weaken the response of the pancreatic islets to damages. The last observation could represent a broader concept whose consideration should lead to the development of experimental plans better reproducing the multiple exposure conditions.

  14. Experimental evaluation and computational modeling of the effects of encapsulation on the time-profile of glucose-stimulated insulin release of pancreatic islets.

    Science.gov (United States)

    Buchwald, Peter; Cechin, Sirlene R; Weaver, Jessica D; Stabler, Cherie L

    2015-03-28

    In type 1 diabetic patients, who have lost their ability to produce insulin, transplantation of pancreatic islet cells can normalize metabolic control in a manner that is not achievable with exogenous insulin. To be successful, this procedure has to address the problems caused by the immune and autoimmune responses to the graft. Islet encapsulation using various techniques and materials has been and is being extensively explored as a possible approach. Within this framework, it is of considerable interest to characterize the effect encapsulation has on the insulin response of pancreatic islets. To improve our ability to quantitatively describe the glucose-stimulated insulin release (GSIR) of pancreatic islets in general and of micro-encapsulated islets in particular, we performed dynamic perifusion experiments with frequent sampling. We used unencapsulated and microencapsulated murine islets in parallel and fitted the results with a complex local concentration-based finite element method (FEM) computational model. The high-resolution dynamic perifusion experiments allowed good characterization of the first-phase and second-phase insulin secretion, and we observed a slightly delayed and blunted first-phase insulin response for microencapsulated islets when compared to free islets. Insulin secretion profiles of both free and encapsulated islets could be fitted well by a COMSOL Multiphysics model that couples hormone secretion and nutrient consumption kinetics with diffusive and convective transport. This model, which was further validated and calibrated here, can be used for arbitrary geometries and glucose stimulation sequences and is well suited for the quantitative characterization of the insulin response of cultured, perifused, transplanted, or encapsulated islets. The present high-resolution GSIR experiments allowed for direct characterization of the effect microencapsulation has on the time-profile of insulin secretion. The multiphysics model, further validated

  15. Functional proteomics screen enables enrichment of distinct cell types from human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Revital Sharivkin

    Full Text Available The current world-wide epidemic of diabetes has prompted attempts to generate new sources of insulin-producing cells for cell replacement therapy. An inherent challenge in many of these strategies is the lack of cell-surface markers permitting isolation and characterization of specific cell types from differentiating stem cell populations. Here we introduce an iterative proteomics procedure allowing tag-free isolation of cell types based on their function. Our method detects and associates specific cell-surface markers with particular cell functionality by coupling cell capture on antibody arrays with immunofluorescent labeling. Using this approach in an iterative manner, we discovered marker combinations capable of enriching for discrete pancreatic cell subtypes from human islets of Langerhans: insulin-producing beta cells (CD9high/CD56+, glucagon-producing alpha cells (CD9-/CD56+ and trypsin-producing acinar cells (CD9-/CD56-. This strategy may assist future beta cell research and the development of diagnostic tools for diabetes. It can also be applied more generally for function-based purification of desired cell types from other limited and heterogeneous biological samples.

  16. Vanadyl Sulfate Treatment Stimulates Proliferation and Regeneration of Beta Cells in Pancreatic Islets

    Directory of Open Access Journals (Sweden)

    Samira Missaoui

    2014-01-01

    Full Text Available We examined the effects of vanadium sulfate (VOSO4 treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4 at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4 also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4 treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats.

  17. Supravital dithizone staining in the isolation of human and rat pancreatic islets

    DEFF Research Database (Denmark)

    Hansen, W A; Christie, M R; Kahn, R

    1989-01-01

    no effect on insulin release in tissue culture, on acute responses to stimulatory glucose concentrations or on the insulin content of cells. These results suggest that dithizone staining can assist in the identification of islets from the human pancreas and may prove to be a useful tool in developing......Dithizone, a zinc chelating agent, is known to selectively stain the islets of Langerhans in the pancreas. In the present study, we have used this stain to aid the identification of islets in material obtained by collagenase digestion of human pancreas. Islets were shown to rapidly and reversibly...... techniques for the large scale isolation of functionally intact human islets....

  18. 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

  19. Microcapsules with Intrinsic Barium Radiopacity for Immunoprotection and X-ray/CT imaging of Pancreatic Islet Cells

    Science.gov (United States)

    Arifin, D.R.; Manek, S.; Call, E.; Arepally, A.; Bulte, J.W.M.

    2012-01-01

    Microencapsulation is a commonly used technique for immunoprotection of engrafted therapeutic cells. We investigated a library of capsule formulations to determine the most optimal formulation for pancreatic beta islet cell transplantation, using barium as the gelating ion and clinical-grade protamine sulfate (PS) as a new cationic capsule cross-linker. Barium-gelated alginate/PS/alginate microcapsules (APSA, diameter = 444±21 μm) proved to be mechanically stronger and supported a higher cell viability as compared to conventional alginate/poly-L-lysine/alginate (APLLA) capsules. Human pancreatic islets encapsulated inside APSA capsules, gelated with 20 mM barium as optimal concentration, exhibited a sustained morphological integrity, viability, and functionality for at least 3–4 weeks in vitro, with secreted human C-peptide levels of 0.2–160 pg/ml/islet. Unlike APLLA capsules that are gelled with calcium, barium-APSA capsules are intrinsically radiopaque and, when engrafted into mice, could be readily imaged in vivo with micro-computed tomography (CT). Without the need of adding contrast agents, these capsules offer a clinically applicable alternative for simultaneous immunoprotection and real-time, non-invasive X-ray/CT monitoring of engrafted cells during and after in vivo administration. PMID:22444642

  20. Microcapsules with intrinsic barium radiopacity for immunoprotection and X-ray/CT imaging of pancreatic islet cells.

    Science.gov (United States)

    Arifin, Dian R; Manek, Sameer; Call, Emma; Arepally, Aravind; Bulte, Jeff W M

    2012-06-01

    Microencapsulation is a commonly used technique for immunoprotection of engrafted therapeutic cells. We investigated a library of capsule formulations to determine the most optimal formulation for pancreatic beta islet cell transplantation, using barium as the gelating ion and clinical-grade protamine sulfate (PS) as a new cationic capsule cross-linker. Barium-gelated alginate/PS/alginate microcapsules (APSA, diameter = 444 ± 21 μm) proved to be mechanically stronger and supported a higher cell viability as compared to conventional alginate/poly-l-lysine/alginate (APLLA) capsules. Human pancreatic islets encapsulated inside APSA capsules, gelated with 20 mm barium as optimal concentration, exhibited a sustained morphological integrity, viability, and functionality for at least 3-4 weeks in vitro, with secreted human C-peptide levels of 0.2-160 pg/ml/islet. Unlike APLLA capsules that are gelled with calcium, barium-APSA capsules are intrinsically radiopaque and, when engrafted into mice, could be readily imaged in vivo with micro-computed tomography (CT). Without the need of adding contrast agents, these capsules offer a clinically applicable alternative for simultaneous immunoprotection and real-time, non-invasive X-ray/CT monitoring of engrafted cells during and after in vivo administration. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Immuno-isolation of pancreatic islet allografts using pegylated nanotherapy leads to long-term normoglycemia in full MHC mismatch recipient mice.

    Directory of Open Access Journals (Sweden)

    Huansheng Dong

    Full Text Available Two major hurdles need to be surmounted for cell therapy for diabetes: (i allo-immune rejection of grafted pancreatic islets, or stem/precursor cell-derived insulin-secreting cells; and (ii continuing auto-immunity against the diabetogenic endogenous target antigen. Nanotherapeutics offer a novel approach to overcome these problems and here we ask if creation of "stealth" islets encapsulated within a thin cage of pegylated material of 100-200 nanometers thick provides a viable option for islet transplantation. The aims of this study were to test islet viability and functionality following encapsulation within the pegylated cage, and functional efficacy in vivo in terms of graft-derived control of normoglycemia in diabetic mice. We first demonstrated that pegylation of the islet surface, plus or minus nanoparticles, improved long-term islet viability in vitro compared to non-pegylated (naked control islets. Moreover, pegylation of the islets with nanoparticles was compatible with glucose-stimulated insulin secretion and insulin biogenesis. We next looked for functionality of the created "stealth" DBA/2 (H-2(d islets in vivo by comparing glycemic profiles across 4 groups of streptozotozin-induced diabetic C57BL/6 (H-2(b recipients of (i naked islets; (ii pegylated islets; (iii pegylated islets with nanoparticles (empty; and (iv pegylated islets with nanoparticles loaded with a cargo of leukemia inhibitory factor (LIF, a factor both promotes adaptive immune tolerance and regulates pancreatic β cell mass. Without any other treatment, normoglycemia was lost after 17 d (+/-7.5 d in control group. In striking contrast, recipients in groups (ii, (iii, and (iv showed long-term (>100 d normoglycemia involving 30%; 43%, and 57% of the recipients in each respective group. In conclusion, construction of "stealth" islets by pegylation-based nanotherapeutics not only supports islet structure and function, but also effectively isolates the islets from immune

  2. Effects of growth hormone, prolactin, and placental lactogen on insulin content and release, and deoxyribonucleic acid synthesis in cultured pancreatic islets

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1982-01-01

    The direct effects of human GH (hGH), ovine pituitary PRL (oPRL), and human chorionic somatomammotropin [placental lactogen (hPL)] on the endocrine pancreas were studied in isolated pancreatic islets maintained in tissue culture. Islets of Langerhans were isolated by collagenase treatment...... of insulin, glucagon, and DNA after culture were determined. The DNA synthesis in the newborn rat islets was evaluated by the incorporation of [methyl-3H]thymidine into islet cell DNA. In mouse islets, 1 micrograms/ml hGH, oPRL, or hPL markedly stimulated insulin release during a 2-week culture period...... and caused a significant increase in the insulin content in the islets after culture. While hGH did not affect the DNA content in adult mouse islets, an increase was observed in adult rat islets after 2-3 weeks of culture. In islets isolated from 3- to 5-day-old rats cultured for 2 weeks with hGH...

  3. Effects of alcoholic extract of Momordica charantia (Linn.) whole fruit powder on the pancreatic islets of alloxan diabetic albino rats.

    Science.gov (United States)

    Singh, N; Gupta, M; Sirohi, P; Varsha

    2008-01-01

    Alcoholic extract of whole fruit of Momordica charantia was prepared. Adult healthy albino rats were divided into four groups and received a dose of 6 mg/l00 gm. body weight of alloxan monohydrate. Animals of group I served as diabetic control group. The animals of II, III, and IV groups received 25 mg, 50 mg and 75 mg doses of the extract respectively for different durations. 75 mg dose showed increase in body weight. All doses of alcoholic extract of M. charantia were able to decrease the blood sugar level significantly. Extract feeding showed definite improvement in the islets of Langerhans. No toxic effect was observed in the liver The significant features of the study have been blood glucose once lowered by the treatment with M. charantia fruit extract remained static even after discontinuation of drug for 15 days. Blood sugar never fell below normal values even with a high dose, in pancreatic islets, beta cells showed definite improvement.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5-/- mice.

    Science.gov (United States)

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C; Vennekens, Rudi

    2010-03-16

    Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5(-/-) cells. Ca(2+)-imaging and electrophysiological analysis show that glucose-induced oscillations of V(m) and [Ca(2+)](cyt) have on average a reduced frequency in Trpm5(-/-) islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5(-/-) pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5(-/-) mice.

  6. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice

    Science.gov (United States)

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F.; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C.; Vennekens, Rudi

    2010-01-01

    Glucose homeostasis is critically dependent on insulin release from pancreatic β-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (Vm) and the cytosolic calcium level ([Ca2+]cyt). We propose that TRPM5, a Ca2+-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca2+-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5−/− cells. Ca2+-imaging and electrophysiological analysis show that glucose-induced oscillations of Vm and [Ca2+]cyt have on average a reduced frequency in Trpm5−/− islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5−/− pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5−/− mice. PMID:20194741

  7. Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Han-Hung Huang

    2011-01-01

    Full Text Available Exercise appears to improve glycemic control for people with type 1 diabetes (T1D. However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and β-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets.

  8. [Age-dependent alteration of insulin and ghrelin expression in pancreatic islets of intrauterine growth-retarded rats].

    Science.gov (United States)

    Wang, Xiu-Min; Liang, Li; Du, Li-Zhong

    2008-05-01

    To evaluate the age-dependent alteration of insulin and ghrelin expression in the pancreatic islets of intrauterine growth-retarded (IUGR) rats during development and to identify the role of ghrelin in insulin resistance induced by IUGR. Neonatal SD rats were divided into normal birth weight group (N group) and intrauterine growth-retarded group (I group). Plasma glucose, ghrelin and serum insulin were analyzed at day 1, 3, 7 and 10 and at week 2, 3, 4,8 and 12 after birth.Entire pancreas samples were collected for determination of ghrelin and insulin mRNA. Immunohistochemical double-staining and confocal microscopy was performed on rat pancreas. Plasma insulin levels of I group were lower than those of N group at day 1, 3 and 7 (P insulin resistance index (HOMA-IR) of I group was higher than that of N group at day 1, 3 and 7 (Pinsulin, HOMA-IR and ghrelin concentrations decreased in an age-dependent manner (F = 4.12 to approximately 125.97, P insulin (+) cells and ghrelin (+) cells in both groups decreased in an age-dependent manner (F = -49.29 to approximately 427.28, PInsulin secretion was negatively correlated with ghrelin contents in both groups (r=-0.895, P=0.000; r=-0.458, P=0.002). Percentage of insulin(+) cells was negatively correlated with the percentage of ghrelin (+) cells in pancreatic islets in both groups (r=-0.810,P=0.000; r=-0.714, P=0.000). The distributions of ghrelin (+) cells in pancreatic islets of I group were different from those of N group. The effects of IUGR on weight, plasma ghrelin levels and insulin secretion of pups rats persist after birth and ghrelin may be involved in the process of insulin resistance in IUGR rats.

  9. Engineering of microscale three-dimensional pancreatic islet models in vitro and their biomedical applications.

    Science.gov (United States)

    Gao, Bin; Wang, Lin; Han, Shuang; Pingguan-Murphy, Belinda; Zhang, Xiaohui; Xu, Feng

    2016-08-01

    Diabetes now is the most common chronic disease in the world inducing heavy burden for the people's health. Based on this, diabetes research such as islet function has become a hot topic in medical institutes of the world. Today, in medical institutes, the conventional experiment platform in vitro is monolayer cell culture. However, with the development of micro- and nano-technologies, several microengineering methods have been developed to fabricate three-dimensional (3D) islet models in vitro which can better mimic the islet of pancreases in vivo. These in vitro islet models have shown better cell function than monolayer cells, indicating their great potential as better experimental platforms to elucidate islet behaviors under both physiological and pathological conditions, such as the molecular mechanisms of diabetes and clinical islet transplantation. In this review, we present the state-of-the-art advances in the microengineering methods for fabricating microscale islet models in vitro. We hope this will help researchers to better understand the progress in the engineering 3D islet models and their biomedical applications such as drug screening and islet transplantation.

  10. Impact of Pancreatic Rat Islet Density on Cell Survival during Hypoxia

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Brotons

    2016-01-01

    Full Text Available In bioartificial pancreases (BP, the number of islets needed to restore normoglycaemia in the diabetic patient is critical. However, the confinement of a high quantity of islets in a limited space may impact islet survival, particularly in regard to the low oxygen partial pressure (PO2 in such environments. The aim of the present study was to evaluate the impact of islet number in a confined space under hypoxia on cell survival. Rat islets were seeded at three different concentrations (150, 300, and 600 Islet Equivalents (IEQ/cm2 and cultured in normal atmospheric pressure (160 mmHg as well as hypoxic conditions (15 mmHg for 24 hours. Cell viability, function, hypoxia-induced changes in gene expression, and cytokine secretion were then assessed. Notably, hypoxia appeared to induce a decrease in viability and increasing islet density exacerbated the observed increase in cellular apoptosis as well as the loss of function. These changes were also associated with an increase in inflammatory gene transcription. Taken together, these data indicate that when a high number of islets are confined to a small space under hypoxia, cell viability and function are significantly impacted. Thus, in order to improve islet survival in this environment during transplantation, oxygenation is of critical importance.

  11. Direct effect of gonadal and contraceptive steroids on insulin release from mouse pancreatic islets in organ culture

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1984-01-01

    Sex steroids are supposed to contribute to the normal glucose homeostasis and to the altered glucose and insulin metabolism in pregnancy and during contraception. In the present study isolated mouse pancreatic islets were maintained in tissue culture medium RPMI 1640 supplemented with 0.5% newborn...... on the glucose-stimulated insulin release probably by increasing the glucose sensitivity. The results suggest that the alterations in glucose and insulin metabolism in pregnancy and during treatment with certain oral contraceptives may in part be due to a direct effect of progestins on the beta-cell....

  12. Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models

    OpenAIRE

    Colsoul, Barbara; Jacobs, Griet; Philippaert, Koenraad; Owsianik, Grzegorz; Segal, Andrei; Nilius, Bernd; Voets, Thomas; Schuit, Frans; Vennekens, Rudi

    2013-01-01

    We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the β cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-i...

  13. Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Angela Subauste

    Full Text Available There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM and it is termed Latent Autoimmune Diabetes in Adults (LADA. We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab. A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at

  14. Islet autoimmunity identifies a unique pattern of impaired pancreatic beta-cell function, markedly reduced pancreatic beta cell mass and insulin resistance in clinically diagnosed type 2 diabetes.

    Science.gov (United States)

    Subauste, Angela; Gianani, Roberto; Chang, Annette M; Plunkett, Cynthia; Pietropaolo, Susan L; Zhang, Ying-Jian; Barinas-Mitchell, Emma; Kuller, Lewis H; Galecki, Andrzej; Halter, Jeffrey B; Pietropaolo, Massimo

    2014-01-01

    There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the

  15. Selection of polymers for application in scaffolds applicable for human pancreatic islet transplantation

    NARCIS (Netherlands)

    Smink, Alexandra M; de Haan, Bart J; Paredes-Juarez, Genaro A; Wolters, Anouk H G; Kuipers, Jeroen; Giepmans, Ben N G; Schwab, Leendert; Engelse, Marten A; van Apeldoorn, Aart A; de Koning, Eelco; Faas, Marijke M; de Vos, Paul

    2016-01-01

    The liver is currently the site for transplantation of islets in humans. This is not optimal for islets, but alternative sites in humans are not available. Polymeric scaffolds in surgically accessible areas are a solution. As human donors are rare, the polymers should not interfere with functional

  16. Pro-inflammatory and pro-oxidant status of pancreatic islet in vitro is controlled by TLR-4 and HO-1 pathways.

    Science.gov (United States)

    Vivot, Kevin; Langlois, Allan; Bietiger, William; Dal, Stéphanie; Seyfritz, Elodie; Pinget, Michel; Jeandidier, Nathalie; Maillard, Elisa; Gies, Jean-Pierre; Sigrist, Séverine

    2014-01-01

    Since their isolation until implantation, pancreatic islets suffer a major stress leading to the activation of inflammatory reactions. The maintenance of controlled inflammation is essential to preserve survival and function of the graft. Identification and targeting of pathway(s) implicated in post-transplant detrimental inflammatory events, is mandatory to improve islet transplantation success. We sought to characterize the expression of the pro-inflammatory and pro-oxidant mediators during islet culture with a focus on Heme oxygenase (HO-1) and Toll-like receptors-4 signaling pathways. Rat pancreatic islets were isolated and pro-inflammatory and pro-oxidant status were evaluated after 0, 12, 24 and 48 hours of culture through TLR-4, HO-1 and cyclooxygenase-2 (COX-2) expression, CCL-2 and IL-6 secretion, ROS (Reactive Oxygen Species) production (Dihydroethidine staining, DHE) and macrophages migration. To identify the therapeutic target, TLR4 inhibition (CLI-095) and HO-1 activation (cobalt protoporphyrin,CoPP) was performed. Activation of NFκB signaling pathway was also investigated. After isolation and during culture, pancreatic islet exhibited a proinflammatory and prooxidant status (increase levels of TLR-4, COX-2, CCL-2, IL-6, and ROS). Activation of HO-1 or inhibition of TLR-4 decreased inflammatory status and oxidative stress of islets. Moreover, the overexpression of HO-1 induced NFκB phosphorylation while the inhibition of TLR-4 had no effect NFκB activation. Finally, inhibition of pro-inflammatory pathway induced a reduction of macrophages migration. These data demonstrated that the TLR-4 signaling pathway is implicated in early inflammatory events leading to a pro-inflammatory and pro-oxidant status of islets in vitro. Moreover, these results provide the mechanism whereby the benefits of HO-1 target in TLR-4 signaling pathway. HO-1 could be then an interesting target to protect islets before transplantation.

  17. Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice

    OpenAIRE

    Colsoul, Barbara; Schraenen, Anica; Lemaire, Katleen; Quintens, Roel; Van Lommel, Leentje; Segal, Andrei; Owsianik, Grzegorz; Talavera, Karel; Voets, Thomas; Margolskee, Robert F.; Kokrashvili, Zaza; Gilon, Patrick; Nilius, Bernd; Schuit, Frans C.; Vennekens, Rudi

    2010-01-01

    Glucose homeostasis is critically dependent on insulin release from pancreatic beta-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V(m)) and the cytosolic calcium level ([Ca(2+)](cyt)). We propose that TRPM5, a Ca(2+)-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca(2+)-activated nonselective cation current with TRPM5-like proper...

  18. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    Energy Technology Data Exchange (ETDEWEB)

    Sekiya, Motohiro [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yagyu, Hiroaki [Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498 (Japan); Gotoda, Takanari [Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Nagai, Ryozo [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Shimano, Hitoshi; Yamada, Nobuhiro [Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaragi 305-8575 (Japan); and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  19. A study of the pancreatic islet β-cell function and insulin resistance of type2 diabetic gastroparesis

    International Nuclear Information System (INIS)

    Zou Gang; Shao Hao; Lu Zeyuan; Ding Yuzhen; Chen Guanrong; Fu Juan

    2005-01-01

    Objective: To study the pancreatic islet β-cell function and insulin resistance of diabetic gastroparesis (DGP). Methods: 31 subjects with normal glucose tolerance (NGT), 32 subjects with impaired glucose tolerance (IGT), 38 subjects with type 2 diabetes mellitus (T2DM) and 31 subjects with DGP were en-rolled in the study, assessed by steamed bread meal tests, the plasma glucose and insulin at 0, 30, 60, 120 and 180 min were respectively measured by using glucose oxidase and radioimmunoassay, investigate the changes of area under insulin cure (INSAUC), Homa-insulin resistance (Homa-IR) index and modified β-cell function index (MBCI). Results: The INSAUC of IGT, T2DM, NGT and DGP fell in turn, there were signif-icantly differences among the groups. The Homa-IR index of NGT, IGT, DGP and T2DM rose in turn, there were significantly differences among the groupsexcept between T2DM and DGP. Conclusions: The pancreatic islet β-cell function of DGP was worse that NGT, IGT and T2DM, and the insulin resistance was stronger than NGT and IGT. (authors)

  20. Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models.

    Science.gov (United States)

    Colsoul, Barbara; Jacobs, Griet; Philippaert, Koenraad; Owsianik, Grzegorz; Segal, Andrei; Nilius, Bernd; Voets, Thomas; Schuit, Frans; Vennekens, Rudi

    2014-03-01

    We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the β cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets. Leptin treatment of ob/ob mice not only reversed the diabetic phenotype seen in these mice but also upregulated Trpm5 expression. Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group. In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin. In conclusion, our data show that increased plasma insulin levels downregulate TRPM5 expression in pancreatic islets from leptin-deficient mouse models of type 2 diabetes.

  1. Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress.

    Science.gov (United States)

    Sadeghimahalli, Forouzan; Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Rostamkhani, Fatemeh

    2015-03-01

    Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination.

  2. Trimodal Gadolinium-Gold Microcapsules Containing Pancreatic Islet Cells Restore Normoglycemia in Diabetic Mice and Can Be Tracked by Using US, CT, and Positive-Contrast MR Imaging

    Science.gov (United States)

    Arifin, Dian R.; Long, Christopher M.; Gilad, Assaf A.; Alric, Christophe; Roux, Stéphane; Tillement, Olivier; Link, Thomas W.; Arepally, Aravind; Bulte, Jeff W. M.

    2011-01-01

    Purpose: To develop microcapsules that immunoprotect pancreatic islet cells for treatment of type I diabetes and enable multimodal cellular imaging of transplanted islet cells. Materials and Methods: All animal experiments were approved by the institutional animal care and use committee. Gold nanoparticles functionalized with DTDTPA (dithiolated diethylenetriaminepentaacetic acid):gadolinium chelates (GG) were coencapsulated with pancreatic islet cells by using protamine sulfate as a clinical-grade alginate cross linker. Conventional poly-l-lysine–cross-linked microcapsules and unencapsulated islets were included as controls. The viability and glucose responsiveness of islet cells were assessed in vitro, and in vivo insulin (C-peptide) secretion was monitored for 6 weeks in (streptozotocin-induced) diabetic mice with (n = 7) or without (n = 8) intraabdominally engrafted islet cells. Five nondiabetic mice were included as controls. Differences between samples were calculated by using a nonparametric Wilcoxon Mann-Whitney method. To adjust for multiple comparisons, a significance level of P microcapsules could be readily visualized with positive-contrast high-field-strength MR imaging, micro-CT, and US both in vitro and in vivo. Conclusion: Cell encapsulation with GG provides a means of trimodal noninvasive tracking of engrafted cells. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101608/-/DC1 PMID:21734156

  3. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans

    DEFF Research Database (Denmark)

    Bendtzen, K; Mandrup-Poulsen, T; Nerup, J

    1986-01-01

    and recombinant IL-1 derived from the predominant pI 7 form of human IL-1, consistently inhibited the insulin response. The pI 6 and pI 5 forms of natural IL-1 were ineffective. Natural and recombinant IL-1 exhibited similar dose responses in their islet-inhibitory effect and their thymocyte-stimulatory activity....... Concentrations of IL-1 that inhibited islet activity were in the picomolar range. Hence, monocyte-derived pI 7 IL-1 may contribute to islet cell damage and therefore to the development of insulin-dependent diabetes mellitus....

  4. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.

    Directory of Open Access Journals (Sweden)

    Décio L Eizirik

    Full Text Available Type 1 diabetes (T1D is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA-seq to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β and interferon-γ (IFN-γ. Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the

  5. Gadolinium- and manganite-based contrast agents with fluorescent probes for both magnetic resonance and fluorescence imaging of pancreatic islets: a comparative study

    Czech Academy of Sciences Publication Activity Database

    Berková, Z.; Jirák, D.; Zacharovová, K.; Lukeš, I.; Kotková, Z.; Kotek, J.; Kačenka, M.; Kaman, Ondřej; Řehoř, I.; Hájek, M.; Saudek, F.

    2013-01-01

    Roč. 8, č. 4 (2013), s. 614-621 ISSN 1860-7179 Institutional support: RVO:68378271 Keywords : contrast agents * gadolinium * magnetic resonance imaging * manganite * pancreatic islets Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 3.046, year: 2013

  6. Xylitol improves pancreatic islets morphology to ameliorate type 2 diabetes in rats: a dose response study.

    Science.gov (United States)

    Rahman, Md Atiar; Islam, Md Shahdiul

    2014-07-01

    Xylitol has been reported as a potential antidiabetic sweetener in a number of recent studies; however, the most effective dietary dose and organ-specific effects are still unclear. Six-week-old male Sprague-Dawley rats were randomly divided into 5 groups: normal control (NC), diabetic control (DBC), diabetic xylitol 2.5% (DXL2.5), diabetic xylitol 5.0% (DXL5), and diabetic xylitol 10.0% (DXL10). Diabetes was induced only in the animals in DBC and DXL groups and considered diabetic when their nonfasting blood glucose level was >300 mg/dL. The DXL groups were fed with 2.5%, 5.0%, and 10% xylitol solution, whereas the NC and DBC groups were supplied with normal drinking water. After 4-wk intervention, body weight, food and fluid intake, blood glucose, serum fructosamine, liver glycogen, serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, creatine kinase, uric acid, creatinine, and most serum lipids were significantly decreased, and serum insulin concentration, glucose tolerance ability, and pancreatic islets morphology were significantly improved in the DXL10 group compared to the DBC group. The data of this study suggest that 10% xylitol has the better antidiabetic effects compared to 2.5% and 5.0% and it can be used as an excellent antidiabetic sweetener and food supplement in antidiabetic foods. Xylitol is widely used as a potential anticariogenic and sweetening agent in a number of oral care and food products when many of its health benefits are still unknown. Due to its similar sweetening power but lower calorific value (2.5 compared with 4 kcal) and lower glycemic index (13 compared with 65) compared to sucrose, recently it has been widely used as a sugar substitute particularly by overweight, obese, and diabetic patients in order to reduce their calorie intake from sucrose. However, the potential antidiabetic effects of xylitol have been discovered recently. The results of this study confirmed the effective dietary dose of xylitol for

  7. Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure

    Directory of Open Access Journals (Sweden)

    Arne Andersson

    2008-01-01

    Full Text Available Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the β-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

  8. Intraocular in vivo imaging of pancreatic islet cell physiology/pathology

    Directory of Open Access Journals (Sweden)

    Ingo B. Leibiger

    2017-09-01

    Major conclusions: Data provided by us and others demonstrate the high versatility of this imaging platform. The use of ‘reporter islets’ engrafted in the eye, reporting on the status of in situ endogenous islets in the pancreas of the same animal, allows the identification of key-events in the development and progression of diabetes. This will not only serve as a versatile research tool but will also lay the foundation for a personalized medicine approach and will serve as a screening platform for new drugs and/or treatment protocols. ‘Metabolic’ islet transplantation, in which islets engrafted in the eye replace the endogenous beta cells, will allow for the establishment of islet-specific transgenic models and ‘humanized’ mouse models as well as serving as the basis for a new clinical transplantation site for the cure of diabetes.

  9. Human Fibroblast Sheet Promotes Human Pancreatic Islet Survival and Function In Vitro.

    Science.gov (United States)

    Matsushima, Hajime; Kuroki, Tamotsu; Adachi, Tomohiko; Kitasato, Amane; Ono, Shinichiro; Tanaka, Takayuki; Hirabaru, Masataka; Kuroshima, Naoki; Hirayama, Takanori; Sakai, Yusuke; Soyama, Akihiko; Hidaka, Masaaki; Takatsuki, Mitsuhisa; Kin, Tatsuya; Shapiro, James; Eguchi, Susumu

    2016-01-01

    In previous work, we engineered functional cell sheets using bone marrow-derived mesenchymal stem cells (BM-MSCs) to promote islet graft survival. In the present study, we hypothesized that a cell sheet using dermal fibroblasts could be an alternative to MSCs, and then we aimed to evaluate the effects of this cell sheet on the functional viability of human islets. Fibroblast sheets were fabricated using temperature-responsive culture dishes. Human islets were seeded onto fibroblast sheets. The efficacy of the fibroblast sheets was evaluated by dividing islets into three groups: the islets-alone group, the coculture with fibroblasts group, and the islet culture on fibroblast sheet group. The ultrastructure of the islets cultured on each fibroblast sheet was examined by electron microscopy. The fibroblast sheet expression of fibronectin (as a component of the extracellular matrix) was quantified by Western blotting. After 3 days of culture, islet viabilities were 70.2 ± 9.8%, 87.4 ± 5.8%, and 88.6 ± 4.5%, and survival rates were 60.3 ± 6.8%, 65.3 ± 3.0%, and 75.8 ± 5.6%, respectively. Insulin secretions in response to high-glucose stimulation were 5.1 ± 1.6, 9.4 ± 3.8, and 23.5 ± 12.4 µIU/islet, and interleukin-6 (IL-6) secretions were 3.0 ± 0.7, 5.1 ± 1.2, and 7.3 ± 1.0 ng/day, respectively. Islets were found to incorporate into the fibroblast sheets while maintaining a three-dimensional structure and well-preserved extracellular matrix. The fibroblast sheets exhibited a higher expression of fibronectin compared to fibroblasts alone. In conclusion, human dermal fibroblast sheets fabricated by tissue-engineering techniques could provide an optimal substrate for human islets, as a source of cytokines and extracellular matrix.

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

    DEFF Research Database (Denmark)

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami

    2015-01-01

    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 ...

  11. Avascular Necrosis

    Science.gov (United States)

    ... that the tissue lacking blood supply (avascular area) bears less weight than an adjacent healthy area. Arthroplasty – ... of Diagnoses Incidence Rates Over Time Childhood Cancer Deaths Per Year 5-Year Survival Rate Childhood Cancer ...

  12. Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in α-cells of mouse pancreatic islets.

    Science.gov (United States)

    Kang, NaNa; Bahk, Young Yil; Lee, NaHye; Jae, YoonGyu; Cho, Yoon Hee; Ku, Cheol Ryong; Byun, Youngjoo; Lee, Eun Jig; Kim, Min-Soo; Koo, JaeHyung

    2015-05-08

    Olfactory receptors (ORs) are extensively expressed in olfactory as well as non-olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic α-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in α-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca(2+) mobilization in pancreatic α-cells. The azelaic acid-induced Ca(2+) response as well as glucagon secretion was concentration- and time-dependent manner. Olfr544 was expressed in α-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 μM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca(2+) mobilization in α-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. How stable is repression of disallowed genes in pancreatic islets in response to metabolic stress?

    Science.gov (United States)

    Lemaire, Katleen; Granvik, Mikaela; Schraenen, Anica; Goyvaerts, Lotte; Van Lommel, Leentje; Gómez-Ruiz, Ana; In 't Veld, Peter; Gilon, Patrick; Schuit, Frans

    2017-01-01

    The specific phenotype of mature differentiated beta cells not only depends on the specific presence of genes that allow beta cell function but also on the selective absence of housekeeping genes ("disallowed genes") that would interfere with this function. Recent studies have shown that both histone modifications and DNA methylation via the de novo methyltransferase DNMT3A are involved in repression of disallowed genes in neonatal beta cells when these cells acquire their mature phenotype. It is unknown, however, if the environmental influence of advanced age, pregnancy and the metabolic stress of high fat diet or diabetes could alter the repression of disallowed genes in beta cells. In the present study, we show that islet disallowed genes-which are also deeply repressed in FACS-purified beta cells-remain deeply repressed in animals of advanced age and in pregnant females. Moreover, the stability of this repression was correlated with strong and stable histone repression marks that persisted in islets isolated from 2 year old mice and with overall high expression of Dnmt3a in islets. Furthermore, repression of disallowed genes was unaffected by the metabolic stress of high fat diet. However, repression of about half of the disallowed genes was weakened in 16 week-old diabetic db/db mice. In conclusion, we show that the disallowed status of islet genes is stable under physiological challenging conditions (advanced age, pregnancy, high fat diet) but partially lost in islets from diabetic animals.

  14. Effect of neonatal hypothyroidism on carbohydrate metabolism, insulin secretion, and pancreatic islets morphology of adult male offspring in rats.

    Science.gov (United States)

    Farahani, H; Ghasemi, A; Roghani, M; Zahediasl, S

    2013-01-01

    Neonatal hypothyroidism has serious effects on growth, development, and metabolism. This study aims to investigate the effects of the neonatal hypothyroidism on carbohydrate metabolism, islet insulin secretion and morphology of the pancreatic islets in adult male offspring. Lactating mothers of Wistar rats consumed 0.02% solution of 6-propyl-2-thiouracil during the weaning period (neonatal hypothyroid group), while mothers of the control group drank merely tap water. Body weight and survival of pups were followed up. Intravenous glucose tolerance test was performed in adult male offspring and 5-6 weeks later, glucose-stimulated insulin secretion (GSIS) was evaluated. During the glucose tolerance test, plasma glucose level of the neonatal hypothyroid group (13.18 ± 0.59 mmol/l) was significantly higher at 5 min compared to the control group (11.54 ± 0.47 mmol/l), whereas plasma insulin concentrations and GSIS of the groups was not significantly different. Homeostasis model assessment of insulin resistance of adult male offspring of the hypothyroid group (9.1 ± 1.0) was significantly higher as compared to the control group (4.5 ± 0.6). Area (14,613.0 ± 2646.3 μm2) and the diameter of the islets (147 ± 3.0 μm) of the neonatal hypothyroid group were significantly lower, as compared to the control group (32,886.3 ± 4690.3 and 206.6 ± 5.9 μm2 and μm, respectively). Neonatal hypothyroidism can alter carbohydrate metabolism in euthyroid adult offspring, which may increase susceptibility to the development of glucose intolerance and occurrence of Type 2 diabetes later in life.

