WorldWideScience

Sample records for beta-cells abolishes part

  1. Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis

    DEFF Research Database (Denmark)

    Carobbio, Stefania; Frigerio, Francesca; Rubi, Blanca;

    2009-01-01

    secretion was reduced by 37% in betaGlud1(-/-). Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in betaGlud1(-/-) islets fully restored......Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been...... glucose-induced insulin release. Thus, GDH appears to account for about 40% of glucose-stimulated insulin secretion and to lack redundant mechanisms. In betaGlud1(-/-) mice, the reduced secretory capacity resulted in lower plasma insulin levels in response to both feeding and glucose load, while body...

  2. 50 years forward: beta cells.

    Science.gov (United States)

    Halban, Philippe A

    2015-08-01

    Our understanding of beta cell development and function has increased substantially these past 50 years but much remains to be learned before this knowledge can be put to clinical use. A comprehensive business plan will be necessary to develop a detailed molecular and functional blueprint of the beta cell in health and disease based on an integrated approach involving all necessary research disciplines. This blueprint will provide a platform for the development of novel therapeutic strategies for the treatment of both major forms of diabetes, foremost among them beta cell replacement therapy. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). PMID:25957776

  3. Androgen excess produces systemic oxidative stress and predisposes to beta-cell failure in female mice.

    Directory of Open Access Journals (Sweden)

    Suhuan Liu

    Full Text Available In women, excess production of the male hormone, testosterone (T, is accompanied by insulin resistance. However, hyperandrogenemia is also associated with beta-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR activation predisposes to beta-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to beta-cell failure. We used normal female mice (CF and mice with androgen resistance by testicular feminization (Tfm. These mice were exposed to androgen excess and a beta-cell stress induced by streptozotocin (STZ. We find that following exposure to T, or the selective AR-agonist dehydrotestosterone (DHT, CF mice challenged with STZ, which are normally protected, are prone to beta-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to beta-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H(2O(2 in cultured mouse and human islets. However, we observe that exposure of CF mice to T or DHT provokes systemic oxidative stress, which is eliminated in Tfm mice. This work has significance for hyperandrogenic women; excess activation of AR by testosterone may provoke systemic oxidative stress. In the presence of a prior beta-cell stress, this may predispose to beta-cell failure.

  4. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.

    Directory of Open Access Journals (Sweden)

    R Charlotte Moffett

    Full Text Available Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1 and gastric inhibitory polypeptide (GIP. Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 and PC1/3 together with significant amounts of GLP-1 and GIP were detected in alpha cells. Knockout of GLP-1R abolished these islet adaptations and paradoxically decreased pancreatic insulin, GLP-1 and GIP. This was associated with abolition of normal pregnancy-induced increases in plasma GIP, L-cell numbers, and intestinal GIP and GLP-1 stores. These data indicate that GLP-1 but not GIP is a key mediator of beta cell mass expansion and related adaptations in pregnancy, triggered in part by generation of intra-islet GLP-1.

  5. The Fas pathway is involved in pancreatic beta cell secretory function

    DEFF Research Database (Denmark)

    Schumann, Desiree M; Maedler, Kathrin; Franklin, Isobel;

    2007-01-01

    Pancreatic beta cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in beta cell apoptosis or proliferation, depending...... on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates beta cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a beta cell......-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient beta cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased beta cell mass. Up-regulation of FLIP enhanced NF-kappaB activity via...

  6. Beta-cell mitochondrial carriers and the diabetogenic stress response.

    Science.gov (United States)

    Brun, Thierry; Maechler, Pierre

    2016-10-01

    Mitochondria play a central role in pancreatic beta-cells by coupling metabolism of the secretagogue glucose to distal events of regulated insulin exocytosis. This process requires transports of both metabolites and nucleotides in and out of the mitochondria. The molecular identification of mitochondrial carriers and their respective contribution to beta-cell function have been uncovered only recently. In type 2 diabetes, mitochondrial dysfunction is an early event and may precipitate beta-cell loss. Under diabetogenic conditions, characterized by glucotoxicity and lipotoxicity, the expression profile of mitochondrial carriers is selectively modified. This review describes the role of mitochondrial carriers in beta-cells and the selective changes in response to glucolipotoxicity. In particular, we discuss the importance of the transfer of metabolites (pyruvate, citrate, malate, and glutamate) and nucleotides (ATP, NADH, NADPH) for beta-cell function and dysfunction. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID:26979549

  7. The pancreatic beta cell surface proteome

    OpenAIRE

    Stützer, I.; Esterházy, D.; Stoffel, M.

    2012-01-01

    The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and prote...

  8. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype.

    Directory of Open Access Journals (Sweden)

    Geert A Martens

    Full Text Available BACKGROUND AND METHODOLOGY: The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser capture microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators. PRINCIPAL FINDINGS: A panel of 332 conserved beta cell biomarker genes was found to discriminate both isolated and laser capture microdissected beta cells from all other examined cell types. Of all conserved beta cell-markers, 15% were strongly beta cell-selective and functionally associated to hormone processing, 15% were shared with neuronal cells and associated to regulated synaptic vesicle transport and 30% with immune plus gut mucosal tissues reflecting active protein synthesis. Fasting specifically down-regulated the latter cluster, but preserved the neuronal and strongly beta cell-selective traits, indicating preserved differentiated state. Analysis of consensus binding site enrichment indicated major roles of CREB/ATF and various nutrient- or redox-regulated transcription factors in maintenance of differentiated beta cell phenotype. CONCLUSIONS: Conserved beta cell marker genes contain major gene clusters defined by their beta cell selectivity or by their additional abundance in either neural cells or in immune plus gut mucosal cells. This panel can be used as a template to identify changes in the differentiated state of beta cells.

  9. Beta cell proliferation and growth factors

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis; Svensson, C; Møldrup, Annette;

    1999-01-01

    Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood litt...

  10. Clusters of conserved beta cell marker genes for assessment of beta cell phenotype

    DEFF Research Database (Denmark)

    Martens, Geert A; Jiang, Lei; Hellemans, Karine H;

    2011-01-01

    of a large panel of other tissue and cell types, and transcripts with beta cell-abundant and -selective expression were identified. Iteration of this analysis in mouse, rat and human tissues generated a panel of conserved beta cell biomarkers. This panel was then used to compare isolated versus laser......The aim of this study was to establish a gene expression blueprint of pancreatic beta cells conserved from rodents to humans and to evaluate its applicability to assess shifts in the beta cell differentiated state. Genome-wide mRNA expression profiles of isolated beta cells were compared to those...... capture microdissected beta cells, monitor adaptations of the beta cell phenotype to fasting, and retrieve possible conserved transcriptional regulators....

  11. Insulin signaling regulates mitochondrial function in pancreatic beta-cells.

    Directory of Open Access Journals (Sweden)

    Siming Liu

    Full Text Available Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in beta-cells that included glucokinase (GK, and the pro-apoptotic protein, BAD(S. Mitochondria isolated from beta-cells derived from beta-cell specific insulin receptor knockout (betaIRKO mice exhibited reduced BAD(S, GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in betaIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BAD(S. The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in betaIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for beta-cell dysfunction in type 2 diabetes.

  12. Beta cell count instead of beta cell mass to assess and localize growth in beta cell population following pancreatic duct ligation in mice.

    Directory of Open Access Journals (Sweden)

    Marie Chintinne

    Full Text Available BACKGROUND: Pancreatic-tail duct ligation (PDL in adult rodents has been reported to induce beta cell generation and increase beta cell mass but increases in beta cell number have not been demonstrated. This study examines whether PDL increases beta cell number and whether this is caused by neogenesis of small clusters and/or their growth to larger aggregates. METHODOLOGY: Total beta cell number and its distribution over small (100 µm clusters was determined in pancreatic tails of 10-week-old mice, 2 weeks after PDL or sham. PRINCIPAL FINDINGS: PDL increased total beta cell mass but not total beta cell number. It induced neogenesis of small beta cell clusters (2.2-fold higher number which contained a higher percent proliferating beta cells (1.9% Ki67+cells than sham tails (<0.2%; their higher beta cell number represented <5% of total beta cell number and was associated with a similar increase in alpha cell number. It is unknown whether the regenerative process is causally related to the inflammatory infiltration in PDL-tails. Human pancreases with inflammatory infiltration also exhibited activation of proliferation in small beta cell clusters. CONCLUSIONS/SIGNIFICANCE: The PDL model illustrates the advantage of direct beta cell counts over beta cell mass measurements when assessing and localizing beta cell regeneration in the pancreas. It demonstrates the ability of the adult mouse pancreas for neogenesis of small beta cell clusters with activated beta cell proliferation. Further studies should investigate conditions under which neoformed small beta cell clusters grow to larger aggregates and hence to higher total beta cell numbers.

  13. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy

    OpenAIRE

    Butler, A. E.; Cao-Minh, L.; Galasso, R; Rizza, R. A.; Corradin, A.; Cobelli, C; Butler, P C

    2010-01-01

    Aims/hypothesis We sought to establish the extent and basis for adaptive changes in beta cell numbers in human pregnancy. Methods Pancreas was obtained at autopsy from women who had died while pregnant (n = 18), post-partum (n = 6) or were not pregnant at or shortly before death (controls; n = 20). Pancreases were evaluated for fractional pancreatic beta cell area, islet size and islet fraction of beta cells, beta cell replication (Ki67) and apoptosis (TUNEL), and indirect markers of beta cel...

  14. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

    Energy Technology Data Exchange (ETDEWEB)

    Kover, Karen, E-mail: kkover@cmh.edu [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States); Yan, Yun; Tong, Pei Ying; Watkins, Dara; Li, Xiaoyu [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States); Tasch, James; Hager, Melissa [Kansas City University Medical Biosciences, Kansas City, MO (United States); Clements, Mark; Moore, Wayne V. [Division of Endocrine/Diabetes, Children' s Mercy Hospital & Clinics, Kansas City, MO 64108 (United States); University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108 (United States)

    2015-06-19

    Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H{sub 2}O{sub 2} assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H{sub 2}O{sub 2} levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose

  15. Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

    International Nuclear Information System (INIS)

    Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H2O2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H2O2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival. - Highlights: • Osteocalcin reduces glucose-induced oxidative stress in beta cells. • Osteocalcin preserves beta cell function and survival under stress conditions. • Osteocalcin reduces glucose-induced TXNIP expression

  16. Measuring and Modeling Xenon Uptake in Plastic Beta-Cells

    Science.gov (United States)

    Suarez, R.; Hayes, J. C.; Harper, W. W.; Humble, P.; Ripplinger, M. D.; Stephenson, D. E.; Williams, R. M.

    2013-12-01

    The precision of the stable xenon volume measurement in atmospheric monitoring radio-xenon systems is a critical parameter used to determine the activity concentration of a radio-xenon sample. Typically these types of systems use a plastic scintillating beta-cell as part of a beta-gamma detection scheme to measure the radioactivity present in the gas sample. Challenges arise when performing the stable xenon calculation during or after radioactive counting of the sample due to xenon uptake into the plastic beta-cells. Plastic beta cells can adsorb as much as 5% of the sample during counting. If quantification is performed after counting, the uptake of xenon into the plastic results in an underestimation of the xenon volume measurement. This behavior also causes what is typically known as 'memory effect' in the cell. Experiments were conducted using a small volume low pressure range thermal conductivity sensor to quantify the amount of xenon uptake into the cell over a given period of time. Understanding the xenon uptake in the cell provides a better estimate of the stable volume which improves the overall measurement capability of the system. The results from these experiments along with modeling will be presented.

  17. Redox Homeostasis in Pancreatic beta Cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Dlasková, Andrea; Plecitá-Hlavatá, Lydie

    2012-01-01

    Roč. 2012, č. 2012 (2012), s. 932838. ISSN 1942-0900 R&D Projects: GA ČR(CZ) GAP302/10/0346; GA ČR(CZ) GPP304/10/P204 Institutional support: RVO:67985823 Keywords : beta cells * reactive oxygen species homeostasis * mitochondria Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 3.393, year: 2012

  18. Characterization of a Commercial Silicon Beta Cell

    Energy Technology Data Exchange (ETDEWEB)

    Foxe, Michael P. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Hayes, James C. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Mayer, Michael F. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); McIntyre, Justin I. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Sivels, Ciara B. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Suarez, Rey [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-03-31

    Silicon detectors are of interest for the verification of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) due to their enhanced energy resolution compared to plastic scintillators beta cells. Previous work developing a figure-of-merit (FOM) for comparison of beta cells suggests that the minimum detectable activity (MDA) could be reduced by a factor of two to three with the use of silicon detectors. Silicon beta cells have been developed by CEA (France) and Lares Ltd. (Russia), with the PIPSBox developed by CEA being commercially available from Canberra for approximately $35k, but there is still uncertainty about the reproducibility of the capabilities in the field. PNNL is developing a high-resolution beta-gamma detector system in the shallow underground laboratory, which will utilize and characterize the operation of the PIPSBox detector. Throughout this report, we examine the capabilities of the PIPSBox as developed by CEA. The lessons learned through the testing and use of the PIPSBox will allow PNNL to strategically develop a silicon detector optimized to better suit the communities needs in the future.

  19. The effect of smoking cessation pharmacotherapies on pancreatic beta cell function

    International Nuclear Information System (INIS)

    The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1 μM) of three test compounds resulted in an ablation of normal glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation. -- Highlights: ► Smoking cessation drugs have the potential to disrupt beta cell function in vitro. ► The effects of nicotine, varenicline and bupropion are similar. ► The impaired beta cell function is mediated by mitochondrial dysfunction. ► If similar effects are seen in vivo, these drugs may increase the risk of diabetes.

  20. The effect of smoking cessation pharmacotherapies on pancreatic beta cell function

    Energy Technology Data Exchange (ETDEWEB)

    Woynillowicz, Amanda K. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Raha, Sandeep [Department of Pediatrics, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Nicholson, Catherine J. [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada); Holloway, Alison C., E-mail: hollow@mcmaster.ca [Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada L8N 3Z5 (Canada)

    2012-11-15

    The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1 μM) of three test compounds resulted in an ablation of normal glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation. -- Highlights: ► Smoking cessation drugs have the potential to disrupt beta cell function in vitro. ► The effects of nicotine, varenicline and bupropion are similar. ► The impaired beta cell function is mediated by mitochondrial dysfunction. ► If similar effects are seen in vivo, these drugs may increase the risk of diabetes.

  1. In vitro proliferation of adult human beta-cells.

    Directory of Open Access Journals (Sweden)

    Sabine Rutti

    Full Text Available A decrease in functional beta-cell mass is a key feature of type 2 diabetes. Glucagon-like peptide 1 (GLP-1 analogues induce proliferation of rodent beta-cells. However, the proliferative capacity of human beta-cells and its modulation by GLP-1 analogues remain to be fully investigated. We therefore sought to quantify adult human beta-cell proliferation in vitro and whether this is affected by the GLP-1 analogue liraglutide.Human islets from 7 adult cadaveric organ donors were dispersed into single cells. Beta-cells were purified by FACS. Non-sorted cells and the beta-cell enriched ("beta-cells" population were plated on extracellular matrix from rat (804G and human bladder carcinoma cells (HTB9 or bovine corneal endothelial ECM (BCEC. Cells were maintained in culture+/-liraglutide for 4 days in the presence of BrdU.Rare human beta-cell proliferation could be observed either in the purified beta-cell population (0.051±0.020%; 22 beta-cells proliferating out of 84'283 beta-cells counted or in the non-sorted cell population (0.055±0.011%; 104 proliferating beta-cells out of 232'826 beta-cells counted, independently of the matrix or the culture conditions. Liraglutide increased human beta-cell proliferation on BCEC in the non-sorted cell population (0.082±0.034% proliferating beta-cells vs. 0.017±0.008% in control, p<0.05.These results indicate that adult human beta-cell proliferation can occur in vitro but remains an extremely rare event with these donors and particular culture conditions. Liraglutide increases beta-cell proliferation only in the non-sorted cell population and only on BCEC. However, it cannot be excluded that human beta-cells may proliferate to a greater extent in situ in response to natural stimuli.

  2. Mitochondrial function in normal and diabetic beta-cells

    OpenAIRE

    Maechler, Pierre; Wollheim, Claes

    2001-01-01

    The aetiology of type 2, or non-insulin-dependent, diabetes mellitus has been characterized in only a limited number of cases. Among these, mitochondrial diabetes, a rare subform of the disease, is the consequence of pancreatic beta-cell dysfunction caused by mutations in mitochondrial DNA, which is distinct from the nuclear genome. The impact of such mutations on beta-cell function reflects the importance of mitochondria in the control of insulin secretion. The beta-cell mitochondria serve a...

  3. Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass.

    Directory of Open Access Journals (Sweden)

    Ji-Hyeon Lee

    Full Text Available Insulin-producing pancreatic islet beta cells (beta-cells are destroyed, severely depleted or functionally impaired in diabetes. Therefore, replacing functional beta-cell mass would advance clinical diabetes management. We have previously demonstrated the importance of Cdk4 in regulating beta-cell mass. Cdk4-deficient mice display beta-cell hypoplasia and develop diabetes, whereas beta-cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase. While beta-cell replication appears to be the primary mechanism responsible for beta-cell mass increase, considerable evidence also supports a contribution from the pancreatic ductal epithelium in generation of new beta-cells. Further, while it is believed that majority of beta-cells are in a state of 'dormancy', it is unclear if and to what extent the quiescent cells can be coaxed to participate in the beta-cell regenerative response. Here, we address these queries using a model of partial pancreatectomy (PX in Cdk4 mutant mice. To investigate the kinetics of the regeneration process precisely, we performed DNA analog-based lineage-tracing studies followed by mathematical modeling. Within a week after PX, we observed considerable proliferation of islet beta-cells and ductal epithelial cells. Interestingly, the mathematical model showed that recruitment of quiescent cells into the active cell cycle promotes beta-cell mass reconstitution in the Cdk4R24C pancreas. Moreover, within 24-48 hours post-PX, ductal epithelial cells expressing the transcription factor Pdx-1 dramatically increased. We also detected insulin-positive cells in the ductal epithelium along with a significant increase of islet-like cell clusters in the Cdk4R24C pancreas. We conclude that Cdk4 not only promotes beta-cell replication, but also facilitates the activation of beta-cell progenitors in the ductal epithelium. In addition, we show that Cdk4 controls beta-cell mass by recruiting quiescent cells to enter the cell

  4. Effect of Exendin-4 on Autophagy Clearance in Beta Cell of Rats with Tacrolimus-induced Diabetes Mellitus

    Science.gov (United States)

    Lim, Sun Woo; Jin, Long; Jin, Jian; Yang, Chul Woo

    2016-01-01

    Growing evidence suggests that GLP-1 protects beta cells against various cellular injuries by modulating autophagy. In this study, we examined whether exendin-4 (Ex-4), a GLP-1 analog, had preventive effects on tacrolimus (Tac)-induced beta cell injury by improving autophagy clearance. Rats with Tac-induced diabetes mellitus exhibited increased autophagy-associated protein expression, light chain 3B levels, and autophagic vacuole numbers in pancreatic beta cells. Additionally, Tac increased autophagy in a dose- and time-dependent manner in vitro, and inhibition of autophagosome using 3-methyladenine reduced Tac-induced islet cell injury by decreasing reactive oxygen species production and apoptosis. Ex-4 treatment decreased Tac-induced hyperglycaemia, oxidative stress, and apoptosis, accompanied by decreased autophagy-associated protein expression and autophagosome numbers. In vivo and in vitro studies showed that Tac treatment impaired lysosomal function and autophagosome-lysosome fusion; these processes were improve by Ex-4 treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effects of Ex-4. Our findings reveal that Tac-induced diabetes mellitus was a state of excessive burden of autophagosomes and impairment of autophagy clearance and that Ex-4 protected against Tac-induced pancreatic islet injury by reducing the burden of autophagosomes via activation of autophagosome clearance. Thus, Ex-4 had therapeutic effects on Tac-induced pancreatic beta cell injury. PMID:27436514

  5. Coherent dynamics of exciatable coupled beta-cells

    DEFF Research Database (Denmark)

    Sørensen, Mads P; Petersen, Mette Vesterager; Aslanidi, Oleg

    Propagation of excitation waves through a cluster of insulin-secreting beta-cells (a pancreatic islet of Langerhans) is modelled, and the results are related to recent image analysis experiments.......Propagation of excitation waves through a cluster of insulin-secreting beta-cells (a pancreatic islet of Langerhans) is modelled, and the results are related to recent image analysis experiments....

  6. Closing in on Mass Production of Mature Human Beta Cells.

    Science.gov (United States)

    Kieffer, Timothy J

    2016-06-01

    Human pluripotent stem cell differentiation protocols based on mimicking developmental pathways are getting close to generating fully fledged pancreatic endocrine cells, including insulin-producing beta cells. However, challenges remain in identifying pathways to trigger the attainment of robust glucose responsiveness that occurs postnatally in beta cells. PMID:27257758

  7. Proliferation of sorted human and rat beta cells

    DEFF Research Database (Denmark)

    Parnaud, G; Bosco, D; Berney, T;

    2008-01-01

    The aim of the study was to determine whether purified beta cells can replicate in vitro and whether this is enhanced by extracellular matrix (ECM) and growth factors.......The aim of the study was to determine whether purified beta cells can replicate in vitro and whether this is enhanced by extracellular matrix (ECM) and growth factors....