  15. Effect of interleukin-1 on the biosynthesis of proinsulin and insulin in isolated rat pancreatic islets

    DEFF Research Database (Denmark)

    Hansen, Birgit Sehested; Linde, S; Spinas, G A

    1988-01-01

    Insulin dependent diabetes mellitus (IDDM) is often preceded or associated with lymphocytic infiltration in the islets of Langerhans (insulitis). We recently demonstrated that interleukin-1 (IL-1) produced by activated macrophages exerts a bimodal effect on insulin release and biosynthesis...... reduced the insulin biosynthesis to 6.1 +/- 2.7% (n = 4). During the 3 h labelling period the labelled proinsulin content compared to insulin was increased from 9.0 +/- 1.3% (control) to 26.6 +/- 6.4% in the IL-1 exposed islets, and the ratio between labelled insulin 1 to 2 was increased from 2.0 +/- 0...

  16. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans

    DEFF Research Database (Denmark)

    Bendtzen, K; Mandrup-Poulsen, T; Nerup, J

    1986-01-01

    Activated mononuclear cells appear to be important effector cells in autoimmune beta cell destruction leading to insulin-dependent (type 1) diabetes mellitus. Conditioned medium from activated mononuclear cells (from human blood) is cytotoxic to isolated rat and human islets of Langerhans....... This cytotoxic activity was eliminated from crude cytokine preparations by adsorption with immobilized, purified antibody to interleukin-1 (IL-1). The islet-inhibitory activity and the IL-1 activity (determined by its comitogenic effect on thymocytes) were recovered by acid wash. Purified natural IL-1...

  17. Apolipoprotein CIII Reduces Proinflammatory Cytokine-Induced Apoptosis in Rat Pancreatic Islets via the Akt Prosurvival Pathway

    DEFF Research Database (Denmark)

    Størling, Joachim; Juntti-Berggren, Lisa; Olivecrona, Gunilla

    2011-01-01

    Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic ß-cells in the absence of inflammatory stress...... µg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1ß + interferon-¿, ApoCIII reduced cytokine-mediated islet cell death and impairment of ß-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had...... of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces...

  18. Evaluation of Porcine Pancreatic Islets Transplanted in the Kidney Capsules of Diabetic Mice Using a Clinically Approved Superparamagnetic Iron Oxide (SPIO) and a 1.5T MR Scanner

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hoe Suk; Kim, Hyoung Su; Park, Kyong Soo; Moon, Woo Kyung [Seoul National University Hospital, Seoul (Korea, Republic of)

    2010-12-15

    To evaluate transplanted porcine pancreatic islets in the kidney capsules of diabetic mice using a clinically approved superparamagnetic iron oxide (SPIO) and a 1.5T MR scanner. Various numbers of porcine pancreatic islets labeled with Resovist, a carboxydextran-coated SPIO, were transplanted into the kidney capsules of normal mice and imaged with a 3D FIESTA sequence using a 1.5T clinical MR scanner. Labeled (n = 3) and unlabeled (n = 2) islets were transplanted into the kidney capsules of streptozotocin-induced diabetic mice. Blood glucose levels and MR signal intensities were monitored for 30 days post-transplantation. There were no significant differences in viability or insulin secretion between labeled and unlabeled islets. A strong correlation ({gamma} {sup 2} > 0.94) was evident between the number of transplanted islets and T{sub 2} relaxation times quantified by MRI. Transplantation with labeled or unlabeled islets helped restore normal sustained glucose levels in diabetic mice, and nephrectomies induced the recurrence of diabetes. The MR signal intensity of labeled pancreatic islets decreased by 80% over 30 days. The transplantation of SPIO-labeled porcine islets into the kidney capsule of diabetic mice allows to restore normal glucose levels, and these islets can be visualized and quantified using a 1.5T clinical MR scanner

  19. Beta Cell Hubs Dictate Pancreatic Islet Responses to Glucose.

    Science.gov (United States)

    Johnston, Natalie R; Mitchell, Ryan K; Haythorne, Elizabeth; Pessoa, Maria Paiva; Semplici, Francesca; Ferrer, Jorge; Piemonti, Lorenzo; Marchetti, Piero; Bugliani, Marco; Bosco, Domenico; Berishvili, Ekaterine; Duncanson, Philip; Watkinson, Michael; Broichhagen, Johannes; Trauner, Dirk; Rutter, Guy A; Hodson, David J

    2016-09-13

    The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Homogenization of heterogeneously coupled bistable ODE's - applied to excitation waves in pancreatic islets of Langerhans

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2004-01-01

    We consider a lattice of coupled identical differential equations. The coupling is between nearest neighbors and of resistance type, but the strength of coupling varies from site to site. Such a lattice can, for example, model an islet of Langerhans, where the sites in the lattice model individua...

  1. Supravital dithizone staining in the isolation of human and rat pancreatic islets

    DEFF Research Database (Denmark)

    Hansen, W A; Christie, M R; Kahn, R

    1989-01-01

    stain red on incubation with dithizone solution. Tissue selected on the basis of dithizone staining was shown to contain insulin-positive cells and to accumulate insulin in the medium during a subsequent period in tissue culture. Experiments with rat islets indicated that the dithizone treatment had...

  2. Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets

    NARCIS (Netherlands)

    DeVos, P; DeHaan, BJ; Wolters, GHJ; Strubbe, JH; VanSchilfgaarde, R; van Schilfgaarde, P.

    Graft failure of alginate-polylysine microencapsulated islets is often interpreted as the consequence of a non-specific foreign body reaction against the microcapsules, initiated by impurities present in crude alginate. The aim of the present study was to investigate if purification of the alginate

  3. Acute Exposure to a Precursor of Advanced Glycation End Products Induces a Dual Effect on the Rat Pancreatic Islet Function

    Directory of Open Access Journals (Sweden)

    Ghada Elmhiri

    2014-01-01

    Full Text Available Aim. Chronic diseases are the leading cause of death worldwide. Advanced glycation end products, known as AGEs, are a major risk factor for diabetes onset and maintenance. Methylglyoxal (MG, a highly reactive metabolite of glucose, is a precursor for the generation of endogenous AGEs. Methods. In this current study we incubated in vitro pancreatic islets from adult rats in absence or presence of MG (10 μmol/l with different concentrations of glucose and different metabolic components (acetylcholine, epinephrine, potassium, forskolin, and leucine. Results. Different effects of MG on insulin secretion were evidenced. In basal glucose stimulation (5.6 mM, MG induced a significant (P<0.05 increase of insulin secretion. By contrast, in higher glucose concentrations (8.3 mM and 16.7 mM, MG significantly inhibited insulin secretion (P<0.05. In the presence of potassium, forskolin, and epinephrine, MG enhanced insulin secretion (P<0.05, while when it was incubated with acetylcholine and leucine, MG resulted in a decrease of insulin secretion (P<0.05. Conclusion. We suggest that MG modulates the secretion activity of beta-cell depending on its level of stimulation by other metabolic factors. These results provide insights on a dual acute effect of MG on the pancreatic cells.

  4. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.

    Directory of Open Access Journals (Sweden)

    Tasnim Dayeh

    2014-03-01

    Full Text Available Impaired insulin secretion is a hallmark of type 2 diabetes (T2D. Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼ 7% and overrepresented in the open sea (∼ 60%. 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These

  5. Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines

    Science.gov (United States)

    Oleson, Bryndon J.; McGraw, Jennifer A.; Broniowska, Katarzyna A.; Annamalai, Mani; Chen, Jing; Bushkofsky, Justin R.; Davis, Dawn B.; Mathews, Clayton E.

    2015-01-01

    While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line. PMID:26084699

  6. The insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet.

    Science.gov (United States)

    Bringhenti, Isabele; Ornellas, Fernanda; Mandarim-de-Lacerda, Carlos Alberto; Aguila, Marcia Barbosa

    2016-10-01

    Mothers fed a high-fat (HF) diet can cause different adverse alterations in their offspring. The study aimed to verify the pancreatic islet structure and insulin-signaling pathway in adulthood of offspring of mothers fed a HF diet during the pregnancy. Female mice (mothers) were randomly assigned to receive either standard chow (Mo-SC) or a HF diet (Mo-HF) ad libitum. After 2 mo on the experimental diets, 3-mo-old female mice were mated with male C57 BL/6 mice that were fed a SC diet. The male offspring was evaluated at 6 mo old. At 6 mo of age, Mo-HF offspring had an increment in body mass and adiposity, hypercholesterolemia, and hypertriacylglycerolemia, higher levels of insulin, and leptin with a concomitant decrease in adiponectin levels. In the islet, we observed an alteration in the structure characterized by the migration of some alpha cells from the edge to the core of the islet in association with an increase in the masses of the islet, beta cell, and alpha cell, featuring a pancreatic islet remodeling. Additionally, the Mo-HF offspring demonstrated a decrease in IRS1, PI3 k p-Akt, Pd-1, and Glut2 protein expressions compared to Mo-SC offspring. However, an increase was observed in FOXO1 and insulin protein expressions in Mo-HF offspring compared to Mo-SC offspring. The present study demonstrated that a maternal HF diet is responsible for remodeling the islet structure coupled with an adverse carbohydrate metabolism and impairment of the insulin-signaling pathway in adult male mice offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Comparison of different compressed sensing algorithms for low SNR19F MRI applications-Imaging of transplanted pancreatic islets and cells labeled with perfluorocarbons.

    Science.gov (United States)

    Liang, Sayuan; Dresselaers, Tom; Louchami, Karim; Zhu, Ce; Liu, Yipeng; Himmelreich, Uwe

    2017-11-01

    Transplantation of pancreatic islets is a possible treatment option for patients suffering from Type I diabetes. In vivo imaging of transplanted islets is important for assessment of the transplantation site and islet distribution. Thanks to its high specificity, the absence of intrinsic background signal in tissue and its potential for quantification, 19 F MRI is a promising technique for monitoring the fate of transplanted islets in vivo. In order to overcome the inherent low sensitivity of 19 F MRI, leading to long acquisition times with low signal-to-noise ratio (SNR), compressed sensing (CS) techniques are a valuable option. We have validated and compared different CS algorithms for acceleration of 19 F MRI acquisition in a low SNR regime using pancreatic islets labeled with perfluorocarbons both in vitro and in vivo. Using offline simulation on both in vitro and in vivo low SNR fully sampled 19 F MRI datasets of labeled islets, we have shown that CS is effective in reducing the image acquisition time by a factor of three to four without seriously affecting SNR, regardless of the particular algorithms used in this study, with the exception of CoSaMP. Using CS, signals can be detected that might have been missed by conventional 19 F MRI. Among different algorithms (SPARSEMRI, OMMP, IRWL1, Two-level and CoSAMP), the two-level l 1 method has shown the best performance if computational time is taken into account. We have demonstrated in this study that different existing CS algorithms can be used effectively for low SNR 19 F MRI. An up to fourfold gain in SNR/scan time could be used either to reduce the scan time, which is beneficial for clinical and translational applications, or to increase the number of averages, to potentially detect otherwise undetected signal when compared with conventional 19 F MRI acquisitions. Potential applications in the field of cell therapy have been demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

  8. Proteins differentially expressed in human beta-cells-enriched pancreatic islet cultures and human insulinomas

    DEFF Research Database (Denmark)

    Terra, Letícia F; Teixeira, Priscila C; Wailemann, Rosangela A M

    2013-01-01

    In view of the great demand for human beta-cells for physiological and medical studies, we generated cell lines derived from human insulinomas which secrete insulin, C-peptide and express neuroendocrine and islet markers. In this study, we set out to characterize their proteomes, comparing them...... to those of primary beta-cells using DIGE followed by MS. The results were validated by Western blotting. An average of 1800 spots was detected with less than 1% exhibiting differential abundance. Proteins more abundant in human islets, such as Caldesmon, are involved in the regulation of cell......, a molecular snapshot of the orchestrated changes in expression of proteins involved in key processes which could be correlated with the altered phenotype of human beta-cells. Collectively our observations prompt research towards the establishment of bioengineered human beta-cells providing a new and needed...

  9. Direct long-term effects of L-asparaginase on rat and human pancreatic islets

    DEFF Research Database (Denmark)

    Clausen, Niels; Nielsen, Jens Høiriis

    1989-01-01

    the glucagon content was unchanged. Removal of the drug resulted in partial recovery of the insulin secretion. To elucidate the mechanisms of of action of the drug, insulin biosynthesis was studied in islets cultured in asparagine-free medium with or without asparaginase. No difference in biosynthesis was seen...... between media with or without asparagine, whereas 0.1 U/mL asparaginase caused about a 50% reduction under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)...

  10. Pancreatic hormones are expressed on the surfaces of human and rat islet cells through exocytotic sites

    DEFF Research Database (Denmark)

    Larsson, L I; Hutton, J C; Madsen, O D

    1989-01-01

    . Electron microscopy reveals the labeling to occur at sites of exocytotic granule release, involving the surfaces of extruded granule cores. The surfaces of islet cells were labeled both by polyclonal and monoclonal antibodies, excluding that receptor-interacting, anti-idiotypic hormone antibodies were...... for these results. It is concluded that the staining reflects interactions between the appropriate antibodies and exocytotic sites of hormone release....

  11. Peptidomic profiling of secreted products from pancreatic islet culture results in a higher yield of full-length peptide hormones than found using cell lysis procedures.

    Science.gov (United States)

    Taylor, Steven W; Nikoulina, Svetlana E; Andon, Nancy L; Lowe, Carolyn

    2013-08-02

    Peptide Hormone Acquisition through Smart Sampling Technique-Mass Spectrometry (PHASST-MS) is a peptidomics platform that employs high resolution liquid chromatography-mass spectrometry (LC-MS) techniques to identify peptide hormones secreted from in vitro or ex vivo cultures enriched in endocrine cells. Application of the methodology to the study of murine pancreatic islets has permitted evaluation of the strengths and weaknesses of the approach, as well as comparison of our results with published islet studies that employed traditional cellular lysis procedures. We found that, while our PHASST-MS approach identified fewer peptides in total, we had greater representation of intact peptide hormones. The technique was further refined to improve coverage of hydrophilic as well as hydrophobic peptides and subsequently applied to human pancreatic islet cultures derived from normal donors or donors with type 2 diabetes. Interestingly, in addition to the expected islet hormones, we identified alpha-cell-derived bioactive GLP-1, consistent with recent reports of paracrine effects of this hormone on beta-cell function. We also identified many novel peptides derived from neurohormonal precursors and proteins related to the cell secretory system. Taken together, these results suggest the PHASST-MS strategy of focusing on cellular secreted products rather than the total tissue peptidome may improve the probability of discovering novel bioactive peptides and also has the potential to offer important new insights into the secretion and function of known hormones.

  12. Ciliary neurotrophic factor (CNTF) signals through STAT3-SOCS3 pathway and protects rat pancreatic islets from cytokine-induced apoptosis.

    Science.gov (United States)

    Rezende, Luiz F; Vieira, André S; Negro, Alessandro; Langone, Francesco; Boschero, Antonio C

    2009-04-01

    CNTF is a cytokine that promotes survival and/or differentiation in many cell types, including rat pancreatic islets. In this work, we studied the mechanism of CNTF signal in neonatal rats pancreatic islets isolated by the collagenase method and cultured for 3 days in RPMI medium without (CTL) or with 1 nM of CNTF. The medium contained, when necessary, specific inhibitors of the PI3K, MAPK and JAK/STAT3 pathways. mRNA expression (RT-PCR) and protein phosphorylation (Western blot) of Akt, ERK1/2 and STAT3, and SOCS-3 (RT-PCR and Western blot), as well as glucose-stimulated insulin secretion (GSIS) (Radioimmunoassay), were analyzed. Our results showed that Akt, ERK1 and STAT3 mRNA expression, as well as phosphorylated Akt and ERK1/2, was not affected by CNTF treatment. CNTF increased cytoplasmatic and nuclear phosphorylated STAT3, and the SOCS3 mRNA and protein expression. In addition, CNTF lowered apoptosis and impaired GSIS. These effects were blocked by the JAK inhibitor, AG490 and by the STAT3 inhibitor Curcumin, but not by the MAPK inhibitor, PD98059, nor by the PI3K inhibitor, Wortmannin. In conclusion, CNTF signals through the JAK2/STAT3 cascade, increases SOCS3 expression, impairs GSIS and protects neonatal pancreatic rat islets from cytokine-induced apoptosis. These findings indicate that CNTF may be a potential therapeutic tool against Type 1 and/or Type 2 diabetes.

  13. Discovery of novel glucose-regulated proteins in isolated human pancreatic islets using LC-MS/MS-based proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Rutledge, Alexandra C.; Fontes, Ghislaine; Gritsenko, Marina A.; Norbeck, Angela D.; Anderson, David J.; Waters, Katrina M.; Adkins, Joshua N.; Smith, Richard D.; Poitout, Vincent; Metz, Thomas O.

    2012-07-06

    The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is due in part to insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent and physiologically important regulators of beta-cell function under physiological conditions, understanding the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins ({approx}p < 0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (Pleiotropic regulator 1), processing (Retinoblastoma binding protein 6), and function (Nuclear RNA export factor 1), in addition to Neuron navigator 1 and Plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and Synaptotagmin-17. Many proteins found to be differentially abundant after high glucose stimulation were uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles.

  14. Renin-angiotensin system blockers protect pancreatic islets against diet-induced obesity and insulin resistance in mice.

    Directory of Open Access Journals (Sweden)

    Eliete Dalla Corte Frantz

    Full Text Available BACKGROUND: The associations between obesity, hypertension and diabetes are well established, and the renin-angiotensin system (RAS may provide a link among them. The effect of RAS inhibition on type 2 diabetes is still unclear; however, RAS seems to play an important role in the regulation of the pancreas and glucose intolerance of mice fed high-fat (HF diet. METHODS: C57BL/6 mice fed a HF diet (8 weeks were treated with aliskiren (50 mg/kg/day, enalapril (30 mg/kg/day or losartan (10 mg/kg/day for 6 weeks, and the protective effects were extensively compared among groups by morphometry, stereological tools, immunostaining, Western blotting and hormonal analysis. RESULTS: All RAS inhibitors significantly attenuated the increased blood pressure in mice fed a HF diet. Treatment with enalapril, but not aliskiren or losartan, significantly attenuated body mass (BM gain, glucose intolerance and insulin resistance, improved the alpha and beta cell mass and prevented the reduction of plasma adiponectin. Furthermore, enalapril treatment improved the protein expression of the pancreatic islet Pdx1, GLUT2, ACE2 and Mas receptors. Losartan treatment showed the greatest AT2R expression. CONCLUSION: Our findings indicate that ACE inhibition with enalapril attenuated several of the deleterious effects of the HF diet. In summary, enalapril appears to be responsible for the normalization of islet morphology and function, of alpha and beta cell mass and of Pdx1 and GLUT2 expression. These protective effects of enalapril were attributed, primarily, to the reduction in body mass gain and food intake and the enhancement of the ACE2/Ang (1-7 /Mas receptor axis and adiponectin levels.

  15. Factors that Affect Pancreatic Islet Cell Autophagy in Adult Rats: Evaluation of a Calorie-Restricted Diet and a High-Fat Diet.

    Directory of Open Access Journals (Sweden)

    Qianqian Sun

    Full Text Available Aging may be a risk factor for type 2 diabetes in the elderly. Dietary intervention can affect glucose tolerance in adults, which may be due to body composition and islet cell autophagy. The aim of this study was to determine the effects of various dietary interventions on islet cell autophagy. Pancreatic tissue and blood samples were collected from Sprague Dawley rats (14-16 months old, n = 15 for each group that received a normal diet (ND, a high-fat diet (HFD, or a calorie-restricted diet (CRD. The body weight (BW, visceral fat, serum lipid levels, fasting serum glucose, insulin levels, and β/α cell area were determined in 14-16-(0-w, 16-18-(8-w, and 18-20(16-w-month-old rats. Pancreatic islet autophagy (LC3B and LAMP2, AP (Acid Phosphatase and apoptosis (apoptosis index, AI (TUNEL assay and cleaved caspase-3 were detected using immunohistochemistry, ELISA and western blot. At 16 weeks, the expressions of LC3B, LAMP2 and AP markedly increased in both the HFD (P<0.01 and CRD (P<0.05 groups; however, an increase in the AI (P<0.05, cleaved caspase-3 and Beclin1 expression and a decrease in the expressions of BCL2 and BCLXL (P<0.05 were observed in only the HFD group. FFA, triglyceride levels, HOMA-IR, insulin levels and glucagon levels were significantly increased in the HFD group but decreased in the CRD group at 16 weeks (P<0.05. The degree of islet cell autophagy was potentially regulated by the levels of FFA and islet cell insulin and glucagon, which may have been due to the effects of Beclin1/BCL2.

  16. Interaction of Glycolysis and Mitochondrial Respiration in Metabolic Oscillations of Pancreatic Islets

    DEFF Research Database (Denmark)

    Bertram, Richard; Satin, Leslie S.; Pedersen, Morten Gram

    2007-01-01

    Insulin secretion from pancreatic ß-cells is oscillatory, with a typical period of 2–7 min, reflecting oscillations in membrane potential and the cytosolic Ca2+ concentration. Our central hypothesis is that the slow 2–7 min oscillations are due to glycolytic oscillations, whereas faster oscillati...

  17. Histomorphological and morphometric studies of the pancreatic islet cells of diabetic rats treated with aqueous extracts of Momordica charantia (karela fruits

    Directory of Open Access Journals (Sweden)

    Mohammad Aftab Hossain

    2014-09-01

    Full Text Available Objective: To investigate the effect of aqueous extract of Momordica charantia (karela (M. charantia fruits on blood glucose level, pancreatic weight changes and histopathology of pancreatic changes in the streptozotocin (STZ induced diabetic rats. Methods: Thirty-six albino rats were used in the experiment; diabetes mellitus was induced in 30 adult albino rats, using intraperitoneal injection of 55 mg/kg STZ. Six non diabetic rats remained as control (T1 . The diabetic rats were randomly assigned into five equal groups: diabetic control (T2 without any treatment, groups T3, T4, T5 and T6 were treated with aqueous extract of karela fruits daily at a doses of 250, 500 and 750 mg/kg and glibenclamide (5 mg/kg up to 90 d, respectively. At Day 90, all rats were sacrificed, the pancreases of the rats were excised and processed. Results: The results of this study indicate that aqueous extract of M. charantia fruits was able to reduce blood glucose level significantly compared with the diabetic control group (P<0.01. Histopathologically, STZ resulted severe necrotic changes in pancreatic islets. Tissues sections of pancreas in the treated groups showed regeneration of β cells and increased size of pancreatic islets. Conclusions: The present study suggests that oral feeding of M. charantia fruit juice has a significant anti-hyperglycemic effect and may have a role in the regeneration of the β cells in STZ diabetic rats.

  18. Growth hormone and prolactin stimulate the expression of rat preadipocyte factor-1/delta-like protein in pancreatic islets

    DEFF Research Database (Denmark)

    Carlsson, C; Tornehave, D; Lindberg, Karen

    1997-01-01

    GH and PRL have been shown to stimulate proliferation and insulin production in islets of Langerhans. To identify genes regulated by GH/PRL in islets, we performed differential screening of a complementary DNA library from neonatal rat islets cultured for 24 h with human GH (hGH). One hGH-induced...

  19. Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors.

    Directory of Open Access Journals (Sweden)

    Paola Llanos

    Full Text Available Glucose-stimulated insulin secretion (GSIS from pancreatic β-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]. Glucose uptake into β-cells promotes Ca2+ influx and reactive oxygen species (ROS generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR channels. Therefore, we explored here if RyR-mediated Ca2+ release contributes to GSIS in β-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated β-cells. Conventional PCR assays and immunostaining confirmed that β-cells express RyR2, the cardiac RyR isoform. Extended incubation of β-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC, which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated β-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose to β-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS.

  20. Pancreatic islet function in omega-3 fatty acid-depleted rats: alteration of calcium fluxes and calcium-dependent insulin release.

    Science.gov (United States)

    Zhang, Y; Oguzhan, B; Louchami, K; Chardigny, J-M; Portois, L; Carpentier, Y A; Malaisse, W J; Herchuelz, A; Sener, A

    2006-09-01

    Considering the insufficient supply of long-chain polyunsaturated omega-3 fatty acids often prevailing in Western populations, this report deals mainly with alterations of Ca(2+) fluxes and Ca(2+)-dependent insulin secretory events in isolated pancreatic islets from omega-3-depleted rats. In terms of (45)Ca(2+) handling, the islets from omega-3-depleted rats, compared with those from normal animals, displayed an unaltered responsiveness to an increase in extracellular K(+) concentration, a lower inflow rate and lower fractional outflow rate of the divalent cation, and higher (45)Ca(2+)-labeled cellular pool(s) at isotopic equilibrium. The latter anomaly was corrected 120 min after intravenous injection of a novel medium-chain triglyceride-fish oil (MCT:FO) emulsion, distinct from a control omega-3-poor MCT-olive oil (MCT:OO) emulsion. At 8.3 mM D-glucose, insulin release was higher in islets from omega-3-depleted rats vs. control animals, coinciding with a higher cytosolic Ca(2+) concentration. The relative magnitude of the increase in insulin output attributable to a rise in D-glucose as well as extracellular Ca(2+) or K(+) concentration, to the absence vs. presence of verapamil and to the presence vs. absence of extracellular Ca(2+), theophylline, phorbol 12-myristate 13-acetate, or Ba(2+), was always more pronounced in islets from omega-3-depleted rats injected with the MCT:OO compared with the MCT:FO emulsion. A comparable situation prevailed when comparing islets from noninjected omega-3-depleted and normal rats. In light of these and previous findings, we propose that an impairment of Na(+),K(+)-ATPase activity plays a major, although not an exclusive, role in the perturbation of Ca(2+) fluxes and Ca(2+)-dependent secretory events in the islets from omega-3-depleted rats.

  1. Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets.

    Science.gov (United States)

    Hall, Elin; Volkov, Petr; Dayeh, Tasnim; Esguerra, Jonathan Lou S; Salö, Sofia; Eliasson, Lena; Rönn, Tina; Bacos, Karl; Ling, Charlotte

    2014-12-03

    Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion. Glucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes. Chromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.

  2. 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.

  3. The effect of glucose stimulation on 45calcium uptake of rat pancreatic islets and their total calcium content as measured by a fluorometric micro-method

    International Nuclear Information System (INIS)

    Wolters, G.H.J.; Wiegman, J.B.; Konijnendijk, W.

    1982-01-01

    Glucose-stimulated 45 calcium uptake and total calcium content of rat pancreatic islets has been studied, using a new fluorometric micro-method to estimate total calcium. Extracellular calcium was separated from incubated tissue by a rapid micro-filtration procedure. Islets incubated up to 60 min with calcium chloride 2.5 mmol/l and glucose 2.5 mmol/l maintained the same calcium content (670 +- 7.5 pmol/μg DNA). When the glucose concentration was raised to 15 mmol/l no change in the total calcium content could be detected. On incubation with glucose 2.5 mmol/l in the absence of calcium, the calcium content decreased to 488 +- 27 pmol/μg DNA. On incubation with 45 calcium chloride 2.5 mmol/l for 5 or 30 min at 2.5 mmol/l glucose, islets exchanged 21 +- 2 and 28 +- 1% of their total calcium content and, at 15 mmol/l glucose, 30 +- 3 and 45 +- 2%, respectively. Thus, islet calcium has a high turn-over rate. Glucose stimulation results in an increase of the calcium uptake without enhancing the total calcium content and hence must increase the calcium-exchangeable pool. (orig.)

  4. Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway

    DEFF Research Database (Denmark)

    Thams, Peter; Anwar, Mohammad R; Capito, Kirsten

    2005-01-01

    OBJECTIVE: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K(+) (K(+)(ATP)) channel-dependent insulin secretion and in glucose amplification of K(+)(ATP) channel-independent insulin secretion. METHODS: Insulin release from cultured perifused mouse...... pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion...... glucose amplification of K(+)(ATP) channel-independent insulin secretion. In the presence of 1 mmol/l ouabain and 250 micromol/l diazoxide, which cause modest Ca(2+) influx, glucose amplification of K(+)(ATP) channel-independent insulin secretion was observed without concomitant Ca(2+) stimulation of PKA...

  5. Unique splicing pattern of the TCF7L2 gene in human pancreatic islets

    DEFF Research Database (Denmark)

    Osmark, P; Hansson, O; Jonsson, Anna Elisabet

    2009-01-01

    Intronic variation in the TCF7L2 gene exhibits the strongest association to type 2 diabetes observed to date, but the mechanism whereby this genetic variation translates into altered biological function is largely unknown. A possible explanation is a genotype-dependent difference in the complex s...... splicing pattern; however, this has not previously been characterised in pancreatic or insulin target tissues. Here, the detailed TCF7L2 splicing pattern in five human tissues is described and dependence on risk genotype explored....

  6. Vitamin D3 supplementation increases insulin level by regulating altered IP3 and AMPA receptor expression in the pancreatic islets of streptozotocin-induced diabetic rat.

    Science.gov (United States)

    Jayanarayanan, Sadanandan; Anju, Thoppil R; Smijin, Soman; Paulose, Cheramadathikudiyil Skaria

    2015-10-01

    Pancreatic islets, particularly insulin-secreting β cells, share common characteristics with neurons. Glutamate is one of the major excitatory neurotransmitter in the brain and pancreas, and its action is mediated through glutamate receptors. In the present work, we analysed the role of vitamin D3 in the modulation of AMPA receptor subunit and their functional role in insulin release. Radio receptor binding study in diabetic rats showed a significant increase in AMPA receptor density. Insulin AMPA colabelling study showed an altered AMPA GluR2 and GluR4 subunit expression in the pancreatic beta cells. We also found lowered IP3 content and decreased IP3 receptor in pancreas of diabetic rats. The alterations in AMPA and IP3 receptor resulted in reduced cytosolic calcium level concentration, which further blocks Ca(2+)-mediated insulin release. Vitamin D3 supplementation restored the alteration in vitamin D receptor expression, AMPA receptor density and AMPA and IP3 receptor expression in the pancreatic islets that helps to restore the calcium-mediated insulin secretion. Our study reveals the antidiabetic property of vitamin D3 that is suggested to have therapeutic role through regulating glutamatergic function in diabetic rats. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Reversal of high pancreatic islet and white adipose tissue blood flow in type 2 diabetic GK rats by administration of the beta3-adrenoceptor inhibitor SR-59230A.

    Science.gov (United States)

    Pettersson, U S; Henriksnäs, J; Jansson, L

    2009-08-01

    Previous studies have shown that the Goto-Kakizaki (GK) rat, a nonobese type 2 diabetes model, has an increased white adipose tissue (WAT) and islet blood flow when compared with control rats. The aim of the study was to examine if these increased blood flow values in GK rats could be affected by the beta(3)-adrenoceptor antagonist SR-59230A. We measured organ blood flow with a microsphere technique 10 min after administration of SR-59230A (1 mg/kg body wt), or the corresponding volume of 0.9% NaCl solution (1 ml/kg body wt) in rats anaesthetized with thiobutabarbital. The GK rat had an increased blood flow in all intra-abdominal adipose tissue depots except for the sternal fat pad compared with Wistar-Furth (WF) rats. However, no differences were seen in the blood perfusion of subcutaneous white or brown adipose tissue. The blood flow was also increased in both the pancreas and in the islets in the GK rat compared with WF rats. SR-59230A treatment affected neither WAT nor pancreatic blood flow in WF rats. In GK rats, on the other hand, SR-59230A decreased both WAT and islet blood flow values to values similar to those seen in control WF rats. The whole pancreatic blood flow was not affected by SR-59230A administration in GK rats. Interestingly, the brown adipose tissue blood flow in GK rats increased after SR-59230A administration. These results suggest that beta(3)-adrenoceptors are involved in regulation of blood flow both in islet and in adipose tissue.

  8. Tropism Analysis of Two Coxsackie B5 Strains Reveals Virus Growth in Human Primary Pancreatic Islets but not in Exocrine Cell Clusters In Vitro.

    Science.gov (United States)

    Hodik, M; Lukinius, A; Korsgren, O; Frisk, G

    2013-01-01

    Human Enteroviruses (HEVs) have been implicated in human pancreatic diseases such as pancreatitis and type 1 diabetes (T1D). Human studies are sparse or inconclusive and our aim was to investigate the tropism of two strains of Coxsackie B virus 5 (CBV-5) in vitro to primary human pancreatic cells. Virus replication was measured with TCID50 titrations of aliquots of the culture medium at different time points post inoculation. The presence of virus particles or virus proteins within the pancreatic cells was studied with immunohistochemistry (IHC) and electron microscopy (EM). None of the strains replicated in the human exocrine cell clusters, in contrast, both strains replicated in the endocrine islets of Langerhans. Virus particles were found exclusively in the endocrine cells, often in close association with insulin granules. In conclusion, CBV-5 can replicate in human endocrine cells but not in human exocrine cells, thus they might not be the cause of pancreatitis in humans. The association of virus with insulin granules might reflect the use of these as replication scaffolds.

  9. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets

    DEFF Research Database (Denmark)

    Adriaenssens, Alice E; Svendsen, Berit; Lam, Brian Y H

    2016-01-01

    expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused...... pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism. CONCLUSIONS/INTERPRETATION: Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate...

  10. Siglec-7 restores β-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes

    NARCIS (Netherlands)

    Dharmadhikari, Gitanjali; Stolz, Katharina; Hauke, Michael; Morgan, Noel G; Varki, Ajit; de Koning, Eelco; Kelm, Sørge; Maedler, Kathrin

    2017-01-01

    Chronic inflammation plays a key role in both type 1 and type 2 diabetes. Cytokine and chemokine production within the islets in a diabetic milieu results in β-cell failure and diabetes progression. Identification of targets, which both prevent macrophage activation and infiltration into islets and

  11. Stimulatory effect of serum from diabetic patients on insulin release from mouse pancreatic islets maintained in tissue culture

    DEFF Research Database (Denmark)

    Eff, C; Deckert, T; Andersson, A

    1981-01-01

    Islets of Langerhans from NMRI-mice were kept for one week in tissue culture in medium supplemented with human serum obtained from either normal healthy subjects or newly diagnosed juvenile diabetic patients before insulin treatment. Islets cultured in diabetic serum released more insulin than...... islets cultured in normal serum, whether tissue culture medium 199 with 5.5-8.3 mmol/l glucose and 10% serum, or culture medium RPMI 1640 with 11 mmol/l glucose and 0.5% serum were used. Islets kept for one week in culture with diabetic serum did not show any decrease in DNA content or glucose induced...... insulin secretion and biosynthesis. It is concluded that serum from newly diagnosed insulin-dependent diabetic patients stimulates insulin release from isolated mouse islets kept in tissue culture. The underlying mechanism is unknown....

  12. Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Anders H Olsson

    2014-11-01

    Full Text Available Genetic and epigenetic mechanisms may interact and together affect biological processes and disease development. However, most previous studies have investigated genetic and epigenetic mechanisms independently, and studies examining their interactions throughout the human genome are lacking. To identify genetic loci that interact with the epigenome, we performed the first genome-wide DNA methylation quantitative trait locus (mQTL analysis in human pancreatic islets. We related 574,553 single nucleotide polymorphisms (SNPs with genome-wide DNA methylation data of 468,787 CpG sites targeting 99% of RefSeq genes in islets from 89 donors. We identified 67,438 SNP-CpG pairs in cis, corresponding to 36,783 SNPs (6.4% of tested SNPs and 11,735 CpG sites (2.5% of tested CpGs, and 2,562 significant SNP-CpG pairs in trans, corresponding to 1,465 SNPs (0.3% of tested SNPs and 383 CpG sites (0.08% of tested CpGs, showing significant associations after correction for multiple testing. These include reported diabetes loci, e.g. ADCY5, KCNJ11, HLA-DQA1, INS, PDX1 and GRB10. CpGs of significant cis-mQTLs were overrepresented in the gene body and outside of CpG islands. Follow-up analyses further identified mQTLs associated with gene expression and insulin secretion in human islets. Causal inference test (CIT identified SNP-CpG pairs where DNA methylation in human islets is the potential mediator of the genetic association with gene expression or insulin secretion. Functional analyses further demonstrated that identified candidate genes (GPX7, GSTT1 and SNX19 directly affect key biological processes such as proliferation and apoptosis in pancreatic β-cells. Finally, we found direct correlations between DNA methylation of 22,773 (4.9% CpGs with mRNA expression of 4,876 genes, where 90% of the correlations were negative when CpGs were located in the region surrounding transcription start site. Our study demonstrates for the first time how genome-wide genetic and

  13. Inflammatory Response in Islet Transplantation

    Directory of Open Access Journals (Sweden)

    Mazhar A. Kanak

    2014-01-01

    Full Text Available Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.

  14. Growth hormone and prolactin stimulate the expression of rat preadipocyte factor-1/delta-like protein in pancreatic islets

    DEFF Research Database (Denmark)

    Carlsson, C; Tornehave, D; Lindberg, Karen

    1997-01-01

    GH and PRL have been shown to stimulate proliferation and insulin production in islets of Langerhans. To identify genes regulated by GH/PRL in islets, we performed differential screening of a complementary DNA library from neonatal rat islets cultured for 24 h with human GH (hGH). One hGH-induced......GH and PRL have been shown to stimulate proliferation and insulin production in islets of Langerhans. To identify genes regulated by GH/PRL in islets, we performed differential screening of a complementary DNA library from neonatal rat islets cultured for 24 h with human GH (hGH). One h......RNA was up-regulated 3- to 4-fold in neonatal rat islets of Langerhans after 48-h culture with hGH, as found also with bovine GH or ovine PRL. During the development of pancreas from embryonic day 12 (E12) to postnatal day 4, we observed a 2-fold increase in Pref-1 mRNA on E17 and a 5-fold increase at birth...

  15. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    Energy Technology Data Exchange (ETDEWEB)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-03-15

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ({sup 14}C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). {sup 14}C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA {sup 14}C content relative to a well-established {sup 14}C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA {sup 14}C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  16. Characterization of pancreatic islet cell tumors and renal tumors induced by a combined treatment of streptozotocin and nicotinamide in male SD rats.

    Science.gov (United States)

    Kato, Yuki; Masuno, Koichi; Fujisawa, Kae; Tsuchiya, Noriko; Torii, Mikinori; Hishikawa, Atsuko; Izawa, Takeshi; Kuwamura, Mitsuru; Yamate, Jyoji

    2017-09-05

    We herein investigated the histopathological features, including proliferative activity and immunoexpression, of pancreatic islet cell tumors (ICTs) in male SD rats induced by streptozotocin (STZ) and nicotinamide (NA), and discussed their relevance to biological behaviors and prognoses. A total of 70 and 43% of rats developed ICTs 37-45 weeks after the treatment with STZ (50 or 75mg/kg, i.v.) and NA (350mg/kg, twice, p.o.), respectively. Among the islet tumors observed in the STZ/NA-treated groups, 75% were adenomas, while 25% were carcinomas. Most STZ/NA-induced carcinomas were characterized by well-differentiated tumor cells with/without local invasion into the surrounding tissues, and weak proliferative activity. No outcome such as distance metastasis and death was noted. All of the ICTs strongly expressed insulin, part of which had hormone productivity; however there were no hypoglycemia-related clinical signs such as convulsion in these rats 36 weeks after the treatment. These results suggested that rat ICTs induced STZ/NA have small impact on biological activity or prognosis. STZ/NA treatment significantly increased of focal proliferative lesions in the kidney, liver and adrenal glands other than pancreatic islets. Of the STZ/NA-induced kidney tumors, more than 60% were renal cell adenomas, and many of them were basophilic type. The incidence of eosinophilic or clear cell type of tumors was less than 10%, respectively. Immunohistochemical analyses revealed that many of the STZ/NA-induced basophilic type of renal tumors were derived from proximal tubules, whereas the clear cell and eosinophilic types were derived from collecting tubules. Copyright © 2017 Elsevier GmbH. All rights reserved.

  17. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    International Nuclear Information System (INIS)

    Perl, S.; Kushner, J.A.; Buchholz, B.A.; Meeker, A.K.; Stein, G.M.; Hsieh, M.; Kirby, M.; Pechhold, S.; Liu, E.H.; Harlan, D.M.; Tisdale, J.F.

    2010-01-01

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ( 14 C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). 14 C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA 14 C content relative to a well-established 14 C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA 14 C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  18. VEGF-conjugated alginate hydrogel prompt angiogenesis and improve pancreatic islet engraftment and function in type 1 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Yin, Nina; Han, Yongming [Department of Anatomy, Basic Medical College, Hubei University of Chinese Medicine, Wuhan, Hubei (China); Xu, Hanlin [Pharmacy Faculty, Hubei University of Chinese Medicine, Wuhan, Hubei (China); Gao, Yisen; Yi, Tao [Acupuncture and Moxibustion College, Hubei University of Chinese Medicine, Wuhan, Hubei (China); Yao, Jiale; Dong, Li; Cheng, Dejun [Basic Medical College, Hubei University of Chinese Medicine, Wuhan, Hubei (China); Chen, Zebin, E-mail: chenzebin-hbtcm@outlook.com [Acupuncture and Moxibustion College, Hubei University of Chinese Medicine/Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion, Wuhan, Hubei (China)

    2016-02-01

    Type 1 diabetes was a life-long disease that affected numerous people around the world. Insulin therapy has its limitations that may involve hyperglycemia and heavy burden of patient by repeated dose. Islet transplantation emerged as a promising approach to reach periodical reverse of diabetes, however, transplanted islets suffer from foreign body reaction and lack of nutrition and oxygen supply, especially in the blood-vessel-shortage subcutaneous site which was preferred by patient and surgeon. In this study, we designed and synthesized a vascular endothelial growth factor (VEGF) conjugated alginate material to encapsulate the transplanted islets via 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction, and successful conjugation was confirmed by Nuclear Magnetic Resonance H1 spectrum. The best VEGF concentration (100 ng/ml) was determined by the combined studies of the mechanical property and endothelial cell growth assay. In vivo study, conjugated VEGF on alginate exhibited sustained promoting angiogenesis property after subcutaneous transplantation by histology study and islets encapsulated in this material achieved long term therapeutic effect (up to 50 days) in the diabetic mice model. In conclusion, this study establishes a simple biomaterial strategy for islet transplantation to enhance islet survival and function, which could be a feasible therapeutic alternative for type 1 diabetes. - Highlights: • We synthesized VEGF-conjugated alginate material to encapsulate the transplanted islets. • The biomaterials improve islet engraftment and function due to angiogenesis. • The biomaterials could be a strong support for cell therapy with islet transplantation in type 1 diabetes.

  19. VEGF-conjugated alginate hydrogel prompt angiogenesis and improve pancreatic islet engraftment and function in type 1 diabetes

    International Nuclear Information System (INIS)

    Yin, Nina; Han, Yongming; Xu, Hanlin; Gao, Yisen; Yi, Tao; Yao, Jiale; Dong, Li; Cheng, Dejun; Chen, Zebin

    2016-01-01

    Type 1 diabetes was a life-long disease that affected numerous people around the world. Insulin therapy has its limitations that may involve hyperglycemia and heavy burden of patient by repeated dose. Islet transplantation emerged as a promising approach to reach periodical reverse of diabetes, however, transplanted islets suffer from foreign body reaction and lack of nutrition and oxygen supply, especially in the blood-vessel-shortage subcutaneous site which was preferred by patient and surgeon. In this study, we designed and synthesized a vascular endothelial growth factor (VEGF) conjugated alginate material to encapsulate the transplanted islets via 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction, and successful conjugation was confirmed by Nuclear Magnetic Resonance H1 spectrum. The best VEGF concentration (100 ng/ml) was determined by the combined studies of the mechanical property and endothelial cell growth assay. In vivo study, conjugated VEGF on alginate exhibited sustained promoting angiogenesis property after subcutaneous transplantation by histology study and islets encapsulated in this material achieved long term therapeutic effect (up to 50 days) in the diabetic mice model. In conclusion, this study establishes a simple biomaterial strategy for islet transplantation to enhance islet survival and function, which could be a feasible therapeutic alternative for type 1 diabetes. - Highlights: • We synthesized VEGF-conjugated alginate material to encapsulate the transplanted islets. • The biomaterials improve islet engraftment and function due to angiogenesis. • The biomaterials could be a strong support for cell therapy with islet transplantation in type 1 diabetes.

  20. A possible role of transglutaminase 2 in the nucleus of INS-1E and of cells of human pancreatic islets.

    Science.gov (United States)

    Sileno, Sara; D'Oria, Valentina; Stucchi, Riccardo; Alessio, Massimo; Petrini, Stefania; Bonetto, Valentina; Maechler, Pierre; Bertuzzi, Federico; Grasso, Valeria; Paolella, Katia; Barbetti, Fabrizio; Massa, Ornella

    2014-01-16

    Transglutaminase 2 (TG2) is a multifunctional protein with Ca(2+)-dependent transamidating and G protein activity. Previously we reported that the role of TG2 in insulin secretion may involve cytoplasmic actin remodeling and a regulative action on other proteins during granule movement. The aim of this study was to gain a better insight into the role of TG2 transamidating activity in mitochondria and in the nucleus of INS-1E rat insulinoma cell line (INS-1E) during insulin secretion. To this end we labeled INS-1E with an artificial donor (biotinylated peptide), in basal condition and after stimulus with glucose for 2, 5, and 8min. Biotinylated proteins of the nuclear/mitochondrial-enriched fraction were analyzed using two-dimensional electrophoresis and mass spectrometry. Many mitochondrial proteins involved in Ca(2+) homeostasis (e.g. voltage-dependent anion-selective channel protein, prohibitin and different ATP synthase subunits) and many nuclear proteins involved in gene regulation (e.g. histone H3, barrier to autointegration factor and various heterogeneous nuclear ribonucleoprotein) were identified among a number of transamidating substrates of TG2 in INS-1E. The combined results provide evidence that a temporal link exists between glucose-stimulation, first phase insulin secretion and the action of TG on histone H3 both in INS-1E and human pancreatic islets. Research into the role of transglutaminase 2 during insulin secretion in INS-1E rat insulinoma cellular model is depicting a complex role for this enzyme. Transglutaminase 2 acts in the different INS-1E compartments in the same way: catalyzing a post-translational modification event of its substrates. In this work we identify some mitochondrial and nuclear substrates of INS-1E during first phase insulin secretion. The finding that TG2 interacts with nuclear proteins that include BAF and histone H3 immediately after (2-5min) glucose stimulus of INS-1E suggests that TG2 may be involved not only in insulin

  1. Pancreatic Islet Transplantation

    Science.gov (United States)

    ... in Edmonton, Canada, reported their findings in the New England Journal of Medicine . Their transplant protocol, known as the Edmonton protocol, has since been adapted by transplant centers around the world and continues ... new combination of immunosuppressive medications, also called anti-rejection ...

  2. Pancreatic islet cell tumor

    Science.gov (United States)

    ... Feeling tired or weak Shaking or sweating Headache Hunger Nervousness, anxiety, or feeling irritable Unclear thinking or ... must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer Support Get ...

  3. AMOUNT AND DISTRIBUTION OF COLLAGEN IN PANCREATIC TISSUE OF DIFFERENT SPECIES IN THE PERSPECTIVE OF ISLET ISOLATION PROCEDURES

    NARCIS (Netherlands)

    VANSUYLICHEM, PTR; VANDEIJNEN, JEHM; WOLTERS, GHJ; VANSCHILFGAARDE, R

    1995-01-01

    Because collagen is the major target in the enzymatic dissociation of the pancreas for islet isolation, we determined the amount of collagen and its distribution in a comparative study comprising normal pancreata of rat, dog, man, young pig, and adult pig. Collagen content was determined using a

  4. Cooperation by Fibroblasts and Bone Marrow-Mesenchymal Stem Cells to Improve Pancreatic Rat-to-Mouse Islet Xenotransplantation

    Science.gov (United States)

    Meana, Alvaro; Otero, Jesus; Esteban, Manuel M.

    2013-01-01

    Experimental and clinical experiences highlight the need to review some aspects of islet transplantation, especially with regard to site of grafting and control of the immune response. The subcutaneous space could be a good alternative to liver but its sparse vasculature is its main limitation. Induction of graft tolerance by using cells with immunoregulatory properties is a promising approach to avoid graft rejection. Both Fibroblasts and Mesenchymal Stem Cells (MSCs) have shown pro-angiogenic and immunomodulatory properties. Transplantation of islets into the subcutaneous space using plasma as scaffold and supplemented with fibroblasts and/or Bone Marrow-MSCs could be a promising strategy to achieve a functional extra-hepatic islet graft, without using immunosuppressive drugs. Xenogenic rat islets, autologous fibroblasts and/or allogenic BM-MSCs, were mixed with plasma, and coagulation was induced to constitute a Plasma-based Scaffold containing Islets (PSI), which was transplanted subcutaneously both in immunodeficient and immunocompetent diabetic mice. In immunodeficient diabetic mice, PSI itself allowed hyperglycemia reversion temporarily, but the presence of pro-angiogenic cells (fibroblasts or BM-MSCs) within PSI was necessary to improve graft re-vascularization and, thus, consistently maintain normoglycemia. In immunocompetent diabetic mice, only PSI containing BM-MSCs, but not those containing fibroblasts, normalized glycemia lasting up to one week after transplantation. Interestingly, when PSI contained both fibroblasts and BM-MSCs, the normoglycemia period showed an increase of 4-times with a physiological-like response in functional tests. Histology of immunocompetent mice showed an attenuation of the immune response in those grafts with BM-MSCs, which was improved by co-transplantation with fibroblasts, since they increased BM-MSC survival. In summary, fibroblasts and BM-MSCs showed similar pro-angiogenic properties in this model of islet

  5. Adoptive infusion of tolerogenic dendritic cells prolongs the survival of pancreatic islet allografts: a systematic review of 13 mouse and rat studies.

    Directory of Open Access Journals (Sweden)

    Guixiang Sun

    Full Text Available OBJECTIVE: The first Phase I study of autologous tolerogenic dendritic cells (Tol-DCs in Type 1 diabetes (T1D patients was recently completed. Pancreatic islet transplantation is an effective therapy for T1D, and infusion of Tol-DCs can control diabetes development while promoting graft survival. In this study, we aim to systematically review islet allograft survival following infusion of Tol-DCs induced by different methods, to better understand the mechanisms that mediate this process. METHODS: We searched PubMed and Embase (from inception to February 29(th, 2012 for relevant publications. Data were extracted and quality was assessed by two independent reviewers. We semiquantitatively analyzed the effects of Tol-DCs on islet allograft survival using mixed leukocyte reaction, Th1/Th2 differentiation, Treg induction, and cytotoxic T lymphocyte activity as mechanisms related-outcomes. We discussed the results with respect to possible mechanisms that promote survival. RESULTS: Thirteen articles were included. The effects of Tol-DCs induced by five methods on allograft survival were different. Survival by each method was prolonged as follows: allopeptide-pulsed Tol-DCs (42.14 ± 44 days, drug intervention (39 days, mesenchymal stem cell induction (23 days, genetic modification (8.99 ± 4.75 days, and other derivation (2.61 ± 6.98 days. The results indicate that Tol-DC dose and injection influenced graft survival. Single-dose injections of 10(4 Tol-DCs were the most effective for allograft survival, and multiple injections were not superior. Tol-DCs were also synergistic with immunosuppressive drugs or costimulation inhibitors. Possible mechanisms include donor specific T cell hyporesponsiveness, Th2 differentiation, Treg induction, cytotoxicity against allograft reduction, and chimerism induction. CONCLUSIONS: Tol-DCs induced by five methods prolong MHC mismatched islet allograft survival to different degrees, but allopeptide-pulsed host DCs

  6. Possible links between glucose-induced changes in the energy state of pancreatic B cells and insulin release. Unmasking by decreasing a stable pool of adenine nucleotides in mouse islets.

    OpenAIRE

    Detimary, P; Jonas, J C; Henquin, J C

    1995-01-01

    Whether adenine nucleotides in pancreatic B cells serve as second messengers during glucose stimulation of insulin secretion remains disputed. Our hypothesis was that the actual changes in ATP and ADP are obscured by the large pool of adenine nucleotides (ATP/ADP ratio close to 1) in insulin granules. Therefore, mouse islets were degranulated acutely with a cocktail of glucose, KCl, forskolin, and phorbol ester or during overnight culture in RPMI-1640 medium containing 10 mM glucose. When the...

  7. Polyphenol-rich extract of Syzygium cumini leaf dually improves peripheral insulin sensitivity and pancreatic islet function in monosodium L-glutamate-induced obese rats

    Directory of Open Access Journals (Sweden)

    Jonas Rodrigues Sanches

    2016-03-01

    Full Text Available Syzygium cumini (L. Skeels (Myrtaceae has been traditionally used to treat a number of illnesses. Ethnopharmacological studies have particularly addressed antidiabetic and metabolic-related effects of extracts prepared from its different parts, especially seed and pulp-fruit, however there is a lack of studies on phytochemical profile and biological properties of its leaf. As there is considerable interest in bioactive compounds to treat metabolic syndrome and its clustered risk factors, we sought to characterize the metabolic effects of hydroethanolic extract of S. cumini leaf (HESc on lean and monosodium L-glutamate (MSG-induced obese rats. HPLC-MS/MS characterization of the HESc polyphenolic profile, at 254 nm, identified 15 compounds pertaining to hydrolysable tannin and flavanol subclasses. At 60 days of age, both groups were randomly assigned to receive HESc (500 mg/kg or vehicle for 30 days. At the end of treatment, obese+HESc exhibited significantly lower body weight gain, body mass index, and white adipose tissue mass, compared to obese rats receiving vehicle. Obese rats treated with HESc showed a 2-fold increase in lipolytic activity in the periepididymal fat pad, as well as, brought triglyceride levels in serum, liver and skeletal muscle back to levels close those found in lean animals. Furthermore, HESc also improved hyperinsulinemia and insulin resistance in obese+HESc rats, which resulted in partial reversal of glucose intolerance, as compared to obese rats. HESc had no effect in lean rats. Assessment of ex vivo glucose-stimulated insulin secretion showed HESc potentiated pancreatic function in islets isolated from both lean and obese rats treated with HESc. In addition, HESc (10 – 1000 ug/mL increased glucose stimulated insulin secretion from both isolated rat islets and INS-1E beta cells. These data demonstrate that S. cumini leaf improved peripheral insulin sensitivity via stimulating/modulating beta cell insulin release

  8. TRANSPLANTE DE ILHOTAS PANCREÁTICAS EM DISPOSITIVOS DE IMUNOISOLAMENTO CELULAR: RESULTADOS INICIAIS PANCREATIC ISLET TRANSPLANTATION IN CAPSULES OF CELLULAR IMMUNOISOLATION: PRELIMINARY RESULTS

    Directory of Open Access Journals (Sweden)

    E. D. Mente

    2001-01-01

    Full Text Available O transplante de pâncreas e de ilhotas pancreáticas vem apresentando grande desenvolvimento nos últimos anos. O isolamento das ilhotas em cápsulas com membrana semi-permeáveis pode ser tratamento de escolha para o diabetes, pois dispensa o uso de imunossupressores. O material ideal para a confecção de uma cápsula para o isolamento celular ainda permanece um sonho. Um novo material a base de látex natural foi implantado no subcutâneo de ratos normais e diabéticos para estudar a biocompatibilidade e a neoformação vascular. A análise após 21 dias de implante mostrou intensa formação capilar na interface membrana-tecido e pouco tecido fibrótico. Estes achados iniciais mostram que o material pode ter algum potencial para a confecção de dispositivos de isolamento celular.There have been great developments in pancreas and pancreatic islet cell transplantion in the last few years. The isolation of the islet cells in capsules with semi-permeable membranes may become ideal means of treating diabetes, and the use of immunossuppression could be avoided. The ideal material for the confection of the capsules has remained a dream. A new material derived from natural latex was implanted in the subcutaneous tissue of normal and diabetic rats to study the biocompatibility and the vascular neoformation. After 21 days, an analysis of the implant showed intense vascular neoformation on the membrane-tissue interface and little fibrotic tissue. The inicial results show great promise for utilization of this material in capsules for the isolation of cells.

  9. Effects of Acute Cytomegalovirus Infection on Rat Islet Allograft Survival

    NARCIS (Netherlands)

    Smelt, M. J.; Faas, M. M.; Melgert, B. N.; de Vos, P.; de Haan, Bart; de Haan, Aalzen

    2011-01-01

    Transplantation of pancreatic islets is a promising therapy for the treatment of type 1 diabetes mellitus. However, long-term islet graft survival rates are still unsatisfactory low. In this study we investigated the role of cytomegalovirus (CMV) in islet allograft failure. STZ-diabetic rats

  10. Factors influencing insulin secretion from encapsulated islets

    NARCIS (Netherlands)

    de Haan, BJ; Faas, MM; de Vos, P

    2003-01-01

    Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The

  11. Prevalence and features of pancreatic islet cell autoimmunity in women with gestational diabetes from different ethnic groups.

    Science.gov (United States)

    Kousta, E; Lawrence, N J; Anyaoku, V; Johnston, D G; McCarthy, M I

    2001-07-01

    To assess the prevalence and characteristics of islet cell autoimmunity amongst women with gestational diabetes selected from South Asian and Afro-Caribbean as well as European populations. Cross-sectional retrospective survey of subject cohort. Three hundred and twenty-one women with a recent history of gestational diabetes (173 European, 86 South Asian and 62 Afro-Caribbean), a median (range) of 22 (1-150) months postpartum. Antibodies to Glutamic acid decarboxylase were found in 13 (4%) of these women. There was no difference in the prevalence of anti-glutamic acid decarboxylase positivity between the three ethnic groups (European 4.6%, South Asian 3.5%, Afro-Caribbean 3.2%). Anti-glutamic acid decarboxylase positive women were leaner than anti-glutamic acid decarboxylase negative women (body mass index, median (upper-lower quartile) 23.9 (22.5-26.7) vs 26.6 (23.4-30.5)kg/m2, P = 0.03, P = 0.049 allowing for ethnicity). There was no difference between glutamic acid decarboxylase-positive and glutamic acid decarboxylase-negative women for age, family history of diabetes, waist/hip ratio, prevalence of insulin treatment during pregnancy, postpartum glucose status, lipid profile and indices of insulin action and beta-cell function. Markers of islet cell autoimmunity are found as frequently in gestational diabetes women of South Asian and Afro-Caribbean origin, as they are in European subjects. Identification of future risk of type 1 diabetes is relevant to the planning of clinical management and intervention strategies in women with gestational diabetes of all major ethnic groups.

  12. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  13. Pancreatitis

    Science.gov (United States)

    ... causes. Treatment Treatment for pancreatitis may include a hospital stay for intravenous (IV) fluids, pain medicine, and other medicines. Surgery is sometimes needed to treat complications. Eating, Diet, & Nutrition If you have pancreatitis, your health care ...

  14. Massive parallel gene expression profiling of RINm5F pancreatic islet beta-cells stimulated with interleukin-1beta

    DEFF Research Database (Denmark)

    Rieneck, K; Bovin, L F; Josefsen, K

    2000-01-01

    Interleukin 1 (IL-1) is a pleiotropic cytokine with the potential to kill pancreatic beta-cells, and this unique property is thought to be involved in the pathogenesis of type I diabetes mellitus. We therefore determined the quantitative expression of 24,000 mRNAs of RINm5F, an insulinoma cell li......, e.g. alpha-endosulfine and K+ channel Kir6.2 are differentially regulated. A number of transcripts in the biosynthesis pathway for cholesterol are also differentially regulated....

  15. Adding efficiency: the role of the CAN ion channels TRPM4 and TRPM5 in pancreatic islets.

    Science.gov (United States)

    Enklaar, Thorsten; Brixel, Lili R; Zabel, Bernhard U; Prawitt, Dirk

    2010-01-01

    Insulin secretion in β-pancreatic cells after glucose stimulation requires the concerted action of a number of different ion channels. The main players seem to be the ATP sensitive K(+) (KATP-) channels, and voltage gated ion channels that drive Ca(2+) influx into β-cells. Recently two calcium activated nonselective (CAN) cation channels (TRPM4 and TRPM5) have been shown to influence efficient insulin response upon glucose stimulation. This addendum summarizes the data known for these two TRP channels in β-cells, discusses some of the remaining open questions and addresses a possible scenario that involves and integrates the triggering and amplifying pathway of glucose mediated insulin secretion.

  16. Islet transplantation in rodents: do encapsulated islets really work?

    Directory of Open Access Journals (Sweden)

    Yngrid Ellyn Dias Maciel de Souza

    2011-06-01

    Full Text Available CONTEXT: Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8% of the population. It has been estimated that the costs of its complications account for 5% to 10% of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. OBJECTIVES: To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. METHODS: A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. RESULTS: In these 56 articles used, 34% were encapsulated and 66% were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. CONCLUSION: While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without

  17. Insights into islet differentiation and maturation through proteomic characterization of a human iPSC-derived pancreatic endocrine model.

    Science.gov (United States)

    Haller, Corinne; Chaskar, Prasad; Piccand, Julie; Cominetti, Ornella; Macron, Charlotte; Dayon, Loïc; Kraus, Marine R-C

    2018-03-26

    Great progresses have been made for generating in vitro pluripotent stem cell pancreatic β-like cells. However, the maturation stage of the cells still requires in vivo maturation to recreate the environmental niche. A deeper understanding of the factors promoting maturation of the cells is of great interest for clinical applications. We performed label-free mass spectrometry-based proteomic analysis of samples from a longitudinal study of differentiation of human-induced pluripotent stem cells towards glucose-responsive insulin producing cells. Proteome patterns correlated with specific transcription factor gene expression levels during in vitro differentiation, showing the relevance of the technology for identification of pancreatic-specific markers. We analyzed proteomes of the implanted cells in a longitudinal study and showed that the neovascularization process linked to the extracellular matrix environment is time-dependent and conditions the proper maturation of the cells in β-like cells secreting insulin in response to glucose. Proteomic profiling is valuable to qualify and better understand in vivo maturation of progenitor cells towards β-cells. This is critical for future clinical trials where in vivo maturation still needs to be improved for robustness and effectiveness of cell therapy. Novel biomarkers for predicting the efficiency of maturation represents non-invasive monitoring tools for following efficiency of the implant. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  18. Massive parallel gene expression profiling of RINm5F pancreatic islet beta-cells stimulated with interleukin-1beta

    DEFF Research Database (Denmark)

    Rieneck, K; Bovin, L F; Josefsen, K

    2000-01-01

    found that 146 full-length genes and a large number of expressed sequence tags were differentially regulated 3-fold or more. Most of the differentially regulated transcripts have not previously been described to be regulated by IL-1beta in beta-cells. We have analysed the expression data and sorted......Interleukin 1 (IL-1) is a pleiotropic cytokine with the potential to kill pancreatic beta-cells, and this unique property is thought to be involved in the pathogenesis of type I diabetes mellitus. We therefore determined the quantitative expression of 24,000 mRNAs of RINm5F, an insulinoma cell line...... derived from rat pancreatic beta-cells, before and after challenge with 30 and 1,000 pg/ml of recombinant human IL-1beta. The highest concentration resulted in decreased insulin production and cell death over a period of 4 days. Using three different time points, 2, 4 and 24 hours after challenge, we...

  19. In vivo and ex vivo 19-fluorine magnetic resonance imaging and spectroscopy of beta-cells and pancreatic islets using GLUT-2 specific contrast agents.

    Science.gov (United States)

    Liang, Sayuan; Louchami, Karim; Kolster, Hauke; Jacobsen, Anna; Zhang, Ying; Thimm, Julian; Sener, Abdullah; Thiem, Joachim; Malaisse, Willy; Dresselaers, Tom; Himmelreich, Uwe

    2016-11-01

    The assessment of the β-cell mass in experimental models of diabetes and ultimately in patients is a hallmark to understand the relationship between reduced β-cell mass/function and the onset of diabetes. It has been shown before that the GLUT-2 transporter is highly expressed in both β-cells and hepatocytes and that D-mannoheptulose (DMH) has high uptake specificity for the GLUT-2 transporter. As 19-fluorine MRI has emerged as a new alternative method for MRI cell tracking because it provides potential non-invasive localization and quantification of labeled cells, the purpose of this project is to validate β-cell and pancreatic islet imaging by using fluorinated, GLUT-2 targeting mannoheptulose derivatives ( 19 FMH) both in vivo and ex vivo. In this study, we confirmed that, similar to DMH, 19 FMHs inhibit insulin secretion and increase the blood glucose level in mice temporarily (approximately two hours). We were able to assess the distribution of 19 FMHs in vivo with a temporal resolution of about 20 minutes, which showed a quick removal of 19 FMH from the circulation (within two hours). Ex vivo MR spectroscopy confirmed a preferential uptake of 19 FMH in tissue with high expression of the GLUT-2 transporter, such as liver, endocrine pancreas and kidney. No indication of further metabolism was found. In summary, 19 FMHs are potentially suitable for visualizing and tracking of GLUT-2 expressed cells. However, current bottlenecks of this technique related to the quick clearance of the compound and relative low sensitivity of 19 F MRI need to be overcome. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Selective Osmotic Shock (SOS)-Based Islet Isolation for Microencapsulation.

    Science.gov (United States)

    Enck, Kevin; McQuilling, John Patrick; Orlando, Giuseppe; Tamburrini, Riccardo; Sivanandane, Sittadjody; Opara, Emmanuel C

    2017-01-01

    Islet transplantation (IT) has recently been shown to be a promising alternative to pancreas transplantation for reversing diabetes. IT requires the isolation of the islets from the pancreas, and these islets can be used to fabricate a bio-artificial pancreas. Enzymatic digestion is the current gold standard procedure for islet isolation but has lingering concerns. One such concern is that it has been shown to damage the islets due to nonselective tissue digestion. This chapter provides a detailed description of a nonenzymatic method that we are exploring in our lab as an alternative to current enzymatic digestion procedures for islet isolation from human and nonhuman pancreatic tissues. This method is based on selective destruction and protection of specific cell types and has been shown to leave the extracellular matrix (ECM) of islets intact, which may thus enhance islet viability and functionality. We also show that these SOS-isolated islets can be microencapsulated for transplantation.

  1. Effects of calcium buffering on glucose-induced insulin release in mouse pancreatic islets: an approximation to the calcium sensor.

    Science.gov (United States)

    Pertusa, J A; Sanchez-Andres, J V; Martín, F; Soria, B

    1999-10-15

    1. The properties of the calcium sensor for glucose-induced insulin secretion have been studied using cell-permeant Ca2+ buffers with distinct kinetics and affinities. In addition, submembrane cytosolic Ca2+ distribution has been modelled after trains of glucose-induced action potential-like depolarizations. 2. Slow Ca2+ buffers (around 1 mmol l-1 intracellular concentration) with different affinities (EGTA and Calcium Orange-5N) did not significantly affect glucose-induced insulin release. Modelling showed no effect on cytosolic Ca2+ concentrations at the outermost shell (0.05 microm), their effects being observed in the innermost shells dependent on Ca2+ affinity. 3. In contrast, fast Ca2+ buffers (around 1 mmol l-1 intracellular concentration) with different affinities (BAPTA and Calcium Green-5N) caused a 50 % inhibition of early insulin response and completely blocked the late phase of glucose-induced insulin response, their simulations showing a decrease of [Ca2+]i at both the inner and outermost shells. 4. These data are consistent with the existence in pancreatic beta-cells of a higher affinity Ca2+ sensor than that proposed for neurons. Moreover, these data are consistent with the proposed existence of two distinct pools of granules: (i) 'primed' vesicles, colocalized with Ca2+ channels and responsible of the first phase of insulin release; and (ii) 'reserved pool' vesicles, not colocalized and responsible for the second phase.

  2. Separation of empty microcapsules after microencapsulation of porcine neonatal islets.

    Science.gov (United States)

    Shin, Soojeong; Yoo, Young Je

    2013-12-01

    Pancreatic islet transplantation is used to treat diabetes mellitus that has minimal complications and avoids hypoglycemic shock. Conformal microencapsulation of pancreatic islets improves their function by blocking immunogenic molecules while protecting fragile islets. However, production of empty alginate capsules during microencapsulation causes enlargement of the transplantation volume of the encapsulated islets and interferes with efficient transfer of nutrients and insulin. In this study, empty alginate capsules were separated after microencapsulation of neonatal porcine islet-like cell clusters (NPCC) using density-gradient centrifugation. Densities of NPCC and alginate capsules were determined using Percoll. Encapsulation products following alginate removal were 97 % of products, with less than 10 % of the capsules remaining empty. The viability of this process compared with manually-selected encapsulated islets indicates the separation process does not harm islets.

  3. 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.

  4. Sericin in the isolating solution improves the yield of islets isolated from the pancreas

    OpenAIRE

    Yokoi, Shigehiro; Murakami, Makoto; Morikawa, Mitsuhiro; Goi, Takanori; Yamaguchi, Akio; Terada, Satoshi

    2016-01-01

    Approximately half of the transplantable pancreatic islet tissue is lost during isolation, including the digestion and purification steps. Modifying the isolation method could increase the yield. This would enable the one donor-one recipient concept and improve the therapeutic effects of islet transplantation. This study aims to improve islet transplantation by increasing the yield of islets from the pancreas, both the number of islets and their size. Therefore, we used a sericin-containing i...

  5. Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin.

    Science.gov (United States)

    Baidwan, Sartaj; Chekuri, Anil; Hynds, DiAnna L; Kowluru, Anjaneyulu

    2017-11-01

    Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic (HG; glucotoxic) conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

  6. Pancreatic islet allograft in spleen with immunossuppression with cyclosporine. Experimental model in dogs Alotransplante de ilhotas pancreáticas no baço com imunossupressão com ciclosporina. Modelo experimental em cães

    Directory of Open Access Journals (Sweden)

    Jaques Waisberg

    2011-01-01

    Full Text Available PURPOSE: To study the functional behavior of the allograft with immunosuppression of pancreatic islets in the spleen. METHODS: Five groups of 10 Mongrel dogs were used: Group A (control underwent biochemical tests; Group B underwent total pancreatectomy; Group C underwent total pancreatectomy and pancreatic islet autotransplant in the spleen; Group D underwent pancreatic islet allograft in the spleen without immunosuppressive therapy; Group E underwent pancreatic islet allograft in the spleen and immunosuppression with cyclosporine. All of the animals with grafts received pancreatic islets prepared by the mechanical-enzymatic method - stationary collagenase digestion and purification with dextran discontinuous density gradient, implanted in the spleen. RESULTS: The animals with autotransplant and those with allografts with immunosuppression that became normoglycemic showed altered results of intravenous tolerance glucose (p OBJETIVO: Avaliar o comportamento funcional do alotransplante com imunossupressão de ilhotas pancreáticas no baço. MÉTODOS: Foram utilizados cinco grupos de 10 cães mestiços: grupo A (controle submetido aos exames bioquímicos; grupo B, submetido à pancreatectomia total; grupo C (autotransplante submetido à pancreatectomia total e autotransplantação de ilhotas pancreáticas no baço; grupo D, submetido à alotransplantação de ilhotas pancreáticas no baço sem terapia imunossupressiva; grupo E, submetido à alotransplantação de ilhotas no baço e imunossupressão com ciclosporina. Todos os animais transplantados receberam ilhotas pancreáticas isoladas pelo método mecânico-enzimático, digestão estacionária com colagenase e purificação com gradiente de densidade descontínua de dextran e foram implantadas no baço. RESULTADOS: Animais autotransplantados e alotransplantados com imunossupressão que se tornaram normoglicêmicos apresentaram testes de tolerância à glicose intravenosa alterados (p<0,001 e o

  7. Ca2+-mediated generation of inositol 1,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate in pancreatic islets. Studies with K+, glucose, and carbamylcholine

    International Nuclear Information System (INIS)

    Biden, T.J.; Peter-Riesch, B.; Schlegel, W.; Wollheim, C.B.