  8. Progress in molecular nuclear medicine imaging of pancreatic beta cells

    International Nuclear Information System (INIS)

    Diabetes mellitus is a common and frequently occurring disease which seriously threaten the health of human beings. Type 1 and type 2 diabetes respectively results from being destroyed and insufficient beta-cell mass. The associated symptoms appear until 50%-60% decrease of beta-cell mass. Because pancreas is deeply located in the body, with few beta-cell mass, the current methods of clinical diagnosis are invasive and late. So diagnosis of metabolism disease of beta-cell early non-invasively becomes more and more popular, imaging diagnosis of diabetes mellitus becomes the focus of researches, but how to estimate the mass of beta-cell still an important subject in imaging technology. (authors)

  9. Chronology of endocrine differentiation and beta-cell neogenesis [Review].

    Science.gov (United States)

    Miyatsuka, Takeshi

    2016-03-31

    Diabetes is a chronic and incurable disease, which results from absolute or relative insulin insufficiency. Therefore, pancreatic beta cells, which are the only type of cell that expresses insulin, is considered to be a potential target for the cure of diabetes. Although the findings regarding beta-cell neogenesis during pancreas development have been exploited to induce insulin-producing cells from non-beta cells, there are still many hurdles towards generating fully functional beta cells that can produce high levels of insulin and respond to physiological signals. To overcome these problems, a solid understanding of pancreas development and beta-cell formation is required, and several mouse models have been developed to reveal the unique features of each endocrine cell type at distinct developmental time points. Here I review our understanding of pancreas development and endocrine differentiation focusing on recent progresses in improving temporal cell labeling in vivo. PMID:26615757

  10. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

    Science.gov (United States)

    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. PMID:26348137

  11. Targeting insulin-producing beta cells for regenerative therapy.

    Science.gov (United States)

    Migliorini, Adriana; Roscioni, Sara S; Lickert, Heiko

    2016-09-01

    Pancreatic beta cells differ in terms of glucose responsiveness, insulin secretion and proliferative capacity; however, the molecular pathways that regulate this cellular heterogeneity are unknown. We have identified the Wnt-planar cell polarity (PCP) effector Flattop (FLTP) as a biomarker that identifies mature beta cells in the islets of Langerhans. Interestingly, three-dimensional architecture and Wnt-PCP ligands are sufficient to trigger mouse and human beta cell maturation. These results highlight the fact that novel biomarkers shed light on the long-standing mystery of beta cell heterogeneity and identify the Wnt-PCP pathway as triggering beta cell maturation. Understanding heterogeneity in the islets of Langerhans might allow targeting of beta cell subpopulations for regenerative therapy and provide building principles for stem cell-derived islets. This review summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Amin Ardestani and Kathrin Maedler, DOI: 10.1007/s00125-016-3892-9 , and by Harry Heimberg and colleagues, DOI: 10.1007/s00125-016-3879-6 ) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2 ). PMID:27412250

  12. Sources of beta cells inside the pancreas.

    Science.gov (United States)

    De Groef, Sofie; Staels, Willem; Van Gassen, Naomi; Lemper, Marie; Yuchi, Yixing; Sojoodi, Mozhdeh; Bussche, Leen; Heremans, Yves; Leuckx, Gunter; De Leu, Nico; Van de Casteele, Mark; Baeyens, Luc; Heimberg, Harry

    2016-09-01

    The generation of beta(-like) cells to compensate for their absolute or relative shortage in type 1 and type 2 diabetes is an obvious therapeutic strategy. Patients first received grafts of donor islet cells over 25 years ago, but this procedure has not become routine in clinical practice because of a donor cell shortage and (auto)immune problems. Transplantation of differentiated embryonic and induced pluripotent stem cells may overcome some but not all the current limitations. Reprogramming exocrine cells towards functional beta(-like) cells would offer an alternative abundant and autologous source of beta(-like) cells. This review focuses on work by our research group towards achieving such a source of cells. It summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Amin Ardestani and Kathrin Maedler, DOI: 10.1007/s00125-016-3892-9 , and by Heiko Lickert and colleagues, DOI: 10.1007/s00125-016-3949-9 ) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2 ). PMID:27053238

  13. Imaging the Beta-cell mass: why and how

    DEFF Research Database (Denmark)

    Saudek, Frantisek; Brogren, Carl-Henrik; Manohar, Srirang

    2008-01-01

    of the fate of beta-cells under disease and therapy conditions. This could pave the way for a new era of intervention by islet replacement and regeneration regimens. Monitoring the beta-cell mass requires a reliable method for noninvasive in vivo imaging. Such a method is not available at present due......-cells. This effect was demonstrated in many previous investigations, and has been further substantiated more recently. Thus, at present, IC2 seems to be the only useful marker for noninvasive functional imaging of native beta-cells. Experiments with a radioisotope-chelated IC2 structure on pancreas ex vivo showed...

  14. Mechanisms of pancreatic beta-cell growth and regeneration

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1989-01-01

    Information about the mechanism of beta-cell growth and regeneration may be obtained by studies of insulinoma cells. In the present study the growth and function of the rat insulinoma cell lines RINm5F and 5AH were evaluated by addition of serum, hormones, and growth factors. It was found...... of insulin mRNA content showed that the insulinoma cells only contained about 2% of that of normal rat beta-cells. These results are discussed in relation to the role of growth factors, oncogenes, and differentiation in the growth and regeneration of beta-cells....

  15. Beta-Cell Preservation…Is Weight Loss the Answer?

    OpenAIRE

    Mazza, Angela D.; Pratley, Richard E.; Smith, Steven R.

    2011-01-01

    Obesity is associated with an increased risk of type 2 diabetes (T2D). Pancreatic beta-cell failure is an early event in the development of glucose dysregulation and diabetes. Interventions to halt beta-cell failure in T2D include diet modification, exercise, and use of pharmacologic agents. There is evidence that abdominal obesity may contribute to diabetes through insulin resistance and beta-cell impairment. Pivotal long-term studies into the prevention of T2D have shown the importance of w...

  16. Ascorbic acid recycling by cultured beta cells: effects of increased glucose metabolism.

    Science.gov (United States)

    Steffner, Robert J; Wu, Lan; Powers, Alvin C; May, James M

    2004-11-15

    Ascorbic acid is necessary for optimal insulin secretion from pancreatic islets. We evaluated ascorbate recycling and whether it is impaired by increased glucose metabolism in the rat beta-cell line INS-1. INS-1 cells, engineered with the potential for overexpression of glucokinase under the control of a tetracycline-inducible gene expression system, took up and reduced dehydroascorbic acid to ascorbate in a concentration-dependent manner that was optimal in the presence of physiologic D-glucose concentrations. Ascorbate uptake did not affect intracellular GSH concentrations. Whereas depletion of GSH in culture to levels about 25% of normal also did not affect the ability of the cells to reduce dehydroascorbic acid, more severe acute GSH depletion to less than 10% of normal levels did impair dehydroascorbic acid reduction. Culture of inducible cells in 11.8 mM D-glucose and doxycycline for 48 h enhanced glucokinase activity, increased glucose utilization, abolished D-glucose-dependent insulin secretion, and increased generation of reactive oxygen species. The latter may have contributed to subsequent decreases in the ability of the cells both to maintain intracellular ascorbate and to recycle it from dehydroascorbic acid. Cultured beta cells have a high capacity to recycle ascorbate, but this is sensitive to oxidant stress generated by increased glucose metabolism due to culture in high glucose concentrations and increased glucokinase expression. Impaired ascorbate recycling as a result of increased glucose metabolism may have implications for the role of ascorbate in insulin secretion in diabetes mellitus and may partially explain glucose toxicity in beta cells. PMID:15477012

  17. Serotonin competence of mouse beta cells during pregnancy.

    Science.gov (United States)

    Goyvaerts, Lotte; Schraenen, Anica; Schuit, Frans

    2016-07-01

    Pregnancy is a key mammalian reproductive event in which growth and differentiation of the fetus imposes extra metabolic and hormonal demands on the mother. Its successful outcome depends on major changes in maternal blood circulation, metabolism and endocrine function. One example is the endocrine pancreas, where beta cells undergo a number of changes in pregnancy that result in enhanced functional beta cell mass in order to compensate for the rising metabolic needs for maternal insulin. During the last 5 years, a series of studies have increased our understanding of the molecular events involved in this functional adaptation. In the mouse, a prominent functional change during pregnancy is the capacity of some beta cells to produce serotonin. In this review we will discuss the mechanism and potential effects of pregnancy-related serotonin production in beta cells, considering functional consequences at the local intra-islet and systemic level. PMID:27056372

  18. On the coherent behavior of pancreatic beta cell clusters

    Energy Technology Data Exchange (ETDEWEB)

    Loppini, Alessandro, E-mail: a.loppini@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Capolupo, Antonio, E-mail: capolupo@sa.infn.it [Physics Department, University of Salerno, Fisciano, 84084 (Italy); Cherubini, Christian, E-mail: c.cherubini@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); International Center for Relativistic Astrophysics, University Campus Bio-Medico, Via A. del Portillo 21, I-00128, Rome (Italy); Gizzi, Alessio, E-mail: a.gizzi@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Bertolaso, Marta, E-mail: m.bertolaso@unicampus.it [Faculty of Engineering and Institute of Philosophy of Scientific and Technological Practice, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); Filippi, Simonetta, E-mail: s.filippi@unicampus.it [Nonlinear Physics and Mathematical Modeling Lab, University Campus Bio-Medico, Via A. del Portillo 21, I-00128 Rome (Italy); International Center for Relativistic Astrophysics, University Campus Bio-Medico, Via A. del Portillo 21, I-00128, Rome (Italy); Vitiello, Giuseppe, E-mail: vitiello@sa.infn.it [Physics Department, University of Salerno, Fisciano, 84084 (Italy)

    2014-09-12

    Beta cells in pancreas represent an example of coupled biological oscillators which via communication pathways, are able to synchronize their electrical activity, giving rise to pulsatile insulin release. In this work we numerically analyze scale free self-similarity features of membrane voltage signal power density spectrum, through a stochastic dynamical model for beta cells in the islets of Langerhans fine tuned on mouse experimental data. Adopting the algebraic approach of coherent state formalism, we show how coherent molecular domains can arise from proper functional conditions leading to a parallelism with “phase transition” phenomena of field theory. - Highlights: • Beta cells in pancreas are coupled oscillators able to synchronize their activity. • We analyze scale free self-similarity features for beta cells. • We adopt the algebraic approach of coherent state formalism. • We show that coherent molecular domains arise from functional conditions.

  19. On the coherent behavior of pancreatic beta cell clusters

    International Nuclear Information System (INIS)

    Beta cells in pancreas represent an example of coupled biological oscillators which via communication pathways, are able to synchronize their electrical activity, giving rise to pulsatile insulin release. In this work we numerically analyze scale free self-similarity features of membrane voltage signal power density spectrum, through a stochastic dynamical model for beta cells in the islets of Langerhans fine tuned on mouse experimental data. Adopting the algebraic approach of coherent state formalism, we show how coherent molecular domains can arise from proper functional conditions leading to a parallelism with “phase transition” phenomena of field theory. - Highlights: • Beta cells in pancreas are coupled oscillators able to synchronize their activity. • We analyze scale free self-similarity features for beta cells. • We adopt the algebraic approach of coherent state formalism. • We show that coherent molecular domains arise from functional conditions

  20. Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells

    DEFF Research Database (Denmark)

    Olsen, Hervør L; Hoy, Marianne; Zhang, Wei;

    2003-01-01

    priming of secretory granules for release and increasing the number of granules residing in a readily releasable pool. Reducing the cytoplasmic ADP concentration in a way mimicking the effects of glucose stimulation activated PI 4-kinase and increased exocytosis whereas changes of the ATP concentration in...... the physiological range had little effect. The PI(4,5)P(2)-binding protein Ca(2+)-dependent activator protein for secretion (CAPS) is present in beta cells, and neutralization of the protein abolished both Ca(2+)- and PI(4,5)P(2)-induced exocytosis. We conclude that ADP-induced changes in PI 4-kinase...

  1. Adult Pancreatic Alpha-Cells: A New Source of Cells for Beta-Cell Regeneration

    OpenAIRE

    Chung, Cheng-Ho; Levine, Fred

    2010-01-01

    Beta-cell deficit is the major pathological feature in type 1 and type 2 diabetes patients, and plays a key role in disease progression. In principle, beta-cell regeneration can occur by replication of pre-existing beta-cells, or by beta-cell neogenesis from stem/progenitors. Unfortunately, beta-cell replication is limited by the almost complete absence of beta-cells in patients with type 1 diabetes, and the increasing recognition that the beta-cell replicative capacity declines severely with...

  2. Cocoa Phenolic Extract Protects Pancreatic Beta Cells against Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Laura Bravo

    2013-07-01

    Full Text Available Diabetes mellitus is associated with reductions in glutathione, supporting the critical role of oxidative stress in its pathogenesis. Antioxidant food components such as flavonoids have a protective role against oxidative stress-induced degenerative and age-related diseases. Flavonoids constitute an important part of the human diet; they can be found in most plant foods, including green tea, grapes or cocoa and possess multiple biological activities. This study investigates the chemo-protective effect of a cocoa phenolic extract (CPE containing mainly flavonoids against oxidative stress induced by tert-butylhydroperoxide (t-BOOH on Ins-1E pancreatic beta cells. Cell viability and oxidative status were evaluated. Ins-1E cells treatment with 5–20 μg/mL CPE for 20 h evoked no cell damage and did not alter ROS production. Addition of 50 μM t-BOOH for 2 h increased ROS and carbonyl groups content and decreased reduced glutathione level. Pre-treatment of cells with CPE significantly prevented the t-BOOH-induced ROS and carbonyl groups and returned antioxidant defences to adequate levels. Thus, Ins-1E cells treated with CPE showed a remarkable recovery of cell viability damaged by t-BOOH, indicating that integrity of surviving machineries in the CPE-treated cells was notably protected against the oxidative insult.

  3. Pancreatic beta cell protection/regeneration with phytotherapy

    Directory of Open Access Journals (Sweden)

    Azar Hosseini

    2015-03-01

    Full Text Available 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 pancreatic beta cell protection/regeneration. Among the hundreds of plants that have been investigated for diabetes, a small fraction has shown the regenerative property and was described in this paper. Processes of pancreatic beta cell degeneration and regeneration were described. Also, the proposed mechanisms for the protective/regenerative effects of such phytochemicals and their potential side effects were discussed.

  4. Foodborne cereulide causes beta-cell dysfunction and apoptosis.

    Directory of Open Access Journals (Sweden)

    Roman Vangoitsenhoven

    Full Text Available To study the effects of cereulide, a food toxin often found at low concentrations in take-away meals, on beta-cell survival and function.Cell death was quantified by Hoechst/Propidium Iodide in mouse (MIN6 and rat (INS-1E beta-cell lines, whole mouse islets and control cell lines (HepG2 and COS-1. Beta-cell function was studied by glucose-stimulated insulin secretion (GSIS. Mechanisms of toxicity were evaluated in MIN6 cells by mRNA profiling, electron microscopy and mitochondrial function tests.24 h exposure to 5 ng/ml cereulide rendered almost all MIN6, INS-1E and pancreatic islets apoptotic, whereas cell death did not increase in the control cell lines. In MIN6 cells and murine islets, GSIS capacity was lost following 24 h exposure to 0.5 ng/ml cereulide (P<0.05. Cereulide exposure induced markers of mitochondrial stress including Puma (p53 up-regulated modulator of apoptosis, P<0.05 and general pro-apoptotic signals as Chop (CCAAT/-enhancer-binding protein homologous protein. Mitochondria appeared swollen upon transmission electron microscopy, basal respiration rate was reduced by 52% (P<0.05 and reactive oxygen species increased by more than twofold (P<0.05 following 24 h exposure to 0.25 and 0.50 ng/ml cereulide, respectively.Cereulide causes apoptotic beta-cell death at low concentrations and impairs beta-cell function at even lower concentrations, with mitochondrial dysfunction underlying these defects. Thus, exposure to cereulide even at concentrations too low to cause systemic effects appears deleterious to the beta-cell.

  5. Pancreatic beta-cell overexpression of the glucagon receptor gene results in enhanced beta-cell function and mass

    DEFF Research Database (Denmark)

    Gelling, Richard W; Vuguin, Patricia M; Du, Xiu Quan;

    2009-01-01

    . beta-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting...... in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic beta-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin...... hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic beta-cell expression of the Gcgr increased insulin...

  6. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

    Science.gov (United States)

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-01-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

  7. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells.

    Science.gov (United States)

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-01-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

  8. Regulation of. beta. -cell glucose transporter gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ling; Alam, Tausif; Johnson, J.H.; Unger, R.H. (Univ. of Texas Southwestern Medical Center, Dallas (USA) Department of Veterans Affairs Medical Center, Dallas, TX (USA)); Hughes, S.; Newgard, C.B. (Univ. of Texas Southwestern Medical Center, Dallas (USA))

    1990-06-01

    It has been postulated that a glucose transporter of {beta} cells (GLUT-2) may be important in glucose-stimulated insulin secretion. To determine whether this transporter is constitutively expressed or regulated, the authors subjected conscious unrestrained Wistar rats to perturbations in glucose homeostasis and quantitated {beta}-cell GLUT-2 mRNA by in situ hybridization. After 3 hr of hypoglycemia, GLUT-2 and proinsulin mRNA signal densities were reduced by 25% of the level in control rats. After 4 days, GLUT-2 and proinsulin mRNA densities were reduced by 85% and 65%, respectively. After 12 days of hypoglycemia, the K{sub m} for 3-O-methyl-D-glucose transport in isolated rat islets, normally 18-20 mM, was 2.5 mM. This provides functional evidence of a profound reduction of high K{sub m} glucose transporter in {beta} cells. In contrast, GLUT-2 was only slightly reduced by hypoglycemia in liver. To determine the effect of prolonged hyperglycemia, they also infused animals with 50% (wt/vol) glucose for 5 days. Hyperglycemic clamping increased GLUT-2 mRNA by 46% whereas proinsulin mRNA doubled. They conclude that GLUT-2 expression in {beta} cells, but not liver, is subject to regulation by certain perturbations in blood glucose homeostasis.

  9. Workshop on programming beta cell development, impairment and regeneration

    DEFF Research Database (Denmark)

    Heller, Scott; Nielsen, Jens Høiriis

    2012-01-01

    Helsingør, the city of Hamlet in Denmark, provided the site for the workshop "Programming Beta Cell Development, Impairment and Regeneration" on October 23-26th, 2011. The same location has held two EASD Islet study group meetings, while the previous three workshops were held in Helsinki, Finland...

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

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2006-01-01

    Pancreatic beta-cells secrete insulin in response to raised glucose levels. Malfunctioning of this system plays an important role in the metabolic disease diabetes. The biological steps from glucose stimulus to the final release of insulin are incompletely understood, and a more complete...... 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 of an...... biological hypotheses. The subjects addressed are: Quasi-steady-state approximations of enzyme reactions, the effect of noise on bursting electrical behavior, exciation wave propagation in pancreatic islets, intra- and inter-islet synchronization and pulsatile insulin secretion, and mitochondrial dynamics....

  11. Stochastic and coherent dynamics of single and coupled beta cells

    DEFF Research Database (Denmark)

    burst period as function of an external applied stochastic term and use a technique for reducing the stochastic differential equations to ODEs for the average and higher order moments. The later method is approximate and we shall discuss the limits of validity. The individual beta cells are coupled...... phenomenon, modeled by a slow-fast nonlinear system of ordinary differential equations (ODEs). The single cell oscillations are complex as the dynamical behavior is a result of traversing a series of saddle node and homoclinic bifurcations, controlled by the slow variable. We shall present results on the...... beta cells in the simple one dimensional case and show how wave patterns can arise and propagate along the chain. These wave patterns can be blocked by inhomogeneous glucose concentration along the chain, and we shall show how the coupled cell model can be connected to the Fishers equation, which is...

  12. Circadian Transcription from Beta Cell Function to Diabetes Pathophysiology.

    Science.gov (United States)

    Perelis, Mark; Ramsey, Kathryn Moynihan; Marcheva, Biliana; Bass, Joseph

    2016-08-01

    The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease. PMID:27440914

  13. Novel genes underlying beta cell survival in metabolic stress

    OpenAIRE

    Singh, Himadri; Farouk, Mohammed; Bose, Barish Baran; Singh, Prabhakar

    2013-01-01

    Relative insulin deficiency, in response to increased metabolic demand (obesity, genetic insulin resistance, pregnancy and aging) lead to Type2 diabetes. Susceptibility of the type 2 diabetes has a genetic basis, as a subset of people with risk factors (obesity, Insulin Resistance, pregnancy), develop Type2 Diabetes. We aimed to identify ‘cluster’ of overexpressed genes, underlying increased beta cell survival in diabetes resistant C57BL/6J ob/ob mice (compared to diabetes susceptible BTBR ob...

  14. Mechanisms of Beta Cell Dysfunction Associated With Viral Infection

    OpenAIRE

    Petzold, Antje; Solimena, Michele; Knoch, Klaus-Peter

    2015-01-01

    Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While s...

  15. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways.

    Science.gov (United States)

    Dudek, Nadine L; Thomas, Helen E; Mariana, Lina; Sutherland, Robyn M; Allison, Janette; Estella, Eugene; Angstetra, Eveline; Trapani, Joseph A; Santamaria, Pere; Lew, Andrew M; Kay, Thomas W H

    2006-09-01

    Cytotoxic T-cells are the major mediators of beta-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to beta-cell destruction using islet-specific CD8(+) T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for beta-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with beta-cells that do not respond to Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by overexpression of suppressor of cytokine signaling-1 (SOCS-1) in beta-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell-mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition. PMID:16936188

  16. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics

    DEFF Research Database (Denmark)

    Sturis, Jeppe; Gotfredsen, Carsten F; Rømer, John;

    2003-01-01

    (1) Liraglutide is a long-acting GLP-1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and beta-cell mass in rat models of beta-cell deficiencies, studies were performed in male Zucker diabetic fatty (ZDF...

  17. Role of MicroRNAs in Islet Beta-Cell Compensation and Failure during Diabetes

    Directory of Open Access Journals (Sweden)

    Valérie Plaisance

    2014-01-01

    Full Text Available Pancreatic beta-cell function and mass are markedly adaptive to compensate for the changes in insulin requirement observed during several situations such as pregnancy, obesity, glucocorticoids excess, or administration. This requires a beta-cell compensation which is achieved through a gain of beta-cell mass and function. Elucidating the physiological mechanisms that promote functional beta-cell mass expansion and that protect cells against death, is a key therapeutic target for diabetes. In this respect, several recent studies have emphasized the instrumental role of microRNAs in the control of beta-cell function. MicroRNAs are negative regulators of gene expression, and are pivotal for the control of beta-cell proliferation, function, and survival. On the one hand, changes in specific microRNA levels have been associated with beta-cell compensation and are triggered by hormones or bioactive peptides that promote beta-cell survival and function. Conversely, modifications in the expression of other specific microRNAs contribute to beta-cell dysfunction and death elicited by diabetogenic factors including, cytokines, chronic hyperlipidemia, hyperglycemia, and oxidized LDL. This review underlines the importance of targeting the microRNA network for future innovative therapies aiming at preventing the beta-cell decline in diabetes.

  18. ATP regulates sodium channel kinetics in pancreatic islet beta cells

    OpenAIRE

    Zou, Na; Rupnik, Marjan

    2015-01-01

    Pancreatic beta cells act as glucose sensors, in which intracellular ATP ([ATP](i)) are altered with glucose concentration change. The characterization of voltage-gated sodium channels under different [ATP](i) remains unclear. Here, we demonstrated that increasing [ATP](i) within a certain range of concentrations (2-8 mM) significantly enhanced the voltage-gated sodium channel currents, compared with 2 mM cytosolic ATP. This enhancement was attenuated by even high intracellular ATP (12 mM). F...

  19. Time-dependent Mechanisms in Beta-cell Glucose Sensing

    OpenAIRE

    Vagn Korsgaard, Thomas; Colding-Jørgensen, Morten

    2006-01-01

    The relation between plasma glucose and insulin release from pancreatic beta-cells is not stationary in the sense that a given glucose concentration leads to a specific rate of insulin secretion. A number of time-dependent mechanisms appear to exist that modify insulin release both on a short and a longer time scale. Typically, two phases are described. The first phase, lasting up to 10 min, is a pulse of insulin release in response to fast changes in glucose concentration. The second phase i...