    1987-01-01

    The role of Ca2+ in the generation of inositol phosphates was investigated using rat pancreatic islets after steady state labeling with myo-[2- 3 H]inositol. Depolarizing K+ concentrations (24 mM) evoked early (2 s) increases in inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) as measured by high performance anion-exchange chromatography. The increase in Ins-1,4,5-P3 was transient and was followed by a more pronounced rise in Ins-1,3,4-P3. These effects were dependent on the presence of extracellular Ca2+ but were not secondary to release of either neurotransmitters or metabolites of arachidonic acid. K+ also promoted the breakdown of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2) and of the other phosphoinositides. Glucose (16.7 mM) was less marked in its effects but still promoted rapid increases in Ins-1,3,4,5-P4 (2 s) and Ins-1,4,5-P3 (10 s) and a slower rise in Ins-1,3,4-P3 (30 s). The levels of all three metabolites rose steadily over 10 min stimulation. These responses to glucose could be largely, although not entirely, inhibited by depletion of extracellular Ca2+ or by Ca2+ channel blockade with verapamil (20 microM). Carbamylcholine (0.5 mM) was the most potent stimulus used evoking early rises in Ins-1,4,5-P3 and Ins-1,3,4,5-P4 (2 s) followed by Ins-1,3,4-P3 (10 s), effects which were only partially dependent on extracellular Ca2+. The results suggest that a Ca2+-mediated PtdIns-4,5-P2 hydrolysis accounts for most of the Ins-1,4,5-P3 generated in response to glucose but not carbamylcholine

  8. Islet Transplantation

    Science.gov (United States)

    ... be successful. However, transplanting islet cells has several advantages over transplanting a pancreas. First, unlike the pancreas ... Email: Sign Up Thank you for signing up ' + ' '); $('.survey-form').show(); }, success: function (data) { $('#survey-errors').remove(); $('. ...

  9. Long-term normalization of diabetes mellitus after xenotransplantation of fetal pancreatic islet cells into the blood stream without immunosuppresive therapy.

    Science.gov (United States)

    Prochorov, A V; Tretjak, S I; Roudenok, V V; Goranov, V A

    2004-11-01

    The article presents a new method of surgical treatment of experimental diabetes mellitus in a rabbit to dog model. Rabbit islet cells, which had been macroencapsulated into a microporous polyamide, were implanted into the dog aorta without immunosuppressive therapy. Euglycemia was reached at 4 to 5 days and persisted for 12 months. Morphological and immunohistochemical investigations showed long-term preservation of islet cell viability, absence of graft rejection, and formation of a biological artificial pancreas in the capsule at 6 months after transplantation. Up to 60% of transplanted cells were still viable 12 months later. The major factor contributing to preservation of islet cells is neo-angiogenesis, which develops during the first weeks after transplantation. Double immune isolation of islet cells by macroencapsulation with implantation into the blood stream allows the use of either xenotransplantation or allotransplantation.

  10. Phenolic Substances from Ocimum Species Enhance Glucose- Stimulated Insulin Secretion and Modulate the Expression of Key Insulin Regulatory Genes in Mice Pancreatic Islets

    DEFF Research Database (Denmark)

    Casanova, Livia Marques; Gu, Wenqian; Costa, Sônia Soares

    2017-01-01

    cinnamic acid derivatives (caftaric, caffeic, chicoric, and rosmarinic acids) or a C-glucosylated flavonoid (vicenin-2). All substances acutely enhanced glucose-stimulated insulin secretion (GSIS) from islets at concentrations from 10−10 to 10−6 M. They also increased GSIS after chronic incubation (10−8 M...... islets. Thus, they may play an important role in diabetes treatment. This is the first report on the insulin-secretory activity of caftaric acid, rosmarinic acid, and vicenin-2....

  11. Overexpression of IRS2 in isolated pancreatic islets causes proliferation and protects human β-cells from hyperglycemia-induced apoptosis

    International Nuclear Information System (INIS)

    Mohanty, S.; Spinas, G.A.; Maedler, K.; Zuellig, R.A.; Lehmann, R.; Donath, M.Y.; Trueb, T.; Niessen, M.

    2005-01-01

    Studies in vivo indicate that IRS2 plays an important role in maintaining functional β-cell mass. To investigate if IRS2 autonomously affects β-cells, we have studied proliferation, apoptosis, and β-cell function in isolated rat and human islets after overexpression of IRS2 or IRS1. We found that β-cell proliferation was significantly increased in rat islets overexpressing IRS2 while IRS1 was less effective. Moreover, proliferation of a β-cell line, INS-1, was decreased after repression of Irs2 expression using RNA oligonucleotides. Overexpression of IRS2 in human islets significantly decreased apoptosis of β-cells, induced by 33.3 mM D-glucose. However, IRS2 did not protect cultured rat islets against apoptosis in the presence of 0.5 mM palmitic acid. Overexpression of IRS2 in isolated rat islets significantly increased basal and D-glucose-stimulated insulin secretion as determined in perifusion experiments. Therefore, IRS2 is sufficient to induce proliferation in rat islets and to protect human β-cells from D-glucose-induced apoptosis. In addition, IRS2 can improve β-cell function. Our results indicate that IRS2 acts autonomously in β-cells in maintenance and expansion of functional β-cell mass in vivo

  12. A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets.

    Directory of Open Access Journals (Sweden)

    Jakob D Wikstrom

    Full Text Available The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets.The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets.The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.

  13. Small Islets Transplantation Superiority to Large Ones: Implications from Islet Microcirculation and Revascularization

    Directory of Open Access Journals (Sweden)

    Wenjuan Li

    2014-01-01

    Full Text Available Pancreatic islet transplantation is a promising therapy to regain glycemic control in diabetic patients. The selection of ideal grafts is the basis to guarantee short-term effectivity and longevity of the transplanted islets. Contradictory to the traditional notion, recent findings implied the superiority of small islets for better transplantation outcomes rather than the large and intact ones. However, the mechanisms remain to be elucidated. Recent evidences emphasized the major impact of microcirculation on islet β-cell mass and function. And potentials in islet graft revascularization are crucial for their survival and preserved function in the recipient. In this study, we verified the distinct histological phenotype and functionality of small islets versus large ones both in vitro and in vivo. With efforts to exploring the differences in microcirculation and revascularization of islet grafts, we further evaluated local expressions of angiotensin and vascular endothelial growth factor A (VEGF-A at different levels. Our findings reveal that, apart from the higher density of insulin-producing β-cells, small islets express less angiotensin and more angiotrophic VEGF-A. We therefore hypothesized a logical explanation of the small islet superiority for transplantation outcome from the aspects of facilitated microcirculation and revascularization intrinsically in small islets.

  14. Avascular Necrosis of the Capitate

    Science.gov (United States)

    Bekele, Wosen; Escobedo, Eva; Allen, Robert

    2011-01-01

    Avascular necrosis of the capitate is a rare entity. The most common reported etiology is trauma. We report a case of avascular necrosis of the capitate in a patient with chronic wrist pain that began after a single episode of remote trauma. PMID:22470799

  15. Avascular Necrosis of the Capitate

    OpenAIRE

    Bekele, Wosen; Escobedo, Eva; Allen, Robert

    2011-01-01

    Avascular necrosis of the capitate is a rare entity. The most common reported etiology is trauma. We report a case of avascular necrosis of the capitate in a patient with chronic wrist pain that began after a single episode of remote trauma.

  16. ORIGINAL ARTICLES Islet neogenesis is stimulated by brief ...

    African Journals Online (AJOL)

    m oper~tion. The animals were. ... New therapies are therefore required to stem this islet depletion and restore pancreatic function. ... destroyed beta cells, Understanding the mechanism by which the pancreas can be stimulated to increase ...

  17. OBSTACLES IN THE APPLICATION OF MICROENCAPSULATION IN ISLET TRANSPLANTATION

    NARCIS (Netherlands)

    DEVOS, P; WOLTERS, GHJ; FRITSCHY, WM; VANSCHILFGAARDE, R

    Several factors stand in the way of successful clinical transplantation of alginate-polylysine-alginate microencapsulated pancreatic islets. These obstacles can be classified into three categories. The first regards the technical aspects of the production process. Limiting factors are the

  18. In vitro effects of bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), or VO(dmpp)2, on insulin secretion in pancreatic islets of type 2 diabetic Goto-Kakizaki rats.

    Science.gov (United States)

    Pelletier, Julien; Domingues, Neuza; Castro, M Margarida C A; Östenson, Claes-Göran

    2016-01-01

    Vanadium compounds have been explored as therapy of diabetes, and most studies have focussed on insulin mimetic effects, i.e. reducing hyperglycemia by improving glucose sensitivity and thus glucose uptake in sensitive tissues. We have recently shown that bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp)2, has promising effects when compared to another vanadium compound, bis(maltolato)oxidovanadium(IV), BMOV, and insulin itself, in isolated adipocytes and in vivo in Goto-Kakizaki (GK) rats, an animal model of hereditary type 2 diabetes (T2D).We now have investigated in GK rats whether VO(dmpp)2 also modulates another important defect in T2D, impaired insulin secretion. VO(dmpp)2, but not BMOV, stimulated insulin secretion from isolated GK rat pancreatic islets at high, 16.7mM, but not at low–normal, 3.3 mM, glucose concentration. Mechanistic studies demonstrate that the insulin releasing effect of VO(dmpp)2 is due to its interaction with several steps in the stimulus-secretion coupling for glucose, including islet glucose metabolism and K-ATP channels, L-type Ca2+ channels, modulation by protein kinases A and C, as well as the exocytotic machinery. In conclusion, VO(dmpp)2 exhibits properties of interest for treatment of the insulin secretory defect in T2D, in addition to its well-described insulin mimetic activity.

  19. Femoral head avascular necrosis

    International Nuclear Information System (INIS)

    Chrysikopoulos, H.; Sartoris, D.J.; Resnick, D.L.; Ashburn, W.; Pretorius, T.

    1988-01-01

    MR imaging has been shown to be more sensitive and specific than planar scintigraphy for avascular necrosis (AVN) of the femoral head. However, experience with single photon emission CT (SPECT) is limited. The authors retrospectively compared 1.5-T MR imaging with SPECT in 14 patients with suspected femoral head AVN. Agreement between MR imaging and SPECT was present in 24 femurs, 14 normal and ten with AVN. MR imaging showed changes of AVN in the remaining four femoral heads. Of these, one was normal and the other three inconclusive for AVN by SPECT. The authors conclude that MR imaging is superior to SPECT for the evaluation of AVN of the hip

  20. Glucose cycling in islets from healthy and diabetic rats

    International Nuclear Information System (INIS)

    Khan, A.; Chandramouli, V.; Ostenson, C.G.; Loew, H.L.; Landau, B.R.; Efendic, S.

    1990-01-01

    Pancreatic islets from healthy (control) and neonatally streptozocin-induced diabetic (STZ-D) rats, a model for non-insulin-dependent diabetes mellitus, were incubated with 3 H 2 O and 5.5 or 16.7 mM glucose. At 5.5 mM glucose, no detectable [ 3 H]glucose was formed. At 16.7 mM, 2.2 patom.islet-1.h-1 of 3 H was incorporated into glucose by the control islets and 5.4 patom.islet-1.h-1 by STZ-D islets. About 75% of the 3 H was bound to carbon-2 of the glucose. Glucose utilization was 35.3 pmol.islet-1.h-1 by the control and 19.0 pmol.islet-1.h-1 by the STZ-D islets. Therefore, 4.5% of the glucose-6-phosphate formed by the control islets and 15.7% by the STZ-D islets was dephosphorylated. This presumably occurred in the beta-cells of the islets catalyzed by glucose-6-phosphatase. An increased glucose cycling, i.e., glucose----glucose-6-phosphate----glucose, in islets of STZ-D rats may contribute to the decreased insulin secretion found in these animals

  1. Islet cytotoxicity of interleukin 1. Influence of culture conditions and islet donor characteristics

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Spinas, G A; Prowse, S J

    1987-01-01

    We recently demonstrated that the macrophage product interleukin 1 (IL-1) is cytotoxic to isolated pancreatic islets and hypothesized that IL-1 is responsible for beta-cell destruction in insulin-dependent diabetes mellitus (IDDM). We studied whether the variation in IDDM preponderance with age...... strains, indicating that age, sex, and genetic background do not influence the susceptibility of the beta-cell to IL-1. Preculture of islets for 1-7 days in normal atmosphere and preculture of islet clusters in 95% O2 to delete passenger cells did not affect IL-1-mediated cytotoxicity, suggesting that IL...

  2. The efficacy of SPA0355 in protecting ? cells in isolated pancreatic islets and in a murine experimental model of type 1 diabetes

    OpenAIRE

    Bae, Ui-Jin; Song, Mi-Young; Jang, Hyun-Young; Jin Gim, Hyo; Ryu, Jae-Ha; Lee, Sang-Myeong; Jeon, Raok; Park, Byung-Hyun

    2013-01-01

    Cytokines activate several inflammatory signals that mediate ?-cell destruction. We recently determined that SPA0355 is a strong anti-inflammatory compound, thus reporting its efficacy in protecting ? cells from various insults. The effects of SPA0355 on ?-cell survival were studied in RINm5F cells and primary islets. The protective effects of this compound on the development of type 1 diabetes were evaluated in non-obese diabetic (NOD) mice. SPA0355 completely prevented cytokine-induced nitr...

  3. The effect of pomegranate fresh juice versus pomegranate seed powder on metabolic indices, lipid profile, inflammatory biomarkers, and the histopathology of pancreatic islets of Langerhans in streptozotocin-nicotinamide induced type 2 diabetic Sprague-Dawley rats.

    Science.gov (United States)

    Taheri Rouhi, Seyedeh Zeinab; Sarker, Md Moklesur Rahman; Rahmat, Asmah; Alkahtani, Saad Ahmed; Othman, Fauziah

    2017-03-14

    Type 2 diabetes mellitus (T2DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles. Several functional foods have therapeutic potential to treat chronic diseases including diabetes. The therapeutic potential of pomegranate has been stated by multitudinous scientists. The present study aimed to evaluate the effects of pomegranate juice and seed powder on the levels of plasma glucose and insulin, inflammatory biomarkers, lipid profiles, and health of the pancreatic islets of Langerhans in streptozotocin (STZ)-nicotinamide (NAD) induced T2DM Sprague Dawley (SD) rats. Forty healthy male SD rats were induced to diabetes with a single dose intra-peritoneal administration of STZ (60 mg/kg b.w.) - NAD (120 mg/kg b.w.). Diabetic rats were orally administered with 1 mL of pomegranate fresh juice (PJ) or 100 mg pomegranate seed powder in 1 mL distilled water (PS), or 5 mg/kg b.w. of glibenclamide every day for 21 days. Rats in all groups were sacrificed on day 22. The obtained data was analyzed by SPSS software (v: 22) using One-way analysis of variance (ANOVA). The results showed that PJ and PS treatment had slight but non-significant reduction of plasma glucose concentration, and no impact on plasma insulin compared to diabetic control (DC) group. PJ lowered the plasma total cholesterol (TC) and triglyceride (TG) significantly, and low-density lipoproteins (LDL) non-significantly compared to DC group. In contrast, PS treatment significantly raised plasma TC, LDL, and high-density lipoproteins (HDL) levels compared to the DC rats. Moreover, the administration of PJ and PS significantly reduced the levels of plasma inflammatory biomarkers, which were actively raised in diabetic rats. Only PJ treated group showed significant repairment and restoration signs in islets of Langerhans. Besides, PJ possessed preventative impact against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals almost 2.5 folds more than PS. Our findings suggest that

  4. CT features of nonfunctioning islet cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Eelkema, E.A.; Stephens, D.H.; Ward, E.M.; Sheedy, P.F. II

    1984-11-01

    To determine the computed tomographic (CT) characteristics of nonfunctioning islet cell carcinoma of the pancreas, the CT scans of 27 patients with that disease were reviewed. The pancreatic tumor was identified as a mass in 26 patients (96%) Of the 25 tumors evaluated with contrast enhancement, 20 became partially diffusely hyperdense relative to nearby normal pancreatic tissue. Hepatic metastases were identified in 15 patients (56%), regional lymphadenopathy in 10 (37%), atrophy of the gland proximal to the tumor in six (22%), dilatation of the biliary ducts in five (19%), and dilatation of the pancreatic duct in four (15%). The CT appearances of the nonfunctioning islet cell tumors were compared with those of 100 ordinary (ductal) pancreatic adenocarcinomas. Although the two types of tumors were sometimes indistinguishable, features found to be more characteristic of islet cell carcinoma included a pancreatic mass of unusually large size, calcification within the tumor, and contrast enhancement of either the primary tumor or hepatic metastases. Involvement of the celiac axis or proximal superior mesenteric artery was limited to ductal carcinoma.

  5. Pigment epithelium-derived factor (PEDF) regulates metabolism and insulin secretion from a clonal rat pancreatic beta cell line BRIN-BD11 and mouse islets.

    Science.gov (United States)

    Chen, Younan; Carlessi, Rodrigo; Walz, Nikita; Cruzat, Vinicius Fernandes; Keane, Kevin; John, Abraham N; Jiang, Fang-Xu; Carnagarin, Revathy; Dass, Crispin R; Newsholme, Philip

    2016-05-05

    Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein, associated with lipid catabolism and insulin resistance. In the present study, PEDF increased chronic and acute insulin secretion in a clonal rat β-cell line BRIN-BD11, without alteration of glucose consumption. PEDF also stimulated insulin secretion from primary mouse islets. Seahorse flux analysis demonstrated that PEDF did not change mitochondrial respiration and glycolytic function. The cytosolic presence of the putative PEDF receptor - adipose triglyceride lipase (ATGL) - was identified, and ATGL associated stimulation of glycerol release was robustly enhanced by PEDF, while intracellular ATP levels increased. Addition of palmitate or ex vivo stimulation with inflammatory mediators induced β-cell dysfunction, effects not altered by the addition of PEDF. In conclusion, PEDF increased insulin secretion in BRIN-BD11 and islet cells, but had no impact on glucose metabolism. Thus elevated lipolysis and enhanced fatty acid availability may impact insulin secretion following PEDF receptor (ATGL) stimulation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats

    DEFF Research Database (Denmark)

    Zumsteg, U; Reimers, J I; Pociot, F

    1993-01-01

    The monokines interleukin-1 alpha and -beta have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of r...

  7. Islet formation during the neonatal development in mice.

    Directory of Open Access Journals (Sweden)

    Kevin Miller

    2009-11-01

    Full Text Available The islet of Langerhans is a unique micro-organ within the exocrine pancreas, which is composed of insulin-secreting beta-cells, glucagon-secreting alpha-cells, somatostatin-secreting delta-cells, pancreatic polypeptide-secreting PP cells and ghrelin-secreting epsilon-cells. Islets also contain non-endocrine cell types such as endothelial cells. However, the mechanism(s of islet formation is poorly understood due to technical difficulties in capturing this dynamic event in situ. We have developed a method to monitor beta-cell proliferation and islet formation in the intact pancreas using transgenic mice in which the beta-cells are specifically tagged with a fluorescent protein. Endocrine cells proliferate contiguously, forming branched cord-like structures in both embryos and neonates. Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas. Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets. We propose that islet formation occurs by a process of fission following contiguous endocrine cell proliferation, rather than by local aggregation or fusion of isolated beta-cells and islets. Mathematical modeling of the fission process in the neonatal islet formation is also presented.

  8. Partial avascular necrosis after talar neck fracture.

    Science.gov (United States)

    Babu, Nina; Schuberth, John M

    2010-09-01

    Recently, it has been shown that avascular necrosis of the talus can occur in only a portion of the talar body. There is little information regarding the geographic location of the avascular segment and the clinical significance of an incomplete avascular process. Seven patients with partial avascular necrosis after Hawkins type II or III fracture dislocations were evaluated with magnetic resonance scans. The precise anatomic location of the avascular segment was determined and assigned to a specific quadrant of the talar body. The operative exposure, incidence of collapse, and time to operative intervention was recorded. The avascular segment of the talar body was located predominantly in the anterior lateral and superior portion in six of the seven patients. Collapse occurred in three of the patients in the area of avascular process. There were no observable trends with regard to operative exposure, Hawkins classification, incidence of collapse, or time to operative intervention to the location of the avascular segment. Partial avascular necrosis can occur after fracture dislocation of the talus. The predominant location of the avascular segment was the anterior lateral and superior portion of the talar body. This observation corresponds to regional damage to the blood supply of the talus and may help clarify the pathogenesis of partial avascular process.

  9. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.

    Science.gov (United States)

    Ramaswamy, S; Grace, C; Mattei, A A; Siemienowicz, K; Brownlee, W; MacCallum, J; McNeilly, A S; Duncan, W C; Rae, M T

    2016-06-06

    Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.

  10. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...... of diabetes type II, while revealing the structure(s) of islet amyloid fibrils is necessary for potential design of therapeutic agents....

  11. Novel culture technique involving an histone deacetylase inhibitor reduces the marginal islet mass to correct streptozotocin-induced diabetes.

    Science.gov (United States)

    Shin, Jun-Seop; Min, Byoung-Hoon; Lim, Jong-Yeon; Kim, Byoung-Keun; Han, Hyun-Ju; Yoon, Kun-Ho; Kim, Sang-Joon; Park, Chung-Gyu

    2011-01-01

    Islet transplantation is limited by the difficulties in isolating the pancreatic islets from the cadaveric donor and maintaining them in culture. To increase islet viability and function after isolation, here we present a novel culture technique involving an histone deacetylase inhibitor (HDACi) to rejuvenate the isolated islets. Pancreatic islets were isolated from Sprague-Dawley (SD) rats and one group (FIs; freshly isolated islets) was used after overnight culture and the other group (RIs; rejuvenated islet) was subjected to rejuvenation culture procedure, which is composed of three discrete steps including degranulation, chromatin remodeling, and regranulation. FIs and RIs were compared with regard to intracellular insulin content, glucose-stimulated insulin secretion (GSIS) capacity, gene expression profile, viability and apoptosis rate under oxidative stresses, and the engraftment efficacy in the xenogeneic islet transplantation models. RIs have been shown to have 1.9 ± 0.28- and 1.7 ± 0.31-fold greater intracellular insulin content and GSIS capacity, respectively, than FIs. HDACi increased overall histone acetylation levels, with inducing increased expression of many genes including insulin 1, insulin 2, GLUT2, and Ogg1. This enhanced islet capacity resulted in more resistance against oxidative stresses and increase of the engraftment efficacy shown by reduction of twofold marginal mass of islets in xenogeneic transplantation model. In conclusion, a novel rejuvenating culture technique using HDACi as chromatin remodeling agents improved the function and viability of the freshly isolated islets, contributing to the reduction of islet mass for the control of hyperglycemia in islet transplantation.

  12. GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

    Directory of Open Access Journals (Sweden)

    Brend Ray-Sea Hsu

    Full Text Available Background and aims: The aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA, exenatide, on clozapine-associated glucose dysregulation in mice. Materials and methods: We randomly separated B6 male mice into four groups (A to D. Mice in groups C and D received a daily oral dose of 13.5 mg/kg body weight of clozapine for 4 months. Mice in groups B and D received 1 μg of exenatide daily. The body weight and blood glucose before and 2 h after clozapine treatment were measured twice a week. Intraperitoneal glucose tolerance test (IPGTT scores and the amount of daily food intake were recorded. The pancreases of the mice were removed for insulin content (PIC measurement and histological examination after sacrifice. Results: The mean non-fasting blood glucose levels were not different, and the mean changes in blood glucose 2 h after oral clozapine were 0 ± 4, −40 ± 2, 25 ± 3, and −39 ± 2, in groups A to D, respectively. There was no significant difference in daily calorie intake or area under the curve of IPGTT among the four groups. At sacrifice, the PIC of mice treated with clozapine was significantly lower than that of the control mice, however the PIC was completely restored in the mice treated with exenatide. Histological examination of the pancreas revealed that exenatide treatment reversed the clozapine-induced apoptosis of islet cells. Conclusion: Our results provide preclinical evidence of a pharmaceutical role of GLP-1RA in managing glucose dysregulation in schizophrenic patients under long-term atypical antipsychotic treatments. Keywords: Clozapine, Exenatide, Glucose dysregulation, Beta cell, Apoptosis

  13. Imaging of avascular necrosis of femoral head: familiar methods and newer trends.

    Science.gov (United States)

    Stoica, Zoia; Dumitrescu, Daniela; Popescu, M; Gheonea, Ioana; Gabor, Mihaela; Bogdan, N

    2009-01-01

    Avascular necrosis of the femoral head (AVN) is an increasingly common cause of musculoskeletal disability, and it poses a major diagnostic and therapeutic challenge. Although patients are initially asymptomatic, AVN usually progresses to joint destruction, requiring total hip replacement, usually before the fifth decade. Avascular necrosis is characterized by osseous cell death due to vascular compromise. Avascular necrosis of bone results generally from corticosteroid use, trauma, pancreatitis, alcoholism, radiation, sickle cell disease, infiltrative diseases (e.g. Gaucher's disease), and Caisson disease. The most commonly affected site is the femoral head and patients usually present with hip and referred knee pain. The aim of diagnostic imaging procedures in avascular femoral head necrosis is to provide the patient with a stage-adapted therapy. Therefore, a differentiated diagnostic work-up is needed. Native radiography of the hip in two planes is still the first step. Over the past years, the diagnosis of femoral head necrosis has experienced tremendous improvement due to the use of MRI and CT scans. Because of these improvements the correct stage can be diagnosed early and the appropriate therapy can be initiated immediately. Today, MRI is the most sensitive diagnostic imaging procedure. CT scans can be particularly useful to exclude subchondral fractures. The use of bone scintigraphy is restricted to exceptional cases. In Europe, the ARCO classification of avascular femoral head necrosis has been widely accepted. In this overview, we describe the specific characteristics of the different diagnostic imaging procedures and illustrate them with appropriate imaging material.

  14. Induction of Protective Genes Leads to Islet Survival and Function

    Directory of Open Access Journals (Sweden)

    Hongjun Wang

    2011-01-01

    Full Text Available Islet transplantation is the most valid approach to the treatment of type 1 diabetes. However, the function of transplanted islets is often compromised since a large number of β cells undergo apoptosis induced by stress and the immune rejection response elicited by the recipient after transplantation. Conventional treatment for islet transplantation is to administer immunosuppressive drugs to the recipient to suppress the immune rejection response mounted against transplanted islets. Induction of protective genes in the recipient (e.g., heme oxygenase-1 (HO-1, A20/tumor necrosis factor alpha inducible protein3 (tnfaip3, biliverdin reductase (BVR, Bcl2, and others or administration of one or more of the products of HO-1 to the donor, the islets themselves, and/or the recipient offers an alternative or synergistic approach to improve islet graft survival and function. In this perspective, we summarize studies describing the protective effects of these genes on islet survival and function in rodent allogeneic and xenogeneic transplantation models and the prevention of onset of diabetes, with emphasis on HO-1, A20, and BVR. Such approaches are also appealing to islet autotransplantation in patients with chronic pancreatitis after total pancreatectomy, a procedure that currently only leads to 1/3 of transplanted patients being diabetes-free.

  15. Abnormal islet sphingolipid metabolism in type 1 diabetes

    DEFF Research Database (Denmark)

    Holm, Laurits J; Krogvold, Lars; Hasselby, Jane P

    2018-01-01

    treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. RESULTS: We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1...... diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise...... of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. METHODS: We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy...

  16. Islet neogenesis is stimulated by brief occlusion of the main ...

    African Journals Online (AJOL)

    The animals were killed 56 days post .occlusion, and the pancreata excised and fiXed tor histological analysis. Body, pancreatic and hepatic weights were .noted at termination. and serum was taken for analysis. The endocrine-to-exocrine. ratio was calculated and the number of endocrine cells in eacn islet from the ...

  17. Overexpression of thioredoxin in islets transduced by a lentiviral vector prolongs graft survival in autoimmune diabetic NOD mice

    Directory of Open Access Journals (Sweden)

    Sytwu Huey-Kang

    2009-08-01

    Full Text Available Abstract Pancreatic islet transplantation is considered an appropriate treatment to achieve insulin independence in type I diabetic patients. However, islet isolation and transplantation-induced oxidative stress and autoimmune-mediated destruction are still the major obstacles to the long-term survival of graft islets in this potential therapy. To protect islet grafts from inflammatory damage and prolong their survival, we transduced islets with an antioxidative gene thioredoxin (TRX using a lentiviral vector before transplantation. We hypothesized that the overexpression of TRX in islets would prolong islet graft survival when transplanted into diabetic non-obese diabetic (NOD mice. Methods Islets were isolated from NOD mice and transduced with lentivirus carrying TRX (Lt-TRX or enhanced green fluorescence protein (Lt-eGFP, respectively. Transduced islets were transplanted under the left kidney capsule of female diabetic NOD mice, and blood glucose concentration was monitored daily after transplantation. The histology of the islet graft was assessed at the end of the study. The protective effect of TRX on islets was investigated. Results The lentiviral vector effectively transduced islets without altering the glucose-stimulating insulin-secretory function of islets. Overexpression of TRX in islets reduced hydrogen peroxide-induced cytotoxicity in vitro. After transplantation into diabetic NOD mice, euglycemia was maintained for significantly longer in Lt-TRX-transduced islets than in Lt-eGFP-transduced islets; the mean graft survival was 18 vs. 6.5 days (n = 9 and 10, respectively, p Conclusion We successfully transduced the TRX gene into islets and demonstrated that these genetically modified grafts are resistant to inflammatory insult and survived longer in diabetic recipients. Our results further support the concept that the reactive oxygen species (ROS scavenger and antiapoptotic functions of TRX are critical to islet survival after

  18. Avascular necrosis of the hip

    International Nuclear Information System (INIS)

    Lang, P.; Genant, H.K.; Lindquist, T.; Chafetz, N.; Steiger, P.; Sanny, J.; Rhodes, M.L.; Rothman, S.L.G.; Delamarter, R.; Kilgus, D.

    1988-01-01

    T1-weighted (repetition time [TR] = 450 msec, echo time [TE] = 20 msec), T2-weighted (TR = 1,800 msec, TE = 20 and 80 msec), and T2*-weighted gradient-echo gradient recalled acquisition in a steady state, TR = 70 msec, TE = 30 msec, theta = 15 0 ) MR images (General Electric Signa, 1.5 T) were generated in 11 patients with avascular necrosis of the hip. Three-dimensional MR image reconstruction was performed on an independent imaging system (IIS, Dimensional Medicine Inc). Pelvic and femoral bone contours were computed based on either the T1-weighted or the T2*-weighted images. Three-dimensional displays of necrotic zones and areas of granulation tissue were computed on the basis of the T2-weighted images. The tissues were simultaneously displayed in the three-dimensional images using different colors and transparencies. The three-dimensional MR images generated demonstrated the extent of the necrotic zone and adjacent granulation tissue and their position relative to the weight-bearing surface. They may soon prove to be useful in preoperative planning and intraoperative localization of complex surgical interventions in avascular necrosis of the hip

  19. Islet Microencapsulation: Strategies and Clinical Status in Diabetes.

    Science.gov (United States)

    Omami, Mustafa; McGarrigle, James J; Reedy, Mick; Isa, Douglas; Ghani, Sofia; Marchese, Enza; Bochenek, Matthew A; Longi, Maha; Xing, Yuan; Joshi, Ira; Wang, Yong; Oberholzer, José

    2017-07-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results from the destruction of insulin-producing pancreatic β cells in the islets of Langerhans. Islet cell transplantation has become a successful therapy for specific patients with T1DM with hypoglycemic unawareness. The reversal of T1DM by islet transplantation is now performed at many major medical facilities throughout the world. However, many challenges must still be overcome in order to achieve continuous, long-term successful transplant outcomes. Two major obstacles to this therapy are a lack of islet cells for transplantation and the need for life-long immunosuppressive treatment. Microencapsulation is seen as a technology that can overcome both these limitations of islet cell transplantation. This review depicts the present state of microencapsulated islet transplantation. Microencapsulation can play a significant role in overcoming the need for immunosuppression and lack of donor islet cells. This review focuses on microencapsulation and the clinical status of the technology in combating T1DM.

  20. Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG protein in fulminant type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Kaoru Aida

    Full Text Available BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs, extracellular matrix (ECM, and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.

  1. MR imaging of pancreatic diseases

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Katsuyoshi E-mail: itokatsu@po.cc.yamaguchi-u.ac.jp; Koike, Shinji; Matsunaga, Naofumi

    2001-05-01

    This article presents current MR imaging techniques for the pancreas, and review a spectrum of MR imaging features of various pancreatic diseases. These include: 1) congenital anomalies such as anomalous union of pancreatobiliary ducts, divisum, and annular pancreas, 2) inflammatory diseases, including acute or chronic pancreatitis with complications, groove pancreatitis, and autoimmune pancreatitis, tumor-forming pancreatitis, 3) pancreatic neoplasms, including adenocarcinoma, islet cell tumors, and cystic neoplasms (microcystic adenoma, mucinous cystic neoplasms, and intraductal mucin-producing pancreatic tumor). Particular attention is paid to technical advances in MR imaging of the pancreas such as fat-suppression, MR pancreatography (single- or multi-slice HASTE), and thin-section 3D multiphasic contrast-enhanced dynamic sequences. Imaging characteristics that may lead to a specific diagnosis or narrow the differential diagnosis are also discussed.

  2. Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets.

    Science.gov (United States)

    Kepsutlu, Burcu; Nazli, Caner; Bal, Tugba; Kizilel, Seda

    2014-01-01

    Type I diabetes mellitus (TIDM), a devastating health issue in all over the world, has been treated by successful transplantation of insulin secreting pancreatic islets. However, serious limitations such as the requirement of immunosuppressive drugs for recipient patients, side effects as a result of long-term use of drugs, and reduced functionality of islets at the transplantation site remain. Bioartificial pancreas that includes islets encapsulated within semi-permeable membrane has been considered as a promising approach to address these requirements. Many studies have focused on micro or nanobased islet immunoisolation systems and tested the efficacy of encapsulated islets using in vitro and in vivo platforms. In this review, we address current progress and obstacles for the development of a bioartificial pancreas using micro/nanobased systems for encapsulation of islets.

  3. Pancreatic islet isolation by mechanical-enzymatic separation, stationary collagenase digestion and dextran discontinuous density gradient purification: experimental study in dogs Isolamento das ilhotas pancreáticas pela separação mecânica-enzimática digestão estacionária com colagenase e purificação com gradiente de densidade descontínua de dextran: estudo experimental em cães

    Directory of Open Access Journals (Sweden)

    Jaques Waisberg

    2002-04-01

    Full Text Available The prospects for allotransplantation of pancreatic islets in man depend on the development of methods that provide sufficient quantities of pancreatic islets from a single donor, which are capable, when transplanted, of achieve the normalization of carbohydrate metabolism. Objective: Evaluate the efficacy of the isolation of Langerhans islets from dogs, by means of mechanical-enzymatic separation technique with stationary digestion using collagenase, and purification with a discontinuous dextran density gradient. Methods: The counting of islet numbers and evaluation of their sizes was accomplished by staining with diphenylthiocarbazone and using stereoscopic microscopes equipped with eyepiece reticule for the measurement of average diameters of stained islets. Results: The results disclosed that the average number of islets isolated was 81032.20 ± 24736.79 and the average number of islets isolated per kg of body weight was 6938.70 ± 1392.43. The average number of islets isolated per kg of body weight showed significant correlation with body weight and weight of the pancreas resected. Conclusion: The number of islets isolated, of a single donor, by mechanical-enzymatic separation, stationary collagenase digestion and discontinuous dextran density gradient purification can be sufficient to success of pancreatic islets transplant in dogs.A perspectiva do alotransplante de ilhotas pancreáticas no homem está na dependência do desenvolvimento de métodos que propiciem quantidades suficientes de ilhotas pancreáticas, originadas de doador único, capazes de, quando transplantadas, levarem à normalização do metabolismo dos hidratos de carbono. Objetivo: Avaliar, em cães, a eficácia do isolamento das ilhotas de Langerhans por meio da técnica de separação mecânica-enzimática, digestão estacionária com colagenase e purificação pelo gradiente de densidade descontínua de dextran. Métodos: A contagem do número e avaliação do tamanho

  4. Islet cell proliferation and apoptosis in insulin-like growth factor binding protein-1 in transgenic mice.

    Science.gov (United States)

    Dheen, S T; Rajkumar, K; Murphy, L J

    1997-12-01

    Transgenic mice which overexpress insulin-like growth factor binding protein-1 (IGFPB-1) demonstrate fasting hyperglycemia, hyperinsulinemia and glucose intolerance in adult life. Here we have examined the ontogeny of pancreatic endocrine dysfunction and investigated islet cell proliferation and apoptosis in this mouse model. In addition we have examined pancreatic insulin content in transgenic mice derived from blastocyst transfer into non-transgenic mice. Transgenic mice were normoglycemic at birth but had markedly elevated plasma insulin levels, 56.2 +/- 4.5 versus 25.4 +/- 1.5 pmol/l, p < 0.001, and pancreatic insulin concentration, 60.5 +/- 2.5 versus 49.0 +/- 2.6 ng/mg of tissue, P < 0.01, compared with wild-type mice. Transgenic mice derived from blastocyst transfer to wild-type foster mothers had an elevated pancreatic insulin content similar to that seen in pups from transgenic mice. There was an age-related decline in pancreatic insulin content and plasma insulin levels and an increase in fasting blood glucose concentrations, such that adult transgenic mice had significantly less pancreatic insulin than wild-type mice. Pancreatic islet number and the size of mature islets were increased in transgenic animals at birth compared with wild-type mice. Both islet cell proliferation, measured by 5-bromo-2'-deoxyuridine labeling, and apoptosis, assessed by the in situ terminal deoxynucleotidyl transferase and nick translation assay, were increased in islets of newborn transgenic mice compared with wild-type mice. In adult mice both islet cell proliferation and apoptosis were low and similar in transgenic and wild-type mice. Islets remained significantly larger and more numerous in adult transgenic mice despite a reduction in pancreatic insulin content. These data suggest that overexpression of IGFBP-1, either directly or indirectly via local or systemic mechanisms, has a positive trophic effect on islet development.

  5. An Exercise‐Only Intervention in Obese Fathers  Restores Glucose and Insulin Regulation in  Conjunction with the Rescue of Pancreatic Islet Cell  Morphology and MicroRNA Expression in Male  Offspring

    Directory of Open Access Journals (Sweden)

    Nicole O. McPherson

    2017-02-01

    Full Text Available Paternal obesity programs metabolic syndrome in offspring. Low‐impact exercise in obese  males improves the metabolic health of female offspring, however whether this occurred in male  offspring remained unknown. C57BL/6NHsd (Harlan mice were fed a control diet (CD; 6% fat, n =  7 or a high‐fat diet (HFD; 21% fat, n = 16 for 18 weeks. After 9 weeks, HFD‐fed mice either remained  sedentary (HH, n = 8 or undertook low–moderate exercise (HE, n = 8 for another 9 weeks. Male  offspring were assessed for glucose/insulin tolerance, body composition, plasma lipids, pancreatic  islet cell morphology and microRNA expression. Founder HH induced glucose intolerance, insulin  insensitivity, and hyperlipidaemia in male offspring (p < 0.05. Metabolic health was fully restored  in male offspring by founder exercise to control levels. Founder HH reduced pancreatic β‐cell area  and islet cell size in male offspring, and altered the expression of 13 pancreatic microRNAs (p <  0.05. Founder HE led to partial restoration of pancreatic islet cell morphology and the expression  of two pancreatic microRNAs (let7d‐5p, 194‐5p in male offspring. Founder HE reduced male  offspring adiposity, increased muscle mass, reduced plasma free fatty acids (FFAs, and further  altered pancreatic microRNAs (35 vs. HH; 32 vs. CD (p < 0.05. Low‐impact exercise in obese fathers  prior to conception, without dietary change, may be a viable intervention strategy to reduce the illeffects of obesity‐induced paternal programming in male offspring.

  6. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  7. Cell therapy for avascular osteonecrosis of femoral head

    Directory of Open Access Journals (Sweden)

    Tomoki Aoyama

    2009-04-01

    Full Text Available Avascular osteonecrosis of femoral head causes severe musculoskeletal disability. There is not standard treatment to cure avascular osteonecrosis.? Recently, cell therapy using bone marrow stromal cells has begun for this disease.

  8. Cell therapy for avascular osteonecrosis of femoral head

    OpenAIRE

    Tomoki Aoyama; Junya Toguchida

    2009-01-01

    Avascular osteonecrosis of femoral head causes severe musculoskeletal disability. There is not standard treatment to cure avascular osteonecrosis.? Recently, cell therapy using bone marrow stromal cells has begun for this disease.

  9. Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow.

    Directory of Open Access Journals (Sweden)

    Raphael P H Meier

    Full Text Available Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow and 10 days (kidney capsule. Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.

  10. Pancreatic effects of GLP-1

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2014-01-01

    -dependent manner. But perhaps equally importantly, GLP-1’s glucose lowering effects are attributable to a strong inhibition of glucagon secretion, and, thereby, a reduction of hepatic glucose output. The effects of GLP-1 on insulin secretion are mediated by binding of the hormone to the receptor (GLP-1r......) on the pancreatic β-cell, which increases intracellular cAMP levels and sets in motion a plethora of events that lead to secretion. In contrast, the inhibitory effect of GLP-1 on the α-cell may be indirect, involving paracrine intra-islet regulation by somatostatin and possibly also insulin, although GLP-1 also...... inhibits glucagon secretion in patients with type 1 diabetes mellitus. Besides these acute effects on the endocrine pancreas, GLP-1 also appears to have a positive effect on β-cell mass. In the following we will review GLP-1’s pancreatic effects with particular focus on its effects on pancreatic islets...

  11. Avascular necrosis of bone complicating corticosteroid replacement therapy.

    OpenAIRE

    Williams, P L; Corbett, M

    1983-01-01

    Two patients who developed widespread severe avascular necrosis of bone while on steroid replacement therapy are described. One, a diabetic, underwent yttrium-90 pituitary ablation for retinopathy and developed avascular necrosis within 18 months of starting prednisolone. The other, who had Addison's disease, developed avascular necrosis within 14 months of starting cortisol replacement therapy. Both cases came to bilateral total hip replacement.

  12. Intra- and Inter-islet Synchronization of Metabolically Driven Insulin Secretion

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram; Bertram, Richard; Sherman, Arthur

    2005-01-01

    Insulin secretion from pancreatic beta-cells is pulsatile with a period of 5-10 min and is believed to be responsible for plasma insulin oscillations with similar frequency. To observe an overall oscillatory insulin pro. le it is necessary that the insulin secretion from individual beta......-cells is synchronized within islets, and that the population of islets is also synchronized. We have recently developed a model in which pulsatile insulin secretion is produced as a result of calcium-driven electrical oscillations in combination with oscillations in glycolysis. We use this model to investigate possible...... mechanisms for intra-islet and inter-islet synchronization. We show that electrical coupling is sufficient to synchronize both electrical bursting activity and metabolic oscillations. We also demonstrate that islets can synchronize by mutually entraining each other by their effects on a simple model "liver...

  13. Analysis of pancreas tissue in a child positive for islet cell antibodies.

    Science.gov (United States)

    Oikarinen, M; Tauriainen, S; Honkanen, T; Vuori, K; Karhunen, P; Vasama-Nolvi, C; Oikarinen, S; Verbeke, C; Blair, G E; Rantala, I; Ilonen, J; Simell, O; Knip, M; Hyöty, H

    2008-10-01

    Type 1 diabetes is caused by an immune-mediated process, reflected by the appearance of autoantibodies against pancreatic islets in the peripheral circulation. Detection of multiple autoantibodies predicts the development of diabetes, while positivity for a single autoantibody is a poor prognostic marker. The present study assesses whether positivity for a single autoantibody correlates with pathological changes in the pancreas. We studied post mortem pancreatic tissue of a child who repeatedly tested positive for islet cell antibodies (ICA) in serial measurements. Paraffin sections were stained with antibodies specific for insulin, glucagon, somatostatin, interferon alpha, CD3, CD68, cyclooxygenase-2 (COX-2), beta-2-microglobulin, coxsackie B and adenovirus receptor (CAR), natural killer and dendritic cells. Apoptosis was detected using Fas-specific antibody and TUNEL assay. Enterovirus was searched for using immunohistochemistry and in situ hybridisation, as well as enterovirus-specific RT-PCR from serum samples. The structure of the pancreas did not differ from normal. The number of beta cells was not reduced and no signs of insulitis were observed. Beta-2-microglobulin and CAR were strongly produced in the islets, but not in the exocrine pancreas. Enterovirus protein was detected selectively in the islets by two enterovirus-specific antibodies, but viral RNA was not found. These observations suggest that positivity for ICA alone, even when lasting for more than 1 year, is not associated with inflammatory changes in the islets. However, it is most likely that the pancreatic islets were infected by an enterovirus in this child.

  14. Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin-1 deficient mice.

    Directory of Open Access Journals (Sweden)

    Carl Johan Drott

    Full Text Available Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1, that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  15. Hereditary Pancreatitis

    Science.gov (United States)

    ... E-News Sign-Up Home Hereditary Pancreatitis Hereditary Pancreatitis Hereditary Pancreatitis (HP) is a rare genetic condition characterized by ... of pancreatic attacks, which can progress to chronic pancreatitis . Symptoms include abdominal pain, nausea, and vomiting. Onset ...

  16. A pancreatic cyst of the anterior mediastinum.

    Science.gov (United States)

    Perez-Ordonez, B; Wesson, D E; Smith, C R; Asa, S L

    1996-03-01

    Although heterotopia of pancreatic tissue is a developmental anomaly found in approximately 2% of all autopsies, pancreatic tissue within the thorax and mediastinum is uncommon. In most of these instances, the pancreatic acini and islets are components of gastroenteric duplication cysts, intralobar pulmonary sequestrations, or teratomas. We describe the clinicopathologic features and hormonal profile of a patient with an anterior mediastinal cyst formed entirely by pancreatic tissue. To our knowledge, the English literature reveals only two previous examples of this lesion. The patient, a previously healthy 16-year-old girl, was found to have a cystic lesion in the anterior mediastinum during investigation of an asymptomatic heart murmur. The lesion measured 12 cm in maximal diameter and contained dark, turbid fluid. The wall was fibrotic and contained a haphazard mixture of ducts, exocrine acini, and islets. In many areas, the ducts and islets formed ductuloinsular complexes resembling those seen in diffuse nesidioblastosis. Immunohistochemical examination showed that the islets contained an increased number of B and PP cells, recapitulating the hormonal profile of the ventral anlage of the fetal pancreas. The similarity between this lesion and a fetal pancreas was further supported by the presence of a significant number of islet cells containing gastrin. The histogenesis of this lesion is unclear; we think that this lesion represents a derivative of the ventral (anterior) primitive foregut, but unidirectional differentiation of a benign cystic teratoma cannot be excluded.

  17. PACAP inhibits β-cell mass expansion in a mouse model of type II diabetes: persistent suppressive effects on islet density

    Directory of Open Access Journals (Sweden)

    Hiroaki eInoue

    2013-03-01

    Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP is a potent insulinotropic G-protein-coupled receptor ligand, for which morphoregulative roles in pancreatic islets have recently been suggested. Here, we evaluated the effects of pancreatic overexpression of PACAP on morphometric changes of islets in a severe type II diabetes model. Following cross-breeding of obese-diabetic model KKAy mice with mice overexpressing PACAP in their pancreatic β-cells, the resulting KKAy mice with or without PACAP transgene (PACAP/+:Ay/+ or Ay/+ mice were fed with a high-fat diet up to the age of 11 months. Pancreatic sections from 5 and 11 month old littermates were examined. Histomorphometric analyses revealed significant suppression of islet mass expansion in PACAP/+:Ay/+ mice compared with Ay/+ mice at 11 months, but no significant difference between PACAP/+ and +/+ (wild-type mice, as previously reported. The suppressed islet mass in PACAP/+:Ay/+ mice was due to a decrease in islet density but not islet size. In addition, the density of tiny islets (<0.001 mm2 and of insulin-positive clusters in ductal structures were markedly decreased in PACAP/+:Ay/+ mice compared with Ay/+ mice at 5 months of age. In contrast, PACAP overexpression caused no significant effects on the level of aldehyde-fuchsin reagent staining (a measure of β-cell granulation or the volume and localization of glucagon-positive cells in the pancreas. These results support previously reported inhibitory effects of PACAP on pancreatic islet mass expansion, and suggest it has persistent suppressive effects on pancreatic islet density which may be related with ductal cell-associated islet neogenesis in type II diabetes.

  18. Pleiotropic effects of GIP on islet function involve osteopontin

    DEFF Research Database (Denmark)

    Lyssenko, Valeriya; Eliasson, Lena; Kotova, Olga

    2011-01-01

    The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits...... Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function....

  19. Improved staging of patients with carcinoid and islet cell tumors with F-18-dihydroxy-phenyl-alanine and C-11-5-hydroxy-tryptophan positron emission tomography

    NARCIS (Netherlands)

    Koopmans, Klaas P.; Neels, Oliver C.; Kema, Ido P.; Elsinga, Philip H.; Sluiter, Wim J.; Vanghillewe, Koen; Brouwers, Adrienne H.; Jager, Pieter L.; de Vries, Elisabeth G. E.

    2008-01-01

    Purpose To evaluate and compare diagnostic sensitivity of positron emission tomography (PET) scanning in carcinoid and islet cell tumor patients with a serotonin and a catecholamine precursor as tracers. Patients and Methods Carcinoid (n = 24) or pancreatic islet cell tumor (n = 23) patients with at

  20. MRI study of avascular necrosis of the knee

    International Nuclear Information System (INIS)

    Simizu, Koh; Suguro, Toru; Tsuchiya, Akihiro; Moriya, Hideshige; Nishikawa, Satoru; Arimizu, Noboru

    1990-01-01

    Magnetic resonance (MR) images of 70 joints were reviewed in 38 patients with avascular necrosis of the knee or hip joint, whose ages ranged from 19 to 62 years with an average of 41 years. According to causes, steroid induced avascular necrosis was the commonest, accounting for 87% of cases. The remainer of the cases were alcoholic avascular necrosis (8%) and idiopathic avascular necrosis (5%). Steroid induced avascular necrosis was greatly different from idiopathic avascular necrosis in view of clinical manifestations, common sites, and complications of femur head necrosis. Idiopathic avascular necrosis was common in the central part of internal condyle and was confined to one joint. Steroid induced avascular necrosis was common in the posterior part of external condyle and was frequently associated with multiple necroses of the diaphysis. Seventy five percent of the cases were associated with avascular necrosis of the knee. The diagnostic accuracy of the other imaging modalities in avascular necrosis was low (33% for plain roentgenography and 50% for RI examination). Thus, MR was the imaging procedure of choice for detecting avascular necrotic lesions. (N.K.)

  1. Avascular necrosis ofbone following renal transplantation

    African Journals Online (AJOL)

    include a direct toxic effect on bone, alcohol-induced calcium diuresis, poor nutritional status, hypogonadism and reduced physical'activity. Pre-existing or persistent hyperparathyroidism after transplantation is regarded by some authors7 as playing an important role in the pathogenesis of avascular necrosis. It is speculated ...

  2. [Pancreatic neuroendocrine tumours. What do we know of their history?].

    Science.gov (United States)

    Navarro, Salvador

    2016-04-01

    Starting with Paul Langerhans, who first described pancreatic islets in 1869, this article reviews the various protagonists who, in the last century and a half, have contributed to the discovery of the main hormones originating in the pancreas, the analytical methods for their measurement, the imaging techniques for identifying tumoural location, and the various pancreatic neoplasms. Copyright © 2015. Published by Elsevier Espana.

  3. Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys.

    Directory of Open Access Journals (Sweden)

    Lindsey E Nicol

    Full Text Available Polycystic ovary syndrome (PCOS is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype.

  4. Abnormal Infant Islet Morphology Precedes Insulin Resistance in PCOS-Like Monkeys

    Science.gov (United States)

    Nicol, Lindsey E.; O’Brien, Timothy D.; Dumesic, Daniel A.; Grogan, Tristan; Tarantal, Alice F.; Abbott, David H.

    2014-01-01

    Polycystic ovary syndrome (PCOS) is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA) exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT) obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype. PMID:25207967

  5. Abnormal islet sphingolipid metabolism in type 1 diabetes.

    Science.gov (United States)

    Holm, Laurits J; Krogvold, Lars; Hasselby, Jane P; Kaur, Simranjeet; Claessens, Laura A; Russell, Mark A; Mathews, Clayton E; Hanssen, Kristian F; Morgan, Noel G; Koeleman, Bobby P C; Roep, Bart O; Gerling, Ivan C; Pociot, Flemming; Dahl-Jørgensen, Knut; Buschard, Karsten

    2018-04-18

    Sphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice. We examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development. We found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals. These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. The RNA expression data is

  6. Effects of methyl mercury on the activity and gene expression of mouse Langerhans islets and glucose metabolism.

    Science.gov (United States)

    Maqbool, Faheem; Bahadar, Haji; Niaz, Kamal; Baeeri, Maryam; Rahimifard, Mahban; Navaei-Nigjeh, Mona; Ghasemi-Niri, Seyedeh Farnaz; Abdollahi, Mohammad

    2016-07-01

    Mercury (Hg) is a well-known heavy metal and causes various toxic effects. It is abundantly present in fish in the form of methyl mercury (MeHg). Also, various other forms of mercury can enter human body either from environment like inhalation or through dental amalgams. The present study was designed to assess MeHg induced toxicity in mouse plasma and pancreatic islets with respect to insulin secretion, oxidative balance, glucose tolerance, gene expression, caspases 3 and 9 activities. MeHg was dissolved in tap water and administered at doses 2.5, 5 and 10 mg/kg/day, for 4 weeks. In mice, MeHg significantly caused increase in plasma insulin as well as C-peptides. Glucose intolerance, insulin resistance and hyperglycemia are main consequences of our study that correlate with the gene expression changes of glucose homeostasis as well. MeHg caused increase lipid peroxidation in a dose-dependent manner in plasma as well as pancreatic islets. In addition, total thiol molecules and ferrous reducing antioxidant power in MeHg treated group was decreased in plasma as well as pancreatic islets. Caspases 3 and 9 activities of pancreatic islets were upregulated in MeHg exposed animals. Reactive oxygen species were extremely high in pancreatic islets of MeHg treated groups. MeHg disrupted gluconeogenesis/glycogenolysis pathways and insulin secretory functions of islets by targeting GDH, GLUT2 and GCK genes of pancreatic islets. In conclusion, the current study revealed that insulin pathways, oxidative balance and glucose metabolism encoded genetic makeup are susceptible to MeHg toxicity and the subsequent oxidative stress and alternations in gene expression could lead toward functional abnormalities in other organs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas.

    Science.gov (United States)

    Kim, Hyo-Sup; Lee, Moon-Kyu

    2016-05-01

    Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β-cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β-cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin-producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β-cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β-cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin-producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin-producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin-producing cells, especially duct and acinar cells.

  8. Chronic fetal hypoglycemia inhibits the later steps of stimulus-secretion coupling in pancreatic beta-cells.

    Science.gov (United States)

    Rozance, Paul J; Limesand, Sean W; Zerbe, Gary O; Hay, William W

    2007-05-01

    We measured the impact of chronic late gestation hypoglycemia on pancreatic islet structure and function to determine the cause of decreased insulin secretion in this sheep model of fetal nutrient deprivation. Late gestation hypoglycemia did not decrease pancreas weight, insulin content, beta-cell area, beta-cell mass, or islet size. The pancreatic islet isolation procedure selected a group of islets that were larger and had an increased proportion of beta-cells compared with islets measured in pancreatic sections, but there were no morphologic differences between islets isolated from control and hypoglycemic fetuses. The rates of glucose-stimulated pancreatic islet glucose utilization (126.2 +/- 25.3 pmol glucose.islet(-1).h(-1), hypoglycemic, vs. 93.5 +/- 5.5 pmol glucose.islet(-1).h(-1), control, P = 0.47) and oxidation (10.5 +/- 1.7 pmol glucose.islet(-1).h(-1), hypoglycemic, vs. 10.6 +/- 1.6 pmol glucose.islet(-1).h(-1), control) were not different in hypoglycemic fetuses compared with control fetuses. Chronic late gestation hypoglycemia decreased insulin secretion in isolated pancreatic islets by almost 70% in response to direct nonnutrient membrane depolarization and in response to increased extracellular calcium entry. beta-Cell ultrastructure was abnormal with markedly distended rough endoplasmic reticulum in three of the seven hypoglycemic fetuses studied, but in vitro analysis of hypoglycemic control islets showed no evidence that these changes represented endoplasmic reticulum stress, as measured by transcription of glucose regulatory protein-78 and processing of X-box binding protein-1. In conclusion, these studies show that chronic hypoglycemia in late gestation decreases insulin secretion by inhibiting the later steps of stimulus-secretion coupling after glucose metabolism, membrane depolarization, and calcium entry.

  9. PROSPECTS OF APPLICATION OF TISSUE-ENGINEERED PANCREATIC CONSTRUCTS IN THE TREATMENT OF TYPE 1 DIABETES

    Directory of Open Access Journals (Sweden)

    G. N. Skaletskaya

    2016-01-01

    Full Text Available Allotransplantation of pancreatic islets remains the most effective method of treatment of diabetes mellitus type 1 being capable under combination of favorable conditions (suffi cient number of isolated islets, effective combination of immunosuppressive drugs to reach the recipients’ insulin independence for several years. However, the overwhelming shortage of donor pancreas and limited post-transplantation islet survival do not allow increasing the number of such transplants and their effectiveness. This review presents a critical analysis of the work done by Russian and foreign authors onto creation of tissue-engineered pancreatic constructs that may lead to the resolution of the three main pancreatic islet transplantation issues: 1 lack of donor material; 2 necessity of immunosuppressive therapy; 3 limited survival and functional activity of the islet.

  10. Robot-assisted pancreatoduodenectomy with preservation of the vascular supply for autologous islet cell isolation and transplantation: a case report

    Directory of Open Access Journals (Sweden)

    Giulianotti Piero

    2012-03-01

    Full Text Available Abstract Introduction For patients with chronic pancreatitis presenting with medically intractable abdominal pain, surgical intervention may be the only treatment option. However, extensive pancreatic resections are typically performed open and are associated with a substantial amount of postoperative pain, wound complications and long recovery time. Minimally invasive surgery offers an avenue to improve results; however, current limitations of laparoscopic surgery render its application in the setting of chronic pancreatitis technically demanding. Additionally, pancreatic resections are associated with a high incidence of diabetes. Transplantation of islets isolated from the resected pancreas portion offers a way to prevent post-surgical diabetes; however, preservation of the vascular supply during pancreatic resection, which determines islet cell viability, is technically difficult using current laparoscopic approaches. With recent advances in the surgical field, robotic surgery now provides a means to overcome these obstacles to achieve the end goals of pain relief and preserved endocrine function. We present the first report of a novel, minimally invasive robotic approach for resection of the pancreatic head that preserves vascular supply and enables the isolation of a high yield of viable islets for transplantation. Case presentation A 35-year old Caucasian woman presented with intractable chronic abdominal pain secondary to chronic pancreatitis, with a stricture of her main pancreatic duct at the level of the ampulla of Vater and distal dilatation. She was offered a robotic-assisted pylorus-preserving pancreatoduodenectomy and subsequent islet transplantation, to both provide pain relief and preserve insulin-secretory reserves. Conclusion We present a novel, minimally invasive robotic approach for resection of the pancreatic head with complete preservation of the vascular supply, minimal warm ischemia time (less than three minutes and

  11. Autoantibodies in chronic pancreatitis

    DEFF Research Database (Denmark)

    Rumessen, J J; Marner, B; Pedersen, N T

    1985-01-01

    In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane, and reti......In 60 consecutive patients clinically suspected of having chronic pancreatitis the serum concentration of the immunoglobulins (IgA, IgG, IgM), the IgG- and IgA-type non-organ-specific autoantibodies against nuclear material (ANA), smooth and striated muscle, mitochondria, basal membrane......, and reticulin, and the IgG- and IgA-type pancreas-specific antibodies against islet cells, acinus cells, and ductal cells (DA) were estimated blindly. In 23 of the patients chronic pancreatitis was verified, whereas chronic pancreatitis was rejected in 37 patients (control group). IgG and IgA were found...... in significantly higher concentrations in the patients with chronic pancreatitis than in the control group but within the normal range. ANA and DA occurred very frequently in both groups but with no statistical difference. Other autoantibodies only occurred sporadically. The findings of this study do not support...

  12. [Avascular necrosis of the femoral head].

    Science.gov (United States)

    Porubský, Peter; Trč, Tomáš; Havlas, Vojtěch; Smetana, Pavel

    Avascular necrosis of the femoral head in adults is not common, but not too rare diseases. In orthopedic practice, it is one of the diseases that are causing implantation of hip replacement at a relatively early age. In the early detection and initiation of therapy can delay the implantation of prosthesis for several years, which is certainly more convenient for the patient and beneficial. This article is intended to acquaint the reader with the basic diagnostic procedures and therapy.

  13. Comparison of modified Celsior solution and M-kyoto solution for pancreas preservation in human islet isolation.

    Science.gov (United States)

    Noguchi, Hirofumi; Naziruddin, Bashoo; Onaca, Nicholas; Jackson, Andrew; Shimoda, Masayuki; Ikemoto, Tetsuya; Fujita, Yasutaka; Kobayashi, Naoya; Levy, Marlon F; Matsumoto, Shinichi

    2010-01-01

    Since the successful demonstration of the Edmonton protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas preservation systems. In this study, we evaluated two different types of organ preservation solutions for human islet isolation. Modified Celsior (Celsior solution with hydroxyethyl starch and nafamostat mesilate; HNC) solution and modified Kyoto (MK) solution were compared for pancreas preservation prior to islet isolation. Islet yield after purification was significantly higher in the MK group than in the HNC group (MK = 6186 ± 985 IE/g; HNC = 3091 ± 344 IE/g). The HNC group had a longer phase I period (digestion time), a higher volume of undigested tissue, and a higher percentage of embedded islets, suggesting that the solution may inhibit collagenase. However, there was no significant difference in ATP content in the pancreata or in the attainability of posttransplant normoglycemia in diabetic nude mice between the two groups, suggesting that the quality of islets was similar among the two groups. In conclusion, MK solution is better for pancreas preservation before islet isolation than HNC solution due to the higher percentage of islets that can be isolated from the donor pancreas. MK solution should be the solution of choice among the commercially available solutions for pancreatic islet isolation leading to transplantation.

  14. Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker.

    Science.gov (United States)

    Bellin, M D; Clark, P; Usmani-Brown, S; Dunn, T B; Beilman, G J; Chinnakotla, S; Pruett, T L; Ptacek, P; Hering, B J; Wang, Z; Gilmore, T; Wilhelm, J J; Hodges, J S; Moran, A; Herold, K C

    2017-04-01

    Beta cell death may occur both after islet isolation and during infusion back into recipients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis. We measured the novel beta cell death marker unmethylated insulin (INS) DNA in TPIAT recipients before and immediately after islet infusion (n = 21) and again 90 days after TPIAT, concurrent with metabolic functional assessments (n = 25). As expected, INS DNA decreased after pancreatectomy (p = 0.0002). All TPIAT recipients had an elevated unmethylated INS DNA ratio in the first hours following islet infusion. In four samples (three patients), INS DNA was also assessed immediately after islet isolation and again before islet infusion to assess the impact of the isolation process: Unmethylated and methylated INS DNA fractions both increased over this interval, suggesting death of beta cells and exocrine tissue before islet infusion. Higher glucose excursion with mixed-meal tolerance testing was associated with persistently elevated INS DNA at day 90. In conclusion, we observed universal early elevations in the beta cell death marker INS DNA after TPIAT, with pronounced elevations in the islet supernatant before infusion, likely reflecting beta cell death induced by islet isolation. Persistent posttransplant elevation of INS DNA predicted greater hyperglycemia at 90 days. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  15. The Beta Cell in Its Cluster: Stochastic Graphs of Beta Cell Connectivity in the Islets of Langerhans.

    Directory of Open Access Journals (Sweden)

    Deborah A Striegel

    2015-08-01

    Full Text Available Pancreatic islets of Langerhans consist of endocrine cells, primarily α, β and δ cells, which secrete glucagon, insulin, and somatostatin, respectively, to regulate plasma glucose. β cells form irregular locally connected clusters within islets that act in concert to secrete insulin upon glucose stimulation. Due to the central functional significance of this local connectivity in the placement of β cells in an islet, it is important to characterize it quantitatively. However, quantification of the seemingly stochastic cytoarchitecture of β cells in an islet requires mathematical methods that can capture topological connectivity in the entire β-cell population in an islet. Graph theory provides such a framework. Using large-scale imaging data for thousands of islets containing hundreds of thousands of cells in human organ donor pancreata, we show that quantitative graph characteristics differ between control and type 2 diabetic islets. Further insight into the processes that shape and maintain this architecture is obtained by formulating a stochastic theory of β-cell rearrangement in whole islets, just as the normal equilibrium distribution of the Ornstein-Uhlenbeck process can be viewed as the result of the interplay between a random walk and a linear restoring force. Requiring that rearrangements maintain the observed quantitative topological graph characteristics strongly constrained possible processes. Our results suggest that β-cell rearrangement is dependent on its connectivity in order to maintain an optimal cluster size in both normal and T2D islets.

  16. Phorbol-ester-induced down-regulation of protein kinase C in mouse pancreatic islets. Potentiation of phase 1 and inhibition of phase 2 of glucose-induced insulin secretion

    DEFF Research Database (Denmark)

    Thams, P; Capito, K; Hedeskov, C J

    1990-01-01

    (45-55 min) was increased from 12.9 +/- 1.5 (4)% in controls to 35.8 +/- 3.9 (4)% in TPA-treated islets (P less than 0.01), and the percentage released during phase 2 (65-85 min) was decreased from 63.2 +/- 3.9 (4)% to 35.3 +/- 1.4 (4)% (P less than 0.005). In contrast, TPA exposure in TCM 199 medium...... (5.5 mM-glucose, 1.26 mM-Ca2+) caused a total abolition of both phases 1 and 2 of glucose-induced secretion. However, inclusion of the alpha 2-adrenergic agonists adrenaline (10 microM) or clonidine (10 microM), or lowering of the Ca2+ concentration in TCM 199 during down-regulation, preserved...

  17. Indomethacin induced avascular necrosis of head of femur

    Science.gov (United States)

    Prathapkumar, K; Smith, I; Attara, G

    2000-01-01

    Chemically induced avascular necrosis of bone is a well documented entity. Indomethacin is one of the causes of this condition but is often difficult to recognise. Review of the literature shows that only one case of indomethacin induced avascular necrosis has been reported in the English language between 1966 and the present.
The case of a young healthy man, who developed avascular necrosis of head of femur after prolonged administration of indomethacin, is reported here.


Keywords: indomethacin; avascular necrosis PMID:10964124

  18. Sequential radionuclide bone imaging in avascular pediatric hip conditions

    International Nuclear Information System (INIS)

    Minikel, J.; Sty, J.; Simons, G.

    1983-01-01

    Radionuclide bone imaging was performed on six patients with various hip conditions. Initial bone images revealed diminished uptake of isotope /sup 99m/Tc-MDP in the capital femoral epiphysis. Following therapeutic intervention, repeat bone scans revealed normal uptake of /sup 99m/Tc-MDP in the capital femoral epiphysis. Subsequent radiographs revealed that avascular necrosis had not occurred. There are two types of avascularity: the potentially reversible, and the irreversible. Attempts should be made toward early recognition of the potentially reversible avascular insult. With early recognition, surgical reconstruction prior to osteophyte death may result in revascularization. If this can be accomplished, avascular necrosis can be avoided

  19. Identification of avascular necrosis in the dysplastic proximal femoral epiphysis

    International Nuclear Information System (INIS)

    Mandell, G.A.; Harcke, H.T.; MacKenzie, W.G.; Bassett, G.S.; Scott, C.I. Jr.; Wills, J.S.

    1989-01-01

    Bilateral radiographic irregularities and deformities of the proximal femoral epiphyses are features of both multiple epiphyseal dysplasia and bilateral idiopathic avascular necrosis. In the past these entities have been difficult to differentiate. This report documents radiographically the occurrence of avascular necrosis in 10 patients with multiple epiphyseal dysplasia by recognizing the superimposition of sclerosis and subchondral fissuring on pre-existing symmetrically irregular proximal femoral ossification centers. Scintigraphic (photopenia) or magnetic resonance (loss of signal) criteria of avascular necrosis confirm its added presence and help to establish an imaging scheme to identify avascular necrosis superimposed on multiple epiphyseal dysplasia. (orig.)

  20. 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

    The inhibitory neurotransmitter GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD) in neurons and in pancreatic β-cells in islets of Langerhans where it functions as a paracrine and autocrine signaling molecule regulating the function of islet endocrine cells. The localization...

  1. 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

    islets, whereas only GAD64 mRNA was detected in human islets. Immunocytochemical analysis of rat and human pancreatic sections or isolated islets with antibodies to GAD64 and GAD67 in combination with antibodies to insulin, glucagon, or SRIF confirmed that a GAD64 and GAD67 expression were beta......The GABA synthesizing enzyme GAD is a prominent islet cell autoantigen in type I diabetes. The two forms of GAD (GAD64 and GAD67) are encoded by different genes in both rats and humans. By in situ hybridization analysis of rat and human pancreases, expression of both genes was detected in rat...... as observed in vivo, whereas GAD67 was localized not only to the beta-cells but also in the alpha-cells and delta-cells. A small but distinct fraction of GAD positive cells in these monolayer cultures did not accumulate GABA immunoreactivity, which may indicate cellular heterogeneity with respect to GABA...

  2. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets

    International Nuclear Information System (INIS)

    Kanno, Ayumi; Asahara, Shun-ichiro; Masuda, Katsuhisa; Matsuda, Tomokazu; Kimura-Koyanagi, Maki; Seino, Susumu; Ogawa, Wataru; Kido, Yoshiaki

    2015-01-01

    A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic β-cells after high fat load, such as increased pancreatic β-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic β-cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage of insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic β-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic β-cells. - Highlights: • More stored insulin was recognized in islets of mice fed a high-fat diet. • Insulin translation was not enhanced by fatty acids, but by insulin demand. • Insulin transcription was not altered in islets of mice fed a high-fat diet. • Insulin translation was markedly enhanced in islets of mice fed a high-fat diet. • Non-radioisotope chemicals were used to measure insulin translation in mouse islets

  3. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets

    Energy Technology Data Exchange (ETDEWEB)

    Kanno, Ayumi, E-mail: akanno@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Asahara, Shun-ichiro, E-mail: asahara@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Masuda, Katsuhisa, E-mail: katsuhisa.m.0707@gmail.com [Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe 654-0142 (Japan); Matsuda, Tomokazu, E-mail: tomokazu@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Kimura-Koyanagi, Maki, E-mail: koyanagi@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Seino, Susumu, E-mail: seino@med.kobe-u.ac.jp [Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0047 (Japan); Ogawa, Wataru, E-mail: ogawa@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Kido, Yoshiaki, E-mail: kido@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017 (Japan); Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe 654-0142 (Japan)

    2015-03-13

    A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic β-cells after high fat load, such as increased pancreatic β-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic β-cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage of insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic β-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic β-cells. - Highlights: • More stored insulin was recognized in islets of mice fed a high-fat diet. • Insulin translation was not enhanced by fatty acids, but by insulin demand. • Insulin transcription was not altered in islets of mice fed a high-fat diet. • Insulin translation was markedly enhanced in islets of mice fed a high-fat diet. • Non-radioisotope chemicals were used to measure insulin translation in mouse islets.