  20. Parathyroid Hormone-Related Peptide (1-36) Enhances Beta Cell Regeneration and Increases Beta Cell Mass in a Mouse Model of Partial Pancreatectomy

    Science.gov (United States)

    Mozar, Anaïs; Lin, Hugo; Williams, Katoura; Chin, Connie; Li, Rosemary; Kondegowda, Nagesha Guthalu; Stewart, Andrew F.; Garcia-Ocaña, Adolfo; Vasavada, Rupangi Chhaya

    2016-01-01

    Aims/Hypothesis Finding ways to stimulate the regeneration of endogenous pancreatic beta cells is an important goal in the treatment of diabetes. Parathyroid hormone-related protein (PTHrP), the full-length (1–139) and amino-terminal (1–36) peptides, enhance beta cell function, proliferation, and survival. Therefore, we hypothesize that PTHrP(1–36) has the potential to regenerate endogenous beta cells. Methods The partial pancreatectomy (PPx) mouse model of beta cell injury was used to test this hypothesis. Male Balb/c mice underwent either sham-operation or PPx, and were subsequently injected with PTHrP(1–36) (160μg/kg) or vehicle (veh), for 7, 30, or 90 days. The four groups of mice, sham-veh, sham-PTHrP, PPx-veh, and PPx-PTHrP were assessed for PTHrP and receptor expression, and glucose and beta cell homeostasis. Results PTHrP-receptor, but not the ligand, was significantly up-regulated in islets from mice that underwent PPx compared to sham-operated mice. This suggests that exogenous PTHrP could further enhance beta cell regeneration after PPx. PTHrP did not significantly affect body weight, blood glucose, plasma insulin, or insulin sensitivity, in either sham or PPx mice. Glucose tolerance improved in the PPx-PTHrP versus PPx-veh mice only in the early stages of treatment. As hypothesized, there was a significant increase in beta cell proliferation in PPx-PTHrP mice at days 7 and 30; however, this was normalized by day 90, compared to PPx-veh mice. Enhanced beta cell proliferation translated to a marked increase in beta cell mass at day 90, in PPx-PTHrP versus PPx-veh mice. Conclusions PTHrP(1–36) significantly enhances beta cell regeneration through increased beta cell proliferation and beta cell mass after PPx. Future studies will determine the potential of PTHrP to enhance functional beta cell mass in the setting of diabetes. PMID:27391423

  1. Regulation of Beta-Cell Function and Mass by the Dual Leucine Zipper Kinase.

    Science.gov (United States)

    Oetjen, Elke

    2016-06-01

    Diabetes mellitus is one of the most rapidly increasing diseases worldwide, whereby approximately 90-95% of patients suffer from type 2 diabetes. Considering its micro- and macrovascular complications like blindness and myocardial infarction, a reliable anti-diabetic treatment is needed. Maintaining the function and the mass of the insulin producing beta-cells despite elevated levels of beta-cell-toxic prediabetic signals represents a desirable mechanism of action of anti-diabetic drugs. The dual leucine zipper kinase (DLK) inhibits the action of two transcription factors within the beta-cell, thereby interfering with insulin secretion and production and the conservation of beta-cell mass. Furthermore, DLK action is regulated by prediabetic signals. Hence, the inhibition of this kinase might protect beta-cells against beta-cell-toxic prediabetic signals and prevent the development of diabetes. DLK might thus present a novel drug target for the treatment of diabetes mellitus type 2. PMID:27100796

  2. Do post-translational beta cell protein modifications trigger type 1 diabetes?

    DEFF Research Database (Denmark)

    Størling, Joachim; Overgaard, Anne Julie; Brorsson, Caroline Anna;

    2013-01-01

    forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create......Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified...... beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading...

  3. Re-expression of IGF-II is important for beta cell regeneration in adult mice.

    Directory of Open Access Journals (Sweden)

    Luxian Zhou

    Full Text Available BACKGROUND: The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration. METHODOLOGY/PRINCIPAL FINDINGS: We employed an in vivo model of 'switchable' c-Myc-induced beta cell ablation, pIns-c-MycER(TAM, in which 90% of beta cells are lost following 11 days of c-Myc (Myc activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycER(TAM/IGF-II(+/+ (MIG mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycER(TAM/IGF-II(+/- (MIGKO mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.

  4. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells.

    OpenAIRE

    Schuit, F C; In't Veld, P A; Pipeleers, D. G

    1988-01-01

    Glucose is a well-known stimulus of proinsulin biosynthesis. In purified beta cells, the sugar induces a 25-fold increase in the synthesis of insulin immunoreactive material over 60-min incubation. Autoradiographic analysis of the individual cells shows that this effect is achieved via dose-dependent recruitment of pancreatic beta cells to biosynthetic activity. Recruitment of beta cells is also seen in isolated islets exposed to glucose. The sigmoidal dose-response curve for glucose-induced ...

  5. Extracellular ATP-induced nuclear Ca{sup 2+} transient is mediated by inositol 1,4,5-trisphosphate receptors in mouse pancreatic {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zheng; Li, Zhengzheng; Peng, Gong; Chen, Xiaoli; Yin, Wenxuan [National Laboratory of Biomacromolecules, Institute of Biophysics of Chinese Academy of Sciences, 15 Datun Rd., Beijing 100101 (China); Kotlikoff, Michael I. [Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853 (United States); Yuan, Zeng-qiang, E-mail: zqyuan@sun5.ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics of Chinese Academy of Sciences, 15 Datun Rd., Beijing 100101 (China); Ji, Guangju, E-mail: gj28@ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics of Chinese Academy of Sciences, 15 Datun Rd., Beijing 100101 (China)

    2009-05-01

    Extracellular ATP (eATP) induces an intracellular Ca{sup 2+} transient by activating phospholipase C (PLC)-associated P2X4 purinergic receptors, leading to production of inositol 1,4,5-trisphosphate (IP3) and subsequent Ca{sup 2+} release from intracellular stores in mouse pancreatic {beta}-cells. Using laser scanning confocal microscopy, Ca{sup 2+} indicator fluo-4 AM, and the cell permeable nuclear indicator Hoechst 33342, we examined the properties of eATP-induced Ca{sup 2+} release in pancreatic {beta}-cell nuclei. eATP induced a higher nuclear Ca{sup 2+} transient in pancreatic {beta}-cell nuclei than in the cytosol. After pretreatment with thapsigargin (TG), an inhibitor of sarco-endoplasmic reticulum Ca{sup 2+}-ATPase (SERCA) pumps, the amplitude of eATP-induced Ca{sup 2+} transients in the nucleus was still much higher than those in the cytosol. This effect of eATP was not altered by inhibition of either the plasma membrane Ca{sup 2+}-ATPase (PMCA) or the plasma membrane Na{sup +}/Ca{sup 2+} exchanger (NCX) by LaCl{sub 3} or by replacement of Na{sup +} with N-Methyl-Glucosamine. eATP-induced nuclear Ca{sup 2+} transients were abolished by a cell-permeable IP3R inhibitor, 2-aminoethoxydiphenyl borate (2-APB), but were not blocked by the ryanodine receptor (RyR) antagonist ryanodine. Immunofluorescence studies showed that IP3Rs are expressed on the nuclear envelope of pancreatic {beta}-cells. These results indicate that eATP triggers nuclear Ca{sup 2+} transients by mobilizing a nuclear Ca{sup 2+} store via nuclear IP3Rs.

  6. Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    2012-01-01

    Full Text Available Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes.

  7. Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells

    Directory of Open Access Journals (Sweden)

    Ling Chen

    2015-07-01

    Full Text Available Background/Aims: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. Methods: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4. We used AAV-Pax4 to transduce a mouse alpha cell line in vitro, and to transduce primary alpha cells in diabetic mice. Reprogramming was examined by double immunostaining and by changes in beta cell number. The effects on blood glucose were evaluated by fasting blood glucose and glucose response. Results: In vitro, Pax4 overexpression neither induced insulin expression, nor suppressed glucagon expression in alpha cells. In vivo, Pax4 overexpression failed to increase beta cell number, and did not alter hyperglycemia and glucose response in diabetic mice. Conclusion: Pax4 expression is not sufficient to transduce pancreatic alpha cells into beta cells. Overexpression of Pax4 in alpha cells may not increase functional beta cell number in diabetic patients.

  8. CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner

    DEFF Research Database (Denmark)

    Huising, Mark O; van der Meulen, Talitha; Vaughan, Joan M;

    2009-01-01

    Corticotropin-releasing factor (CRF), originally characterized as the principal neuroregulator of the hypothalamus-pituitary-adrenal axis, has broad central and peripheral distribution and actions. We demonstrate the presence of CRF receptor type 1 (CRFR1) on primary beta cells and show that...... MIN6 insulinoma line and primary rat islets with CRF also activates the MAPK signaling cascade leading to rapid phosphorylation of Erk1/2 in response to CRFR1-selective ligands, which induce proliferation in primary rat neonatal beta cells. Importantly, CRFR1 stimulates insulin secretion only during......1 on beta cells adds another layer of complexity to the intricate network of paracrine and autocrine factors and their cognate receptors whose coordinated efforts can dictate islet hormone output and regulate beta cell proliferation....

  9. Testosterone abolishes implicit subordination in social anxiety.

    Science.gov (United States)

    Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah J; Stein, Dan J; Honk, Jack van

    2016-10-01

    Neuro-evolutionary theories describe social anxiety as habitual subordinate tendencies acquired through a recursive cycle of social defeat and submissive reactions. If so, the steroid hormone testosterone might be of therapeutic value, as testosterone is a main force behind implicit dominance drive in many species including humans. We combined these two theories to investigate whether the tendency to submit to the dominance of others is an implicit mechanism in social anxiety (Study-1), and whether this can be relieved through testosterone administration (Study-2). Using interactive eye-tracking we demonstrate that socially anxious humans more rapidly avert gaze from subliminal angry eye contact (Study-1). We replicate this effect of implicit subordination in social anxiety in an independent sample, which is subsequently completely abolished after a single placebo-controlled sublingual testosterone administration (Study-2). These findings provide crucial evidence for hormonal and behavioral treatment strategies that specifically target mechanisms of dominance and subordination in social anxiety. PMID:27448713

  10. Cell therapies for pancreatic beta-cell replenishment.

    Science.gov (United States)

    Okere, Bernard; Lucaccioni, Laura; Dominici, Massimo; Iughetti, Lorenzo

    2016-01-01

    The current treatment approach for type 1 diabetes is based on daily insulin injections, combined with blood glucose monitoring. However, administration of exogenous insulin fails to mimic the physiological activity of the islet, therefore diabetes often progresses with the development of serious complications such as kidney failure, retinopathy and vascular disease. Whole pancreas transplantation is associated with risks of major invasive surgery along with side effects of immunosuppressive therapy to avoid organ rejection. Replacement of pancreatic beta-cells would represent an ideal treatment that could overcome the above mentioned therapeutic hurdles. In this context, transplantation of islets of Langerhans is considered a less invasive procedure although long-term outcomes showed that only 10 % of the patients remained insulin independent five years after the transplant. Moreover, due to shortage of organs and the inability of islet to be expanded ex vivo, this therapy can be offered to a very limited number of patients. Over the past decade, cellular therapies have emerged as the new frontier of treatment of several diseases. Furthermore the advent of stem cells as renewable source of cell-substitutes to replenish the beta cell population, has blurred the hype on islet transplantation. Breakthrough cellular approaches aim to generate stem-cell-derived insulin producing cells, which could make diabetes cellular therapy available to millions. However, to date, stem cell therapy for diabetes is still in its early experimental stages. This review describes the most reliable sources of stem cells that have been developed to produce insulin and their most relevant experimental applications for the cure of diabetes. PMID:27400873

  11. 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.

  12. NOX, NOX who is there?, The contribution of NADPH Oxidase to beta cell dysfunction.

    Directory of Open Access Journals (Sweden)

    David eTaylor-Fishwick

    2013-04-01

    Full Text Available Predictions of diabetes prevalence over the next decades warrant the aggressive discovery of new approaches to stop or reverse loss of functional beta cell mass. Beta cells are recognized to have a relatively high sensitivity to reactive oxygen species (ROS and become dysfunctional under oxidative stress conditions. New discoveries have identified NADPH oxidases in beta cells as contributors to elevated cellular ROS. Reviewed are recent reports that evidence a role for NADPH oxidase-1 (NOX-1 in beta cell dysfunction. NOX-1 is stimulated by inflammatory cytokines that are elevated in diabetes. First, regulation of cytokine-stimulated NOX-1 expression has been linked to inflammatory lipid mediators derived from 12-lipoxyganase activity. For the first time in beta cells these data integrate distinct pathways associated with beta cell dysfunction. Second, regulation of NOX-1 in beta cells involves feed-forward control linked to elevated ROS and Src-kinase activation. This potentially results in unbridled ROS generation and identifies candidate targets for pharmacologic intervention. Third, consideration is provided of new, first-in-class, selective inhibitors of NOX-1. These compounds could have an important role in assessing a disruption of NOX-1/ROS signaling as a new approach to preserve and protect beta cell mass in diabetes.

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

    DEFF Research Database (Denmark)

    Efrat, S; Linde, S; Kofod, Hans;

    1988-01-01

    Three pancreatic beta-cell lines have been established from insulinomas derived from transgenic mice carrying a hybrid insulin-promoted simian virus 40 tumor antigen gene. The beta tumor cell (beta TC) lines maintain the features of differentiated beta cells for about 50 passages in culture. The ...

  14. An imidazoline compound completely counteracts interleukin-1[beta] toxic effects to rat pancreatic islet [beta] cells

    DEFF Research Database (Denmark)

    Papaccio, Gianpaolo; Nicoletti, Ferdinando; Pisanti, Francesco A; Galdieri, Michela; Bendtzen, Klaus

    2002-01-01

    In vitro studies have demonstrated that interleukin (IL)-1beta decreases insulin and DNA contents in pancreatic islet beta cells, causing structural damage, that it is toxic to cultured human islet beta cells and that it is able to induce apoptosis in these cells....

  15. CRFR1 activation protects against cytokine-induced beta cell death

    DEFF Research Database (Denmark)

    Blaabjerg, Lykke; Christensen, Gitte Lund; Matsumoto, Masahito; van der Meulen, Talitha; Huising, Mark O; Billestrup, Nils; Vale, Wylie

    2014-01-01

    During diabetes development beta cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL-1β which in vitro, induce beta cell death. The class B G-protein-coupled receptors (GPCRs): Corticotropin releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreat...

  16. An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells.

    NARCIS (Netherlands)

    Schulze, D.U.; Dufer, M.; Wieringa, B.; Krippeit-Drews, P.; Drews, G.

    2007-01-01

    AIMS/HYPOTHESIS: In a previous study, we demonstrated that a creatine kinase (CK) modulates K(ATP) channel activity in pancreatic beta cells. To explore phosphotransfer signalling pathways in more detail, we examined whether K(ATP) channel regulation in beta cells is determined by a metabolic intera

  17. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Rasmussen, D N; Mascagni, P; Dinarello, C A; Billestrup, N; Grunnet, L G; Mandrup-Poulsen, T

    2010-01-01

    Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the...

  18. 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...... 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...... source of cultured human beta-cells for beta-cell research, along with the development of new therapeutic strategies for detection, characterization and treatment of insulinomas....

  19. Implications for the offspring of circulating factors involved in beta cell adaptation in pregnancy

    DEFF Research Database (Denmark)

    Nalla, Amarnadh; Ringholm, Lene; Søstrup, Birgitte;

    2014-01-01

    proliferation of rat beta cells was studied using [3H]thymidine incorporation and 5-ethynyl-2'-deoxyuridine proliferation assays. In addition, serum from pregnant and nonpregnant women was fractionated by gel filtration and high performance liquid chromatography. The fractionated serum was screened for......OBJECTIVE: Several studies have shown an increase in beta cell mass during pregnancy. Somatolactogenic hormones are known to stimulate the proliferation of existing beta cells in rodents whereas the mechanism in humans is still unclear. We hypothesize that in addition to somatolactogenic hormones...... there are other circulating factors involved in beta cell adaptation to pregnancy. This study aimed at screening for potential pregnancy-associated circulating beta cell growth factors. SAMPLES: Serum samples from nonpregnant and pregnant women. METHODS: The effect of serum from pregnant women on the...

  20. Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

    Directory of Open Access Journals (Sweden)

    Hao Yin

    Full Text Available AIMS/HYPOTHESIS: Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes. METHODS: In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass. RESULTS: Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery. CONCLUSIONS/INTERPRETATION: These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

  1. Bmal1 and Beta cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced Beta cell failure in mice

    Science.gov (United States)

    Circadian disruption has deleterious effects on metabolism. Global deletion of Bmal1, a core clock gene, results in Beta cell dysfunction and diabetes. However, it is unknown if this is due to loss of cell-autonomous function of Bmal1 in Beta cells. To address this, we generated mice with Beta cell ...

  2. Pancreatic beta cell function in the fetal pig and sow.

    Science.gov (United States)

    Fowden, A L; Comline, R S; Silver, M

    1982-04-01

    Insulin secretion was investigated in acutely anaesthetized and chronically catheterized sows and their fetuses during late gestation. In the conscious animals, the mean fetal concentration of plasma insulin was 8.4 +/- 1.5 microunits/ml which was significantly less than the corresponding maternal value of 33.9 +/- 6.5 microunits/ml (n = 12, P less than 0.01). The plasma concentrations of insulin and glucose in the new-born piglets from these litters were not significantly different from the values observed in utero. The plasma concentration of insulin in the anaesthetized fetuses was significantly less than that in the chronically catheterized piglets over the same range of glucose levels. In the chronically catheterized animals, both fetal and maternal levels of insulin rose with increasing concentrations of plasma glucose while under acute conditions there was no correlation between the endogenous concentrations of insulin and glucose in either the fetuses or their mothers. Infusion of exogenous glucose (0.5 g as a 50% solution in 0.9% NaCl) stimulated the release of insulin in all the chronically catheterized fetuses studied but rarely increased the concentration of insulin in the anaesthetized fetusus. The present findings show that anaesthesia and surgery depress pancreatic beta cell function in the pig, particularly in the fetus. PMID:7043523

  3. Present and future cell therapies for pancreatic beta cell replenishment

    Institute of Scientific and Technical Information of China (English)

    Juan Domínguez-Bendala; Camillo Ricordi

    2012-01-01

    If only at a small scale,islet transplantation has successfully addressed what ought to be the primary endpoint of any cell therapy:the functional replenishment of damaged tissue in patients.After years of less-thanoptimal approaches to immunosuppression,recent advances consistently yield long-term graft survival rates comparable to those of whole pancreas transplantation.Limited organ availability is the main hurdle that stands in the way of the widespread clinical utilization of this pioneering intervention.Progress in stem cell research over the past decade,coupled with our decades-long experience with islet transplantation,is shaping the future of cell therapies for the treatment of diabetes.Here we review the most promising avenues of research aimed at generating an inexhaustible supply of insulin-producing cells for islet regeneration,including the differentiation of pluripotent and multipotent stem cells of embryonic and adult origin along the beta cell lineage and the direct reprogramming of non-endocrine tissues into insulin-producing cells.

  4. Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

    OpenAIRE

    van der Meulen, Talitha; Huising, Mark O.

    2014-01-01

    Type 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulin-producing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully ge...

  5. Beta cell imaging - a key tool in optimized diabetes prevention and treatment.

    Science.gov (United States)

    Gotthardt, Martin; Eizirik, Decio L; Cnop, Miriam; Brom, Maarten

    2014-08-01

    The prevalence of diabetes is 382 million worldwide, and is expected to rise to 592 million in 2035 (http://www.idf.org/diabetesatlas); 2.5-15% of national annual healthcare budgets are related to diabetes care, potentially increasing to 40% in high-prevalence countries. Beta cell dysfunction and death are central events in diabetes pathogenesis, but the natural history of beta cell loss remains unknown. Clinical imaging of beta cells will play a pivotal role in developing strategies for optimized diabetes prevention and treatment. PMID:24726483

  6. Hypoglycemic and beta cell protective effects of andrographolide analogue for diabetes treatment

    OpenAIRE

    Larrick James W; Zeng Xiangping; Yu Pei; Jiang Jie; Zhang Zaijun; Wang Yuqiang

    2009-01-01

    Abstract Background While all anti-diabetic agents can decrease blood glucose level directly or indirectly, few are able to protect and preserve both pancreatic beta cell mass and their insulin-secreting functions. Thus, there is an urgent need to find an agent or combination of agents that can lower blood glucose and preserve pancreatic beta cells at the same time. Herein, we report a dual-functional andrographolide-lipoic acid conjugate (AL-1). The anti-diabetic and beta cell protective act...

  7. MST1: a promising therapeutic target to restore functional beta cell mass in diabetes.

    Science.gov (United States)

    Ardestani, Amin; Maedler, Kathrin

    2016-09-01

    The loss of insulin-producing beta cells by apoptosis is a hallmark of all forms of diabetes mellitus. Strategies to prevent beta cell apoptosis and dysfunction are urgently needed to restore the insulin-producing cells and to prevent severe diabetes progression. We recently identified the serine/threonine kinase known as mammalian sterile 20-like kinase 1 (MST1) as a critical regulator of apoptotic beta cell death and dysfunction. MST1 activates several apoptotic signalling pathways, which further stimulate its own cleavage, leading to a vicious cycle of cell death. This led us to hypothesise that MST1 signalling is central to the initiation of beta cell death in diabetes. We found that MST1 is strongly activated in a diabetic beta cell and induces not only its death but also directly impairs insulin secretion through promoting proteasomal degradation of key beta cell transcription factor, pancreatic and duodenal homeobox 1 (PDX1), which is critical for insulin production.Pre-clinical studies in various animal models of diabetes have reported that MST1 deficiency remarkably restores normoglycaemia and beta cell function and prevents the development of diabetes. Importantly, MST1 deficiency can revert fully diabetic beta cells to a non-diabetic state. MST1 may serve as a target for the development of novel therapies for diabetes that trigger the cause of the disease, namely, the destruction of the beta cells. The major current focus of our investigation is to identify and test the efficacy of potent inhibitors of this death signalling pathway to protect beta cells against the effects of autoimmune attack in type 1 diabetes and to preserve beta cell mass and function in type 2 diabetes. This review summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Heiko Lickert and colleagues, DOI: 10.1007/s00125-016-3949-9 , and by Harry

  8. Targeting Homeostatic T Cell Proliferation to Control Beta-Cell Autoimmunity.

    Science.gov (United States)

    Vignali, Debora; Monti, Paolo

    2016-05-01

    Immunomodulation of the autoreactive T cell response is considered a major strategy to control beta-cell autoimmunity, both in the natural history of type 1 diabetes and in islet transplantation, which can be affected by autoimmunity recurrence. So far, these strategies have had modest results, prompting efforts to define novel cellular and molecular targets to control autoreactive T cell expansion and activation. Novel findings highlighted the important role of the homeostatic cytokine interleukin-7 in inducing proliferation and differentiation of autoreactive T cell clones that causes beta-cell autoimmunity. In this review, we discuss recent evidences and novel findings on the role of IL-7 mediated homeostatic T cell proliferation in the process of beta-cell destruction and evidences of how targeting IL-7 and its receptor could be an innovative and effective strategy to control beta-cell autoimmunity. PMID:26983628

  9. Assessment of beta-cell function and insulin secretion in subjects that underwent renal transplantation.

    Science.gov (United States)

    Tura, Andrea; Hecking, Manfred; Wolzt, Michael; Saemann, Marcus D; Pacini, Giovanni

    2015-08-01

    In this study we aimed to assess the performance of various indices of beta-cell function derived from oral glucose tolerance test (OGTT) in subjects that underwent renal transplantation. Impaired insulin secretion seems in fact central for development of new onset diabetes after transplantation, but its assessment has not been systematically evaluated. Twenty subjects underwent a 75 g 2h-OGTT for measurement of glucose, insulin, C-peptide. OGTT indices of beta-cell function were either derived by mathematical modeling (yielding the reference index: glucose sensitivity) or were empirical: insulinogenic index (IGI), IGI derived indices, whole shape C-peptide (WHOSH_CP). Indices of beta cell function, showed significant correlation with glucose sensitivity (R(2)=0.40-0.86, all Pbody mass index, mean glycemia. In conclusion, in transplanted subjects OGTT empirical indices are typically acceptable for the estimation of beta-cell function. PMID:26736770

  10. Connexin implication in the control of the murine beta-cell mass.

    Science.gov (United States)

    Klee, Philippe; Lamprianou, Smaragda; Charollais, Anne; Caille, Dorothée; Sarro, Rossella; Cederroth, Manon; Haefliger, Jacques-Antoine; Meda, Paolo

    2011-08-01

    Diabetes develops when the insulin needs of peripheral cells exceed the availability or action of the hormone. This situation results from the death of most beta-cells in type 1 diabetes, and from an inability of the beta-cell mass to adapt to increasing insulin needs in type 2 and gestational diabetes. We analyzed several lines of transgenic mice and showed that connexins (Cxs), the transmembrane proteins that form gap junctions, are implicated in the modulation of the beta-cell mass. Specifically, we found that the native Cx36 does not alter islet size or insulin content, whereas the Cx43 isoform increases both parameters, and Cx32 has a similar effect only when combined with GH. These findings open interesting perspectives for the in vitro and in vivo regulation of the beta-cell mass. PMID:21527868

  11. Effect of aerobic exercise on Pancreas Beta-cells function in adult obese males

    Directory of Open Access Journals (Sweden)

    Mojtaba Eizadi

    2014-08-01

    Conclusion: Aerobic exercise training increases beta cells function and decreases FBS in obese men. These findings support the hypothesis that regular physical activity postpones the occurrence of type 2 diabetes in adult obese subjects.