  4. Sustained NF-κB activation and inhibition in β-cells have minimal effects on function and islet transplant outcomes.

    Directory of Open Access Journals (Sweden)

    Aileen J F King

    Full Text Available The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation. Transgenic mice expressing a dominant active IKKβ (constitutively active or a non-degradable form of IκBα (constitutive inhibition under control of the rat insulin promoter were generated. Islets from these mice were transplanted into streptozotocin diabetic mice in suboptimal numbers. Further, the effects of salicylate (an inhibitor of NF-κB treatment of normal islets prior to transplantation, and the effects of salicylate administration to mice prior to and after islet implantation were evaluated. Transplantation outcomes were not affected using islets expressing a non-degradable form of IκBα when compared to wild type controls. However, the transplantation outcomes using islets isolated from mice expressing a constitutively active mutant of NF-κB were marginally worse, although no aberrations of islet function in vitro could be detected. Salicylate treatment of normal islets or mice had no effect on transplantation outcome. The current study draws attention to the complexities of NF-κB in pancreatic beta cells by suggesting that they can adapt with normal or near normal function to both chronic activation and inhibition of this important transcription factor.

  5. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes

    DEFF Research Database (Denmark)

    Bacos, Karl; Gillberg, Linn; Volkov, Petr

    2016-01-01

    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA...... methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes...... identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we...

  6. Application of Rotating Wall Vessel (RWV) Cell Culture for Pancreas Islet Cell Transplantation

    Science.gov (United States)

    Rutzky, Lynne P.

    1998-01-01

    Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.

  7. Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

    DEFF Research Database (Denmark)

    Kofod, Hans; Lernmark, A; Hedeskov, C J

    1986-01-01

    Column perifusion of mouse pancreatic islets was used to study the ability of amino acids and their methyl esters to influence insulin release and activate islet glutamate dehydrogenase activity. In the absence of L-glutamine, L-serine and the methyl ester of L-phenylalanine, but neither L...... glutamate dehydrogenase activity showed that only the two methyl esters of L-phenylalanine and L-serine activated the enzyme. It is concluded that the mechanism by which methyl esters of amino acids potentiate insulin release is most likely to be mediated by the activation of pancreatic beta-cell glutamate...

  8. Insulin resistance alters islet morphology in nondiabetic humans

    DEFF Research Database (Denmark)

    Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio

    2014-01-01

    Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects...... pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared...... insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from...

  9. Somatostatin receptor expression and biological functions in endocrine pancreatic cells: review based on a doctoral thesis.

    Science.gov (United States)

    Ludvigsen, Eva

    2007-01-01

    Type 1 diabetes is resulting from the selective destruction of insulin-producing betacells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5). All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species. The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction. Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via costimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect. In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of

  10. Avascular necrosis of bone following renal transplantation | Naiker ...

    African Journals Online (AJOL)

    Alcohol conswnption and radiological evidence of osteoporosis were more prevalent in the avascular necrosis group (42,8% v. 29,0% and 28,5% v. 7,2% respectively). Avascular necrosis did not correlate with age, sex, renal function at 1 year or severe secondary hyperparathyroidism. This study suggests that corticosteroid ...

  11. Atraumatic Pantalar Avascular Necrosis in a Patient With Alcohol Dependence.

    Science.gov (United States)

    Callachand, Fayaz; Milligan, David; Wilson, Alistair

    2016-01-01

    In the United States, an estimated 10,000 to 20,000 new cases of avascular necrosis are diagnosed each year. We present an unusual case of atraumatic avascular necrosis with widespread hindfoot and midfoot involvement. A 62-year-old female with a history of alcohol dependence and smoking, who had previously been treated for avascular necrosis of the knee, presented with right-sided foot pain and difficulty weightbearing. Imaging studies revealed extensive avascular necrosis of the hindfoot and midfoot, which precluded simple surgical intervention. The patient was followed up for 18 months. In the last 8 months of the 18-month period, the patient managed her symptoms using an ankle-foot orthosis. A diagnosis of avascular necrosis should be considered in patients with atraumatic foot and ankle pain, especially in the presence of risk factors such as alcohol excess and smoking. Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

  12. A Case of Trapezium Avascular Necrosis Treated Conservatively.

    Science.gov (United States)

    Petsatodis, Evangelos; Ditsios, Konstantinos; Konstantinou, Panagiotis; Pinto, Iosafat; Kostretzis, Lazaros; Theodoroudis, Ioannis; Pilavaki, Mayia

    2017-01-01

    Avascular necrosis (AVN) of the bones of the wrist most commonly involves the lunate followed by the proximal pole of the scaphoid and the capitate. Trapezium avascular necrosis is extremely rare with only two cases reported in the literature, both of which were treated surgically. In this article, we report a unique case of trapezium avascular necrosis treated conservatively. A 38-year-old man complaining of a 4-month history of mild pain on the base of his right thumb. MRI scan was performed. The clinical presentation and the imaging findings indicated avascular osteonecrosis of the trapezium. The patient was treated with immobilization of the wrist joint for a period of six weeks. Three months later, the patient was free of symptoms and the MRI scan revealed a normal trapezium. AVN of trapezium is extremely rare. Our case shows that immobilization of an early stage avascular necrosis of the trapezium might be a treatment option.

  13. Insulin secretion and glucose uptake by isolated islets of the hamster

    International Nuclear Information System (INIS)

    Dunbar, J.C.; McLaughlin, W.J.; Walsh, M.F.J.; Foa, P.P.

    1976-01-01

    Isolated pancreatic islets of normal hamsters were perfused either in a closed or in a open system. When the buffer was recirculated and the endogenous insulin was allowed to accumulate, the islets secreted significantly less insulin than when the system was open and the endogenous insulin was washed away. The addition of monocomponent insulin or of proinsulin to the perfusion buffer significantly decreased insulin secretion. The inhibitory action of proinsulin was significantly greater than that of monocomponent insulin. C peptide had no effect. When pancreatic islets were incubated in a fixed volume of stationary buffer containing unlabeled glucose (1.0 mg or 3.0 mg/ml) and glucose-U- 14 C (1.0 μC/ml), the amount of insulin secreted and the 14 CO 2 produced by each islet decreased progressively as the number of islets in the sample increased. Under these conditions, the concentration of insulin required to inhibit insulin secretion increased with the concentration of glucose in the medium. Proinsulin did not alter the incorporation of leucine-4.5- 3 H into total extractable insulin (insulin + proinsulin). Thus, insulin and proinsulin appear to inhibit insulin release, but not insulin synthesis. (orig.) [de

  14. Contrast-enhanced helical CT of the pancreas. Optimal timing of imaging for pancreatic tumor evaluation

    International Nuclear Information System (INIS)

    Koide, Kazuki; Sekiguchi, Ryuzo

    2001-01-01

    We performed three-phase helical CT in patients suspected pancreatic tumors and investigated the optimal timing of imaging for evaluation of the pancreatic mass. The pancreatic-phase was superior in detecting pancreatic tumors, including islet cell tumors that may show strong enhancement. However, portal vein-phase imaging was also superior in 16.7% of our patients. Taking into account examination for hepatic metastasis, helical CT of any pancreatic tumor should include images obtained in the pancreatic and portal vein phases. (author)

  15. Pancreatic Cysts

    Science.gov (United States)

    ... enzymes become prematurely active and irritate the pancreas (pancreatitis). Pseudocysts can also result from injury to the ... alcohol use and gallstones are risk factors for pancreatitis, and pancreatitis is a risk factor for pseudocysts. ...

  16. Pancreatic Cancer

    Science.gov (United States)

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  17. Acute pancreatitis

    Science.gov (United States)

    ... its blood vessels. This problem is called acute pancreatitis. Acute pancreatitis affects men more often than women. Certain ... well it can be treated. Complications of acute pancreatitis may include: Acute kidney failure Long-term lung damage (ARDS) Buildup ...

  18. The hyperbolic effect of density and strength of inter beta-cell coupling on islet bursting: a theoretical investigation

    Directory of Open Access Journals (Sweden)

    Wang Xujing

    2008-08-01

    Full Text Available Abstract Background Insulin, the principal regulating hormone of blood glucose, is released through the bursting of the pancreatic islets. Increasing evidence indicates the importance of islet morphostructure in its function, and the need of a quantitative investigation. Recently we have studied this problem from the perspective of islet bursting of insulin, utilizing a new 3D hexagonal closest packing (HCP model of islet structure that we have developed. Quantitative non-linear dependence of islet function on its structure was found. In this study, we further investigate two key structural measures: the number of neighboring cells that each β-cell is coupled to, nc, and the coupling strength, gc. Results β-cell clusters of different sizes with number of β-cells nβ ranging from 1–343, nc from 0–12, and gc from 0–1000 pS, were simulated. Three functional measures of islet bursting characteristics – fraction of bursting β-cells fb, synchronization index λ, and bursting period Tb, were quantified. The results revealed a hyperbolic dependence on the combined effect of nc and gc. From this we propose to define a dimensionless cluster coupling index or CCI, as a composite measure for islet morphostructural integrity. We show that the robustness of islet oscillatory bursting depends on CCI, with all three functional measures fb, λ and Tb increasing monotonically with CCI when it is small, and plateau around CCI = 1. Conclusion CCI is a good islet function predictor. It has the potential of linking islet structure and function, and providing insight to identify therapeutic targets for the preservation and restoration of islet β-cell mass and function.

  19. Hyaluronan and Hyaluronan-Binding Proteins Accumulate in Both Human Type 1 Diabetic Islets and Lymphoid Tissues and Associate With Inflammatory Cells in Insulitis

    Science.gov (United States)

    Bogdani, Marika; Johnson, Pamela Y.; Potter-Perigo, Susan; Nagy, Nadine; Day, Anthony J.; Bollyky, Paul L.

    2014-01-01

    Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that is present in pancreatic islets, but little is known about its involvement in the development of human type 1 diabetes (T1D). We have evaluated whether pancreatic islets and lymphoid tissues of T1D and nondiabetic organ donors differ in the amount and distribution of HA and HA-binding proteins (hyaladherins), such as inter-α-inhibitor (IαI), versican, and tumor necrosis factor–stimulated gene-6 (TSG-6). HA was dramatically increased both within the islet and outside the islet endocrine cells, juxtaposed to islet microvessels in T1D. In addition, HA was prominent surrounding immune cells in areas of insulitis. IαI and versican were present in HA-rich areas of islets, and both molecules accumulated in diabetic islets and regions exhibiting insulitis. TSG-6 was observed within the islet endocrine cells and in inflammatory infiltrates. These patterns were only observed in tissues from younger donors with disease duration of <10 years. Furthermore, HA and IαI amassed in follicular germinal centers and in T-cell areas in lymph nodes and spleens in T1D patients compared with control subjects. Our observations highlight potential roles for HA and hyaladherins in the pathogenesis of diabetes. PMID:24677718

  20. In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Daniel J Moore

    2010-10-01

    Full Text Available Insulin-dependent Type 1 diabetes (T1D is a devastating autoimmune disease that destroys beta cells within the pancreatic islets and afflicts over 10 million people worldwide. These patients face life-long risks for blindness, cardiovascular and renal diseases, and complications of insulin treatment. New therapies that protect islets from autoimmune destruction and allow continuing insulin production are needed. Increasing evidence regarding the pathomechanism of T1D indicates that islets are destroyed by the relentless attack by autoreactive immune cells evolving from an aberrant action of the innate, in addition to adaptive, immune system that produces islet-toxic cytokines, chemokines, and other effectors of islet inflammation. We tested the hypothesis that targeting nuclear import of stress-responsive transcription factors evoked by agonist-stimulated innate and adaptive immunity receptors would protect islets from autoimmune destruction.Here we show that a first-in-class inhibitor of nuclear import, cSN50 peptide, affords in vivo islet protection following a 2-day course of intense treatment in NOD mice, which resulted in a diabetes-free state for one year without apparent toxicity. This nuclear import inhibitor precipitously reduces the accumulation of islet-destructive autoreactive lymphocytes while enhancing activation-induced cell death of T and B lymphocytes derived from autoimmune diabetes-prone, non-obese diabetic (NOD mice that develop T1D. Moreover, in this widely used model of human T1D we noted attenuation of pro-inflammatory cytokine and chemokine production in immune cells.These results indicate that a novel form of immunotherapy that targets nuclear import can arrest inflammation-driven destruction of insulin-producing beta cells at the site of autoimmune attack within pancreatic islets during the progression of T1D.

  1. Gene expression in rat models for inter-generational transmission of islet dysfunction and obesity

    Directory of Open Access Journals (Sweden)

    Ruby C.Y. Lin

    2014-12-01

    Full Text Available Paternal high fat diet (HFD consumption triggers unique gene signatures, consistent with premature aging and chronic degenerative disorders, in both white adipose tissue (RpWAT and pancreatic islets of daughters. In addition to published data in Nature, 2010, 467, 963–966 (GSE: 19877, islet and FASEB J 2014, 28, 1830–1841 (GSE: 33551, RpWAT, we describe here additional details on systems-based approaches and analysis to develop our observations. Our data provides a resource for exploring the complex molecular mechanisms that underlie intergenerational transmission of obesity.

  2. Cytokines cause functional and structural damage to isolated islets of Langerhans

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Bendtzen, K; Bendixen, G

    1985-01-01

    Cytokines are soluble, antigen non-specific, non-immunoglobulin mediators produced and secreted by blood mononuclear cells interacting in the cellular immune-response. To test the possibility that cytokines participate in the autoimmune destruction of the pancreatic beta-cells leading to insulin-......-release, and contents of insulin and glucagon in islets incubated with cytokine-rich supernatants were markedly reduced. This impairment of islet function was due to a cytotoxic effect of cytokine-rich supernatants as judged by disintegration of normal light-microscopic morphology....

  3. Growth hormone is a growth factor for the differentiated pancreatic beta-cell

    DEFF Research Database (Denmark)

    Linde, S; Welinder, B S; Billestrup, N

    1989-01-01

    The regulation of the growth of the pancreatic beta-cell is poorly understood. There are previous indications of a role of GH in the growth and insulin production of the pancreatic islets. In the present study we present evidence for a direct long-term effect of GH on proliferation and insulin...... biosynthesis of pancreatic beta-cells in monolayer culture. In culture medium RPMI 1640 supplemented with 2% normal human serum islets or dissociated islet cells from newborn rats maintained their insulin-producing capacity. When supplemented with 1-1000 ng/ml pituitary or recombinant human GH the islet cells...... was accompanied with a continuous increase in insulin release to the culture medium reaching a 10- 20-fold increase after 2-3 months with a half-maximal effect at about 10 ng/ml human GH. The biosynthesis of (pro)insulin was markedly increased with a normal rate of conversion of proinsulin to insulin...

  4. Acute Pancreatitis and Pregnancy

    Science.gov (United States)

    ... Information Acute Pancreatitis Acute Pancreatitis and Pregnancy Acute Pancreatitis and Pregnancy Timothy Gardner, MD Acute pancreatitis is ... of acute pancreatitis in pregnancy. Reasons for Acute Pancreatitis and Pregnancy While acute pancreatitis is responsible for ...

  5. GeneSpeed Beta Cell: An Online Genomics Data Repository and Analysis Resource Tailored for the Islet Cell Biologist

    Directory of Open Access Journals (Sweden)

    Nayeem Quayum

    2008-01-01

    Full Text Available Objective. We here describe the development of a freely available online database resource, GeneSpeed Beta Cell, which has been created for the pancreatic islet and pancreatic developmental biology investigator community. Research Design and Methods. We have developed GeneSpeed Beta Cell as a separate component of the GeneSpeed database, providing a genomics-type data repository of pancreas and islet-relevant datasets interlinked with the domain-oriented GeneSpeed database. Results. GeneSpeed Beta Cell allows the query of multiple published and unpublished select genomics datasets in a simultaneous fashion (multiexperiment viewing and is capable of defining intersection results from precomputed analysis of such datasets (multidimensional querying. Combined with the protein-domain categorization/assembly toolbox provided by the GeneSpeed database, the user is able to define spatial expression constraints of select gene lists in a relatively rigid fashion within the pancreatic expression space. We provide several demonstration case studies of relevance to islet cell biology and development of the pancreas that provide novel insight into islet biology. Conclusions. The combination of an exhaustive domain-based compilation of the transcriptome with gene array data of interest to the islet biologist affords novel methods for multidimensional querying between individual datasets in a rapid fashion, presently not available elsewhere.

  6. Avascular necrosis of the femoral head presenting as trochanteric bursitis.

    Science.gov (United States)

    Mandell, B F

    1990-01-01

    Five patients are described with avascular necrosis of the femoral head who presented with ipsilateral trochanteric bursitis, in the absence of clearcut hip joint disease. Avascular necrosis was indicated by magnetic resonance imaging. It is suggested that clinical trochanteric bursitis, especially when refractory to local corticosteroid treatment, may be the initial sign of hip disease. In the patient with risk factor(s) for avascular necrosis that diagnosis should be considered and evaluated with appropriate studies, such as magnetic resonance imaging, to prevent weight bearing at an early stage and permit possible surgical decompression in the hope of postponing or obviating the need for total hip replacement. PMID:2241294

  7. Avascular necrosis of the trapezoid bone following carpometacarpal arthroplasty.

    Science.gov (United States)

    Kane, Patrick; Waryasz, Greg; Katarincic, Julie

    2014-03-03

    A 58-year-old female developed avascular necrosis of her trapezoid approximately 3 months after undergoing carpometacarpal arthroplasty. The patient was treated conservatively with immobilization and had complete resolution of her clinical symptoms during her year of follow-up. Additionally, radiographic examination showed complete restoration of the height of her trapezoid approximately 1 year after the index procedure. Avascular necrosis of the trapezoid is extremely rare with very few cases described in the literature. This is the first description of avascular necrosis following carpometacarpal arthroplasty.

  8. Avascular osteonecrosis of the femoral condyle after arthroscopic surgery

    International Nuclear Information System (INIS)

    Al-Kaar, M.; Garcia, J.; Fritschy, D.; Bonvin, J.C.

    1997-01-01

    Avascular osteonecrosis of the femoral condyle after arthroscopic surgery. Retrospective review of 10 patients who presented with avascular necrosis of the ipsilateral femoral condyle following arthroscopic meniscectomy (9 medial, 1 lateral). The bone lesions were evaluated by radiography and MRI, which were repeated for few patients. MRI allows earlier diagnosis of avascular necrosis of the femoral condyle and offers an evaluation of extent of the lesions whose evolution is variable: 3 patients required a knee prosthesis, the other 7 patients were treated medically. (authors)

  9. Avascular necrosis of the femoral head

    International Nuclear Information System (INIS)

    Kokubo, Takashi; Takatori, Yoshio; Ninomiya, Setsuo; Sasaki, Yasuhito

    1993-01-01

    Magnetic resonance (MR) images and conventional radiographs were compared in 142 hips with avascular necrosis, and a staging system for the disease based on MR imaging was developed. MR images were classified into three patterns: a band of low signal intensity (class I); an area of low signal intensity with internal spot(s) of high signal (class II); and an area of low signal intensity without internal spots of high signal (class III). Most MR class I lesions were in radiographic stage I (normal) or II (sclerotic or cystic changes without collapse). Most MR class II lesions were in radiographic stage III (segmental collapse), and most MR class III lesions were in stage III or IV (secondary degenerative changes). The MR image classification was closely correlated with radiographic staging (p<0.01, using χ square test). We considered that this classification closely reflected the different stages of the disease according to the histopathology of the bone marrow. (author)

  10. Altered TNF-Alpha, Glucose, Insulin and Amino Acids in Islets Langerhans Cultured in a Microgravity Model System

    Science.gov (United States)

    Tobin, Brian W.; Leeper-Woodford, Sandra K.; Hashemi, Brian B.; Smith, Scott M.; Sams, Clarence F.

    2001-01-01

    The present studies were designed to determine effects of a microgravity model system upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) activity and indices of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1726+/-1 17,150 u IEU) from Wistar Furth rats were treated as: 1) HARV (High Aspect Ratio Vessel cell culture) , 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (pinsulin concentration was demonstrated in the LPS stimulated HARV culture (palterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV. These alterations in fuel homeostasis may be promulgated by gravity averaged cell culture methods or by three dimensional cell assembly.

  11. Potentiation of insulin release in response to amino acid methyl esters correlates to activation of islet glutamate dehydrogenase activity

    DEFF Research Database (Denmark)

    Kofod, Hans; Lernmark, A; Hedeskov, C J

    1986-01-01

    Column perifusion of mouse pancreatic islets was used to study the ability of amino acids and their methyl esters to influence insulin release and activate islet glutamate dehydrogenase activity. In the absence of L-glutamine, L-serine and the methyl ester of L-phenylalanine, but neither L......-phenylalanine nor L-serine methyl ester, stimulate insulin secretion. In the presence of L-glutamine, however, the effect of L-serine was additive, while the methyl esters of L-serine and L-phenylalanine as well as native L-phenylalanine, potentiated the glucose-stimulated release of insulin. Measurements of islet...... glutamate dehydrogenase activity showed that only the two methyl esters of L-phenylalanine and L-serine activated the enzyme. It is concluded that the mechanism by which methyl esters of amino acids potentiate insulin release is most likely to be mediated by the activation of pancreatic beta-cell glutamate...

  12. Recent progress in the use and tracking of transplanted islets as a personalized treatment for type 1 diabetes

    NARCIS (Netherlands)

    Paredes-Juarez, Genaro A; de Vos, Paul; Bulte, Jeff W M

    2017-01-01

    Introduction: Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which the pancreas produces insufficient amounts of insulin. T1DM patients require exogenous sources of insulin to maintain euglycemia. Transplantation of naked or microencapsulated pancreatic islets represents an alternative

  13. Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    J. W. M. Höppener

    2008-01-01

    Full Text Available Human islet amyloid polypeptide (hIAPP, a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2. To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.

  14. Cytokines cause functional and structural damage to isolated islets of Langerhans

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Bendtzen, K; Bendixen, G

    1985-01-01

    Cytokines are soluble, antigen non-specific, non-immunoglobulin mediators produced and secreted by blood mononuclear cells interacting in the cellular immune-response. To test the possibility that cytokines participate in the autoimmune destruction of the pancreatic beta-cells leading to insulin......-dependent diabetes mellitus, isolated human or rat islets of Langerhans were incubated for 7 days with cytokine-rich, cell-free supernatants of blood mononuclear cells from healthy human donors stimulated with or without purified protein derivative of tuberculin or phytohaemagglutinin. Glucose stimulated insulin......-release, and contents of insulin and glucagon in islets incubated with cytokine-rich supernatants were markedly reduced. This impairment of islet function was due to a cytotoxic effect of cytokine-rich supernatants as judged by disintegration of normal light-microscopic morphology....

  15. Long-term effect of pH on B-cell function in isolated islets of Langerhans in tissue culture

    DEFF Research Database (Denmark)

    Brunstedt, J; Nielsen, Jens Høiriis

    1978-01-01

    Collagenase isolated mouse pancreatic islets were maintained in tissue culture for up to 5 months in a culture medium buffered with Hepes and the pH varying between 6.8 and 7.6. The amount of insulin released into the medium and the insulin response to glucose and glucose plus theophylline were...... measured during the culture period. It was found that islets cultured at pH 7.2 maintained the ability to release insulin into the medium for at least 5 months, which was longer than islets cultured at the other pH values. During the first weeks, the islets cultured at pH 7.6 had a higher response to both...... glucose and glucose plus theophylline than islets cultured at the other pH values, but later they lost their insulin releasing ability....

  16. Effects of Imatinib Mesylate (Gleevec) on Human Islet NF-kappaB Activation and Chemokine Production In Vitro

    Science.gov (United States)

    Mokhtari, Dariush; Li, Tingting; Lu, Tao; Welsh, Nils

    2011-01-01

    Purpose Imatinib Mesylate (Gleevec) is a drug that potently counteracts diabetes both in humans and in animal models for human diabetes. We have previously reported that this compound in human pancreatic islets stimulates NF-κB signaling and islet cell survival. The aim of this study was to investigate control of NF-κB post-translational modifications exerted by Imatinib and whether any such effects are associated with altered islet gene expression and chemokine production in vitro. Procedures Human islets were either left untreated or treated with Imatinib for different timepoints. IκB-α and NF-κB p65 phosphorylation and methylation were assessed by immunoblot analysis. Islet gene expression was assessed using a commercial Pathway Finder microarray kit and RT-PCR. Islet chemokine production was determined by flow cytometric bead array analysis. Findings Human islet IκB-α and Ser276-p65 phosphorylation were increased by a 20 minute Imatinib exposure. Methylation of p65 at position Lys221 was increased after 60 min of Imatinib exposure and persisted for 3 hours. Microarray analysis of islets exposed to Imatinib for 4 hours revealed increased expression of the inflammatory genes IL-4R, TCF5, DR5, I-TRAF, I-CAM, HSP27 and IL-8. The islet release of IL-8 was augmented in islets cultured over night in the presence of Imatinib. Following 30 hours of Imatinib exposure, the cytokine-induced IκB-α and STAT1 phosphorylation was abolished and diminished, respectively. The cytokine-induced release of the chemokines MIG and IP10 was lower in islets exposed to Imatinib for 30 hours. Conclusion Imatinib by itself promotes a modest activation of NF-κB. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-κB preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation. PMID:21935477

  17. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats

    International Nuclear Information System (INIS)

    Lubaczeuski, C.; Balbo, S.L.; Ribeiro, R.A.; Vettorazzi, J.F.; Santos-Silva, J.C.; Carneiro, E.M.; Bonfleur, M.L.

    2015-01-01

    The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca 2+ mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca 2+ mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats

  18. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats

    Energy Technology Data Exchange (ETDEWEB)

    Lubaczeuski, C.; Balbo, S.L. [Laboratório de Fisiologia Endócrina e Metabolismo, Centro de Ciências Biológicas e da Saúde, Universidade Estadual do Oeste do Paraná, Cascavel, PR (Brazil); Ribeiro, R.A. [Universidade Federal do Rio de Janeiro, Macaé, RJ (Brazil); Vettorazzi, J.F.; Santos-Silva, J.C.; Carneiro, E.M. [Laboratório de Pâncreas Endócrino e Metabolismo, Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP (Brazil); Bonfleur, M.L. [Laboratório de Fisiologia Endócrina e Metabolismo, Centro de Ciências Biológicas e da Saúde, Universidade Estadual do Oeste do Paraná, Cascavel, PR (Brazil)

    2015-02-24

    The parasympathetic nervous system is important for β-cell secretion and mass regulation. Here, we characterized involvement of the vagus nerve in pancreatic β-cell morphofunctional regulation and body nutrient homeostasis in 90-day-old monosodium glutamate (MSG)-obese rats. Male newborn Wistar rats received MSG (4 g/kg body weight) or saline [control (CTL) group] during the first 5 days of life. At 30 days of age, both groups of rats were submitted to sham-surgery (CTL and MSG groups) or subdiaphragmatic vagotomy (Cvag and Mvag groups). The 90-day-old MSG rats presented obesity, hyperinsulinemia, insulin resistance, and hypertriglyceridemia. Their pancreatic islets hypersecreted insulin in response to glucose but did not increase insulin release upon carbachol (Cch) stimulus, despite a higher intracellular Ca{sup 2+} mobilization. Furthermore, while the pancreas weight was 34% lower in MSG rats, no alteration in islet and β-cell mass was observed. However, in the MSG pancreas, increases of 51% and 55% were observed in the total islet and β-cell area/pancreas section, respectively. Also, the β-cell number per β-cell area was 19% higher in MSG rat pancreas than in CTL pancreas. Vagotomy prevented obesity, reducing 25% of body fat stores and ameliorated glucose homeostasis in Mvag rats. Mvag islets demonstrated partially reduced insulin secretion in response to 11.1 mM glucose and presented normalization of Cch-induced Ca{sup 2+} mobilization and insulin release. All morphometric parameters were similar among Mvag and CTL rat pancreases. Therefore, the higher insulin release in MSG rats was associated with greater β-cell/islet numbers and not due to hypertrophy. Vagotomy improved whole body nutrient homeostasis and endocrine pancreatic morphofunction in Mvag rats.

  19. Radiological contrast media and pancreatic blood perfusion in anesthetized rats.

    Science.gov (United States)

    Linder, G; Carlsson, P O; Källskog, Ö; Hansell, P; Jansson, L; Riesenfeld Källskog, V

    2007-12-01

    Radiological contrast media (CM) have been suggested to be able to impair pancreatic microcirculation. To evaluate the effects of an iso-osmolar (iodixanol, 290 mOsm/kg H2O) and a low-osmolar (iopromide, 660 mOsm/kg H2O) CM on total pancreatic and islet blood perfusion. Thiobutabarbital-anesthetized rats were injected with iodine equivalent doses (600 mg I/kg body weight) of iodixanol or iopromide. Saline or low-osmolar mannitol (660 mOsm/kg H2O) solutions served as control substances. Blood perfusion measurements were then carried out with a microsphere technique. Iso-osmolar iodixanol had no effects on blood perfusion. Low-osmolar iopromide increased total pancreatic blood perfusion, whereas islet blood perfusion was unchanged. No differences were seen when mannitol solutions were given. Neither an iso-osmolar nor a low-osmolar CM affected pancreatic islet blood perfusion, whereas the low-osmolar CM increased total pancreatic blood perfusion. The absence of hemodynamic effect of low-osmolar mannitol suggests that the hyperosmolality per se of iopromide versus iodixanol does not induce the hemodynamic effect. The consequences of the effect of iopromide for pancreatic function remain to be established.

  20. Metabolic aspects of neonatal rat islet hypoxia tolerance.

    Science.gov (United States)

    Hyder, Ayman; Laue, Christiane; Schrezenmeir, Jürgen

    2010-01-01

    Sensitivity of pancreatic islets to hypoxia is one of the most important of the obstacles responsible for their failure to survive within the recipients. The aim of this study was to compare the in vitro hypoxia tolerance of neonatal and adult rat islet cells and to study the glucose metabolism in these cells after exposure to hypoxia. Islet cells from both age categories were cultured in different hypoxic levels for 24 h and insulin secretion and some metabolites of glucose metabolism were analysed. Glucose-stimulated insulin secretion decreased dramatically in both cell preparations in response to the decrease in oxygen level. The reduction of insulin secretion was more detectable in adult cells and started at 5% O(2), while a significant reduction was obtained at 1% O(2) in neonatal cells. Moreover, basal insulin release of neonatal cells showed an adaptation to hypoxia after a 4-day culture in hypoxia. Intracellular pyruvate was higher in neonatal cells than in adult ones, while no difference in lactate level was observed between them. Similar results to that of pyruvate were observed for adenosine triphosphate (ATP) and the second messenger cyclic adenosine monophosphate (cAMP). The study reveals that neonatal rat islet cells are more hypoxia-tolerant than the adult ones. The most obvious metabolic observation was that both pyruvate and lactate were actively produced in neonatal cells, while adult cells depended mainly on lactate production as an end-product of glycolysis, indicating a more enhanced metabolic flexibility of neonatal cells to utilize the available oxygen and, at the same time, maintain metabolism anaerobically.

  1. Minireview: Directed Differentiation and Encapsulation of Islet β-Cells-Recent Advances and Future Considerations.

    Science.gov (United States)

    Tse, Hubert M; Kozlovskaya, Veronika; Kharlampieva, Eugenia; Hunter, Chad S

    2015-10-01

    Diabetes mellitus has rapidly become a 21st century epidemic with the promise to create vast economic and health burdens, if left unchecked. The 2 major forms of diabetes arise from unique causes, with outcomes being an absolute (type 1) or relative (type 2) loss of functional pancreatic islet β-cell mass. Currently, patients rely on exogenous insulin and/or other pharmacologies that restore glucose homeostasis. Although these therapies have prolonged countless lives over the decades, the striking increases in both type 1 and type 2 diabetic diagnoses worldwide suggest a need for improved treatments. To this end, islet biologists are developing cell-based therapies by which a patient's lost insulin-producing β-cell mass is replenished. Pancreatic or islet transplantation from cadaveric donors into diabetic patients has been successful, yet the functional islet demand far surpasses supply. Thus, the field has been striving toward transplantation of renewable in vitro-derived β-cells that can restore euglycemia. Challenges have been numerous, but progress over the past decade has generated much excitement. In this review we will summarize recent findings that have placed us closer than ever to β-cell replacement therapies. With the promise of cell-based diabetes therapies on the horizon, we will also provide an overview of cellular encapsulation technologies that will deliver critical protection of newly implanted cells.

  2. Islet amyloid polypeptide in the control of food intake : An experimental study in the rat

    OpenAIRE

    Arnelo, Urban

    1997-01-01

    Control of food intake and satiety are physiologically complex processes, thatonly partly are understood. Several hormonal peptides have been proposed to mediatesatiety. Islet amyloid polypeptide (IAPP) is a recently discovered 37 amino acidpeptide, mainly produced by the pancreatic ß-cells. Initially, IAPP was shownto impair glucose tolerance at supra-physiological plasma concentrations and wasspeculated to be involved in the development of type-2 diabetes. More recent stud...

  3. Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes

    Science.gov (United States)

    Nyalwidhe, Julius O.; Gallagher, Glen R.; Glenn, Lindsey M.; Morris, Margaret A.; Vangala, Pranitha; Jurczyk, Agata; Bortell, Rita; Harlan, David M.; Nadler, Jerry L.

    2017-01-01

    Enteroviral infections have been associated with the development of type 1 diabetes (T1D), a chronic inflammatory disease characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Cultured human islets, including the insulin-producing beta cells, can be infected with coxsackievirus B4 (CVB4) and thus are useful for understanding cellular responses to infection. We performed quantitative mass spectrometry analysis on cultured primary human islets infected with CVB4 to identify molecules and pathways altered upon infection. Corresponding uninfected controls were included in the study for comparative protein expression analyses. Proteins were significantly and differentially regulated in human islets challenged with virus compared with their uninfected counterparts. Complementary analyses of gene transcripts in CVB4-infected primary islets over a time course validated the induction of RNA transcripts for many of the proteins that were increased in the proteomics studies. Notably, infection with CVB4 results in a considerable decrease in insulin. Genes/proteins modulated during CVB4 infection also include those involved in activation of immune responses, including type I interferon pathways linked to T1D pathogenesis and with antiviral, cell repair, and inflammatory properties. Our study applies proteomics analyses to cultured human islets challenged with virus and identifies target proteins that could be useful in T1D interventions. PMID:29264452

  4. Avascular necrosis of the femoral head

    International Nuclear Information System (INIS)

    Kokubo, Takeshi; Takatori, Yoshio; Kamogawa, Morihide; Nakamura, Toshitaka; Ninomiya, Setsuo; Yoshikawa, Kohki; Itai, Yuji; Iio, Masahiro; Mitamura, Tadayuki

    1990-01-01

    T1-weighted MR images of thirty-six hips in 25 patients with avascular necrosis of the femoral head were obtained two to five times during the course of 2 to 26 months. We investigated these MR images in the light of the chronological change and compared them with plain radiographs. MR images changes in 16 femoral head; in general, the abnormal low intensity area in the femoral head reduced in extent and the internal high intensity area became smaller of disappeared. Thirteen femoral heads among them became more flattened on plain radiographs in the same period. It is noted that four different zones are defined in the femoral head after bone necrosis takes place: the dead bone marrow, the dead marrow which still contains fat, the reactive interface and the hyperemic bone marrow. In T1-weighted MR images, the dead bone marrow, the reactive interface and the hyperemic bone marrow are demonstrated as low intensity area, while the dead marrow containing fat may remain high in intensity. On the basis of this knowledge of histopathology and MR images of this disease, we suggest that reduction of the abnormal low intensity area and disappearance of the internal high intensity area on MR images can be regarded as diminution of hyperemia in the living bone marrow and loss of fat in the dead bone marrow, respectively. (author)

  5. An avascular necrosis in Gaucher's disease

    International Nuclear Information System (INIS)

    Mansberg, R.; Uren, R.; Howman-Giles, R.

    1999-01-01

    Full text: Avascular necrosis is frequently associated with sickle cell disease and other haemoglobinopathies. It is less commonly associated with Gaucher's disease. A case with multi-modality imaging is presented. A 33-year-old male patient presented with a 4-day history of severe right knee pain. He was a febrile with mild swelling of the right knee. A diagnosis of Gaucher's disease had been made by bone marrow biopsy on a clinical picture of hepatosplenomegaly and thrombocytopenia some years earlier. A radiograph of the knee demonstrated an Erlenmeyer flask deformity of the distal femur. A bone scan demonstrated reduced perfusion to the distal right femoral shaft and femoral condyles. Delayed images demonstrated decreased tracer uptake in the distal right femur extending to the right medial femoral condyle consistent with a vascular necrosis. An MRI of the thighs demonstrated lipid accumulation in the marrow space of both femora consistent with Gaucher's disease associated with changes of bone oedema in the metadiaphysis and epiphysis of the right femur. The patient was treated with supportive measures and made an uneventful recovery and is being commenced on enzyme replacement therapy (Algucerase)

  6. Pancreatitis - children

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007679.htm Pancreatitis - children To use the sharing features on this page, please enable JavaScript. Pancreatitis in children occurs when the pancreas becomes swollen ...

  7. Pancreatitis - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100149.htm Pancreatitis - series—Normal anatomy To use the sharing features ... A.M. Editorial team. Related MedlinePlus Health Topics Pancreatitis A.D.A.M., Inc. is accredited by ...

  8. Complicated Pancreatitis

    NARCIS (Netherlands)

    Bakker, O.J.

    2015-01-01

    Research questions addressed in this thesis: What is the accuracy of serum blood urea nitrogen as early predictor of complicated pancreatitis? ; What is difference in clinical outcome between patients with pancreatic parenchymal necrosis and patients with extrapancreatic necrosis without necrosis

  9. Incorporation of bone marrow cells in pancreatic pseudoislets improves posttransplant vascularization and endocrine function.

    Directory of Open Access Journals (Sweden)

    Christine Wittig

    Full Text Available Failure of revascularization is known to be the major reason for the poor outcome of pancreatic islet transplantation. In this study, we analyzed whether pseudoislets composed of islet cells and bone marrow cells can improve vascularization and function of islet transplants. Pancreatic islets isolated from Syrian golden hamsters were dispersed into single cells for the generation of pseudoislets containing 4×10(3 cells. To create bone marrow cell-enriched pseudoislets 2×10(3 islet cells were co-cultured with 2×10(3 bone marrow cells. Pseudoislets and bone marrow cell-enriched pseudoislets were transplanted syngeneically into skinfold chambers to study graft vascularization by intravital fluorescence microscopy. Native islet transplants served as controls. Bone marrow cell-enriched pseudoislets showed a significantly improved vascularization compared to native islets and pseudoislets. Moreover, bone marrow cell-enriched pseudoislets but not pseudoislets normalized blood glucose levels after transplantation of 1000 islet equivalents under the kidney capsule of streptozotocin-induced diabetic animals, although the bone marrow cell-enriched pseudoislets contained only 50% of islet cells compared to pseudoislets and native islets. Fluorescence microscopy of bone marrow cell-enriched pseudoislets composed of bone marrow cells from GFP-expressing mice showed a distinct fraction of cells expressing both GFP and insulin, indicating a differentiation of bone marrow-derived cells to an insulin-producing cell-type. Thus, enrichment of pseudoislets by bone marrow cells enhances vascularization after transplantation and increases the amount of insulin-producing tissue. Accordingly, bone marrow cell-enriched pseudoislets may represent a novel approach to increase the success rate of islet transplantation.

  10. Angiotensin converting enzyme-independent, local angiotensin II-generation in human pancreatic ductal cancer tissues.

    Science.gov (United States)

    Ohta, Tetsuo; Amaya, Kohji; Yi, Shuangqin; Kitagawa, Hirohisa; Kayahara, Masato; Ninomiya, Itasu; Fushida, Sachio; Fujimura, Takashi; Nishimura, Gen-Ichi; Shimizu, Koichi; Miwa, Koichi

    2003-09-01

    Hypovascularity is an outstanding characteristic of pancreatic ductal cancer by diagnostic imaging: most pancreatic ductal cancers are hypovascular or avascular, and tumor vessels are seldom seen on angiography. However, we found that the vasculature was not always poor on angiography of surgically resected specimens of locally advanced pancreatic ductal cancers. To elucidate these controversial findings, we focused on angiotensin II, a vasoconstrictor which is directly produced from angiotensinogen at acidic pH by active trypsin. We examined whether a local angiotensin II-generating system exists in pancreatic ductal cancer tissue. We measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues from normal pancreas, pancreatic ductal cancers, colon cancers, and hepatocellular carcinomas. After surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and the Kasahara method, respectively. Tissue angiotensin II levels in pancreatic ductal cancer (n=13) were significantly higher than those of normal pancreas (n=7), colon cancers (n=7), or hepatocellular carcinomas (n=7). However, there was no significant difference in the ACE activity in tissue between them. This study provides in vivo evidence of an ACE-independent, angiotensin II-generating system in pancreatic ductal cancer tissues and suggests that locally formed angiotensin II may act on the pre-existing pancreatic arteries around the tumor, leading to formation of hypovascular or avascular regions.

  11. Glucose-induced time-dependent potentiation of insulin release, but not islet blood perfusion, in anesthetized rats.

    Science.gov (United States)

    Jansson, Leif; Bodin, Birgitta; Källskog, Orjan

    2008-01-01

    Repeated administration of glucose in vivo leads to a time-dependent potentiation of insulin release. Glucose is also known to stimulate pancreatic islet blood flow, but whether this is associated with a time-dependent potentiation is unknown. We therefore repeatedly administered glucose to anesthetized rats and evaluated effects on insulin release and islet blood flow. Male Wistar-Furth rats, anesthetized with thiobutabarbital, were injected intravenously with 1 ml of saline or glucose at times 0, 30 and 60 min. The combinations used were saline + saline + saline (SSS), glucose + saline + saline (GSS), saline + saline + glucose (SSG) and glucose + glucose + glucose (GGG). Regional organ blood flow values were measured 3 min after the final injection with a microsphere technique, and at this time also serum insulin concentrations were determined with ELISA. Serum insulin concentrations as well as total pancreatic, pancreatic islet and duodenal blood flow were higher in SSG and GGG-treated rats when compared to those given SSS and GSS. However, only insulin concentrations, not blood flow values, were higher in GGG rats when compared to SSG animals. Glucose-induced time-dependent potentiation of insulin release occurs in vivo in thiobutabarbital-anesthetized rats, but is not associated with a further increase in islet blood flow.

  12. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

    Science.gov (United States)

    D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

    2006-11-01

    Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

  13. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes.

    Science.gov (United States)

    Richardson, Sarah J; Rodriguez-Calvo, Teresa; Gerling, Ivan C; Mathews, Clayton E; Kaddis, John S; Russell, Mark A; Zeissler, Marie; Leete, Pia; Krogvold, Lars; Dahl-Jørgensen, Knut; von Herrath, Matthias; Pugliese, Alberto; Atkinson, Mark A; Morgan, Noel G

    2016-11-01

    Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of β2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both 'classical' HLA class I isoforms (i.e. HLA-ABC) as well as a 'non-classical' HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin-containing islets of patients with recent-onset type 1

  14. Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation.

    Science.gov (United States)

    Jin, Sang-Man; Oh, Seung-Hoon; Oh, Bae Jun; Shim, Wooyoung; Choi, Jin Myung; Yoo, Dongkyeom; Hwang, Yong Hwa; Lee, Jung Hee; Lee, Dong Yun; Kim, Jae Hyeon

    2015-06-01

    There is a clinical need for an alternative labeling agent for magnetic resonance imaging (MRI) in islet transplantation. We aimed to evaluate the feasibility of islet MRI using ferumoxytol, which is the only clinically-available ultrasmall superparamagnetic iron oxide. We compared islet function and viability of control islets and islets labeled with ferumoxytol and/or a heparin-protamine complex (HPF). Efficacy of ferumoxytol labeling was assessed in both ex vivo and in vivo models. Labeling for 48 h with HPF, but not up to 800 μg/mL ferumoxytol, deranged ex vivo islet viability and function. The T2∗ relaxation time was optimal when islets were labeled with 800 μg/mL of ferumoxytol for 48 h. Prussian blue stain, iron content assay, transmission electron microscopy (TEM) supported internalization of ferumoxytol particles. However, the labeling intensity in the ex vivo MRI of islets labeled with ferumoxytol was much weaker than that of islets labeled with ferucarbotran. In syngeneic intraportal islet transplantation, there was a correlation between the total area of visualized islets and the transplanted islet mass. In conclusion, islet MRI using ferumoxytol was feasible in terms of in vitro and in vivo efficacy and safety. However, the weak labeling efficacy is still a hurdle for the clinical application. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Foveal avascular zone area in normal subjects

    Directory of Open Access Journals (Sweden)

    Chang Xu

    2017-03-01

    Full Text Available AIM: To measure the foveal avascular zone(FAZarea and to investigate the characteristics of the FAZ area in normal eyes, using optical coherence tomography(OCTangiography.METHODS: This was a cross-sectional study. The FAZ area was measured in 69 participants, for a total of 138 eyes, using RTVue-100 OCT. The relations between the FAZ area and the potential factors were evaluated by univariate and multivariate linear regression analysis. Differences between the right and left eyes were calculated, and values were compared by means of a paired t test. Pearson correlation analysis was performed to assess the relationships of the FAZ area between the right and left eyes. RESULTS: The mean FAZ area was 0.30±0.11mm2 in all subjects. For the male subjects, the mean FAZ area was 0.29±0.13mm2, and for the female subjects 0.31±0.09mm2, with no significant difference(t=-1.346,P=0.180. The FAZ area did not correlate with all the potential factors. The mean FAZ area in the right eye was 0.30±0.11mm2, and in the left eye was 0.30±0.10mm2,with no significant difference(P=0.943. There was a strong correlation between the right and left eyes for the FAZ area. CONCLUSION: OCT angiography is a noninvasive method of visualizing and measuring the FAZ area in normal subjects. The FAZ area does not correlate with old age, sex and other factors. It shows significant interocular symmetry in normal subjects.

  16. p13 overexpression in pancreatic β-cells ameliorates type 2 diabetes in high-fat-fed mice.

    Science.gov (United States)

    Higashi, Shintaro; Katagi, Kazuhiko; Shintani, Norihito; Ikeda, Kazuya; Sugimoto, Yukihiko; Tsuchiya, Soken; Inoue, Naoki; Tanaka, Shota; Koumoto, Mai; Kasai, Atsushi; Nakazawa, Takanobu; Hayata-Takano, Atsuko; Hamagami, Ken-Ichi; Tomimoto, Shuhei; Yoshida, Takuya; Ohkubo, Tadayasu; Nagayasu, Kazuki; Ago, Yukio; Onaka, Yusuke; Hashimoto, Ryota; Ichikawa, Atsushi; Baba, Akemichi; Hashimoto, Hitoshi

    2015-06-12

    We examined the pancreatic function of p13 encoded by 1110001J03Rik, whose expression is decreased in pancreatic islets in high-fat-fed diabetic mice, by generating transgenic mice overexpressing p13 (p13-Tg) in pancreatic β-cells. p13-Tg mice showed normal basal glucose metabolism; however, under high-fat feeding, these animals showed augmented glucose-induced first-phase and total insulin secretion, improved glucose disposal, greater islet area and increased mitotic insulin-positive cells. In addition, high-fat diet-induced 4-hydroxynonenal immunoreactivity, a reliable marker and causative agent of lipid peroxidative stress, was significantly decreased in p13-Tg mouse islets. These results indicate that p13 is a novel pancreatic factor exerting multiple beneficial effects against type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Cyclooxygenase-2 is overexpressed in chronic pancreatitis.

    Science.gov (United States)

    Schlosser, Wolfgang; Schlosser, Sophia; Ramadani, Marco; Gansauge, Frank; Gansauge, Susanne; Beger, Hans-Günter

    2002-07-01

    Cyclooxygenase enzymes catalyze a critical step in the conversion of arachidonic acid to prostaglandins, which are important mediators of acute and chronic inflammation. The constitutively expressed cyclooxygenase-1 (COX-1) appears to regulate many normal physiologic functions in several cell types, whereas the inducible cyclooxygenase-2 (COX-2) enzyme mediates the inflammatory response. We investigated the expression of COX-2 in tissues of 35 patients with chronic pancreatitis, 6 patients with pancreatic cancer, and 5 control patients by immunohistochemical analysis and correlations to clinicopathologic features. We found an overexpression of COX-2 in the atrophic acinar cells (80% of patients), hyperplastic ductal cells (86% of patients), and islets cells (97% of patients) but not in normal pancreatic tissues. The COX-2 overexpression in the tissue of patients with chronic pancreatitis was significantly correlated with the frequency of acute attacks of pancreatitis. Tissue from patients who had more than five acute attacks of pancreatitis (n = 10) exhibited COX-2 immunoreactivity of a significantly higher score in atrophic acinar cells (p = 0.004). No correlation could be found with other examined clinical features such as duration of the disease, diabetes, alcohol consumption, smoking, or pain. Our results support the hypothesis that COX-2 may be involved in inflammatory responses in chronic pancreatitis and in the progression of this chronic inflammatory disease.

  18. Autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Davorin Dajčman

    2007-05-01

    Full Text Available Background: Autoimmune pancreatitis is a recently described type of pancreatitis of presumed autoimmune etiology. Autoimmune pancreatitis is often misdiagnosed as pancreatic cancer difficult, since their clinical presentations are often similar. The concept of autoimmune pancreatitis was first published in 1961. Since then, autoimmune pancreatitis has often been treated not as an independent clinical entity but rather as a manifestation of systemic disease. The overall prevalence and incidence of the disease have yet to be determined, but three series have reported the prevalence as between 5 and 6 % of all patients with chronic pancreatitis. Patient vary widely in age, but most are older than 50 years. Patients with autoimmune pancreatitis usually complain of the painless jaundice, mild abdominal pain and weight loss. There is no laboratory hallmark of the disease, even if cholestatic profiles of liver dysfunction with only mild elevation of amylase and lipase levels have been reported.Conclusions: Proposed diagnostic criteria contains: (1 radiologic imaging, diffuse enlargement of the pancreas and diffusely irregular narrowing of the main pancreatic duct, (2 laboratory data, elevated levels of serum ã-globulin and/or IgG, specially IgG4, or the presence of autoantibodies and (3 histopathologic examination, fibrotic change with dense lymphoplasmacytic infiltration in the pancreas. For correct diagnosis of autoimmune pancreatitis, criterion 1 must be present with criterion 2 and/or 3. Autoimmune pancreatitis is frequently associated with rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease, tubulointersticial nephritis, primary sclerosing cholangitis and idiopathic retroperitoneal fibrosis. Pancreatic biopsy using an endoscopic ultrasound-guided fine needle aspiration biopsy is the most important diagnostic method today. Treatment with corticosteroids leads to the and resolution of pancreatic inflamation, obstruction and

  19. Femoroacetabular impingement mimicking avascular osteonecrosis on bone scintigraphy

    International Nuclear Information System (INIS)

    Suarez, Juan Pablo; Domínguez, María Luz; Nogareda, Zulema; Gómez, María Asunción; Muñoz, Jose

    2016-01-01

    Femoroacetabular impingement (FAI) is a structural abnormality of proximal femur and/or acetabulum. It has been recently described, and there are limited reports in nuclear medicine literature because bone scintigraphy is not listed in its diagnostic protocol, but it should be included on differential diagnosis when evaluating patients, with hip-related symptoms because it may be misinterpreted as degenerative changes or avascular necrosis, and its early treatment avoid progression to osteoarthritis. We describe the case of a male who suffered from hip pain. Bone planar scintigraphic appearance mimicked avascular necrosis, but single photon emission computed tomography (CT) imaging and CT examination confirmed the diagnosis of FAI

  20. Avascular necrosis of the epiphysis of the first metatarsal bone

    International Nuclear Information System (INIS)

    Souverijns, G.; Peene, P.; Cleeren, P.; Raes, M.; Steenwerckx, A.

    2002-01-01

    We report a case of avascular necrosis of the epiphysis of the right first metatarsal in a 6-year-old boy. Radiographs showed sclerosis, collapse and a crescent sign in the epiphysis. The diagnosis was confirmed by magnetic resonance imaging and scintigraphy. Arch support was the therapy of choice. Six months after the onset of symptoms, a definite reossification was present. To our knowledge, this is the first radiological report of avascular necrosis of the epiphysis of the first metatarsal bone in the world literature, which prompted a review of the osteochondroses and their etiology. (orig.)

  1. MR imaging of avascular necrosis of carpal bones

    International Nuclear Information System (INIS)

    Taniguchi, Yasunori; Funaoka, Nobuhiko; Yoshida, Munehito; Iwahashi, Toshiyuki; Egawa, Hiromitsu; Shima, Kimihiro; Tamaoki, Tetsuya.

    1991-01-01

    The usefulness of MRI in carpal avascular necrosis was investigated in 20 cases, 16 in lunates, 3 in scaphoids and 1 in triquetrum, with T1 and T2 weighted images of the spin echo and T2 weighted images of the field echo. Early diagnosis of carpal bone necrosis was possible when the T1 weighted image showed a moderate low intensity signal. A high intensity signal in the T2 weighted image indicated the onset of revascularization, and a favorable prognosis. A normal signal indicated healing of carpal avascular necrosis. MRI was found to be very useful in establishing the diagnosis and in determining the prognosis of carpal osteonecrosis. (author)

  2. Avascular necrosis associated with nailing of femoral neck fracture

    International Nuclear Information System (INIS)

    Stroemqvist, B.; Hansson, L.I.

    1983-01-01

    Two patients with femoral neck fractures, one displaced and one undisplaced, are presented. Preoperative intravital staining with tetracycline and Tc-MDP scintimetry both showed intact femoral head circulation while Tc-MDP-scintimetry 1 week after operation showed pronounced circulatory deficiency. SR 85 -scintimetry performed at the same time was inconclusive. Segmental collapse was observed radiographically, 8 and 12 months postoperatively. The major vascular injury resulting in avascularity most probably occured during the procedure of osteosynthesis, and Tc-MDP-scintimetry was found suitable for early postoperative recognition of avascular necrosis in both fractures. (author)

  3. Avascular necrosis of the epiphysis of the first metatarsal bone

    Energy Technology Data Exchange (ETDEWEB)

    Souverijns, G.; Peene, P.; Cleeren, P. [Department of Radiology, Virga Jesse Hospital, Hasselt (Belgium); Raes, M. [Department of Pediatrics, Virga Jesse Hospital, Hasselt (Belgium); Steenwerckx, A. [Department of Orthopaedics, Virga Jesse Hospital, Hasselt (Belgium)

    2002-06-01

    We report a case of avascular necrosis of the epiphysis of the right first metatarsal in a 6-year-old boy. Radiographs showed sclerosis, collapse and a crescent sign in the epiphysis. The diagnosis was confirmed by magnetic resonance imaging and scintigraphy. Arch support was the therapy of choice. Six months after the onset of symptoms, a definite reossification was present. To our knowledge, this is the first radiological report of avascular necrosis of the epiphysis of the first metatarsal bone in the world literature, which prompted a review of the osteochondroses and their etiology. (orig.)

  4. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Science.gov (United States)

    Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony; Lechler, Robert; Lombardi, Giovanna

    2014-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  5. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Directory of Open Access Journals (Sweden)

    Fang Xiao

    Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  6. PROGRESS IN CLINICAL ENCAPSULATED ISLET XENOTRANSPLANTATION

    Science.gov (United States)

    Cooper, David K.C.; Matsumoto, Shinichi; Abalovich, Adrian; Itoh, Takeshi; Mourad, Nizar I.; Gianello, Pierre R; Wolf, Eckhard; Cozzi, Emanuele

    2016-01-01

    At the 2015 combined congress of the CTS, IPITA, and IXA, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics – (i) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (ii) the inflammatory response to encapsulated pig islets, (iii) methods to improve the secretion of insulin by pig islets, (iv) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (v) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (i) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (ii) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (iii) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (iv) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic-engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally-harmonized ethical and regulatory framework. PMID:27482959

  7. Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model.

    Science.gov (United States)

    McCall, Michael D; Maciver, Allison M; Kin, Tatsuya; Emamaullee, Juliet; Pawlick, Rena; Edgar, Ryan; Shapiro, A M James

    2012-07-15

    Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model. Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month. There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group. IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation.

  8. Rotational Transport of Islets: The Best Way for Islets to Get around?

    Directory of Open Access Journals (Sweden)

    Rupert Oberhuber

    2013-01-01

    Full Text Available Islet transplantation is a valid treatment option for patients suffering from type 1 diabetes mellitus. To assure optimal islet cell quality, specialized islet isolation facilities have been developed. Utilization of such facilities necessitates transportation of islet cells to distant institutions for transplantation. Despite its importance, a clinically feasible solution for the transport of islets has still not been established. We here compare the functionality of isolated islets from C57BL/6 mice directly after the isolation procedure as well as after two simulated transport conditions, static versus rotation. Islet cell quality was assessed using real-time live confocal microscopy. In vivo islet function after syngeneic transplantation was determined by weight and blood sugar measurements as well as by intraperitoneal glucose tolerance tests. Vascularization of islets was documented by fluorescence microscopy and immunohistochemistry. All viability parameters documented comparable cell viability in the rotary group and the group transplanted immediately after isolation. Functional parameters assessed in vivo displayed no significant difference between these two groups. Moreover, vascularization of islets was similar in both groups. In conclusion, rotary culture conditions allows the maintenance of highest islet quality for at least 15 h, which is comparable to that of freshly isolated islets.

  9. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice.

    Directory of Open Access Journals (Sweden)

    Vikash Chandra

    Full Text Available BACKGROUND: Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual. Adopting methods of islet encapsulation in immuno-isolatory devices would eliminate the need for immuno-suppressants. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we explore the potential of human adipose tissue derived adult stem cells (h-ASCs to differentiate into functional islet like cell aggregates (ICAs. Our stage specific differentiation protocol permit the conversion of mesodermic h-ASCs to definitive endoderm (Hnf3β, TCF2 and Sox17 and to PDX1, Ngn3, NeuroD, Pax4 positive pancreatic endoderm which further matures in vitro to secrete insulin. These ICAs are shown to produce human C-peptide in a glucose dependent manner exhibiting in-vitro functionality. Transplantation of mature ICAs, packed in immuno-isolatory biocompatible capsules to STZ induced diabetic mice restored near normoglycemia within 3-4 weeks. The detection of human C-peptide, 1155±165 pM in blood serum of experimental mice demonstrate the efficacy of our differentiation approach. CONCLUSIONS: h-ASC is an ideal population of personal stem cells for cell replacement therapy, given that they are abundant, easily available and autologous in origin. Our findings present evidence that h-ASCs could be induced to differentiate into physiologically competent functional islet like cell aggregates, which may provide as a source of alternative islets for cell replacement therapy in type 1 diabetes.

  10. A Cost-Effective High-Throughput Plasma and Serum Proteomics Workflow Enables Mapping of the Molecular Impact of Total Pancreatectomy with Islet Autotransplantation

    DEFF Research Database (Denmark)

    Bennike, Tue Bjerg; Stensballe, Allan

    2018-01-01

    acquisition liquid chromatography/mass spectrometry; the data were queried using feature quantification with Spectronaut. To show the applicability of our workflow to serum, we analyzed a unique set of samples from 48 chronic pancreatitis patients, pre and post total pancreatectomy with islet...

  11. DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1

    NARCIS (Netherlands)

    Paredes-Juarez, Genaro A.; Sahasrabudhe, Neha M.; Tjoelker, Reina S.; de Haan, Bart J.; Engelse, Marten A.; de Koning, Eelco J. P.; Faas, Marijke M.; de Vos, Paul

    2015-01-01

    In between the period of transplantation and revascularization, pancreatic islets are exposed to low-oxygen and low-nutrient conditions. In the present study we mimicked those conditions in vitro to study the involvement of different cell death processes, release of danger-associated molecular

  12. Increased expression of toll-like receptor 4 and inflammatory cytokines, interleukin-6 in particular, in islets from a mouse model of obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Ladefoged, Mette; Buschard, Karsten; Hansen, Ann Maria Kruse

    2013-01-01

    Toll-like receptor 4 (TLR4) has received much attention in the recent years due to its role in development of insulin resistance in type 2 diabetes mellitus. Its expression is elevated in fat and muscle from insulin-resistant mice. Several cells of the pancreatic islets, including β-cells and res...

  13. In Vitro and In Vivo Investigation of the Angiogenic Effects of Liraglutide during Islet Transplantation.

    Directory of Open Access Journals (Sweden)

    Allan Langlois

    Full Text Available This study investigated the angiogenic properties of liraglutide in vitro and in vivo and the mechanisms involved, with a focus on Hypoxia Inducible Factor-1α (HIF-1α and mammalian target of rapamycin (mTOR.Rat pancreatic islets were incubated in vitro with 10 μmol/L of liraglutide (Lira for 12, 24 and 48 h. Islet viability was studied by fluorescein diacetate/propidium iodide staining and their function was assessed by glucose stimulation. The angiogenic effect of liraglutide was determined in vitro by the measure of vascular endothelial growth factor (VEGF secretion using enzyme-linked immunosorbent assay and by the evaluation of VEGF and platelet-derived growth factor-α (PDGFα expression with quantitative polymerase chain reaction technic. Then, in vitro and in vivo, angiogenic property of Lira was evaluated using immunofluorescence staining targeting the cluster of differentiation 31 (CD31. To understand angiogenic mechanisms involved by Lira, HIF-1α and mTOR activation were studied using western blotting. In vivo, islets (1000/kg body-weight were transplanted into diabetic (streptozotocin Lewis rats. Metabolic control was assessed for 1 month by measuring body-weight gain and fasting blood glucose.Islet viability and function were respectively preserved and enhanced (p<0.05 with Lira, versus control. Lira increased CD31-positive cells, expression of VEGF and PDGFα (p<0.05 after 24 h in culture. Increased VEGF secretion versus control was also observed at 48 h (p<0.05. Moreover, Lira activated mTOR (p<0.05 signalling pathway. In vivo, Lira improved vascular density (p<0.01, body-weight gain (p<0.01 and reduced fasting blood glucose in transplanted rats (p<0.001.The beneficial effects of liraglutide on islets appeared to be linked to its angiogenic properties. These findings indicated that glucagon-like peptide-1 analogues could be used to improve transplanted islet revascularisation.

  14. Pancreatic islet-cell viability, functionality and oxidative status ...

    Indian Academy of Sciences (India)

    Unknown

    Environmental factors such as diet, physical activity, drugs, pollution and life style play an important role in the progression and/or precipitation of diseases like diabetes, hypertension, obesity and cardiovascular disorders. Indiscriminate use of antibiotics to combat infectious diseases is one of the commonest forms of ...

  15. Alteration in pancreatic islet function in human immunodeficiency virus.

    Science.gov (United States)

    Haugaard, Steen B

    2014-09-01

    Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. The HETE Is on FFAR1 and Pancreatic Islet Cells

    DEFF Research Database (Denmark)

    Trauelsen, Mette; Lückmann, Michael; Frimurer, Thomas M

    2018-01-01

    It is known but generally unappreciated that the fatty acid receptor FFAR1 (GPR40) is responsible for a major part of glucose-induced insulin secretion. This puzzling fact is now explained by Tunaru et al. (2018), who demonstrate that glucose-induced 20-hydroxyeicosatetraenoic acid (20-HETE) ampl...

  17. Alteration in pancreatic islet function in human immunodeficiency virus

    DEFF Research Database (Denmark)

    Haugaard, Steen B

    2014-01-01

    Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell...

  18. Treatment Option Overview (Pancreatic Neuroendocrine Tumors / Islet Cell Tumors)

    Science.gov (United States)

    ... This is also called the Whipple procedure . Distal pancreatectomy : Surgery to remove the body and tail of ... of the pancreas, treatment is usually a distal pancreatectomy (surgery to remove the body and tail of ...

  19. Factors influencing the adequacy of microencapsulation of rat pancreatic islets

    NARCIS (Netherlands)

    DeVos, P; DeHaan, B; Wolters, GHJ; VanSchilfgaarde, R

    1996-01-01

    The observation that only a portion of all alginate-polylysine microcapsules are overgrown after implantation suggests that physical imperfections of individual capsules, rather than the chemical composition of the material applied, are responsible for inducing insufficient biocompatibility and

  20. Avascular necrosis of the hip in multiple epiphyseal dysplasia

    International Nuclear Information System (INIS)

    Mackenzie, W.G.; Bassett, G.S.; Mandell, G.A.; Scott, C.I. Jr.

    1989-01-01

    We observed radiographic changes of avascular necrosis (AVN) of the capital femoral epiphysis in 9 hips of 11 patients with multiple epiphyseal dysplasia (MED). Plain roentgenography, bone scintigraphy, and magnetic resonance imaging (MRI) studies all revealed characteristic asymmetric changes in the presence of AVN superimposed on dysplastic femoral heads

  1. Prevalence of HIV infection among the patients with an avascular ...

    African Journals Online (AJOL)

    Objective: To study the prevalence of HIV infection among the risk factors associated with the avascular necrosis of the femoral head in Ouagadougou, Burkina Faso. Design: Multicenter retrospective study. Setting: Rheumatology consultations and Orthopedic-Traumatology Surgery Department Of The University Hospital ...

  2. Vascularized bone grafting in a canine carpal avascular necrosis model

    NARCIS (Netherlands)

    Willems, Wouter F.; Alberton, Gregory M.; Bishop, Allen T.; Kremer, Thomas

    2011-01-01

    Limited experimental research has been performed on the treatment of avascular necrosis (AVN) by vascularized bone grafting. A new model simulating carpal AVN was created to investigate surgical revascularization of necrotic bone. In seven mongrel dogs, AVN was induced by removal of the radial

  3. Avascular necrosis in sickle cell (homozygous S) patients: Predictive ...

    African Journals Online (AJOL)

    ... with the development of AVN. Conclusion: In conclusion, patients with a raised steady state platelet count may have a higher tendency to develop AVN and may require closer orthopedic review and prophylactic intervention. Key words: Avascular necrosis, homozygous S, platelet count, sickle cell anemia, white cell count ...

  4. Pentoxifylline Treatment in Acute Pancreatitis (AP)

    Science.gov (United States)

    2018-02-21

    Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

  5. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism.

    Science.gov (United States)

    Roomp, Kirsten; Kristinsson, Hjalti; Schvartz, Domitille; Ubhayasekera, Kumari; Sargsyan, Ernest; Manukyan, Levon; Chowdhury, Azazul; Manell, Hannes; Satagopam, Venkata; Groebe, Karlfried; Schneider, Reinhard; Bergquist, Jonas; Sanchez, Jean-Charles; Bergsten, Peter

    2017-01-01

    Studies on the pathophysiology of type 2 diabetes mellitus (T2DM) have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/ or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucose-stimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24:1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our findings provide

  6. Combined lipidomic and proteomic analysis of isolated human islets exposed to palmitate reveals time-dependent changes in insulin secretion and lipid metabolism.

    Directory of Open Access Journals (Sweden)

    Kirsten Roomp

    Full Text Available Studies on the pathophysiology of type 2 diabetes mellitus (T2DM have linked the accumulation of lipid metabolites to the development of beta-cell dysfunction and impaired insulin secretion. In most in vitro models of T2DM, rodent islets or beta-cell lines are used and typically focus is on specific cellular pathways or organs. Our aim was to, firstly, develop a combined lipidomics and proteomics approach for lipotoxicity in isolated human islets and, secondly, investigate if the approach could delineate novel and/ or confirm reported mechanisms of lipotoxicity. To this end isolated human pancreatic islets, exposed to chronically elevated palmitate concentrations for 0, 2 and 7 days, were functionally characterized and their levels of multiple targeted lipid and untargeted protein species determined. Glucose-stimulated insulin secretion from the islets increased on day 2 and decreased on day 7. At day 7 islet insulin content decreased and the proinsulin to insulin content ratio doubled. Amounts of cholesterol, stearic acid, C16 dihydroceramide and C24:1 sphingomyelin, obtained from the lipidomic screen, increased time-dependently in the palmitate-exposed islets. The proteomic screen identified matching changes in proteins involved in lipid biosynthesis indicating up-regulated cholesterol and lipid biosynthesis in the islets. Furthermore, proteins associated with immature secretory granules were decreased when palmitate exposure time was increased despite their high affinity for cholesterol. Proteins associated with mature secretory granules remained unchanged. Pathway analysis based on the protein and lipid expression profiles implicated autocrine effects of insulin in lipotoxicity. Taken together the study demonstrates that combining different omics approaches has potential in mapping of multiple simultaneous cellular events. However, it also shows that challenges exist for effectively combining lipidomics and proteomics in primary cells. Our

  7. Autoreactive effector/memory CD4+ and CD8+ T cells infiltrating grafted and endogenous islets in diabetic NOD mice exhibit similar T cell receptor usage.

    Directory of Open Access Journals (Sweden)

    Ramiro Diz

    Full Text Available Islet transplantation provides a "cure" for type 1 diabetes but is limited in part by recurrent autoimmunity mediated by β cell-specific CD4(+ and CD8(+ T cells. Insight into the T cell receptor (TCR repertoire of effector T cells driving recurrent autoimmunity would aid the development of immunotherapies to prevent islet graft rejection. Accordingly, we used a multi-parameter flow cytometry strategy to assess the TCR variable β (Vβ chain repertoires of T cell subsets involved in autoimmune-mediated rejection of islet grafts in diabetic NOD mouse recipients. Naïve CD4(+ and CD8(+ T cells exhibited a diverse TCR repertoire, which was similar in all tissues examined in NOD recipients including the pancreas and islet grafts. On the other hand, the effector/memory CD8(+ T cell repertoire in the islet graft was dominated by one to four TCR Vβ chains, and specific TCR Vβ chain usage varied from recipient to recipient. Similarly, islet graft- infiltrating effector/memory CD4(+ T cells expressed a limited number of prevalent TCR Vβ chains, although generally TCR repertoire diversity was increased compared to effector/memory CD8(+ T cells. Strikingly, the majority of NOD recipients showed an increase in TCR Vβ12-bearing effector/memory CD4(+ T cells in the islet graft, most of which were proliferating, indicating clonal expansion. Importantly, TCR Vβ usage by effector/memory CD4(+ and CD8(+ T cells infiltrating the islet graft exhibited greater similarity to the repertoire found in the pancreas as opposed to the draining renal lymph node, pancreatic lymph node, or spleen. Together these results demonstrate that effector/memory CD4(+ and CD8(+ T cells mediating autoimmune rejection of islet grafts are characterized by restricted TCR Vβ chain usage, and are similar to T cells that drive destruction of the endogenous islets.

  8. Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Damgaard Nielsen, M

    2012-01-01

    AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs...... mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were...... of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine...

  9. Human Recombinant Antithrombin (ATryn®) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model.

    Science.gov (United States)

    Gmyr, Valery; Bonner, Caroline; Moerman, Ericka; Tournoys, Antoine; Delalleau, Nathalie; Quenon, Audrey; Thevenet, Julien; Chetboun, Mikael; Kerr-Conte, Julie; Pattou, François; Hubert, Thomas; Jourdain, Merce

    2017-02-16

    Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.