  12. Activation of the GLP-1 Receptor Signalling Pathway: A Relevant Strategy to Repair a Deficient Beta-Cell Mass

    Directory of Open Access Journals (Sweden)

    Bernard Portha

    2011-01-01

    Full Text Available Recent preclinical studies in rodent models of diabetes suggest that exogenous GLP-1R agonists and DPP-4 inhibitors have the ability to increase islet mass and preserve beta-cell function, by immediate reactivation of beta-cell glucose competence, as well as enhanced beta-cell proliferation and neogenesis and promotion of beta-cell survival. These effects have tremendous implication in the treatment of T2D because they directly address one of the basic defects in T2D, that is, beta-cell failure. In human diabetes, however, evidence that the GLP-1-based drugs alter the course of beta-cell function remains to be found. Several questions surrounding the risks and benefits of GLP-1-based therapy for the diabetic beta-cell mass are discussed in this review and require further investigation.

  13. Free radicals and the pathogenesis of type 1 diabetes: beta-cell cytokine-mediated free radical generation via cyclooxygenase-2.

    Science.gov (United States)

    Tabatabaie, Tahereh; Vasquez-Weldon, Angelica; Moore, Danny R; Kotake, Yashige

    2003-08-01

    Free radical formation evoked by proinflammatory cytokines has been suggested to be involved in the destruction of beta-cells in the course of type 1 diabetes development. However, there is no direct evidence to support this hypothesis. In this study, we used electron paramagnetic resonance spectroscopy in conjunction with spin-trapping methodology to directly determine whether cytokines give rise to free radical formation in the islets. Our results demonstrate that direct, in vivo administration of tumor necrosis factor-alpha (1,000 units), interleukin-1beta (1,000 units), and interferon-gamma (2,000 units) into the rat pancreas through a bile duct cannula leads to the formation of lipid-derived free radicals in this tissue. These free radicals most likely are generated by the beta-cells because previous depletion of these cells by streptozotocin abolished the cytokine-induced free radical formation. Furthermore, macrophage depletion was found to decrease the production of free radicals. Inhibition of the enzyme inducible cyclooxygenase (COX-2) and the transcription factor nuclear factor-kappaB (NF-kappaB) significantly diminished the free radicals' signal intensity, implicating these factors in the formation of free radicals. We have also demonstrated that cytokine treatment leads to the activation of NF-kappaB in the pancreatic islets of the rats. PMID:12882915

  14. ALDH expression characterizes G1-phase proliferating beta cells during pregnancy.

    Directory of Open Access Journals (Sweden)

    Lijuan Zhang

    Full Text Available High levels of aldehyde dehydrogenase (ALDH activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases. To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co-stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells. Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas.

  15. ALDH Expression Characterizes G1-Phase Proliferating Beta Cells during Pregnancy

    Science.gov (United States)

    Zhang, Lijuan; Wang, Lin; Liu, Xiaoliang; Zheng, Dongming; Liu, Sishi; Liu, Caixia

    2014-01-01

    High levels of aldehyde dehydrogenase (ALDH) activity have been detected in various progenitor and stem cells. Thus, Aldefluor fluorescence, which represents precisely the ALDH activity, has been widely used for the identification, evaluation, and isolation of stem and progenitor cells. Recently, ALDH activity was detected in embryonic and adult mouse pancreas, specifically in adult centroacinar and terminal duct cells supposed to harbor endocrine and exocrine progenitor cells in the adult pancreas. Nevertheless, ALDH activity and aldeflour fluorescence have not been examined in beta cells. Here, we report a dynamic increase in the number of aldeflour+ beta cells during pregnancy. Interestingly, nearly all these aldeflour+ beta cells are positive for Ki-67, suggesting that they are in an active cell cycle (G1, S and M phases). To determine precisely at which phase beta cells activate ALDH activity and thus become aldeflour+, we co-stained insulin with additional proliferation markers, phosphohistone3 (PHH3, a marker for M-phase proliferating cells) and Bromodeoxyuridine (BrdU, a marker for S-phase proliferating cells). Our data show little aldeflour+ beta cells that were positive for either PHH3, or BrdU, suggesting that beta cells activate ALDH and become Aldefluor+ when they enter G1-phase of active cell cycle, but may downregulate ALDH when they leave G1-phase and enter S phase. Our data thus reveal a potential change in ALDH activity of proliferating beta cells during pregnancy, which provides a novel method for isolation and analysis of proliferating beta cells. Moreover, our data also suggest that caution needs to be taken on interpretation of Aldefluor lineage-tracing data in pancreas. PMID:24787690

  16. SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments

    OpenAIRE

    Wael A. Eter; Parween, Saba; Joosten, Lieke; Frielink, Cathelijne; Eriksson, Maria; Brom, Maarten; Ahlgren, Ulf; Gotthardt, Martin

    2016-01-01

    Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Altern...

  17. Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans.

    OpenAIRE

    Seaquist, E. R.; Kahn, S. E.; Clark, P. M.; Hales, C. N.; Porte, D; Robertson, R. P.

    1996-01-01

    The cause of disproportionate hyperproinsulinemia in patients with type II diabetes is controversial. To examine whether increased beta cell demand might contribute, we measured proinsulin and insulin concentrations in clinically healthy humans who had undergone hemipancreatectomy for the purpose of organ donation, a procedure previously demonstrated to increase beta cell demand and diminish insulin secretory reserve capacity. Subjects were studied at least 1 yr after hemipancreatectomy. Seve...

  18. Quercetin Stimulates Insulin Secretion and Reduces the Viability of Rat INS-1 Beta-Cells

    Directory of Open Access Journals (Sweden)

    Michael Kittl

    2016-06-01

    Full Text Available Background/Aims: Previously we described insulinotropic effects of Leonurus sibiricus L. plant extracts used for diabetes mellitus treatment in Traditional Mongolian Medicine. The flavonoid quercetin and its glycoside rutin, which exert anti-diabetic properties in vivo by interfering with insulin signaling in peripheral target tissues, are constituents of these extracts. This study was performed to better understand short- and long-term effects of quercetin and rutin on beta-cells. Methods: Cell viability, apoptosis, phospho-protein abundance and insulin release were determined using resazurin, annexin-V binding assays, Western blot and ELISA, respectively. Membrane potentials (Vmem, whole-cell Ca2+ (ICa- and ATP-sensitive K+ (IKATP currents were measured by patch clamp. Intracellular Ca2+ (Cai levels were measured by time-lapse imaging using the ratiometric Ca2+ indicator Fura-2. Results: Rutin, quercetin and the phosphoinositide-3-kinase (PI3K inhibitor LY294002 caused a dose-dependent reduction in cell viability with IC50 values of ∼75 µM, ∼25 µM and ∼3.5 µM, respectively. Quercetin (50 µM significantly increased the percentage of Annexin-V+ cells within 48 hrs. The mean cell volume (MCV of quercetin-treated cells was significantly lower. Within 2 hrs, quercetin significantly decreased basal- and insulin-stimulated Akt(T308 phosphorylation and increased Erk1/2 phosphorylation, without affecting P-Akt(S473 abundance. Basal- and glucose-stimulated insulin release were significantly stimulated by quercetin. Quercetin significantly depolarized Vmem by ∼25 mV which was prevented by the KATP-channel opener diazoxide, but not by the L-type ICa inhibitor nifedipine. Quercetin significantly stimulated ICa and caused a 50% inhibition of IKATP. The effects on Vmem, ICa and IKATP rapidly reached peak values and then gradually diminished to control values within ∼1 minute. With a similar time-response quercetin induced an elevation in Cai

  19. Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs

    Directory of Open Access Journals (Sweden)

    Jonathan L. S. Esguerra

    2014-11-01

    Full Text Available Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs is termed “stimulus-secretion coupling.” Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D. The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D.

  20. Incretin hormones and beta cell function in chronic pancreatitis

    DEFF Research Database (Denmark)

    Knop, Filip Krag

    2010-01-01

    regulated by the mere presence of nutrients in the small intestine, but also that the assimilation of such nutrients is involved, as well. Furthermore, we gauged the incretin effect in 8 patients with CP and normal glucose tolerance and in 8 patients with CP and secondary DM. Eight healthy subjects and 8......Type 2 diabetes mellitus (T2DM) has been shown to be characterised by an almost abolished incretin effect. The incretin effect refers to the phenomenon of oral glucose eliciting a higher insulin response than intravenous glucose at identical plasma glucose profiles. It is conveyed by the two...... insulinotropic incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are secreted from the small intestines in response to ingestion of nutrients. The incretin defect of T2DM has been characterised by a virtually lost insulinotropic effect of GIP...

  1. Factors that influence age of type 1 diabetes onset and beta cell function in children and adults with newly diagnosed type 1 diabetes

    OpenAIRE

    Giannopoulou, Eleni

    2016-01-01

    This thesis investigates whether type 1 and type 2 diabetes associated single nucleotide polymorphisms (SNPs) influence age of type 1 diabetes onset and residual beta cell function in children and adults with newly diagnosed type 1 diabetes. In the second part, a pilot, non-randomized, controlled intervention trial is performed, in order to examine whether a single autologous cord blood infusion can change the natural course of metabolic and immune function in children type 1 diabetes. Di...

  2. Markers of beta cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes

    Science.gov (United States)

    Jones, Angus G; McDonald, Timothy J; Shields, Beverley M; Hill, Anita V; Hyde, Christopher J; Knight, Bridget A; Hattersley, Andrew T

    2016-01-01

    Objective To assess whether clinical characteristics and simple biomarkers of beta cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist therapy in patients with type 2 diabetes. Research Design and Methods We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58mmol/mol (7.5%) commencing GLP-1 receptor agonist therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with beta cell failure and glycemic response (HbA1c change 0 to 6 months, primary outcome) with change in weight (0 to 6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and co-treatment change. Results Reduced glycemic response to GLP-1R agonists was associated with longer duration diabetes, insulin co-treatment, lower fasting C-peptide, lower post meal urine C-peptide creatinine ratio and positive GAD or IA2 islet autoantibodies (p≤0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ≤0.25nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies: mean HbA1c change -5.2 vs -15.2 mmol/mol (-0.5 vs -1.4%), p=0.005 C-peptide diabetes. PMID:26242184

  3. Fetal and neonatal nicotine exposure in Wistar rats causes progressive pancreatic mitochondrial damage and beta cell dysfunction.

    Directory of Open Access Journals (Sweden)

    Jennifer E Bruin

    Full Text Available Nicotine replacement therapy (NRT is currently recommended as a safe smoking cessation aid for pregnant women. However, fetal and neonatal nicotine exposure in rats causes mitochondrial-mediated beta cell apoptosis at weaning, and adult-onset dysglycemia, which we hypothesize is related to progressive mitochondrial dysfunction in the pancreas. Therefore in this study we examined the effect of fetal and neonatal exposure to nicotine on pancreatic mitochondrial structure and function during postnatal development. Female Wistar rats were given saline (vehicle control or nicotine bitartrate (1 mg/kg/d via subcutaneous injection for 2 weeks prior to mating until weaning. At 3-4, 15 and 26 weeks of age, oral glucose tolerance tests were performed, and pancreas tissue was collected for electron microscopy, enzyme activity assays and islet isolation. Following nicotine exposure mitochondrial structural abnormalities were observed beginning at 3 weeks and worsened with advancing age. Importantly the appearance of these structural defects in nicotine-exposed animals preceded the onset of glucose intolerance. Nicotine exposure also resulted in significantly reduced pancreatic respiratory chain enzyme activity, degranulation of beta cells, elevated islet oxidative stress and impaired glucose-stimulated insulin secretion compared to saline controls at 26 weeks of age. Taken together, these data suggest that maternal nicotine use during pregnancy results in postnatal mitochondrial dysfunction that may explain, in part, the dysglycemia observed in the offspring from this animal model. These results clearly indicate that further investigation into the safety of NRT use during pregnancy is warranted.

  4. 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.

  5. Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting beta-cell line, INS-1

    DEFF Research Database (Denmark)

    Frödin, M; Sekine, N; Roche, E; Filloux, C; Prentki, M; Wollheim, C B; Van Obberghen, E

    1995-01-01

    of this kinase is not sufficient for secretion. In the presence of glucose, however, nerve growth factor potentiated insulin secretion. In INS-1 cells, activation of 44-kDa MAP kinase was partially correlated with the induction of early response genes junB, nur77, and zif268 but not with stimulation......The signaling pathways whereby glucose and hormonal secretagogues regulate insulin-secretory function, gene transcription, and proliferation of pancreatic beta-cells are not well defined. We show that in the glucose-responsive beta-cell line INS-1, major secretagogue-stimulated signaling pathways...... glucagon-like peptide-1 and pituitary adenylate cyclase-activating polypeptide. Activation of 44-kDa MAP kinase by glucose was dependent on Ca2+ influx and may in part be mediated by MEK-1, a MAP kinase kinase. Stimulation of Ca2+ influx by KCl was in itself sufficient to activate 44-kDa MAP kinase and MEK...

  6. Joe Doupe lecture: emerging strategies for the preservation of pancreatic beta-cell function in early type 2 diabetes.

    Science.gov (United States)

    Retnakaran, Ravi

    2014-01-01

    A fundamental problem in the clinical management of type 2 diabetes is the inability to prevent the ongoing deterioration of pancreatic beta-cell function over time that underlies the chronic progressive nature of this condition. Importantly, beta-cell dysfunction has both reversible and irreversible components. Furthermore, the amelioration of reversible beta-cell dysfunction through the early institution of short-term insulin-based therapy has emerged as a strategy that can yield temporary remission of type 2 diabetes. In this context, we have forwarded a novel therapeutic paradigm consisting of initial induction therapy to improve beta-cell function early in the course of diabetes followed by maintenance therapy aimed at preserving this beneficial beta-cell effect. Ultimately, this approach may yield an optimized therapeutic strategy for the durable preservation of beta-cell function and consequent modification of the natural history of type 2 diabetes. PMID:25618275

  7. New Therapeutic Approaches to Prevent or Delay Beta-Cell Failure in Diabetes

    Directory of Open Access Journals (Sweden)

    Ionica Floriana Elvira

    2015-09-01

    Full Text Available Background and aims: The most recent estimates of International Diabetes Federation indicate that 382 million people have diabetes, and the incidence of this disease is increasing. While in type 1 diabetes mellitus (T1DM beta-cell death is autoimmunemediated, type 2 diabetes mellitus (T2DM results from an interaction between genetic and environmental factors that impair beta-cell function and insulin action. Many people with T2DM remain unaware of their illness for a long time because symptoms may take years to appear or be recognized, while the body is affected by excess blood glucose. These patients are often diagnosed only when diabetes complications have already developed. The aim of this article was to perform a review based on literature data on therapeutic modalities to prevent/delay beta cell function decline. Material and Methods: We searched MEDLINE from 2000 to the present to identify the therapeutic approaches to prevent or delay beta-cell failure in patients with T2DM. Results and conclusions: Several common polymorphisms in genes linked to monogenic forms of diabetes appear to influence the response to T2DM pharmacotherapy. Recent studies report the role of the G protein coupled receptor 40 (GPR40, also known as Free Fatty Acids Receptor 1 (FFAR1 in the regulation of beta-cell function- CNX-011-67 (a GPR40 agonist has the potential to provide good and durable glycemic control in T2DM patients.

  8. T cells cooperate with palmitic acid in induction of beta cell apoptosis

    Directory of Open Access Journals (Sweden)

    Miljković Djordje

    2009-05-01

    Full Text Available Abstract Background Diabetes is characterized by progressive failure of insulin producing beta cells. It is well known that both saturated fatty acids and various products of immune cells can contribute to the reduction of beta cell viability and functionality during diabetes pathogenesis. However, their joint action on beta cells has not been investigated, so far. Therefore, we explored the possibility that leukocytes and saturated fatty acids cooperate in beta cell destruction. Results Rat pancreatic islets or insulinoma cells (RIN were co-cultivated with concanavalin A (ConA-stimulated rat lymph node cells (LNC, or they were treated with cell-free supernatants (Sn obtained from ConA-stimulated spleen cells or from activated CD3+ cells, in the absence or presence of palmitic acid (PA. ConA-stimulated LNC or Sn and PA cooperated in inducing caspase-3-dependent RIN cell apoptosis. The observed effect of PA and Sn on RIN cell viability was mediated by p38 mitogen-activated protein kinase (MAPK-signaling and was achieved through auto-destructive nitric oxide (NO production. The cooperative effect of Sn was mimicked with the combination of interleukin-1β, interleukin-2, interleukin-6, interleukin-17, interferon-γ and tumor necrosis factor-α. Conclusion These results imply that stimulated T cells produce cytokines that cooperate with saturated free fatty acids in beta cell destruction during diabetes pathogenesis.

  9. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function

    International Nuclear Information System (INIS)

    This review focuses on the emerging evidence that reactive oxygen species (ROS) derived from glucose metabolism, such as H2O2, act as metabolic signaling molecules for glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells. Particular emphasis is placed on the potential inhibitory role of endogenous antioxidants, which rise in response to oxidative stress, in glucose-triggered ROS and GSIS. We propose that cellular adaptive response to oxidative stress challenge, such as nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant induction, plays paradoxical roles in pancreatic beta-cell function. On the one hand, induction of antioxidant enzymes protects beta-cells from oxidative damage and possible cell death, thus minimizing oxidative damage-related impairment of insulin secretion. On the other hand, the induction of antioxidant enzymes by Nrf2 activation blunts glucose-triggered ROS signaling, thus resulting in reduced GSIS. These two premises are potentially relevant to impairment of beta-cells occurring in the late and early stage of Type 2 diabetes, respectively. In addition, we summarized our recent findings that persistent oxidative stress due to absence of uncoupling protein 2 activates cellular adaptive response which is associated with impaired pancreatic beta-cell function.

  10. NADPH oxidase mediates glucolipotoxicity-induced beta cell dysfunction--clinical implications.

    Science.gov (United States)

    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2010-03-01

    An impairment of glucose-stimulated insulin secretion--reflecting decreased glucokinase expression--and a moderate decrease in beta cell mass attributable to increased apoptosis, constitute the key features of beta cell failure in type 2 diabetes. Oxidative stress, provoked by prolonged exposure to excessive levels of glucose and/or fatty acids (glucolipotoxicity), appears to be a key mediator of these defects. Oxidant-provoked JNK activation induces nuclear export of the PDX-1 transcription factor, required for expression of glucokinase and other beta cell proteins. Conversely, increases in cAMP induced by incretin hormones promote the nuclear importation of PDX-1, counteracting the diabetogenic impact of oxidant stress; this may explain the utility of measures that slow dietary carbohydrate absorption for diabetes prevention. The ability of oxidative stress to boost apoptosis in beta cells is poorly understood, but may also entail JNK activation. Recent work establishes a phagocyte-type NADPH oxidase as the chief source of glucotoxicity-mediated oxidative stress in beta cells. Since bilirubin is now known to function physiologically as an inhibitor of NADPH oxidase, and phycocyanobilin (PCB) derived from spirulina likewise can inhibit this enzyme complex, supplemental PCB may have utility in the prevention and control of diabetes, and Gilbert syndrome, associated with chronically elevated free bilirubin, may be associated with decreased diabetes risk. PMID:19576699

  11. Abnormal mitochondrial function impairs calcium influx in diabetic mouse pancreatic beta cells

    Institute of Scientific and Technical Information of China (English)

    LI Fei; D. Marshall Porterfield; ZHENG Xi-yan; WANG Wen-jun; XU Yue; ZHANG Zong-ming

    2012-01-01

    Background Abnormal insulin secretion of pancreatic beta cells is now regarded as the more primary defect than the insulin function in the etiology of type 2 diabetes.Previous studies found impaired mitochondrial function and impaired Ca2+ influx in beta cells in diabetic patients and animal models,suggesting a role for these processes in proper insulin secretion.The aim of this study was to investigate the detailed relationship of mitochondrial function,Ca2+ influx,and defective insulin secretion.Methods We investigated mitochondrial function and morphology in pancreatic beta cell of diabetic KK-Ay mice and C57BL/6J mice.Two types of Ca2+ channel activities,L-type and store-operated Ca2+ (SOC),were evaluated using whole-cell patch-clamp recording.The glucose induced Ca2+ influx was measured by a non-invasive micro-test technique (NMT).Results Mitochondria in KK-Ay mice pancreatic beta cells were swollen with disordered cristae,and mitochondrial function decreased compared with C57BL/6J mice.Ca2+ channel activity was increased and glucose induced Ca2+ influx was impaired,but could be recovered by genipin.Conclusion Defective mitochondrial function in diabetic mice pancreatic beta cells is a key cause of abnormal insulin secretion by altering Ca2+ influx,but not via Ca2+ channel activity.

  12. Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice

    OpenAIRE

    Cox, Aaron R.; Carol J Lam; Bonnyman, Claire W.; Chavez, Julia; Rios, Jacqueline S.; Kushner, Jake A.

    2015-01-01

    Aims/hypothesis The identification of novel targets that stimulate endogenous regeneration of beta cells would represent a significant advance in the treatment of patients with diabetes. The betatrophin hypothesis suggests that increased expression of angiopoietin-like protein 8 (ANGPTL8) induces dramatic and specific beta cell proliferation and subsequent beta cell mass expansion with improved glucose tolerance. In light of recent controversy, we further investigated the effects of ANGPTL8 o...