  10. Human Recombinant Antithrombin (ATryn®) Administration Improves Survival and Prevents Intravascular Coagulation after Intraportal Islet Transplantation in a Piglet Model

    Science.gov (United States)

    Gmyr, Valery; Bonner, Caroline; Moerman, Ericka; Tournoys, Antoine; Delalleau, Nathalie; Quenon, Audrey; Thevenet, Julien; Chetboun, Mikael; Kerr-Conte, Julie; Pattou, François; Hubert, Thomas; Jourdain, Merce

    2017-01-01

    Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects. PMID:27938471

  11. Total pancreatectomy and islet autotransplantation: A decade nationwide analysis.

    Science.gov (United States)

    Fazlalizadeh, Reza; Moghadamyeghaneh, Zhobin; Demirjian, Aram N; Imagawa, David K; Foster, Clarence E; Lakey, Jonathan R; Stamos, Michael J; Ichii, Hirohito

    2016-03-24

    To investigate outcomes and predictors of in-hospital morbidity and mortality after total pancreatectomy (TP) and islet autotransplantation. The nationwide inpatient sample (NIS) database was used to identify patients who underwent TP and islet autotransplantation (IAT) between 2002-2012 in the United States. Variables of interest were inherent variables of NIS database which included demographic data (age, sex, and race), comorbidities (such as diabetes mellitus, hypertension, and deficiency anemia), and admission type (elective vs non-elective). The primary endpoints were mortality and postoperative complications according to the ICD-9 diagnosis codes which were reported as the second to 25(th) diagnosis of patients in the database. Risk adjusted analysis was performed to investigate morbidity predictors. Multivariate regression analysis was used to identify predictors of in-hospital morbidity. We evaluated a total of 923 patients who underwent IAT after pancreatectomy during 2002-2012. Among them, there were 754 patients who had TP + IAT. The most common indication of surgery was chronic pancreatitis (86%) followed by acute pancreatitis (12%). The number of patients undergoing TP + IAT annually significantly increased during the 11 years of study from 53 cases in 2002 to 155 cases in 2012. Overall mortality and morbidity of patients were 0% and 57.8 %, respectively. Post-surgical hypoinsulinemia was reported in 42.3% of patients, indicating that 57.7% of patients were insulin independent during hospitalization. Predictors of in-hospital morbidity were obesity [adjusted odds ratio (AOR): 3.02, P = 0.01], fluid and electrolyte disorders (AOR: 2.71, P < 0.01), alcohol abuse (AOR: 2.63, P < 0.01), and weight loss (AOR: 2.43, P < 0.01). TP + IAT is a safe procedure with no mortality, acceptable morbidity, and achieved high rate of early insulin independence. Obesity is the most significant predictor of in-hospital morbidity.

  12. Pancreatic Juice Culture in Acute Pancreatitis and Other Pancreatic Disorders

    OpenAIRE

    Masataka Kikuyama; Tatsunori Sato; Takafumi Kurokami; Yuji Ota; Yoshihiro Yokoi

    2016-01-01

    We retrospectively evaluated the results of pancreatic juice cultures of patients with acute pancreatitis and other pancreatic disorders. Methods Twenty patients who underwent pancreatic juice culture were studied. Nine had acute pancreatitis due to alcohol (n=5), idiopathic causes (n=2), drugs (n=1), or gallstones (n=1), and remaining 11 had other pancreatic disorders such as an intraductal papillary mucin-producing neoplasm (n=3) and main pancreatic duct dilatation with a stricture due to a...

  13. Increased expression of SNARE proteins and synaptotagmin IV in islets from pregnant rats and in vitro prolactin-treated neonatal islets

    Directory of Open Access Journals (Sweden)

    DANIEL A CUNHA

    2006-01-01

    Full Text Available During pregnancy and the perinatal period of life, prolactin (PRL and other lactogenic substances induce adaptation and maturation of the stimulus-secretion coupling system in pancreatic β-cells. Since the SNARE molecules, SNAP-25, syntaxin 1, VAMP-2, and synaptotagmins participate in insulin secretion, we investigated whether the improved secretory response to glucose during these periods involves alteration in the expression of these proteins. mRNA was extracted from neonatal rat islets cultured for 5 days in the presence of PRL and from pregnant rats (17th-18th days of pregnancy and reverse transcribed. The expression of genes was analyzed by semi-quantitative RT-PCR assay. The expression of proteins was analyzed by Western blotting and confocal microscopy. Transcription and expression of all SNARE genes and proteins were increased in islets from pregnant and PRL-treated neonatal rats when compared with controls. The only exception was VAMP-2 production in islets from pregnant rats. Increased mRNA and protein expression of synaptotagmin IV, but not the isoform I, also was observed in islets from pregnant and PRL-treated rats. This effect was not inhibited by wortmannin or PD098059, inhibitors of the PI3-kinase and MAPK pathways, respectively. As revealed by confocal laser microscopy, both syntaxin 1A and synaptotagmin IV were immunolocated in islet cells, including the insulin-containing cells. These results indicate that PRL modulates the final steps of insulin secretion by increasing the expression of proteins involved in membrane fusion.

  14. Deletion of 12/15-lipoxygenase alters macrophage and islet function in NOD-Alox15(null mice, leading to protection against type 1 diabetes development.

    Directory of Open Access Journals (Sweden)

    Shamina M Green-Mitchell

    Full Text Available AIMS: Type 1 diabetes (T1D is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. METHODS: 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. RESULTS: 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. CONCLUSIONS: These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.

  15. Pancreatitis in Children.

    Science.gov (United States)

    Sathiyasekaran, Malathi; Biradar, Vishnu; Ramaswamy, Ganesh; Srinivas, S; Ashish, B; Sumathi, B; Nirmala, D; Geetha, M

    2016-11-01

    Pancreatic disease in children has a wide clinical spectrum and may present as Acute pancreatitis (AP), Acute recurrent pancreatitis (ARP), Chronic pancreatitis (CP) and Pancreatic disease without pancreatitis. This article highlights the etiopathogenesis and management of pancreatitis in children along with clinical data from five tertiary care hospitals in south India [Chennai (3), Cochin and Pune].

  16. Autoimmune pancreatitis

    DEFF Research Database (Denmark)

    Detlefsen, Sönke; Drewes, Asbjørn M

    2009-01-01

    bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two...

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

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Yoo Jin; Yu, Jeong Sik; Park, Chan Il; Kwon, Ji Eun; Chung, Jae Joon; Kim, Joo Hee; Kim, Ki Whang [Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2010-11-15

    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

  18. Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

    Directory of Open Access Journals (Sweden)

    Feng-Cheng Chou

    2012-01-01

    Full Text Available Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1 detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2 inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.

  19. Uptake of the glycosphingolipid sulfatide in the gastrointestinal tract and pancreas in vivo and in isolated islets of Langerhans

    Directory of Open Access Journals (Sweden)

    Fredman Pam

    2006-10-01

    Full Text Available Abstract Background The glycosphingolipid sulfatide has previously been found in several mammalian tissues, but information on the uptake of exogenously administered sulfatide in different organs in vivo is limited. In pancreatic beta cells, sulfatide has been shown to be involved in insulin processing and secretion in vitro. In this study, we examined the uptake of exogenously administered sulfatide and its distribution to the pancreatic beta cells. This might encourage future studies of the function(s of sulfatide in beta cell physiology in vivo. Radioactive sulfatide was given orally to mice whereafter the uptake of sulfatide in the gastrointestinal tract and subsequent delivery to the pancreas was examined. Sulfatide uptake in pancreas was also studied in vivo by i.p. administration of radioactive sulfatide in mice, and in vitro in isolated rat islets. Isolated tissue/islets were analysed by scintillation counting, autoradiography and thin-layer chromatography-ELISA. Results Sulfatide was taken up in the gastrointestinal tract for degradation or further transport to other organs. A selective uptake of short chain and/or hydroxylated sulfatide fatty acid isoforms was observed in the small intestine. Exogenously administered sulfatide was found in pancreas after i.p, but not after oral administration. The in vitro studies in isolated rat islets support that sulfatide, independently of its fatty acid length, is endocytosed and metabolised by pancreatic islets. Conclusion Our study supports a selective uptake and/or preservation of sulfatide in the gastrointestinal tract after oral administration and with emphasises on pancreatic sulfatide uptake, i.p. administration results in sulfatide at relevant location.

  20. Relationship between pancreatic hormones and glucose metabolism: A cross-sectional study in patients after acute pancreatitis.

    Science.gov (United States)

    Pendharkar, Sayali A; Asrani, Varsha M; Xiao, Amy Y; Yoon, Harry D; Murphy, Rinki; Windsor, John A; Petrov, Maxim S

    2016-07-01

    Abnormal glucose metabolism is present in almost 40% of patients after acute pancreatitis, but its pathophysiology has been poorly investigated. Pancreatic hormone derangements have been sparingly studied to date, and their relationship with abnormal glucose metabolism is largely unknown. The aim was to investigate the associations between pancreatic hormones and glucose metabolism after acute pancreatitis, including the effect of potential confounders. This was a cross-sectional study of 83 adult patients after acute pancreatitis. Fasting venous blood was collected from all patients and used for analysis of insulin, glucagon, pancreatic polypeptide, amylin, somatostatin, C-peptide, glucose, and hemoglobin A1c. Statistical analyses were conducted using the modified Poisson regression, multivariable linear regression, and Spearman's correlation. Age, sex, body mass index, recurrence of acute pancreatitis, duration from first attack, severity, and etiology were adjusted for. Increased insulin was significantly associated with abnormal glucose metabolism after acute pancreatitis, in both unadjusted (P = 0.038) and adjusted (P = 0.001) analyses. Patients with abnormal glucose metabolism also had significantly decreased pancreatic polypeptide (P = 0.001) and increased amylin (P = 0.047) in adjusted analyses. Somatostatin, C-peptide, and glucagon were not changed significantly in both unadjusted and adjusted analyses. Increased insulin resistance and reduced insulin clearance may be important components of hyperinsulinemic compensation in patients after acute pancreatitis. Increased amylin and reduced pancreatic polypeptide fasting levels characterize impaired glucose homeostasis. Clinical studies investigating islet-cell hormonal responses to mixed-nutrient meal testing and euglycemic-hyperinsulinemic clamps are now warranted for further insights into the role of pancreatic hormones in glucose metabolism derangements secondary to pancreatic diseases. Copyright © 2016

  1. Islet isolation and GMP, ISO 9001:2000: what do we need--a 3-year experience.

    Science.gov (United States)

    Hengster, P; Hermann, M; Pirkebner, D; Draxl, A; Margreiter, R

    2005-10-01

    Pancreatic islet cell isolation and transplantation has been performed for many years at several institutions. Although all institutions aim to produce high-quality islets, applied standards widely deviate from standards in the pharmaceutical industry. The legal situation within the European Union has changed requirements for setting up and running such a laboratory. The process is now clearly defined as a production of a pharmaceutical and therefore must be licensed by federal authorities. Analysis of workload for establishing an islet isolation program that fulfil GMP and ISO 9001 criteria including an estimation of costs and the impact of such a system on the isolation process. The definition of quality parameters and documentation is a central issue of all islet isolation laboratories. Therefore, GMP and ISO 9001:2000 do not add additional work per se. On the other hand, clear guidelines, a clear policy, working place descriptions, forms, checklists, and, particularly standard operating procedures, are instrumental for smooth functioning within the department. Collection of data such as errors, improvement measures, and preventive measures reduces subsequent costs. A clear definition of responsibilities minimizes organizational problems. Steering of inspection devices prevents bias errors and validating the processes clearly points out incorrect assumptions. Documentation helps to prove the correctness of the production at any time and is of use also for scientific evaluations. We strongly feel that GMP criteria are mandatory and together with an ISO 9001:2000 quality management system offers significant advantages for the process of islet isolation and a continuous improvement process.

  2. Cirrhosis is a risk factor for total hip arthroplasty for avascular necrosis

    DEFF Research Database (Denmark)

    Deleuran, Thomas; Overgaard, Søren; Vilstrup, Hendrik

    2016-01-01

    Background and purpose - There are limited data on risk factors for avascular necrosis of the hip, but cirrhosis has been proposed as a risk factor. We examined the association between cirrhosis and incidence of total hip arthroplasty for avascular necrosis. Methods - We used nationwide healthcare......,052 reference individuals. Their median age was 57 years, and 65% were men. 45 cirrhosis patients and 44 reference individuals underwent total hip arthroplasty for avascular necrosis. Cirrhosis patients' HR for a total hip arthroplasty for avascular necrosis was 10 (95% CI: 6-17), yet their 5-year risk...... of avascular necrosis was only 0.2%. For the reference individuals, the 5-year risk was 0.02%. Interpretation - Cirrhosis is a strong risk factor for avascular necrosis of the hip, but it is rare even in cirrhosis patients....

  3. Angiographic analysis of avascular necrosis of a femoral head -selective angiography of medial femoral circumflex artery-

    International Nuclear Information System (INIS)

    Ryu, Kyung Nam; Yoon, Yup; Lee, Sun Wha; Lim, Jae Hoon

    1991-01-01

    The degree of anatomical revascularization of a necrotic femoral head and traumatic hip would provide information about treatment and prognosis. The authors analyzed the vascular changes of femoral head among unilateral avascular necrosis, bilateral avascular necrosis, and traumatic hips. Forty - four patients with avascular necrosis and 19 patients with traumatic hips were examined by selective angiography of the medial femoral circumflex artery. In the traumatic hip cases, 12 (63%) showed occlusion, 2 (11%) hypertrophy of the capsular branches, and 5 ( 26 % ) were normal . In the avascular necrosis cases, 15 (25%) showed occlusion, 39 (67%) had hypertrophy of the capsular branches, and 4 (7%) had normal findings. Hypertrophy of the superior capsular branch of the medial femoral circumflex artery is more frequently observed in avascular necrosis than in traumatic hip. Bilateral avascular necrosis reveals more frequent incidences than unilateral cases. Selective angiography could help in the therapy plan and also provide information about the contralateral side

  4. Avascular necrosis of the femoral head and M. R. I

    Energy Technology Data Exchange (ETDEWEB)

    Gires, F.; Leroy-Willig, A; Chevrot, A.; Wolff, J.L. and others

    Normal and pathologic femoral heads have been studied by MRI at 1.5 Tesla. The study was centered upon avascular necrosis (53 lesions). Twenty normal subjects and three patients with algodystrophy were examined. The osteonecrosis patterns were established from known lesions. A low signal rim surrounds an upper polar zone of conserved (Type I) or decreased (Type II) signal. The lesions age correlates significatively with their type: amongst type I lesions, 6 are asymptomatic and the 21 others have a mean age of 5.5 months; Type II lesions have a mean age of 12.7 months. Fourteen lesions were not seen on plain radiographs and six were not detected by bone scan. The older lesions with femoral head deformation are better depicted by standard radiologic techniques. Conservely MRI is the most efficient examination for recent avascular necrosis lesions.

  5. Morphometric findings in avascular necrosis of the femoral head.

    Science.gov (United States)

    Kamal, Diana; Trăistaru, Rodica; Alexandru, D O; Kamal, C K; Pirici, D; Pop, O T; Mălăescu, D Gh

    2012-01-01

    Avascular necrosis of the femoral head is an illness with a controversial etiology, the trigger event being the suppression of blood flow to the femoral head. The disease affects mostly young adults within their third and fifth decade, the majority of the patients being men. The main risk factors are trauma, chronic alcohol consumption, smoking, corticotherapy. The main goal of our study is to describe the morphometric changes found in the bone tissue of patients diagnosed with avascular necrosis of the femoral head, with different risk factors, by comparing the area of bone trabeculae inside the area of necrosis with that from the adjacent viable tissue. The morphometric study used biological material from 16 patients with ages between 29 and 57 years, who underwent surgery for avascular necrosis of the femoral head. They were admitted in the Orthopedics Department at the Emergency County Hospital in Craiova between 2010 and 2011 and were split into four groups. Group I presented trauma as the main risk factor, Group II had corticotherapy as the defining risk factor, Group III presented chronic alcohol consumption and Group IV was represented by the patients who smoked and exhibited chronic alcohol consumption. There was not a significant statistical difference between the areas of bone trabeculae of the four groups when we compared viable bone tissue to the necrotized one. Knowing the risk factors of the avascular necrosis of the femoral head is critical to the management of the disease, because diagnosing it in an early stage is a necessity for obtaining a good result for conservative treatment.

  6. Pravastatin Protects Against Avascular Necrosis of Femoral Head via Autophagy.

    Science.gov (United States)

    Liao, Yun; Zhang, Ping; Yuan, Bo; Li, Ling; Bao, Shisan

    2018-01-01

    Autophagy serves as a stress response and may contribute to the pathogenesis of avascular necrosis of the femoral head induced by steroids. Statins promote angiogenesis and ameliorate endothelial functions through apoptosis inhibition and necrosis of endothelial progenitor cells, however the process used by statins to modulate autophagy in avascular necrosis of the femoral head remains unclear. This manuscript determines whether pravastatin protects against dexamethasone-induced avascular necrosis of the femoral head by activating endothelial progenitor cell autophagy. Pravastatin was observed to enhance the autophagy activity in endothelial progenitor cells, specifically by upregulating LC3-II/Beclin-1 (autophagy related proteins), and autophagosome formation in vivo and in vitro . An autophagy inhibitor, 3-MA, reduced pravastatin protection in endothelial progenitor cells exposed to dexamethasone by attenuating pravastatin-induced autophagy. Adenosine monophosphate-activated protein kinase (AMPK) is a key autophagy regulator by sensing cellular energy changes, and indirectly suppressing activation of the mammalian target of rapamycin (mTOR). We found that phosphorylation of AMPK was upregulated however phosphorylation of mTOR was downregulated in pravastatin-treated endothelial progenitor cells, which was attenuated by AMPK inhibitor compound C. Furthermore, liver kinase B1 (a phosphorylase of AMPK) knockdown eliminated pravastatin regulated autophagy protein LC3-II in endothelial progenitor cells in vitro . We therefore demonstrated pravastatin rescued endothelial progenitor cells from dexamethasone-induced autophagy dysfunction through the AMPK-mTOR signaling pathway in a liver kinase B1-dependent manner. Our results provide useful information for the development of novel therapeutics for management of glucocorticoids-induced avascular necrosis of the femoral head.

  7. Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells

    Directory of Open Access Journals (Sweden)

    Sergiy V. Korol

    2018-04-01

    Full Text Available In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100–1000 nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1 but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D. Keywords: GABA, GABAA receptor, Pancreatic islet, Type 2 diabetes

  8. Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

    DEFF Research Database (Denmark)

    Rosengren, Anders H; Braun, Matthias; Mahdi, Taman

    2012-01-01

    The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features...... in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis...

  9. Chronic Pancreatitis in Children

    Science.gov (United States)

    ... Information Children/Pediatric Chronic Pancreatitis in Children Chronic Pancreatitis in Children What symptoms would my child have? ... will develop diabetes in adolescence. Who gets chronic pancreatitis? Those at risk for chronic pancreatitis are children ...

  10. Pancreatic Cysts

    Science.gov (United States)

    ... Pancreatic cysts Symptoms & causes Diagnosis & treatment Doctors & departments Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  11. Pancreatic Enzymes

    Science.gov (United States)

    ... Medical Advisory Board Volunteer Advisory Council Survivor Council Influencers of Hope Ambassador Circle Learn about the people ... is registered as a 501©3 nonprofit organization. Contributions to the Pancreatic Cancer Action Network are tax- ...

  12. Pancreatic Enzymes

    Science.gov (United States)

    ... the severity of the pancreatic insufficiency. As further alterations may be needed from time to time, it ... m. PT), or email patientcentral@pancan.org to speak with a knowledgeable and compassionate associate. Information provided ...

  13. Pancreatic pseudocysts

    International Nuclear Information System (INIS)

    Contrera, J.D.; Uemura, L.; Palma, J.K.; Souza, L.P. de; Ferraz, L.R.L.; Magalhaes, P.J.A.

    1984-01-01

    Radiological and ultrasonographic studies of ten patients with surgically confirmed pancreatic pseudocysts were reviewed. All of them were male, with previous story of chronic alcoholism and clinical evidences of pancreatitis. The most important radiological finding consisted of a mass opacifying the epigastrium, displacing the stomach and bowel loops. ultrasound studies showed that the lesions were predominantly cystic, rounded or oval-shaped with smooth or irregular contours and of various sizes. (Author) [pt

  14. mTOR links incretin signaling to HIF induction in pancreatic beta cells.

    Science.gov (United States)

    Van de Velde, Sam; Hogan, Meghan F; Montminy, Marc

    2011-10-11

    Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1α in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta cell viability, these results demonstrate how a pathway associated with tumor growth also mediates salutary effects of an incretin hormone on pancreatic islet function.

  15. Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians

    DEFF Research Database (Denmark)

    de Courten, Barbora; Weyer, Christian; Stefan, Norbert

    2004-01-01

    of pancreatic polypeptide (PP), an islet hormone considered a surrogate marker of parasympathetic nervous system (PNS) drive to the pancreas. To test if hyperinsulinemia in Pima Indians is due to increased vagal input to the beta-cell, we examined the effect of PNS blockade in 17 Caucasian (aged 35 +/- 8 years...

  16. Dynamical complexity and temporal plasticity in pancreatic ββ-cells

    Indian Academy of Sciences (India)

    We discuss some of the biological and mathematical issues involved in understanding and modelling the bursting electrical activity in pancreatic -cells. These issues include single-cell versus islet behaviour, parameter heterogeneity, channel noise, the effects of hormones, neurotransmitters, and ions, and multiple slow ...

  17. Pancreatic beta cell protection/regeneration with phytotherapy

    OpenAIRE

    Hosseini, Azar; Shafiee-Nick, Reza; Ghorbani, Ahmad

    2015-01-01

    Although currently available drugs are useful in controlling early onset complications of diabetes, serious late onset complications appear in a large number of patients. Considering the physiopathology of diabetes, preventing beta cell degeneration and stimulating the endogenous regeneration of islets will be essential approaches for the treatment of insulin-dependent diabetes mellitus. The current review focused on phytochemicals, the antidiabetic effect of which has been proved by pancreat...

  18. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

    Science.gov (United States)

    Aggarwal, Gaurav; Ramachandran, Vijaya; Javeed, Naureen; Arumugam, Thiruvengadam; Dutta, Shamit; Klee, George G; Klee, Eric W; Smyrk, Thomas C; Bamlet, William; Han, Jing Jing; Rumie Vittar, Natalia B; de Andrade, Mariza; Mukhopadhyay, Debabrata; Petersen, Gloria M; Fernandez-Zapico, Martin E; Logsdon, Craig D; Chari, Suresh T

    2012-12-01

    New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice

  19. Increase of larger-sized islets in C57/black mice during the long-term space flight.

    Science.gov (United States)

    Proshchina, Alexandra; Krivova, Yulia

    Alteration of metabolism has been suggested as a major limiting factor to long-term space flight. Metabolic studies during simulated microgravity and true microgravity in flight have shown changes in blood glucose and in insulin and glucagon concentrations. It was suggested that endocrine pancreas undergoes subclinical diabetogenic changes such as alterations in insulin secretion, insulin sensitivity, glucose tolerance in microgravity conditions. In this study, we analyzed pancreata of the C57 black mice in order to estimate the effects of the long-term space flight. 5 mice, which were flown on the “Bion-M1” satellite for 30 days, were served for this study (flight group). Five animals were used as the vivarium ground control and five mice as the delayed synchronous ground control. The mice from synchronous control were put into container, similar to that one of the flight group for 30 days. Interestingly, the mean body weight of researched animals was higher in the flight group than in two control groups. Body weight in synchronous ground control group was higher than in vivarium control. From each mouse, the splenic part of the pancreas was removed and immediately fixed in 4% formaldehyde. Samples were embedded in paraffin, and 10 mcm serial sections were prepared. Double immunohistochemical staining with anti-insulin(Sigma,USA) and anti-glucagon (Thermo Fisher Scientific, USA) antibodies were performed. Signals were visualized using the MultiVision Polymer Detection System (Thermo Fisher Scientific, USA). Stained sections were photographed, using a 10 x objective and morphometrical parameters were examined. The size of each islet in ten non-overlapping observation fields in pancreatic sections of each mouse was measured using Image J software and analyzed. A software statistical package was used (Statistica 6.0, Statsoft Inc., Tusla, USA). A nonparametric tests (Kruskal -Wallis and Mann-Whitney tests) were used, because the islets number in the examined

  20. RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity.

    Science.gov (United States)

    Abedini, Andisheh; Cao, Ping; Plesner, Annette; Zhang, Jinghua; He, Meilun; Derk, Julia; Patil, Sachi A; Rosario, Rosa; Lonier, Jacqueline; Song, Fei; Koh, Hyunwook; Li, Huilin; Raleigh, Daniel P; Schmidt, Ann Marie

    2018-02-01

    Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis-induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP-induced (h-IAPP-induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand-binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP-induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.

  1. Multimodality preoperative imaging of pancreatic insulinomas

    International Nuclear Information System (INIS)

    McAuley, G.; Delaney, H.; Colville, J.; Lyburn, I.; Worsley, D.; Govender, P.; Torreggiani, W.C.

    2005-01-01

    Pancreatic insulinomas are rare tumours of the islet cells of the pancreas, which account for the majority of functional neuroendocrine tumours of the pancreas. There is often a typical history of recurrent hypoglycaemic collapse and dizzy spells. Insulinomas are usually solitary, and the vast majority are intra-pancreatic in location. They are characteristically small with approximately 66% being less than 2 cm at presentation. Insulinomas continue to pose a diagnostic challenge to physicians, surgeons and radiologists alike. The role of imaging is to detect and provide precise anatomical localization and staging of tumours prior to surgery. Due to their small size at clinical presentation, they are notoriously difficult to localize radiologically, and specifically designed protocols are necessary to aid detection. In this review, we describe the current 'state of the art' imaging protocols that may be used in the preoperative localization of insulinomas

  2. Islet cytotoxicity of interleukin 1. Influence of culture conditions and islet donor characteristics

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Spinas, G A; Prowse, S J

    1987-01-01

    strains, indicating that age, sex, and genetic background do not influence the susceptibility of the beta-cell to IL-1. Preculture of islets for 1-7 days in normal atmosphere and preculture of islet clusters in 95% O2 to delete passenger cells did not affect IL-1-mediated cytotoxicity, suggesting that IL...

  3. Using computed tomography to assist with diagnosis of avascular necrosis complicating chronic scaphoid nonunion.

    Science.gov (United States)

    Smith, Michael L; Bain, Gregory I; Chabrel, Nick; Turner, Perry; Carter, Chris; Field, John

    2009-01-01

    The primary aim of our study was to investigate use of long axis computed tomography (CT) in predicting avascular necrosis of the proximal pole of the scaphoid and subsequent fracture nonunion after internal fixation. In addition, we describe a new technique of measuring the position of a scaphoid fracture and provide data on its reproducibility. Thirty-one patients operated on by the senior author for delayed union or nonunion of scaphoid fracture were included. Preoperative CT scans were independently assessed for increased radiodensity of the proximal pole, converging trabeculae, degree of deformity, comminution, and fracture position. Intraoperative biopsies of the proximal pole were obtained and histologically assessed for evidence of avascular necrosis. The radiologic variables were statistically compared with the histologic findings. The presence of avascular necrosis was also compared with postoperative union status, identified on longitudinal CT scans. Preoperative CT features that statistically correlated with histologic evidence of avascular necrosis were increased radiodensity of the proximal pole and the absence of any converging trabeculae between the fracture fragments. The radiologic changes of avascular necrosis and the histologic confirmation of avascular necrosis were associated with persistent nonunion. Preoperative longitudinal CT of scaphoid nonunion is of great value in identifying avascular necrosis and predicting subsequent fracture union. If avascular necrosis is suspected based on preoperative CT, management options include vascularized bone grafts and bone morphogenic protein for younger patients and limited wrist arthrodesis for older patients. Diagnostic II.

  4. Global microRNA profiling of pancreatic neuroendocrine neoplasias.

    Science.gov (United States)

    Thorns, Chistoph; Schurmann, Claudia; Gebauer, Niklas; Wallaschofski, Henri; Kümpers, Christiane; Bernard, Veronica; Feller, Alfred C; Keck, Tobias; Habermann, Jens K; Begum, Nehara; Lehnert, Hendrik; Brabant, Georg

    2014-05-01

    Pancreatic neuroendocrine neoplasms (pNEN) are rare tumors with a poor prognosis. Although increasing data have accumulated on the molecular pathology of pNEN, very scarce data exist on microRNAs in pNEN and no data are published on microRNAs as potential biomarkers of pNEN in serum. This study aimed to identify microRNA signatures of pNEN in tissue and serum. We included tissue samples from 37 patients with pNEN, 9 patients with non-neoplastic pancreatic pathology, seven samples of micro-dissected pancreatic islets and serum samples of 27 patients with pNEN, as well as of 15 healthy volunteers. MicroRNA expression profiles were established using real-time quantitative Polymerase Chain reaction (PCR) for 754 microRNAs. MicroRNA signatures differed between pNEN, pancreatic islets and total pancreas, with virtually no overlap between the groups of de-regulated microRNAs. Expression of miR-642 correlated with Ki67 (MiB1) score and miR-210 correlated with metastatic disease. When comparing microRNA levels in serum from patients with pNEN and healthy volunteers, 13 microRNAs were more abundant in the serum of patients. MiR-193b was also up-regulated in pNEN tissue when compared to pancreatic islets and remained significantly increased in serum even when corrected for multiple testing. Evaluation of microRNAs appears to be promising in the assessment of pNEN. In particular, miR-193b, which is also increased in serum, may be a potential new biomarker of pNEN.

  5. Beneficial effect of 17β-estradiol on hyperglycemia and islet β-cell functions in a streptozotocin-induced diabetic rat model

    International Nuclear Information System (INIS)

    Yamabe, Noriko; Kang, Ki Sung; Zhu Baoting

    2010-01-01

    The modulating effect of estrogen on glucose homeostasis remains a controversial issue at present. In this study, we sought to determine the beneficial effect of 17β-estradiol (E 2 ) on hyperglycemia and islet β-cell functions in streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were injected i.p. with STZ to induce a relatively mild diabetic condition. The rats were then treated with E 2 orally at 500 μg/kg body weight/day for 15 days to evaluate the modulating effect on hyperglycemia, insulin secretion, and islet β-cell proliferation. E 2 administration for 10 days significantly lowered plasma glucose levels, increased plasma insulin levels, and improved glucose tolerance by attenuating insulin response to oral glucose loading. These beneficial effects of E 2 were accompanied by increases in islet number and volume, rate of islet cell proliferation, and the amount of insulin secreted. The growth-stimulatory effect of E 2 on islet cells was linked to the functions of the estrogen receptor α. Notably, these protective effects of E 2 on diabetic conditions were basically not observed when the STZ-treated rats had a more severe degree of islet damage and hyperglycemia. Taken together, we conclude that E 2 can promote the regeneration of damaged pancreatic islets by stimulating β-cell proliferation in diabetic rats, and this effect is accompanied by improvements in glucose tolerance and a decrease in plasma glucose levels. These findings suggest that oral administration of E 2 may be beneficial in diabetic patients with an accelerated loss of islet β-cells.

  6. [Pancreatic ultrasonography].

    Science.gov (United States)

    Fernández-Rodríguez, T; Segura-Grau, A; Rodríguez-Lorenzo, A; Segura-Cabral, J M

    2015-04-01

    Despite the recent technological advances in imaging, abdominal ultrasonography continues to be the first diagnostic test indicated in patients with a suspicion of pancreatic disease, due to its safety, accessibility and low cost. It is an essential technique in the study of inflammatory processes, since it not only assesses changes in pancreatic parenchyma, but also gives an indication of the origin (bile or alcoholic). It is also essential in the detection and tracing of possible complications as well as being used as a guide in diagnostic and therapeutic punctures. It is also the first technique used in the study of pancreatic tumors, detecting them with a sensitivity of around 70% and a specificity of 90%. Copyright © 2014 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

  7. Islet Oxygen Consumption Rate (OCR Dose Predicts Insulin Independence in Clinical Islet Autotransplantation.

    Directory of Open Access Journals (Sweden)

    Klearchos K Papas

    Full Text Available Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR in predicting clinical islet autotransplant (IAT insulin independence (II. IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity.Membrane integrity staining (FDA/PI, OCR normalized to DNA (OCR/DNA, islet equivalent (IE and OCR (viable IE normalized to recipient body weight (IE dose and OCR dose, and OCR/DNA normalized to islet size index (ISI were used to characterize autoislet preparations (n = 35. Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis.Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001. These islet characterization methods were highly correlated with II at 6-12 months post-IAT (area-under-the-curve (AUC = 0.94 for IE dose and 0.96 for OCR dose. FDA/PI (AUC = 0.49 and OCR/DNA (AUC = 0.58 did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72.Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations.

  8. Islet inflammation, hemosiderosis, and fibrosis in intrauterine growth-restricted and high fat-fed Sprague-Dawley rats.

    Science.gov (United States)

    Delghingaro-Augusto, Viviane; Madad, Leili; Chandra, Arin; Simeonovic, Charmaine J; Dahlstrom, Jane E; Nolan, Christopher J

    2014-05-01

    Prenatal and postnatal factors such as intrauterine growth restriction (IUGR) and high-fat (HF) diet contribute to type 2 diabetes. Our aim was to determine whether IUGR and HF diets interact in type 2 diabetes pathogenesis, with particular attention focused on pancreatic islet morphology including assessment for inflammation. A surgical model of IUGR (bilateral uterine artery ligation) in Sprague-Dawley rats with sham controls was used. Pups were fed either HF or chow diets after weaning. Serial measures of body weight and glucose tolerance were performed. At 25 weeks of age, rat pancreases were harvested for histologic assessment. The birth weight of IUGR pups was 13% lower than that of sham pups. HF diet caused excess weight gain, dyslipidemia, hyperinsulinemia, and mild glucose intolerance, however, this was not aggravated further by IUGR. Markedly abnormal islet morphology was evident in 0 of 6 sham-chow, 5 of 8 sham-HF, 4 of 8 IUGR-chow, and 8 of 9 IUGR-HF rats (chi-square, P = 0.007). Abnormal islets were characterized by larger size, irregular shape, inflammation with CD68-positive cells, marked fibrosis, and hemosiderosis. β-Cell mass was not altered by IUGR. In conclusion, HF and IUGR independently contribute to islet injury characterized by inflammation, hemosiderosis, and fibrosis. This suggests that both HF and IUGR can induce islet injury via converging pathways. The potential pathogenic or permissive role of iron in this process of islet inflammation warrants further investigation. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  9. Neural network diagnosis of avascular necrosis from magnetic resonance images

    Science.gov (United States)

    Manduca, Armando; Christy, Paul S.; Ehman, Richard L.

    1993-09-01

    We have explored the use of artificial neural networks to diagnose avascular necrosis (AVN) of the femoral head from magnetic resonance images. We have developed multi-layer perceptron networks, trained with conjugate gradient optimization, which diagnose AVN from single sagittal images of the femoral head with 100% accuracy on the training data and 97% accuracy on test data. These networks use only the raw image as input (with minimal preprocessing to average the images down to 32 X 32 size and to scale the input data values) and learn to extract their own features for the diagnosis decision. Various experiments with these networks are described.

  10. A mouse model for monitoring islet cell genesis and developing therapies for diabetes

    Directory of Open Access Journals (Sweden)

    Yoshinori Shimajiri

    2011-03-01

    Transient expression of the transcription factor neurogenin-3 marks progenitor cells in the pancreas as they differentiate into islet cells. We developed a transgenic mouse line in which the surrogate markers secreted alkaline phosphatase (SeAP and enhanced green florescent protein (EGFP can be used to monitor neurogenin-3 expression, and thus islet cell genesis. In transgenic embryos, cells expressing EGFP lined the pancreatic ducts. SeAP was readily detectable in embryos, in the media of cultured embryonic pancreases and in the serum of adult animals. Treatment with the γ-secretase inhibitor DAPT, which blocks Notch signaling, enhanced SeAP secretion rates and increased the number of EGFP-expressing cells as assayed by fluorescence-activated cell sorting (FACS and immunohistochemistry in cultured pancreases from embryos at embryonic day 11.5, but not in pancreases harvested 1 day later. By contrast, treatment with growth differentiation factor 11 (GDF11 reduced SeAP secretion rates. In adult mice, partial pancreatectomy decreased, whereas duct ligation increased, circulating SeAP levels. This model will be useful for studying signals involved in islet cell genesis in vivo and developing therapies that induce this process.

  11. Minireview: 12-Lipoxygenase and Islet β-Cell Dysfunction in Diabetes

    Science.gov (United States)

    Tersey, Sarah A.; Bolanis, Esther; Holman, Theodore R.; Maloney, David J.; Nadler, Jerry L.

    2015-01-01<