  13. RX871024 reduces NO production but does not protect against pancreatic beta-cell death induced by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Zaitseva, Irina I; Sharoyko, Vladimir; Størling, Joachim; Efendic, Suad; Guerin, Christopher; Mandrup-Poulsen, Thomas; Nicotera, Pierluigi; Berggren, Per-Olof; Zaitsev, Sergei V

    2006-01-01

    The imidazoline compound RX871024 reduces IL-1beta-induced NO production thereby protecting against IL-1beta-induced beta-cell apoptosis. The aim of this study was to evaluate whether imidazolines RX871024 and efaroxan protect beta-cells against death in the presence of a combination of the......, induces pancreatic beta-cell death that does not directly correlate with NO production and cannot be counteracted with imidazoline compounds....

  14. Glucose enhances collectrin protein expression in insulin-producing MIN6 {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Saisho, Kenji; Fukuhara, Atsunori [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Yasuda, Tomoko [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Sato, Yoshifumi; Fukui, Kenji; Iwahashi, Hiromi; Imagawa, Akihisa [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Hatta, Mitsutoki [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Shimomura, Iichiro [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Yamagata, Kazuya, E-mail: k-yamaga@kumamoto-u.ac.jp [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan)

    2009-11-06

    Collectrin is a novel target gene of hepatocyte nuclear factor-1{alpha} in pancreatic {beta}-cells and controls insulin exocytosis. Although glucose is known to stimulate the expression of genes of the insulin secretory pathway, there is no information on how glucose regulates collectrin expression. We investigated the effects of glucose on the expression of collectrin in MIN6 {beta}-cell line. Glucose, in a dose-dependent manner, increased collectrin protein levels without changing collectrin mRNA levels and protein stability, indicating that glucose stimulation of collectrin protein expression is primarily mediated at a translational level. Although mannose and pyruvate also increased collectrin protein expression level, neither 2-deoxyglucose, mitochondrial fuels leucine and glutamate, sulphonylurea nor Ca{sup 2+} channel blockers, mimicked the effects of glucose. These data indicate the involvement of mitochondrial TCA cycle intermediates, distal to pyruvate, in the regulation of collectrin protein expression in {beta}-cells.

  15. Pancreatic hormone secretion in chronic pancreatitis without residual beta-cell function

    DEFF Research Database (Denmark)

    Larsen, S; Hilsted, J; Tronier, B;

    1988-01-01

    Hormonal responses (glucagon, pancreatic polypeptide and somatostatin) to iv glucagon, iv arginine, and ingestion of a mixed meal were investigated in 6 patients with insulin-dependent diabetes secondary to chronic pancreatitis without beta-cell function, in 8 Type I (insulin-dependent) diabetics...... without beta-cell function, and 8 healthy subjects. No significant differences were found between the two diabetic groups regarding glucagon responses to arginine and meal ingestion. In the patients with diabetes secondary to chronic pancreatitis compared with Type I diabetics and normal controls...... no residual beta-cell function. These findings suggest that pancreatic glucagon deficiency is not absolute in insulin-dependent diabetes secondary to chronic pancreatitis. A high level of somatostatin may contribute to a lower blood glucose level in patients with chronic pancreatitis....

  16. Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells

    DEFF Research Database (Denmark)

    Grunnet, Lars G; Aikin, Reid; Tonnesen, Morten F;

    2009-01-01

    OBJECTIVE: Proinflammatory cytokines are cytotoxic to beta-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced beta-cell death is unclear. Here, cytokine activation of the...... intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in beta-cells. RESEARCH DESIGN AND METHODS: Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis...... factor-alpha). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to...

  17. A subset of human pancreatic beta cells express functional CD14 receptors: a signaling pathway fot beta cell-related glycolipids, sulfatide and beta-galactosylceramide

    Czech Academy of Sciences Publication Activity Database

    Osterbye, T.; Funda, David; Fundová, Petra; Mansson, J.-E.; Tlaskalová-Hogenová, Helena; Buschard, K.

    2010-01-01

    Roč. 26, č. 8 (2010), s. 656-667. E-ISSN 1520-7560 R&D Projects: GA ČR GA303/06/1329; GA ČR GA310/07/0414; GA ČR GA310/09/1640 Institutional research plan: CEZ:AV0Z50200510 Keywords : human beta-cell * cd14 * innate immunity Subject RIV: EE - Microbiology, Virology

  18. Insulin-producing cells generated from dedifferentiated human pancreatic beta cells expanded in vitro.

    Directory of Open Access Journals (Sweden)

    Holger A Russ

    Full Text Available BACKGROUND: Expansion of beta cells from the limited number of adult human islet donors is an attractive prospect for increasing cell availability for cell therapy of diabetes. However, attempts at expanding human islet cells in tissue culture result in loss of beta-cell phenotype. Using a lineage-tracing approach we provided evidence for massive proliferation of beta-cell-derived (BCD cells within these cultures. Expansion involves dedifferentiation resembling epithelial-mesenchymal transition (EMT. Epigenetic analyses indicate that key beta-cell genes maintain open chromatin structure in expanded BCD cells, although they are not transcribed. Here we investigated whether BCD cells can be redifferentiated into beta-like cells. METHODOLOGY/PRINCIPAL FINDING: Redifferentiation conditions were screened by following activation of an insulin-DsRed2 reporter gene. Redifferentiated cells were characterized for gene expression, insulin content and secretion assays, and presence of secretory vesicles by electron microscopy. BCD cells were induced to redifferentiate by a combination of soluble factors. The redifferentiated cells expressed beta-cell genes, stored insulin in typical secretory vesicles, and released it in response to glucose. The redifferentiation process involved mesenchymal-epithelial transition, as judged by changes in gene expression. Moreover, inhibition of the EMT effector SLUG (SNAI2 using shRNA resulted in stimulation of redifferentiation. Lineage-traced cells also gave rise at a low rate to cells expressing other islet hormones, suggesting transition of BCD cells through an islet progenitor-like stage during redifferentiation. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate for the first time that expanded dedifferentiated beta cells can be induced to redifferentiate in culture. The findings suggest that ex-vivo expansion of adult human islet cells is a promising approach for generation of insulin-producing cells for

  19. Determination of Insulin Resistance and Beta Cell Function in Healthy Obese and Non-obese Individuals

    International Nuclear Information System (INIS)

    Objective: To determine insulin resistance and beta cell function in healthy obese and nonobese individuals of the local population. Study Design: Case control study. Place and Duration of Study: AFIP Rawalpindi in collaboration with department of medicine military hospital(MH) Rawalpindi, from Aug 2008 to Mar 2009. Methods: Eighty obese(n=40) and non-obese(n=40) subjects were selected by non-probability convenience sampling. Plasma insulin, glucose, and serum total cholestrol were estimated in fasting state. Insulin resistance was calculated by HOMA-IR and beta cell function by HOMA- equation. Results: Significant differences were observed between obese and non-obese individuals regarding insulin resistance, beta cell function, and BMI and serum total cholesterol. Mean insulin resistance in obese group was found to be 11.1 +- 5.1(range 7.0-16.2) and in non-obese group it was 0.9+-0.4 (range 0.5-1.3). This difference was highly significant (p=0.001). There was a highly significant difference between the two groups in term of beta cell function with mean rank 60.1 for obese group and 20.9 non obese groups (Asym sig. 2 tailed 0.000). Also the correlation (r = 0.064) between insulin resistance and beta cell function in obese group is highly significant (p = 0.000). Mean serum leptin levels were lower (6.3 ng/ml) in non-obese, and high (57.2 ng/ml) in the obese group. Conclusions: Insulin resistance is found higher in obese individuals. Beta cell function is significantly different between obese and non-obese groups. (author)

  20. Tissue-specific methylation of human insulin gene and PCR assay for monitoring beta cell death.

    Directory of Open Access Journals (Sweden)

    Mohamed I Husseiny

    Full Text Available The onset of metabolic dysregulation in type 1 diabetes (T1D occurs after autoimmune destruction of the majority of pancreatic insulin-producing beta cells. We previously demonstrated that the DNA encoding the insulin gene is uniquely unmethylated in these cells and then developed a methylation-specific PCR (MSP assay to identify circulating beta cell DNA in streptozotocin-treated mice prior to the rise in blood glucose. The current study extends to autoimmune non-obese diabetic (NOD mice and humans, showing in NOD mice that beta cell death occurs six weeks before the rise in blood sugar and coincides with the onset of islet infiltration by immune cells, demonstrating the utility of MSP for monitoring T1D. We previously reported unique patterns of methylation of the human insulin gene, and now extend this to other human tissues. The methylation patterns of the human insulin promoter, intron 1, exon 2, and intron 2 were determined in several normal human tissues. Similar to our previous report, the human insulin promoter was unmethylated in beta cells, but methylated in all other tissues tested. In contrast, intron 1, exon 2 and intron 2 did not exhibit any tissue-specific DNA methylation pattern. Subsequently, a human MSP assay was developed based on the methylation pattern of the insulin promoter and human islet DNA was successfully detected in circulation of T1D patients after islet transplantation therapy. Signal levels of normal controls and pre-transplant samples were shown to be similar, but increased dramatically after islet transplantation. In plasma the signal declines with time but in whole blood remains elevated for at least two weeks, indicating that association of beta cell DNA with blood cells prolongs the signal. This assay provides an effective method to monitor beta cell destruction in early T1D and in islet transplantation therapy.

  1. Tissue-Specific Methylation of Human Insulin Gene and PCR Assay for Monitoring Beta Cell Death

    Science.gov (United States)

    Husseiny, Mohamed I.; Kaye, Alexander; Zebadua, Emily; Kandeel, Fouad; Ferreri, Kevin

    2014-01-01

    The onset of metabolic dysregulation in type 1 diabetes (T1D) occurs after autoimmune destruction of the majority of pancreatic insulin-producing beta cells. We previously demonstrated that the DNA encoding the insulin gene is uniquely unmethylated in these cells and then developed a methylation-specific PCR (MSP) assay to identify circulating beta cell DNA in streptozotocin-treated mice prior to the rise in blood glucose. The current study extends to autoimmune non-obese diabetic (NOD) mice and humans, showing in NOD mice that beta cell death occurs six weeks before the rise in blood sugar and coincides with the onset of islet infiltration by immune cells, demonstrating the utility of MSP for monitoring T1D. We previously reported unique patterns of methylation of the human insulin gene, and now extend this to other human tissues. The methylation patterns of the human insulin promoter, intron 1, exon 2, and intron 2 were determined in several normal human tissues. Similar to our previous report, the human insulin promoter was unmethylated in beta cells, but methylated in all other tissues tested. In contrast, intron 1, exon 2 and intron 2 did not exhibit any tissue-specific DNA methylation pattern. Subsequently, a human MSP assay was developed based on the methylation pattern of the insulin promoter and human islet DNA was successfully detected in circulation of T1D patients after islet transplantation therapy. Signal levels of normal controls and pre-transplant samples were shown to be similar, but increased dramatically after islet transplantation. In plasma the signal declines with time but in whole blood remains elevated for at least two weeks, indicating that association of beta cell DNA with blood cells prolongs the signal. This assay provides an effective method to monitor beta cell destruction in early T1D and in islet transplantation therapy. PMID:24722187

  2. Precise expression of Fis1 is important for glucose responsiveness of beta cells.

    Science.gov (United States)

    Schultz, Julia; Waterstradt, Rica; Kantowski, Tobias; Rickmann, Annekatrin; Reinhardt, Florian; Sharoyko, Vladimir; Mulder, Hindrik; Tiedge, Markus; Baltrusch, Simone

    2016-07-01

    Mitochondrial network functionality is vital for glucose-stimulated insulin secretion in pancreatic beta cells. Altered mitochondrial dynamics in pancreatic beta cells are thought to trigger the development of type 2 diabetes mellitus. Fission protein 1 (Fis1) might be a key player in this process. Thus, the aim of this study was to investigate mitochondrial morphology in dependence of beta cell function, after knockdown and overexpression of Fis1. We demonstrate that glucose-unresponsive cells with impaired glucose-stimulated insulin secretion (INS1-832/2) showed decreased mitochondrial dynamics compared with glucose-responsive cells (INS1-832/13). Accordingly, mitochondrial morphology visualised using MitoTracker staining differed between the two cell lines. INS1-832/2 cells formed elongated and clustered mitochondria, whereas INS1-832/13 cells showed a homogenous mitochondrial network. Fis1 overexpression using lentiviral transduction significantly improved glucose-stimulated insulin secretion and mitochondrial network homogeneity in glucose-unresponsive cells. Conversely, Fis1 downregulation by shRNA, both in primary mouse beta cells and glucose-responsive INS1-832/13 cells, caused unresponsiveness and significantly greater numbers of elongated mitochondria. Overexpression of FIS1 in primary mouse beta cells indicated an upper limit at which higher FIS1 expression reduced glucose-stimulated insulin secretion. Thus, FIS1 was overexpressed stepwise up to a high concentration in RINm5F cells using the RheoSwitch system. Moderate FIS1 expression improved glucose-stimulated insulin secretion, whereas high expression resulted in loss of glucose responsiveness and in mitochondrial artificial loop structures and clustering. Our data confirm that FIS1 is a key regulator in pancreatic beta cells, because both glucose-stimulated insulin secretion and mitochondrial dynamics were clearly adapted to precise expression levels of this fission protein. PMID:27179109

  3. Ryanodine receptors are involved in nuclear calcium oscillation in primary pancreatic {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Ji [Urological Surgery Research Institute, Southwest Hospital, Third Military Medical University, Chongqing (China); National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing (China); Chen, Zheng [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing (China); Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI (United States); Yin, Wenxuan; Miao, Lin [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing (China); Zhou, Zhansong, E-mail: Zhouzhansong@sohu.com [Urological Surgery Research Institute, Southwest Hospital, Third Military Medical University, Chongqing (China); Ji, Guangju, E-mail: Gj28@ibp.ac.cn [National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing (China)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer We found that RyRs are expressed on the nuclear envelope in single primary pancreatic {beta}-cells and isolated nuclei. Black-Right-Pointing-Pointer We showed that the pattern of glucose-induced Ca{sup 2+} oscillation in the nucleus and cytosol was similar. Black-Right-Pointing-Pointer Our results demonstrate that ryanodine-sensitive Ca{sup 2+} stores exist and have function in the pancreatic {beta}-cell nucleus. -- Abstract: Ryanodine receptors (RyRs) are mainly located on the endoplasmic reticulum (ER) and play an important role in regulating glucose-induced cytosolic Ca{sup 2+} oscillation in pancreatic {beta}-cells. However, subcellular locations and functions of RyRs on other cell organelles such as nuclear envelope are not well understood. In order to investigate the role of RyRs in nuclear Ca{sup 2+} oscillation we designed and conducted experiments in intact primary pancreatic {beta}-cells. Immunocytochemistry was used to examine the expression of RYRs on the nuclear envelope. Confocal microscopy was used to evaluate the function of RYRs on the nuclear envelope. We found that RyRs are expressed on the nuclear envelope in single primary pancreatic {beta}-cells and isolated nuclei. Laser scanning confocal microscopy studies indicated that application of glucose to the cells co-incubated with Ca{sup 2+} indicator Fluo-4 AM and cell-permeable nuclear indicator Hoechst 33342 resulted in nuclear Ca{sup 2+} oscillation. The pattern of glucose-induced Ca{sup 2+} oscillation in the nucleus and cytosol was similar. The reduction of Ca{sup 2+} oscillation amplitude by ryanodine was much greater in the nucleus though both the cytosol and the nucleus Ca{sup 2+} amplitude decreased by ryanodine. Our results suggest that functional ryanodine receptors not only exist in endoplasmic reticulum but are also expressed in nuclear envelope of pancreatic {beta}-cells.

  4. Planar Cell Polarity Controls Pancreatic Beta Cell Differentiation and Glucose Homeostasis

    DEFF Research Database (Denmark)

    Cortijo, Cedric; Gouzi, Mathieu; Tissir, Fadel;

    2012-01-01

    .5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased...... glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal that...

  5. Permeation and gating properties of the L-type calcium channel in mouse pancreatic beta cells

    OpenAIRE

    1993-01-01

    Ba2+ currents through L-type Ca2+ channels were recorded from cell- attached patches on mouse pancreatic beta cells. In 10 mM Ba2+, single- channel currents were recorded at -70 mV, the beta cell resting membrane potential. This suggests that Ca2+ influx at negative membrane potentials may contribute to the resting intracellular Ca2+ concentration and thus to basal insulin release. Increasing external Ba2+ increased the single-channel current amplitude and shifted the current-voltage relation...

  6. Regulation of pancreatic beta-cell mass and proliferation by SOCS-3

    DEFF Research Database (Denmark)

    Lindberg, K; Rønn, S G; Tornehave, D;

    2005-01-01

    Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT...... tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell...

  7. Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting

    DEFF Research Database (Denmark)

    Højlund, Kurt; Wildner-Christensen, M; Eshøj, O;

    2001-01-01

    of counterregulatory factors increased during the fast [P Growth hormone secretion increased from the first to third day of fasting (P ...To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P ... the fast (P fast. We observed a diminished beta-cell response concomitant with an increased secretion of counterregulatory hormones. These results should be of clinical and scientific value...

  8. Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase.

    Directory of Open Access Journals (Sweden)

    Karine H Hellemans

    Full Text Available Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/- and LXRalphabeta(-/-, beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids.

  9. Role of Ink4a/Arf Locus in Beta Cell Mass Expansion under Physiological and Pathological Conditions

    Directory of Open Access Journals (Sweden)

    Elisabet Salas

    2014-01-01

    Full Text Available The ARF/INK4A (Cdkn2a locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.

  10. Role of Ink4a/Arf Locus in Beta Cell Mass Expansion under Physiological and Pathological Conditions

    Science.gov (United States)

    Salas, Elisabet; Rabhi, Nabil; Froguel, Philippe; Annicotte, Jean-Sébastien

    2014-01-01

    The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin. PMID:24672805

  11. Glucose transport by radiation-induced insulinoma and clonal pancreatic beta-cells

    International Nuclear Information System (INIS)

    Sugar uptake was measured in dispersed cells prepared from radiation-induced insulinomas transplantable in NEDH rats and in three clonal beta-cell lines maintained in continuous culture (RIN m5F, RIN 1046, HIT). Uptake of D-glucose and 3-O-methyl-D-glucose by insulinoma cells was rapid so that the intracellular concentration of D-hexoses approximated the concentration in the incubation medium by 15-30 s. L-Glucose was taken up only slowly. 3-O-methyl-D-glucose uptake by RIN m5F, RIN 1046, and HIT cells was slow; with 1 mM 3-O-methylglucose in the medium, equilibrium was attained at 20 min, but with 10 mM 3-O-methylglucose, equilibrium was not attained even at 20 min. In HIT cells incubated with D-glucose for 30 min, the intracellular concentration of glucose was less than the medium glucose concentration, indicating glucose transport is a nonequilibrium reaction in this cell line. These data indicate that radiation-induced insulinoma cells retain the capacity of normal beta-cells to transport sugar at high rates. RIN m5F, RIN 1046, and HIT cells transport sugar slowly, however, and thus differ from normal beta-cells. In RIN m5F, RIN 1046, and HIT cells, unlike in normal beta-cells, glucose transport may be the site regulating glucose metabolism

  12. Effects of meal size and composition on incretin, alpha-cell, and beta-cell responses

    DEFF Research Database (Denmark)

    Rijkelijkhuizen, Josina M; McQuarrie, Kelly; Girman, Cynthia J;

    2009-01-01

    The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the beta-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insu...

  13. Cytokines and beta-cell biology: from concept to clinical translation

    DEFF Research Database (Denmark)

    Donath, M.Y.; Storling, J.; Berchtold, L.A.;

    2007-01-01

    The tale of cytokines and the beta-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo...

  14. MicroRNAs as regulators of beta-cell function and dysfunction.

    Science.gov (United States)

    Osmai, Mirwais; Osmai, Yama; Bang-Berthelsen, Claus H; Pallesen, Emil M H; Vestergaard, Anna L; Novotny, Guy W; Pociot, Flemming; Mandrup-Poulsen, Thomas

    2016-05-01

    In the last decade, there has been an explosion in both the number of and knowledge about miRNAs associated with both type 1 and type 2 diabetes. Even though we are presently in the initial stages of understanding how this novel class of posttranscriptional regulators are involved in diabetes, recent studies have demonstrated that miRNAs are important regulators of the islet transcriptome, controlling apoptosis, differentiation and proliferation, as well as regulating unique islet and beta-cell functions and pathways such as insulin expression, processing and secretion. Furthermore, a large number of miRNAs have been linked to diabetogenic processes induced by elevated levels of glucose, free fatty acids and inflammatory cytokines. Thus, miRNAs are novel therapeutic targets with the potential of protecting the beta-cell, and there is proof of principle that miRNA antagonists, so-called antagomirs, are effective in vivo for other disorders. miRNAs are exported out of cells in exosomes, raising the intriguing possibility of cell-to-cell communication between distant tissues via miRNAs and that miRNAs can be used as biomarkers of beta-cell function, mass and survival. The purpose of this review is to provide a status on how miRNAs control beta-cell function and viability in health and disease. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26418758

  15. Cocaine- and amphetamine-regulated transcript (CART) protects beta cells against glucotoxicity and increases cell proliferation.

    Science.gov (United States)

    Sathanoori, Ramasri; Olde, Björn; Erlinge, David; Göransson, Olga; Wierup, Nils

    2013-02-01

    Cocaine- and amphetamine-regulated transcript (CART) is an islet peptide that promotes glucose-stimulated insulin secretion in beta cells via cAMP/PKA-dependent pathways. In addition, CART is a regulator of neuronal survival. In this study, we examined the effect of exogenous CART 55-102 on beta cell viability and dissected its signaling mechanisms. Evaluation of DNA fragmentation and chromatin condensation revealed that CART 55-102 reduced glucotoxicity-induced apoptosis in both INS-1 (832/13) cells and isolated rat islets. Glucotoxicity in INS-1 (832/13) cells also caused a 50% reduction of endogenous CART protein. We show that CART increased proliferation in INS-1 (832/13) cells, an effect that was blocked by PKA, PKB, and MEK1 inhibitors. In addition, CART induced phosphorylation of CREB, IRS, PKB, FoxO1, p44/42 MAPK, and p90RSK in INS-1 (832/13) cells and isolated rat islets, all key mediators of cell survival and proliferation. Thus, we demonstrate that CART 55-102 protects beta cells against glucotoxicity and promotes proliferation. Taken together our data point to the potential use of CART in therapeutic interventions targeted at enhancing functional beta cell mass and long-term insulin secretion in T2D. PMID:23250745

  16. The effects of glucagon-like peptide-1 on the beta cell

    DEFF Research Database (Denmark)

    Vilsbøll, Tina

    2009-01-01

    type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that...

  17. Visualizing pancreatic {beta}-cell mass with [{sup 11}C]DTBZ

    Energy Technology Data Exchange (ETDEWEB)

    Simpson, Norman Ray [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Souza, Fabiola [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Witkowski, Piotr [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Maffei, Antonella [Institute of Genetics and Biophysics ' Adriano Buzzati-Traverso' , CNR, Naples 80131 (Italy); Raffo, Anthony [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Herron, Alan [Center for Comparative Medicine and The Department of Pathology, Baylor College of Medicine, Houston, TX 77030 (United States); Kilbourn, Michael [Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0638 (United States); Jurewicz, Agata [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Herold, Kevan [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States); Liu, Eric [Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20854 (United States); Hardy, Mark Adam [Department of Medicine, Columbia University Medical School, New York, NY 10032 (United States); Van Heertum, Ronald [Department of Radiology, Columbia University Medical School, New York, NY 10032 (United States); Harris, Paul Emerson [Department of Surgery, Columbia University Medical School, New York, NY 10032 (United States)]. E-mail: peh1@columbia.edu

    2006-10-15

    {beta}-Cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, {beta}-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by {beta} cells, with [{sup 11}C]dihydrotetrabenazine ([{sup 11}C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocin-induced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in {beta} cells with the use of [{sup 11}C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

  18. Hepatic fat is not associated with beta-cell function or postprandial free fatty acid response

    NARCIS (Netherlands)

    Rijkelijkhuizen, J.M.; Doesburg, T.; Girman, C.J.; Mari, A.; Rhodes, T.; Gastaldelli, A.; Nijpels, M.G.A.A.M.; Dekker, J.M.

    2009-01-01

    We evaluated the association of hepatic fat with beta-cell function estimated from the oral glucose tolerance test. In addition, we tested the hypothesis that postprandial free fatty acid (FFA) suppression after a meal tolerance test (MTT) is linked to hepatic fat. Individuals with normal glucose me

  19. Vitamin D and diabetes: Its importance for beta cell and immune function

    DEFF Research Database (Denmark)

    Wolden-Kirk, Heidi; Overbergh, Lut; Christesen, Henrik Thybo; Brusgaard, Klaus; Mathieu, Chantal

    D supplementation may decrease the risk of these disorders. The protective effects of vitamin D are mediated through the regulation of several components such as the immune system and calcium homeostasis. However, an increasing amount of evidence suggests that vitamin D also affects beta cells...

  20. Imaging of beta-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus

    NARCIS (Netherlands)

    Di Gialleonardo, Valentina; de Vries, Erik F. J.; Di Girolamo, Marco; Quintero, Ana M.; Dierckx, Rudi A. J. O.; Signore, Alberto

    2012-01-01

    Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic beta-cells, called insulitis, confirmed in pancreatic samples obtained at

  1. PANCREATIC BETA-CELL FUNCTION AND ISLET-CELL PROLIFERATION - EFFECT OF HYPERINSULINEMIA

    NARCIS (Netherlands)

    KOITER, TR; WIJKSTRA, S; VANDERSCHAAFVERDONK, GCJ; MOES, H; SCHUILING, GA

    1995-01-01

    Pancreatic beta-cell function was studied in adult female rats, in which endogenous insulin demand was fully met by SC infusion of human insulin (4.8 IU/24 h) for 6 days, resulting in hyperinsulinaemia and severe hypoglycaemia. The amount of pancreatic endocrine tissue declined by 40%, (pro)insulin

  2. Coating nanofiber scaffolds with beta cell membrane to promote cell proliferation and function

    Science.gov (United States)

    Chen, Wansong; Zhang, Qiangzhe; Luk, Brian T.; Fang, Ronnie H.; Liu, Younian; Gao, Weiwei; Zhang, Liangfang

    2016-05-01

    The cell membrane cloaking technique has emerged as an intriguing strategy in nanomaterial functionalization. Coating synthetic nanostructures with natural cell membranes bestows the nanostructures with unique cell surface antigens and functions. Previous studies have focused primarily on development of cell membrane-coated spherical nanoparticles and the uses thereof. Herein, we attempt to extend the cell membrane cloaking technique to nanofibers, a class of functional nanomaterials that are drastically different from nanoparticles in terms of dimensional and mechanophysical characteristics. Using pancreatic beta cells as a model cell line, we demonstrate successful preparation of cell membrane-coated nanofibers and validate that the modified nanofibers possess an antigenic exterior closely resembling that of the source beta cells. When such nanofiber scaffolds are used to culture beta cells, both cell proliferation rate and function are significantly enhanced. Specifically, glucose-dependent insulin secretion from the cells is increased by near five-fold compared with the same beta cells cultured in regular, unmodified nanofiber scaffolds. Overall, coating cell membranes onto nanofibers could add another dimension of flexibility and controllability in harnessing cell membrane functions and offer new opportunities for innovative applications.

  3. Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Maria Jose Garcia Barrado

    Full Text Available The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen, and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01, by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01 after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01 following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets.

  4. Hypoglycemic and beta cell protective effects of andrographolide analogue for diabetes treatment

    Directory of Open Access Journals (Sweden)

    Larrick James W

    2009-07-01

    Full Text Available Abstract Background While all anti-diabetic agents can decrease blood glucose level directly or indirectly, few are able to protect and preserve both pancreatic beta cell mass and their insulin-secreting functions. Thus, there is an urgent need to find an agent or combination of agents that can lower blood glucose and preserve pancreatic beta cells at the same time. Herein, we report a dual-functional andrographolide-lipoic acid conjugate (AL-1. The anti-diabetic and beta cell protective activities of this novel andrographolide-lipoic acid conjugate were investigated. Methods In alloxan-treated mice (a model of type 1 diabetes, drugs were administered orally once daily for 6 days post-alloxan treatment. Fasting blood glucose and serum insulin were determined. Pathologic and immunohistochemical analysis of pancreatic islets were performed. Translocation of glucose transporter subtype 4 in soleus muscle was detected by western blot. In RIN-m cells in vitro, the effect of AL-1 on H2O2-induced damage and reactive oxidative species production stimulated by high glucose and glibenclamide were measured. Inhibition of nuclear factor kappa B (NF-κB activation induced by IL-1β and IFN-γ was investigated. Results In alloxan-induced diabetic mouse model, AL-1 lowered blood glucose, increased insulin and prevented loss of beta cells and their dysfunction, stimulated glucose transport protein subtype 4 (GLUT4 membrane translocation in soleus muscles. Pretreatment of RIN-m cells with AL-1 prevented H2O2-induced cellular damage, quenched glucose and glibenclamide-stimulated reactive oxidative species production, and inhibited cytokine-stimulated NF-κB activation. Conclusion We have demonstrated that AL-1 had both hypoglycemic and beta cell protective effects which translated into antioxidant and NF-κB inhibitory activity. AL-1 is a potential new anti-diabetic agent.

  5. Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass

    Directory of Open Access Journals (Sweden)

    Vivas Yurena

    2011-12-01

    Full Text Available Abstract Background The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion Results Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell. Conclusions Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

  6. Prolonged inhibition of bacterial protein synthesis abolishes Salmonella invasion.

    OpenAIRE

    MacBeth, K J; Lee, C. A.

    1993-01-01

    We have found that prolonged inhibition of bacterial protein synthesis abolishes the ability of Salmonella typhimurium to enter HEp-2 cells. Our results suggest that an essential invasion factor has a functional half-life that is seen as a gradual loss of invasiveness in the absence of protein synthesis. Therefore, Salmonella invasiveness appears to be a transient phenotype that is lost unless protein synthesis is maintained. This finding may explain why salmonellae grown to stationary phase ...

  7. Barriers to entry : abolishing the barriers to understanding

    OpenAIRE

    Keppler, Jan Horst

    2009-01-01

    BARRIERS TO ENTRY: ABOLISHING THE BARRIERS TO UNDERSTANDING by Jan-Horst Keppler Professor of economics Université Paris – Dauphine, LEDa, and Université Paris I Panthéon-Sorbonne, PHARE Port.: (+33 6) 77 81 37 46; Email: . Abstract The concept of a barrier to entry has been discussed least since Bain (1956) with important contributions by Spence (1977), Dixit (1980) or Milgrom and Roberts (1982). The more recent discussion is synth...

  8. Does Abolishing Fees Reduce School Quality? Evidence from Kenya

    OpenAIRE

    Tessa Bold; Mwangi Kimenyi; Germano Mwabu; Justin Sandefur

    2011-01-01

    In 2003 Kenya abolished user fees in all government primary schools. We find that this Free Primary Education (FPE) policy resulted in a decline in public school quality and increased demand for private schooling. However, the former did not reflect a decline in value added by public schools - as anticipated if fees contribute to local accountability - but rather the selection of weaker pupils into free education. In contrast, affluent children who exited to the private sector in response to ...

  9. ER stress in pancreatic beta cells: the thin red line between adaptation and failure.

    Science.gov (United States)

    Eizirik, Decio L; Cnop, Miriam

    2010-01-01

    Secretory cells, such as pancreatic beta cells, face the challenge of increasing protein synthesis severalfold during acute or chronic stimulation. This poses a burden on the endoplasmic reticulum (ER), the organelle where proinsulin synthesis and folding takes place. Thus, beta cells use various adaptive mechanisms to adjust the functional capacity of the ER to the prevailing demand. These check-and-balance mechanisms are collectively known as the unfolded protein response (UPR). It remains unclear how UPR signaling is ultimately regulated and what delineates the boundaries between a physiological and a pathological response. New discoveries point to the divergent effects of acute and chronic metabolic fluxes and chemical ER stressors on the formation of complexes among UPR transducers, scaffold proteins, and phosphatases. These and other findings provide a first glimpse on how different signals trigger diverging UPR outcomes. PMID:20179270

  10. The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells

    DEFF Research Database (Denmark)

    Rønn, Sif G; Hansen, Johnny A; Lindberg, Karen;

    2002-01-01

    . Furthermore, using Northern blot analysis it was shown that SOCS-3 can completely inhibit GH-induced insulin production in these cells. Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells. These......GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in beta-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway....... Recently it has been found that suppressors of cytokine signaling (SOCS) proteins are able to inhibit GH-induced signal transduction. In the present study, the role of SOCS-3 in GH signaling was investigated in the pancreatic beta-cell lines RIN-5AH and INS-1 by means of inducible expression systems. Via...

  11. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

    DEFF Research Database (Denmark)

    Larsen, L; Tonnesen, M; Ronn, S G;

    2007-01-01

    were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1beta and IFNgamma. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFkappaB activity were measured by...... B (NFkappaB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of pro-apoptotic genes. NFkappaB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone...... effect was seen on IkappaBalpha degradation and NFkappaB DNA binding. CONCLUSIONS/INTERPRETATION: HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFkappaB transactivating activity....

  12. Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

    Directory of Open Access Journals (Sweden)

    David Vallois

    Full Text Available Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms.We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed.Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation.Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes.

  13. Role of clathrin in the regulated secretory pathway of pancreatic beta-cells

    OpenAIRE

    Molinete, M.; Dupuis, S.; Brodsky, F M; Halban, Philippe A.

    2001-01-01

    The role of clathrin in the sorting of proinsulin to secretory granules, the formation of immature granules and their subsequent maturation is not known. To this end, primary rat pancreatic beta-cells were infected with a recombinant adenovirus co-expressing the Hub fragment, a dominant-negative peptide of the clathrin heavy chain and enhanced green fluorescent protein (EGFP as a marker of infected cells). A population of cells expressing the highest levels of EGFP (and thus Hub) was obtained...

  14. Model for synchronization of pancreatic beta-cells by gap junction coupling.

    OpenAIRE

    Sherman, A.; Rinzel, J

    1991-01-01

    Pancreatic beta-cells coupled by gap junctions in sufficiently large clusters exhibit regular electrical bursting activity, which is described by the Chay-Keizer model and its variants. According to most reports, however, isolated cells exhibit disorganized spiking. We have previously (Sherman, A. J. Rinzel, and J. Keizer, 1988. Biophys. J. 54:411-425) modeled these behaviors by hypothesizing that stochastic channel fluctuations disrupt the bursts. We showed that when cells are coupled by inf...

  15. MicroRNAs as regulators of beta-cell function and dysfunction

    DEFF Research Database (Denmark)

    Osmai, Mirwais; Osmai, Yama; Bang-Berthelsen, Claus Heiner;

    2016-01-01

    In the last decade, there has been an explosion in both the number of and knowledge about miRNAs associated with both type 1 and type 2 diabetes. Even though we are presently in the initial stages of understanding how this novel class of posttranscriptional regulators are involved in diabetes, re...... review is to provide a status on how miRNAs control beta-cell function and viability in health and disease....

  16. Properties of the Ca-activated K+ channel in pancreatic beta-cells.

    Science.gov (United States)

    Atwater, I; Rosario, L; Rojas, E

    1983-12-01

    The existence of [Ca2+]i-activated K+-channels in the pancreatic beta-cell membrane is based in two observations: quinine inhibits K+-permeability and, increasing intracellular Ca2+ stimulates it. The changes in K+-permeability of the beta-cell have been monitored electrically by combining measurements of the dependence of the membrane potential on external K+ concentration and input resistance. The changes in the passive 42K and 86Rb efflux from the whole islet have been measured directly. Intracellular Ca2+ has been increased by various means, including increasing extracellular Ca2+, addition of the Ca2+-ionophore A23187 or noradrenaline and application of mitochondrial uncouplers and blockers. In addition to quinine, many other substances have been found to inhibit or modulate the [Ca2+]i-activated K+-channel. The most important of these is the natural stimulus for insulin secretion, glucose. Glucose may inhibit K+-permeability by lowering intracellular Ca2+. Glibenclamide, a hypoglycaemic sulphonylurea, is about 25 times more active than quinine in blocking the K+-channel in beta-cells. The methylxanthines, c-AMP, various calmodulin inhibitors and Ba2+ also inhibit K+-permeability. Genetically diabetic mice have been studied and show an alteration in the [Ca2+]i-activated K+-channel. It is concluded that the [Ca2+]i-activated K+-channel plays a major role in the normal function of the pancreatic beta-cell. The study of its properties should prove valuable for the understanding and treatment of diabetes. PMID:6323007

  17. 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.

  18. In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use.

    Science.gov (United States)

    Eriksson, Olof; Laughlin, Maren; Brom, Maarten; Nuutila, Pirjo; Roden, Michael; Hwa, Albert; Bonadonna, Riccardo; Gotthardt, Martin

    2016-07-01

    Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation. PMID:27094935

  19. Factors associated with beta-cell dysfunction in type 2 diabetes: the BETADECLINE study.

    Directory of Open Access Journals (Sweden)

    Giuseppina T Russo

    Full Text Available AIMS: Beta-cell dysfunction is an early event in the natural history of type 2 diabetes. However, its progression is variable and potentially influenced by several clinical factors. We report the baseline data of the BetaDecline study, an Italian prospective multicenter study on clinical predictors of beta-cell dysfunction in type 2 diabetes. MATERIALS AND METHODS: Clinical, lifestyle, and laboratory data, including circulating levels of inflammatory markers and non-esterified fatty acids, were collected in 507 type 2 diabetic outpatients on stable treatment with oral hypoglycemic drugs or diet for more than 1 year. Beta-cell dysfunction was evaluated by calculating the proinsulin/insulin ratio (P/I. RESULTS: At baseline, the subjects in the upper PI/I ratio quartile were more likely to be men and receiving secretagogue drugs; they also showed a borderline longer diabetes duration (P = 0.06 and higher serum levels of glycated hemoglobin (HbA1c, fasting blood glucose, and triglycerides. An inverse trend across all PI/I quartiles was noted for BMI and serum levels of total cholesterol (T-C, LDL-C, HDL-C and C reactive protein (CRP, and with homeostatic model assessment (HOMA-B and HOMA of insulin resistance (HOMA-IR values (P<0.05 for all. At multivariate analysis, the risk of having a P/I ratio in the upper quartile was higher in the subjects on secretagogue drugs (odds ratio [OR] 4.2; 95% confidence interval [CI], 2.6-6.9 and in the males (OR 1.8; 95% CI, 1.1-2.9. CONCLUSIONS: In the BetaDecline study population, baseline higher PI/I values, a marker of beta-cell dysfunction, were more frequent in men and in patients on secretagogues drugs. Follow-up of this cohort will allow the identification of clinical predictors of beta-cell failure in type 2 diabetic outpatients.

  20. Polysaccharide Multilayer Nanoencapsulation of Insulin-Producing beta-Cells Grown as Pseudoislets for Potential Cellular Delivery of Insulin

    OpenAIRE

    Zhi, Zheng-liang; Liu, Bo; Jones, Peter M.; Pickup, John C

    2010-01-01

    This paper describes the use of a layer-by-layer nanocoating technique for the encapsulation Of insulin-producing pancreatic beta-cell spheroids (pseudoislets) within chitosan/alginate multilayers. We used pseudoislets self-organized from a population of the insulinoma cell line MIN6, derived from a transgenic mouse expressing the large T-antigen of SV40 in pancreatic beta-cells, its an experimental model for the study of cell nanoencapsulation. The maintenance of spheroid morphology and rete...

  1. New approach to beta cell function screening by nitric oxide assessment of obese individuals at the population level

    OpenAIRE

    Chaim EA; Gobato RC

    2012-01-01

    Elinton Adami Chaim, Renata Cristina GobatoUniversity of Campinas (UNICAMP), Faculty of Medical Sciences, Department of Surgery, Cidade Universitária Zeferino Vaz, Barão Geraldo, BrazilBackground: Approximately 27% of Americans today are obese, and this condition increases the prevalence of metabolic syndrome and diabetes. The UK Prospective Diabetes Study suggests that loss of beta cell function can begin at least 10 years before diagnosis, and mean beta cell function i...

  2. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity.

    Directory of Open Access Journals (Sweden)

    Ashleigh E Schaffer

    Full Text Available All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin(+ cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC-derived insulin(+ cells, our study has significant implications for developing cell replacement therapies.

  3. Bioluminescence Imaging Reveals Dynamics of Beta Cell Loss in the Non-Obese Diabetic (NOD) Mouse Model

    OpenAIRE

    John Virostko; Armandla Radhika; Greg Poffenberger; Dula, Adrienne N.; Moore, Daniel J.; Alvin C Powers

    2013-01-01

    We generated a mouse model (MIP-Luc-VU-NOD) that enables non-invasive bioluminescence imaging (BLI) of beta cell loss during the progression of autoimmune diabetes and determined the relationship between BLI and disease progression. MIP-Luc-VU-NOD mice displayed insulitis and a decline in bioluminescence with age which correlated with beta cell mass, plasma insulin, and pancreatic insulin content. Bioluminescence declined gradually in female MIP-Luc-VU-NOD mice, reaching less than 50% of the ...

  4. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy.

    OpenAIRE

    Moffett R.C.; Vasu S; Thorens B.; Drucker D.J.; Flatt P.R.

    2014-01-01

    Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 a...

  5. Incretin Receptor Null Mice Reveal Key Role of GLP-1 but Not GIP in Pancreatic Beta Cell Adaptation to Pregnancy

    OpenAIRE

    Moffett, R. Charlotte; Vasu, Srividya; Thorens, Bernard; Drucker, Daniel J.; Peter R. Flatt

    2014-01-01

    Islet adaptations to pregnancy were explored in C57BL6/J mice lacking functional receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). Pregnant wild type mice and GIPRKO mice exhibited marked increases in islet and beta cell area, numbers of medium/large sized islets, with positive effects on Ki67/Tunel ratio favouring beta cell growth and enhanced pancreatic insulin content. Alpha cell area and glucagon content were unchanged but prohormone convertases PC2 a...

  6. Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival.

    Science.gov (United States)

    Martin, David; Allagnat, Florent; Gesina, Emilie; Caille, Dorothee; Gjinovci, Asllan; Waeber, Gerard; Meda, Paolo; Haefliger, Jacques-Antoine

    2012-01-01

    The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST) in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice), and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival. PMID:23029270

  7. Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival.

    Directory of Open Access Journals (Sweden)

    David Martin

    Full Text Available The absence of the transcriptional repressor RE-1 Silencing Transcription Factor (REST in insulin-secreting beta cells is a major cue for the specific expression of a large number of genes. These REST target genes were largely ascribed to a function of neurotransmission in a neuronal context, whereas their role in pancreatic beta cells has been poorly explored. To identify their functional significance, we have generated transgenic mice expressing REST in beta cells (RIP-REST mice, and previously discovered that REST target genes are essential to insulin exocytosis. Herein we characterized a novel line of RIP-REST mice featuring diabetes. In diabetic RIP-REST mice, high levels of REST were associated with postnatal beta cell apoptosis, which resulted in gradual beta cell loss and sustained hyperglycemia in adults. Moreover, adenoviral REST transduction in INS-1E cells led to increased cell death under control conditions, and sensitized cells to death induced by cytokines. Screening for REST target genes identified several anti-apoptotic genes bearing the binding motif RE-1 that were downregulated upon REST expression in INS-1E cells, including Gjd2, Mapk8ip1, Irs2, Ptprn, and Cdk5r2. Decreased levels of Cdk5r2 in beta cells of RIP-REST mice further confirmed that it is controlled by REST, in vivo. Using siRNA-mediated knock-down in INS-1E cells, we showed that Cdk5r2 protects beta cells against cytokines and palmitate-induced apoptosis. Together, these data document that a set of REST target genes, including Cdk5r2, is important for beta cell survival.

  8. Should the Catholic Church abolish the rule of Celibacy?

    OpenAIRE

    Men-Andri Benz; Reto Foellmi; Egon Franck; Urs Meister

    2009-01-01

    Since the Middle Ages, celibacy has been a requirement for those becoming priests in the Roman Catholic Church. In the ongoing discussions about reforms, a wide range of church members have asked for the abolishment of the celibacy requirement in order to meet the changed social and moral standards of believers and to increase the quality and quantity of priests. However, this paper shows that from a strategic point of view, there are good reasons for the Catholic Church to keep, or even to i...

  9. Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression.

    Directory of Open Access Journals (Sweden)

    Lisa Cadavez

    Full Text Available In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide (hIAPP. The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response (UPR, perturbing endoplasmic reticulum (ER homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa (GRP78, also known as BiP or protein disulfite isomerase (PDI, and chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA or 4-phenylbutyrate (PBA, alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.

  10. Effect of Hypertriglyceridemia on Beta Cell Mass and Function in ApoC3 Transgenic Mice.

    Science.gov (United States)

    Liu, Yun-Zi; Cheng, Xiaoyun; Zhang, Ting; Lee, Sojin; Yamauchi, Jun; Xiao, Xiangwei; Gittes, George; Qu, Shen; Jiang, Chun-Lei; Dong, H Henry

    2016-07-01

    Hypertriglyceridemia results from increased production and decreased clearance of triglyceride-rich very low-density lipoproteins, a pathological condition that accounts for heightened risk of ischemic vascular diseases in obesity and type 2 diabetes. Despite its intimate association with insulin resistance, whether hypertriglyceridemia constitutes an independent risk for beta cell dysfunction in diabetes is unknown. Answering this fundamental question is stymied by the fact that hypertriglyceridemia is intertwined with hyperglycemia and insulin resistance in obese and diabetic subjects. To circumvent this limitation, we took advantage of apolipoprotein C3 (ApoC3)-transgenic mice, a model with genetic predisposition to hypertriglyceridemia. We showed that ApoC3-transgenic mice, as opposed to age/sex-matched wild-type littermates, develop hypertriglyceridemia with concomitant elevations in plasma cholesterol and non-esterified fatty acid levels. Anti-insulin and anti-glucagon dual immunohistochemistry in combination with morphometric analysis revealed that ApoC3-transgenic and wild-type littermates had similar beta cell and alpha cell masses as well as islet size and architecture. These effects correlated with similar amplitudes of glucose-stimulated insulin secretion and similar degrees of postprandial glucose excursion in ApoC3-transgenic versus wild-type littermates. Oil Red O histology did not visualize lipid infiltration into islets, correlating with the lack of ectopic triglyceride and cholesterol depositions in the pancreata of ApoC3-transgenic versus wild-type littermates. ApoC3-transgenic mice, despite persistent hypertriglyceridemia, maintained euglycemia under both fed and fasting conditions without manifestation of insulin resistance and fasting hyperinsulinemia. Thus, hypertriglyceridemia per se is not an independent risk factor for beta cell dysfunction in ApoC3 transgenic mice. PMID:27226540

  11. Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein.

    OpenAIRE

    Watanabe, T; Yonemura, Y.; Yonekura, H; Suzuki, Y.; Miyashita, H; Sugiyama, K; Moriizumi, S; Unno, M; Tanaka, O.; Kondo, H.

    1994-01-01

    We previously isolated from a rat regenerating islet cDNA library a gene named Reg, which is expressed in regenerating islets but is not expressed in normal islets. Here we examined the effect of rat Reg protein on pancreatic beta-cell replication using both 90% depancreatized rats and isolated islets. The depancreatized rats that received i.p. administration of recombinant rat Reg protein (1 mg/kg per day) for 2 months showed amelioration of the surgical diabetes, as evidenced by a significa...

  12. Antioxidant and regulatory role of mitochondrial uncoupling protein UCP2 in pancreatic beta-cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Olejár, Tomáš; Smolková, Katarína; Ježek, Jan; Dlasková, Andrea; Plecitá-Hlavatá, Lydie; Zelenka, Jaroslav; Špaček, Tomáš; Engstová, Hana; Reguera Pajuelo, David; Jabůrek, Martin

    2014-01-01

    Roč. 63, Suppl.1 (2014), S73-S91. ISSN 0862-8408 R&D Projects: GA ČR(CZ) GAP302/10/0346; GA ČR(CZ) GAP305/12/1247; GA ČR(CZ) GPP304/10/P204; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : mitochondria * uncoupling protein UCP2 * pancreatic beta-cells * reactive oxygen species * glucose-stimulated insulin secretion Subject RIV: EA - Cell Biology Impact factor: 1.293, year: 2014

  13. Prolonged inhibition of bacterial protein synthesis abolishes Salmonella invasion.

    Science.gov (United States)

    MacBeth, K J; Lee, C A

    1993-01-01

    We have found that prolonged inhibition of bacterial protein synthesis abolishes the ability of Salmonella typhimurium to enter HEp-2 cells. Our results suggest that an essential invasion factor has a functional half-life that is seen as a gradual loss of invasiveness in the absence of protein synthesis. Therefore, Salmonella invasiveness appears to be a transient phenotype that is lost unless protein synthesis is maintained. This finding may explain why salmonellae grown to stationary phase lose their ability to enter cultured cells. In addition, a short-lived capacity to enter cells may be important during infection so that bacterial invasiveness is limited to certain times and host sites during pathogenesis. PMID:8454361

  14. Inactivation of Efflux Pumps Abolishes Bacterial Biofilm Formation

    DEFF Research Database (Denmark)

    Kvist, Malin; Hancock, Viktoria; Klemm, Per

    2008-01-01

    Bacterial biofilms cause numerous problems in health care and industry; notably, biofilms are associated with a large number of infections. Biofilm-dwelling bacteria are particularly resistant to antibiotics, making it hard to eradicate biofilm-associated infections. Bacteria rely on efflux pumps...... to get rid of toxic substances. We discovered that efflux pumps are highly active in bacterial biofilms, thus making efflux pumps attractive targets for antibiofilm measures. A number of efflux pump inhibitors (EPIs) are known. EPIs were shown to reduce biofilm formation, and in combination they...... could abolish biofilm formation completely. Also, EPIs were able to block the antibiotic tolerance of biofilms. The results of this feasibility study might pave the way for new treatments for biofilm-related infections and may be exploited for prevention of biofilms in general....

  15. Femoral venous reflux abolished by greater saphenous vein stripping.

    Science.gov (United States)

    Walsh, J C; Bergan, J J; Beeman, S; Comer, T P

    1994-11-01

    Preoperative venous duplex scanning has revealed unexpected deep venous incompetence in patients with apparently only varicose veins. Acting on the hypothesis that the deep vein reflux was secondary to deep vein dilation caused by reflux volume, the following was done. Between July 1990 and April 1993, 29 limbs in 21 patients (16 females) were examined by color-flow duplex imaging to determine valve closure by the method of van Bemmelen. Instrumentation included high-resolution ATL-9 venous interrogation using a pneumatic cuff deflation stimulus of reflux in the standing, nonweight-bearing limb. All limbs showed greater saphenous vein reflux. Twenty-nine showed superficial femoral vein reflux and of these three showed popliteal vein reflux. Duplex testing was performed by a certified vascular technologist whose interpretation was blinded as to the results of clinical examination and grading of the severity of venous insufficiency. Surgery was performed on an outpatient basis under general anesthesia using groin-to-knee removal of the greater saphenous vein by the vein inversion technique of Van Der Strict. Stab avulsion of varicose tributary veins was accomplished during the same period of anesthesia. In 27 of 29 limbs with preoperative femoral reflux, that reflux was abolished by greater saphenous stripping. In patients with popliteal reflux both femoral and popliteal reflux was abolished. Improvement of deep venous hemodynamics by ablation of superficial reflux supports the reflux circuit theory of venous overload. Furthermore, preoperative evaluation of venous hemodynamics by duplex scanning appears to provide useful pre- and postoperative information regarding venous insufficiency in individual patients. PMID:7865395

  16. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    Science.gov (United States)

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  17. The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

    DEFF Research Database (Denmark)

    Narendran, Parth; Solomon, Thomas; Kennedy, Amy;

    2015-01-01

    evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that......Type 1 diabetes is characterised by immune-mediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30 years have seen a number...... of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the...

  18. Analysis of the effect of diabetes type 2 duration on beta cell secretory function and insulin resistance

    Directory of Open Access Journals (Sweden)

    Popović Ljiljana

    2006-01-01

    Full Text Available Diabetes type 2 is a chronic metabolic disorder. Pathogenesis of diabetes type 2 results from the impaired insulin secretion, impaired insulin action and increased endogenous glucose production. Diabetes evolves through several phases characterized by qualitative and quantitative changes of beta cell secretory function. The aim of our study was to analyze the impact of diabetes duration on beta cell secretory function and insulin resistance. The results indicated significant negative correlation of diabetes duration and fasting insulinemia, as well as beta cell secretory function assessed by HOMA β index. Our study also found significant negative correlation of diabetes duration and insulin resistance assessed by HOMA IR index. Significant positive correlation was established between beta cell secretory capacity (fasting insulinemia and HOMA β and insulin resistance assessed by HOMA IR index, independently of diabetes duration. These results indicate that: beta cell secretory capacity, assessed by HOMA β index, significantly decreases with diabetes duration. In parallel with decrease of fasting insulinemia, reduction of insulin resistance assessed by HOMA IR index was found as well.

  19. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Zumsteg, U; Reimers, J; Pociot, F; Mørch, L; Helqvist, S; Dinarello, C A; Nerup, J

    1993-01-01

    In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1...... potentiated by other cytokines (tumor necrosis factor alpha, interferon gamma) is an important effector molecule involved in both early and late events in the immune-mediated process that leads to beta-cell destruction and IDDM. We also point out that surprisingly high molar excesses of IL-1ra over IL-1 are...... necessary to block the action of IL-1 on islet beta-cells compared to islet alpha-cells in vitro and in animals. We suggest that the selectivity of beta-cell destruction in IDDM may be conferred on several levels: (1) homing of beta-cell antigen specific T cells, (2) targeted delivery of cytokines by...

  20. Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance

    DEFF Research Database (Denmark)

    Muscelli, Elza; Mari, Andrea; Natali, Andrea;

    2006-01-01

    The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolu......The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C......-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered......, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity. In IGT, beta...

  1. Effect on pancreatic beta cells and nerve cells by low let x-ray

    International Nuclear Information System (INIS)

    Cultured pancreatic beta cells and nerve cells, it is given normal condition of 10% FBS (fetal bovine serum), 11.1 mM glucose and hyperglycemia condition of 1% FBS, 30 mM glucose. For low LET X-ray irradiated with 0.5 Gy/hr dose-rate(total dose: 0.5 to 5 Gy). Survival rates were measured by MTT assay. When non irradiated, differentiated in the pancreatic beta cells experiment is hyperglycemia conditions survival rate compared to normal conditions survival rate seemed a small reduction. However increasing the total dose of X-ray, the survival rate of normal conditions decreased slightly compared to the survival rate of hyperglycemia conditions, the synergistic effect was drastically reduced. When non irradiated, undifferentiated in the nerve cells experiment is hyperglycemia conditions survival rate compared to normal conditions survival rate seemed a large reduction. As the cumulative dose of X-ray normal conditions and hyperglycemia were all relatively rapid cell death. But the rate of decreased survivals by almost parallel to the reduction proceed and it didn't show synergistic effect

  2. The Role of Helicobacter pylori Seropositivity in Insulin Sensitivity, Beta Cell Function, and Abnormal Glucose Tolerance

    Directory of Open Access Journals (Sweden)

    Lou Rose Malamug

    2014-01-01

    Full Text Available Infection, for example, Helicobacter pylori (H. pylori, has been thought to play a role in the pathogenesis of type 2 diabetes mellitus (T2DM. Our aim was to determine the role of H. pylori infection in glucose metabolism in an American cohort. We examined data from 4,136 non-Hispanic white (NHW, non-Hispanic black (NHB, and Mexican Americans (MA aged 18 and over from the NHANES 1999-2000 cohort. We calculated the odds ratios for states of glucose tolerance based on the H. pylori status. We calculated and compared homeostatic model assessment insulin resistance (HOMA-IR and beta cell function (HOMA-B in subjects without diabetes based on the H. pylori status. The results were adjusted for age, body mass index (BMI, poverty index, education, alcohol consumption, tobacco use, and physical activity. The H. pylori status was not a risk factor for abnormal glucose tolerance. After adjustment for age and BMI and also adjustment for all covariates, no difference was found in either HOMA-IR or HOMA-B in all ethnic and gender groups except for a marginally significant difference in HOMA-IR in NHB females. H. pylori infection was not a risk factor for abnormal glucose tolerance, nor plays a major role in insulin resistance or beta cell dysfunction.

  3. Bradykinin enhances membrane electrical activity of pancreatic beta cells in the presence of low glucose concentrations

    Directory of Open Access Journals (Sweden)

    A.S. Moura

    2000-09-01

    Full Text Available In most of cells bradykinin (BK induces intracellular calcium mobilization. In pancreatic beta cells intracellular calcium is a major signal for insulin secretion. In these cells, glucose metabolism yields intracellular ATP which blocks membrane potassium channels. The membrane depolarizes, voltage-dependent Ca2+ channels are activated and the intracellular calcium load allows insulin secretion. Repolarization occurs due to activation of the Ca2+-dependent K+ channel. The insulin secretion depends on the integrity of this oscillatory process (bursts. Therefore, we decided to determine whether BK (100 nM induces bursts in the presence of a non-stimulatory glucose concentration (5.6 mM. During continuous membrane voltage recording, our results showed that bursts were obtained with 11 mM glucose, blocked with 5.6 mM glucose and recovered with 5.6 mM glucose plus 100 nM BK. Thus, the stimulatory process obtained in the presence of BK and of a non-stimulatory concentration of glucose in the present study suggests that BK may facilitate the action of glucose on beta cell secretion.

  4. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    Energy Technology Data Exchange (ETDEWEB)

    Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

    2009-12-18

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  5. Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

    International Nuclear Information System (INIS)

    Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

  6. Prolonged exposure of human beta cells to elevated glucose levels results in sustained cellular activation leading to a loss of glucose regulation.

    OpenAIRE

    Z. Ling; Pipeleers, D G

    1996-01-01

    Human beta cells can be maintained in serum-free culture at 6 mmol/liter glucose, with 80% cell recovery and preserved glucose-inducible functions after 1 wk. Between 0 and 10 mmol/liter, glucose dose-dependently increases the number of beta cells in active protein synthesis (15% at 0 mmol/liter glucose, 60% at 5 mmol/liter, and 82% at 10 mmol/liter), while lacking such an effect in islet non-beta cells (> 75% activated irrespective of glucose concentrations). As in rat beta cells, this inter...

  7. An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production

    OpenAIRE

    Ku, Gregory M.; Zachary Pappalardo; Chun Chieh Luo; German, Michael S.; McManus, Michael T.

    2012-01-01

    The prevalence of type 2 diabetes in the United States is projected to double or triple by 2050. We reasoned that the genes that modulate insulin production might be new targets for diabetes therapeutics. Therefore, we developed an siRNA screening system to identify genes important for the activity of the insulin promoter in beta cells. We created a subclone of the MIN6 mouse pancreatic beta cell line that expresses destabilized GFP under the control of a 362 base pair fragment of the human i...

  8. 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 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...

  9. Rising Intracellular Zinc by Membrane Depolarization and Glucose in Insulin-Secreting Clonal HIT-T15 Beta Cells

    OpenAIRE

    Slepchenko, Kira G.; Li, Yang V

    2012-01-01

    Zinc (Zn2+) appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30–60 mM) was able to induce a rapid increase in...

  10. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  11. Short communication: Pasteurization of milk abolishes bovine herpesvirus 4 infectivity.

    Science.gov (United States)

    Bona, C; Dewals, B; Wiggers, L; Coudijzer, K; Vanderplasschen, A; Gillet, L

    2005-09-01

    Bovine herpesvirus 4 (BoHV-4) is a gammaherpesvirus highly prevalent in the cattle population that has been isolated from the milk and the serum of healthy infected cows. Several studies reported the sensitivity and the permissiveness of some human cells to BoHV-4 infection. Moreover, our recent study demonstrated that some human cells sensitive but not permissive to BoHV-4 support a persistent infection protecting them from tumor necrosis factor-alpha-induced apoptosis. Together, these observations suggested that BoHV-4 could represent a danger for public health. To evaluate the risk of human infection by BoHV-4 through milk or serum derivatives, we investigated the resistance of BoHV-4 to the mildest thermal treatments usually applied to these products. The results demonstrated that milk pasteurization and thermal decomplementation of serum abolish BoHV-4 infectivity by inactivation of its property to enter permissive cells. Consequently, our results demonstrate that these treatments drastically reduce the risk of human infection by BoHV-4 through treated milk or serum derivatives. PMID:16107396

  12. Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes?

    Science.gov (United States)

    Kahraman, Sevim; Okawa, Erin R; Kulkarni, Rohit N

    2016-08-01

    Diabetes is a progressive disease affecting millions of people worldwide. There are several medications and treatment options to improve the life quality of people with diabetes. One of the strategies for the treatment of diabetes could be the use of human pluripotent stem cells or induced pluripotent stem cells. The recent advances in differentiation of stem cells into insulin-secreting beta-like cells in vitro make the transplantation of the stem cell-derived beta-like cells an attractive approach for treatment of type 1 and type 2 diabetes. While stem cell-derived beta-like cells provide an unlimited cell source for beta cell replacement therapies, these cells can also be used as a platform for drug screening or modeling diseases. PMID:27313072

  13. Beta-cell function in isolated human pancreatic islets in long-term tissue culture

    DEFF Research Database (Denmark)

    Nielsen, Jens Høiriis

    1981-01-01

    Human pancreatic islets were isolated by collagenase treatment of pancreatic tissue obtained from 27 individuals aged 12 to 69 years. The islets were maintained free floating in tissue culture medium RPMI 1640 supplemented with calf or human serum. In two cases the insulin production was followed...... adult human pancreatic tissue and that their beta-cell function can be maintained for up to two years. The variation in insulin production rate could not be ascribed to age or sex and may reflect both physiological and methodological factors....... up to nearly two years. The insulin production rate of the individual islet preparations varied between 0.2 and 8 ng per islet per day. No significant correlation with donor age or sex was found. The glucose concentration in the medium influenced the insulin release in a dose dependent manner. The...

  14. New ways to test beta cell functionality in health and diabetes

    DEFF Research Database (Denmark)

    Korsgaard, Thomas Vagn

    and divided the subjects into five groups. Interestingly, when correcting for the FPG, the mean plasma glucose concentration profiles from each of the five groups are strikingly similar, despite quite large differences in the corresponding mean plasma insulin profiles. From the graphs of the means of...... the differentiated individual glucose profiles within the respective groups of subjects with diabetes, this similarity of the glucose profiles is even more evident. Same results are obtained when analysing the data from the database, where the subjects with type 2 diabetes have been followed...... the brain participating in the overall control of glucose concentration and fluxes of glucose equivalents. Hence, neural effects seem to be an important component that needs to be added to models that are set up to describe beta cell functionality as well as glucose uptake in a physiological relevant...

  15. Effects of meal size and composition on incretin, alpha-cell, and beta-cell responses.

    Science.gov (United States)

    Rijkelijkhuizen, Josina M; McQuarrie, Kelly; Girman, Cynthia J; Stein, Peter P; Mari, Andrea; Holst, Jens J; Nijpels, Giel; Dekker, Jacqueline M

    2010-04-01

    The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the beta-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non-model-based and model-based estimates of beta-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes. PMID:19846181

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

    Directory of Open Access Journals (Sweden)

    Ansaya Thonpho

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

  17. Study of beta-cell function (by HOMA model in metabolic syndrome

    Directory of Open Access Journals (Sweden)

    M K Garg

    2011-01-01

    Full Text Available Introduction: The clustering of cardiovascular risk factors is termed the metabolic syndrome (MS, which strongly predict risk of diabetes and cardiovascular disease. Many studies implicate insulin resistance (IR in the development of diabetes, but ignore the contribution of beta-cell dysfunction. Hence, we studied beta-cell function, as assessed by HOMA model, in subjects with MS. Materials and Methods: We studied 50 subjects with MS diagnosed by IDF criteria and 24 healthy age- and sex-matched controls. Clinical evaluation included anthropometry, body fat analysis by bioimpedance, biochemical, and insulin measurement. IR and secretion were calculated by HOMA model. Results: Subjects with MS had more IR (HOMA-IR than controls (3.35 ± 3.14 vs. 1.76 ± 0.53, P = 0.029 and secreted less insulin (HOMA-S than controls (66.80 ± 69.66 vs. 144.27 ± 101.61, P = 0.0003, although plasma insulin levels were comparable in both groups (10.7 ± 10.2 vs. 8.2 ± 2.38, P = 0.44. HOMA-IR and HOMA-S were related with number of metabolic abnormalities. HOMA-IR was positively associated with body mass index, waist hip ratio, body fat mass, and percent body fat. HOMA-S was negatively associated with waist hip ratio, fasting plasma glucose and total cholesterol and positively with basal metabolic rate. Percent body fat was an independent predictor of HOMA-IR and waist hip ratio of HOMA-S in multiple regression analysis. Conclusions: Subjects with MS have increased IR and decreased insulin secretion compared with healthy controls. Lifestyle measures have been shown to improve IR, insulin secretion, and various components and effects of MS. Hence, there is an urgent need for public health measures to prevent ongoing epidemic of diabetes and cardiovascular disease.

  18. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Bagge, Annika; Clausen, Trine R; Larsen, Sylvester;

    2012-01-01

    Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate...

  19. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial

    NARCIS (Netherlands)

    Bunck, M.C.M.; Diamant, M.; Corner, A.; Eliasson, B.; Malloy, J.L.; Shaginian, R.M.; Deng, W.; Kendall, D.M.; Taskinen, M.R.; Smith, U.; Yki-Jarvinen, H.; Heine, R.J.

    2009-01-01

    0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS: Exenatide significantly improves beta-cell

  20. The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion

    NARCIS (Netherlands)

    Spinnler, R.; Gorski, T.; Stolz, K.; Schuster, S.; Garten, A.; Beck-Sickinger, A.G.; Engelse, M.A.; de Koning, E.J.; Korner, A.; Kiess, W.; Maedler, K.

    2013-01-01

    AIMS/HYPOTHESIS: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) and its enz

  1. Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes

    Science.gov (United States)

    Using the hyperglycemic and euglycemic clamp, we demonstrated impaired Beta-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled Beta-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. Bet...

  2. Induction of beta-cell resistance to hypoxia and technologies for oxygen delivery to transplanted pancreatic islets.

    Science.gov (United States)

    Lazard, Daniel; Vardi, Pnina; Bloch, Konstantin

    2012-09-01

    Hypoxia is believed to be a crucial factor involved in cell adaptation to environmental stress. Islet transplantation, especially with immunoisolated islets, interrupts vascular connections, resulting in the substantially decreased delivery of oxygen and nutrients to islet cells. Insulin-producing pancreatic beta cells are known to be highly susceptible to oxygen deficiency. Such susceptibility to hypoxia is believed to be one of the main causes of beta-cell death in the post-transplantation period. Different strategies have been developed for the protection of beta cells against hypoxic injury and for oxygen delivery to transplanted islets. The enhancement of beta-cell defense properties against hypoxia has been achieved using various techniques such as gene transfection, drug supplementation, co-culturing with stem cells and cell selection. Technologies for oxygen delivery to transplanted islets include local neovascularization of subcutaneous sites, electrochemical and photosynthetic oxygen generation, oxygen refuelling of bio-artificial pancreas and whole body oxygenation by using hyperbaric therapy. Progress in the field of oxygen technologies for islet transplantation requires a multidisciplinary approach to explore and optimize the interaction between components of the biological system and different technological processes. This review article focuses mainly on the recently developed strategies for oxygenation and protection from hypoxic injury - to achieve stable and long-term normoglycaemia in diabetic patients with transplanted pancreatic islets. PMID:22389124

  3. Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Feigh, M; Andreassen, K V; Neutzsky-Wulff, A V;

    2012-01-01

    Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty...

  4. Immune-mediated beta-cell destruction in vitro and in vivo-A pivotal role for galectin-3

    DEFF Research Database (Denmark)

    Karlsen, Allan E; Størling, Zenia M; Sparre, Thomas;

    2006-01-01

    Pro-apoptotic cytokines are toxic to the pancreatic beta-cells and have been associated with the pathogenesis of Type 1 diabetes (T1D). Proteome analysis of IL-1beta exposed isolated rat islets identified galectin-3 (gal-3) as the most up-regulated protein. Here analysis of human and rat islets a...

  5. High normal fasting glucose level in obese youth: a marker for insulin resistance and beta cell dysregulation.

    LENUS (Irish Health Repository)

    O'Malley, G

    2010-06-01

    A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol\\/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth.

  6. Proinsulin maturation disorder is a contributor to the defect of subsequent conversion to insulin in {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jie, E-mail: jie.wang2@osumc.edu [Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH (United States); Osei, Kwame [Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH (United States)

    2011-07-22

    Highlights: {yields} Primary proinsulin maturation disorder is inherent in Ins2{sup +/Akita} islets/{beta}-cells. {yields} A consequence is the inefficient conversion of proinsulin to insulin. {yields} Post-translational defects occur as well in the involved PC1/3 and PC2 convertases. {yields} Proinsulin maturation chaos results in defects in the following conversion process. {yields} A link of the proinsulin maturation disorder and hyperproinsulinemia is suggested. -- Abstract: Disproportionate hyperproinsulinemia is an indicator of {beta}-cell dysfunction in diabetes and the basis underlying this abnormality remains obscure. Recently, we have found proinsulin is an aggregation-prone molecule inherent with a low relative folding rate and maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) in normal {beta}-cells as a result of the integration of maturation and disposal processes. PIHO is susceptible to environmental and genetic influences. Perturbation of PIHO produces a number of toxic consequences with known association to {beta}-cell failure in diabetes. To explore whether the perturbation of PIHO has a link to disproportionate hyperproinsulinemia, we investigated proinsulin conversion and the involved prohormone convertase 1/3 (PC1/3) and 2 (PC2) in mouse Ins2{sup +/Akita} islets/{beta}-cells that preserve a primary PIHO disorder due to a mutation (C96Y) in the insulin 2 (Ins2) gene. Our metabolic-labeling studies found an increased ratio of proinsulin to insulin in the cellular or released proteins of Ins2{sup +/Akita} islets. Histological, metabolic-labeling, and RT-PCR analyses revealed decreases of the PC1/3 and PC2 immunoreactivities in the {beta}-cells of Ins2{sup +/Akita} islets in spite of no declines of these two convertases at the transcriptional and translational levels. Immunoblot analyses in cloned Ins2{sup +/Akita} {beta}-cells further confirmed the increased ratio of proinsulin

  7. PARP-1 and YY1 are important novel regulators of CXCL12 gene transcription in rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Jelena Marković

    Full Text Available Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12 transcription. The roles of poly(ADP-ribose polymerase-1 (PARP-1 and transcription factor Yin Yang 1 (YY1 in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the

  8. Beta Cell Pancreas Dysfunction and Hyperglycemia in Patient Schizophrenia that Uses Haloperidol at Region Special Dadi Hospital Province South Sulawesi

    Directory of Open Access Journals (Sweden)

    Rahmawati

    2016-01-01

    Full Text Available Schizophrenic patients at high risk for development of type 2 diabetes as a side effect of the antipsychotic medication This research is aimed to find out (1 the level of HbA1c and the description of hyperglycemia incidence, (2 the value of HOMA-β and the description of beta cell dysfunction incidence, (3 the correlation between HOMA-β value with HbA1c level, (4 the duration correlation between the use of haloperidol with the HOMA-β value and the HbA1c level, (5 the duration correlation the use of haloperidol and the HbA1c level through HOMA-β value. This study was conducted at the inpatient ward of Dadi Hospital, South Sulawesi Province using quantitative method with cross sectional study. By using total sampling way, 64 were chosen. The data were then analyzed by using frequency distribution test and Spearman correlation. The result of the study indicates that sufferer schizophrenia at Dadi Hospital who use haloperidol have problems of hyperglycemia (HbA1c >5,5%. The longer the use of haloperidol the more the excelsior level of HbA1c found. About 4,3% hyperglycemia in use of haloperidol 1 year. The mechanism the hyperglycemia incidence mentioned above suffered through dysfunction of beta cell. The longer the use of haloperidol the lower the HOMA-β value. It reaches 28,3% dysfunction of beta cell in use of haloperidol 1 year. The dysfunction of beta cell has relation with the duration in the use of haloperidol. The lower HOMA-β value level the more the excelsior level of HbA1c. The incidence of Hyperglycemia is correlated with the dysfunction of beta cell.

  9. 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)

    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 (14C). 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). 14C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA 14C content relative to a well-established 14C 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 14C 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.

  10. 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.

  11. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Bagge, Annika [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Clausen, Trine R. [Diabetes Biology, Novo Nordisk, Maaloev (Denmark); Larsen, Sylvester [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Ladefoged, Mette [Diabetes Biology, Novo Nordisk, Maaloev (Denmark); Rosenstierne, Maiken W. [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Department of Virology, Statens Serum Institut (Denmark); Larsen, Louise [Department of Biomedical Sciences, University of Copenhagen, Copenhagen (Denmark); Vang, Ole [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Nielsen, Jens H. [Department of Biomedical Sciences, University of Copenhagen, Copenhagen (Denmark); Dalgaard, Louise T., E-mail: ltd@ruc.dk [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark)

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. Black-Right-Pointing-Pointer miR-29a increases proliferation of INS-1E beta-cells. Black-Right-Pointing-Pointer Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). Black-Right-Pointing-Pointer Depletion of beta-cell miR-29a improves GSIS. Black-Right-Pointing-Pointer miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cells and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.

  12. Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1.

    Directory of Open Access Journals (Sweden)

    Etti Bachar

    Full Text Available BACKGROUND: Palmitate is a potent inducer of endoplasmic reticulum (ER stress in beta-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic beta-cells, leading to beta-cell dysfunction and death. Why glucose exacerbates beta-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased beta-cell ER stress. PRINCIPAL FINDINGS: We found that glucose amplifies palmitate-induced ER stress by increasing IRE1alpha protein levels and activating the JNK pathway, leading to increased beta-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased beta-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in beta-cells incubated at high glucose with palmitate. However, it decreased IRE1alpha expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased beta-cell apoptosis under conditions of glucolipotoxicity. CONCLUSIONS/SIGNIFICANCE: Collectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in beta-cell glucolipotoxicity. Moreover, in stressed beta-cells mTORC1 inhibition decreases IRE1alpha protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the beta-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific

  13. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    International Nuclear Information System (INIS)

    Highlights: ► MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. ► miR-29a increases proliferation of INS-1E beta-cells. ► Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). ► Depletion of beta-cell miR-29a improves GSIS. ► miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cells and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.

  14. Marked over expression of uncoupling protein-2 in beta cells exerts minor effects on mitochondrial metabolism

    International Nuclear Information System (INIS)

    Highlights: ► The impact of UCP-2 over expression on mitochondrial function is controversial. ► We tested mitochondrial functions at defined levels of overexpression. ► We find minor increases of fatty acid oxidation and uncoupling. ► Effects were seen only at high level (fourfold) of over expression. ► Hence it is doubtful whether these effects are of importance in diabetes. -- Abstract: Evidence is conflicting as to the impact of elevated levels of uncoupling protein-2 (UCP-2) on insulin-producing beta cells. Here we investigated effects of a fourfold induction of UCP-2 protein primarily on mitochondrial parameters and tested for replication of positive findings at a lower level of induction. We transfected INS-1 cells to obtain a tet-on inducible cell line. A 48 h exposure to 1 μg/ml of doxycycline (dox) induced UCP-2 fourfold (424 ± 113%, mean ± SEM) and 0.1 μg/ml twofold (178 ± 29%, n = 3). Fourfold induced cells displayed normal viability (MTT, apoptosis), normal cellular insulin contents and, glucose-induced insulin secretion (+27 ± 11%) as well as D-[U-14C]-glucose oxidation (+5 ± 9% at 11 mM glucose). Oxidation of [1-14C]-oleate was increased from 4088 to 5797 fmol/μg prot/2 h at 3.3 mM glucose, p 14C(U)]-glutamine was unaffected. Induction of UCP-2 did not significantly affect measures of mitochondrial membrane potential (Rhodamine 123) or mitochondrial mass (Mitotracker Green) and did not affect ATP levels. Oligomycin-inhibited oxygen consumption (a measure of mitochondrial uncoupling) was marginally increased, the effect being significant in comparison with dox-only treated cells, p < 0.05. Oxygen radicals, assessed by dichlorofluorescin diacetate, were decreased by 30%, p < 0.025. Testing for the lower level of UCP-2 induction did not reproduce any of the positive findings. A fourfold induction of UCP-2 was required to exert minor metabolic effects. These findings question an impact of moderately elevated UCP-2 levels in beta cells as

  15. Marked over expression of uncoupling protein-2 in beta cells exerts minor effects on mitochondrial metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Hals, Ingrid K., E-mail: ingrid.hals@ntnu.no [Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim (Norway); Ogata, Hirotaka; Pettersen, Elin [Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim (Norway); Ma, Zuheng; Bjoerklund, Anneli [Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm (Sweden); Skorpen, Frank [Department of Laboratory Medicine, NTNU, Trondheim (Norway); Egeberg, Kjartan Wollo [Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim (Norway); Grill, Valdemar [Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim (Norway); Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm (Sweden)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer The impact of UCP-2 over expression on mitochondrial function is controversial. Black-Right-Pointing-Pointer We tested mitochondrial functions at defined levels of overexpression. Black-Right-Pointing-Pointer We find minor increases of fatty acid oxidation and uncoupling. Black-Right-Pointing-Pointer Effects were seen only at high level (fourfold) of over expression. Black-Right-Pointing-Pointer Hence it is doubtful whether these effects are of importance in diabetes. -- Abstract: Evidence is conflicting as to the impact of elevated levels of uncoupling protein-2 (UCP-2) on insulin-producing beta cells. Here we investigated effects of a fourfold induction of UCP-2 protein primarily on mitochondrial parameters and tested for replication of positive findings at a lower level of induction. We transfected INS-1 cells to obtain a tet-on inducible cell line. A 48 h exposure to 1 {mu}g/ml of doxycycline (dox) induced UCP-2 fourfold (424 {+-} 113%, mean {+-} SEM) and 0.1 {mu}g/ml twofold (178 {+-} 29%, n = 3). Fourfold induced cells displayed normal viability (MTT, apoptosis), normal cellular insulin contents and, glucose-induced insulin secretion (+27 {+-} 11%) as well as D-[U-{sup 14}C]-glucose oxidation (+5 {+-} 9% at 11 mM glucose). Oxidation of [1-{sup 14}C]-oleate was increased from 4088 to 5797 fmol/{mu}g prot/2 h at 3.3 mM glucose, p < 0.03. Oxidation of L-[{sup 14}C(U)]-glutamine was unaffected. Induction of UCP-2 did not significantly affect measures of mitochondrial membrane potential (Rhodamine 123) or mitochondrial mass (Mitotracker Green) and did not affect ATP levels. Oligomycin-inhibited oxygen consumption (a measure of mitochondrial uncoupling) was marginally increased, the effect being significant in comparison with dox-only treated cells, p < 0.05. Oxygen radicals, assessed by dichlorofluorescin diacetate, were decreased by 30%, p < 0.025. Testing for the lower level of UCP-2 induction did not reproduce any of the

  16. Thyrotropin releasing hormone (TRH) affects gene expression in pancreatic beta-cells.

    Science.gov (United States)

    Luo, LuGuang; Yano, Naohiro

    2005-01-01

    Thyrotropin-releasing hormone (TRH), originally identified as a hypothalamic hormone, is expressed in the pancreas. The peptide has been shown to control glycemia, although the role of TRH in the pancreas has not yet been clarified. In quiescent INS-1 cells (rat immortalized beta-cell line), 200 nM of TRH for 24 hours significantly increased insulin levels in the culture medium and in cell extracts. In studies with gene array technology where about 60% to 75% of the 1081 genes were detected, TRH significantly stimulated multiple groups of gene expressions, including G-protein-coupled receptor and related signaling, such as insulin secretion, endoplasmic reticulum traffic mechanisms, cell-cycle regulators, protein turnover factors, DNA recombination, and growth factors. Noticeably, TRH suppressed the genes of proapoptotic Bcl-2-associated protein X, Bcl-xL/ Bcl-2-associated death promoter, and Fas. The multiple gene expressions in response to TRH in pancreatic cells suggest that the changed microenvironment brought about by TRH may influence beta-cellfunction. PMID:16392621

  17. The Cytotoxic Role of Intermittent High Glucose on Apoptosis and Cell Viability in Pancreatic Beta Cells

    Directory of Open Access Journals (Sweden)

    Zhen Zhang

    2014-01-01

    Full Text Available Objectives. Glucose fluctuations are both strong predictor of diabetic complications and crucial factor for beta cell damages. Here we investigated the effect of intermittent high glucose (IHG on both cell apoptosis and proliferation activity in INS-1 cells and the potential mechanisms. Methods. Cells were treated with normal glucose (5.5 mmol/L, constant high glucose (CHG (25 mmol/L, and IHG (rotation per 24 h in 11.1 or 25 mmol/L for 7 days. Reactive oxygen species (ROS, xanthine oxidase (XOD level, apoptosis, cell viability, cell cycle, and expression of cyclinD1, p21, p27, and Skp2 were determined. Results. We found that IHG induced more significant apoptosis than CHG and normal glucose; intracellular ROS and XOD levels were more markedly increased in cells exposed to IHG. Cells treated with IHG showed significant decreased cell viability and increased cell proportion in G0/G1 phase. Cell cycle related proteins such as cyclinD1 and Skp2 were decreased significantly, but expressions of p27 and p21 were increased markedly. Conclusions. This study suggested that IHG plays a more toxic effect including both apoptosis-inducing and antiproliferative effects on INS-1 cells. Excessive activation of cellular stress and regulation of cyclins might be potential mechanism of impairment in INS-1 cells induced by IHG.

  18. Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans

    DEFF Research Database (Denmark)

    Ahrén, Bo; Holst, Jens Juul; Mari, Andrea

    2003-01-01

    have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted...... overnight were served a breakfast (450 kcal) with intravenous infusion of saline or synthetic GLP-1 (0.75 pmol x kg(-1) x min(-1)), and beta-cell function was evaluated by estimating the relationship between glucose concentration and insulin secretion (calculated by deconvolution of C-peptide data). RESULTS......: -GLP-1 markedly augmented insulin secretion, despite lower glucose. Total insulin secretion was 29.7 +/- 4.2 nmol/m(2) with GLP-1 versus 21.0 +/- 1.6 nmol/m(2) with saline (P = 0.048). GLP-1 increased the dose-response relationship between glucose concentration and insulin secretion (70 +/- 26 with GLP...

  19. Profile of blood glucose and ultrastucture of beta cells pancreatic islet in alloxan compound induced rats

    Directory of Open Access Journals (Sweden)

    I Nyoman Suarsana

    2010-06-01

    Full Text Available Diabetes is marked by elevated levels of blood glucose, and progressive changes of the structure of pancreatic islet histopathology. The objective of this research was to analyse the glucose level and histophatological feature in pancreatic islet in alloxan compound induced rats. A total of ten male Spraque Dawley rats of 2 months old were used in this study. The rats were divided into two groups: (1 negative control group (K-, and (2 positif induced alloxan group (diabetic group =DM. The rats were induced by a single dose intraperitonial injection of alloxan compound 120 mg/kg of body weight. The treatment was conducted for 28 days. Blood glucose levels of rats were analysed at 0, 4, 7, 14, 21, and 28 days following treatment. At the end of the experiment, rats were sacrificed by cervical dislocation. Pancreas was collected for analysis of histopathological study by Immunohistochemical technique, and ultrastructural study using transmission electron microscope (TEM. The result showed that Langerhans islet of diabetic rat (rat of DM group showed a marked reduction of size, number of Langerhans islet of diabetic rat decrease, and characterized by hyperglycemic condition. By using TEM, beta cells of DM group showed the rupture of mitochondrial membrane, the lost of cisternal structure of inner membrane of mitocondria, reduction of insulin secretory granules, linkage between cells acinar with free Langerhans islet, and the caryopicnotic of nucleus.

  20. Engineering on abolishment measure of nuclear fuel facilities. Application of 3D-CAD to abolishment measure of nuclear fuel facilities

    International Nuclear Information System (INIS)

    The Japan Nuclear Cycle Development Institute (JNC) progresses some advancing R and Ds required for establishment of the nuclear fuel cycle under considering on safety, economical efficiency, environmental compatibility, and so on. An important item among them is a technology on safe abolishment of a nuclear energy facility ended its role, which is called the abolishment measure technique. Here was introduced at a center of viewpoint called on use of three dimensional CAD (3D-CAD), on outlines of engineering system for abolishment measure (subdivision engineering system) under an object of nuclear fuel facilities, constructed through subdivision and removal of refinement conversion facilities, by the Ningyo-toge Environmental Engineering Center of JNC. (G.K.)

  1. Measuring phospholipase D activity in insulin-secreting pancreatic beta-cells and insulin-responsive muscle cells and adipocytes.

    Science.gov (United States)

    Cazzolli, Rosanna; Huang, Ping; Teng, Shuzhi; Hughes, William E

    2009-01-01

    Phospholipase D (PLD) is an enzyme producing phosphatidic acid and choline through hydrolysis of phosphatidylcholine. The enzyme has been identified as a member of a variety of signal transduction cascades and as a key regulator of numerous intracellular vesicle trafficking processes. A role for PLD in regulating glucose homeostasis is emerging as the enzyme has recently been identified in events regulating exocytosis of insulin from pancreatic beta-cells and also in insulin-stimulated glucose uptake through controlling GLUT4 vesicle exocytosis in muscle and adipose tissue. We present methodologies for assessing cellular PLD activity in secretagogue-stimulated insulin-secreting pancreatic beta-cells and also insulin-stimulated adipocyte and muscle cells, two of the principal insulin-responsive cell types controlling blood glucose levels. PMID:19160674

  2. 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

    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......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......, 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....

  3. A proteomic study of the regulatory role for STAT-1 in cytokine-induced beta-cell death

    DEFF Research Database (Denmark)

    Rondas, Dieter; Gudmundsdottir, Valborg; D’Hertog, Wannes; Crèvecoeur, Inne; Waelkens, Etienne; Brunak, Søren; Mathieu, Chantal; Overbergh, Lut

    PURPOSE: Signal transducer and activator of transcription 1 (STAT-1) plays a crucial role in cytokine-induced beta-cell destruction. However, its precise downstream pathways have not been completely clarified. We performed a proteome analysis of cytokine-exposed C57Bl/6 and STAT-1-/- mouse islets...... assigned to small ubiquitin-related modifier 4 (SUMO4). CONCLUSIONS AND CLINICAL RELEVANCE: These findings confirm a central role for STAT-1 in pancreatic islet inflammation induced destruction and most importantly elucidate the underlying proteomic pathways involved.......PURPOSE: Signal transducer and activator of transcription 1 (STAT-1) plays a crucial role in cytokine-induced beta-cell destruction. However, its precise downstream pathways have not been completely clarified. We performed a proteome analysis of cytokine-exposed C57Bl/6 and STAT-1-/- mouse islets...

  4. The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose

    DEFF Research Database (Denmark)

    Utzschneider, Kristina M; Tong, Jenny; Montgomery, Brenda; Udayasankar, Jayalakshmi; Gerchman, Fernando; Marcovina, Santica M; Watson, Catherine E; Ligueros-Saylan, Monica A; Foley, James E; Holst, Jens J; Deacon, Carolyn F; Kahn, Steven E

    2007-01-01

    OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD...... age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test...... (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR(g)) and insulin sensitivity index (S(I)) were determined and used to compute the disposition index (AIR(g) x S(I)) as a measure of beta-cell function...

  5. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells

    DEFF Research Database (Denmark)

    Collombat, Patrick; Xu, Xiaobo; Ravassard, Philippe;

    2009-01-01

    We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-spec...... cell mass and curing diabetes in animals that have been chemically depleted of beta cells....

  6. Combined Optical Coherence and Fluorescence Microscopy to assess dynamics and specificity of pancreatic beta-cell tracers

    OpenAIRE

    Corinne Berclaz; Christophe Pache; Arno Bouwens; Daniel Szlag; Antonio Lopez; Lieke Joosten; Selen Ekim; Maarten Brom; Martin Gotthardt; Anne Grapin-Botton; Theo Lasser

    2015-01-01

    The identification of a beta-cell tracer is a major quest in diabetes research. However, since MRI, PET and SPECT cannot resolve individual islets, optical techniques are required to assess the specificity of these tracers. We propose to combine Optical Coherence Microscopy (OCM) with fluorescence detection in a single optical platform to facilitate these initial screening steps from cell culture up to living rodents. OCM can image islets and vascularization without any labeling. Thereby, it ...

  7. Prolactin Stimulates Proliferation of the Glucose-Dependent Beta-Cell Line INS-1 via Different IRS-Proteins

    Directory of Open Access Journals (Sweden)

    Sigrun R Hügl

    2007-11-01

    Full Text Available Context Prolactin is one of the most potent growth stimulating growth hormones of pancreatic beta cells. Objective We investigated the role of prolactin on the proliferation of the beta-cell line INS-1. Design In particular, we investigated the involvement of intracellular signal transduction molecules in prolactin-dependent upregulation of INS-1 growth. Setting The effect of prolactin on the growth of INS-1 cells was assessed in vitro under various feeding conditions. Main outcome measures Cell proliferation was measured in the pancreatic beta-cell line INS-1 using 3H-thymidine incorporation. The activation of mitogenic signaling proteins was assessed by co-immunoprecipitation, immunoblot analysis and in proliferation assays using specific protein inhibitors. Results Prolactin (0.5-2 nM increased INS-1 cell proliferation in the presence of 3-24 mM glucose up to 48 fold, having a maximum in the presence of physiological glucose concentrations (6 mM. Prolactin activated the JAK2/STAT5 pathway and phosphatidylinositol- 3’-kinase (PI3’K in the presence of all the glucose concentrations used (3-15 mM. At low glucose concentrations (3 mM, PI3’K activation occurred through IRS-2 phosphorylation whereas, in the presence of physiological glucose concentration IRS4 and at high glucose concentrations (15 mM, IRS- 1 triggered a proliferative effect. PI3’K activation was essential for prolactin and glucose stimulated INS-1 cell proliferation. Co-stimulation with different growth factors (IGF-I, growth hormone in addition to prolactin and glucose had no additive effects. Conclusion These results define prolactin as an important hormone. mediating glucosedependent pancreatic beta-cell proliferation primarily by the activation of PI3’Kdependent signaling pathways.

  8. Effects of low intensity laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes

    Science.gov (United States)

    Xiong, Guoxin; Xiong, Leilei; Li, Xinzhong

    2016-09-01

    To investigate the effects of low intensity semiconductor laser acupoint irradiation on inhibiting islet beta-cell apoptosis in rats with type 2 diabetes, a method using a high-fat diet and low-dose intraperitoneal injections of streptozotocin established a type 2 diabetes mellitus rat model. Model rats were randomly divided into a laser acupoint irradiation group, rosiglitazone control group, and placebo group; each group had 10 rats. In addition, 10 normal male rats were selected for the normal control group. The Housanli, Neiting and Yishu acupoints of the rats in the laser acupoint irradiation group were irradiated with a 10 mW semiconductor laser; each point was irradiated for 15 min, once every 2 d over 28 d, for a total of 14 episodes of irradiation. The rosiglitazone group rats were given rosiglitazone (0.2 mg kg‑1) intragastrically; the placebo group rats were given 0.9% brine (0.2 mg kg‑1) intragastrically, once daily, for four consecutive weeks. The change of fasting blood glucose was determined before and after each treatment. The islet beta-cell apoptosis was determined. The islet beta-cell apoptosis rates of the laser acupoint irradiation group and the rosiglitazone group were significantly lower than the rate of the placebo group. Even though the rate was lower in the laser acupoint irradiation group than in the rosiglitazone group, there was no significant difference between them. It is shown that acupoint irradiation with a semiconductor laser can effectively inhibit islet beta-cell apoptosis in rats with type 2 diabetes.

  9. IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice.

    Science.gov (United States)

    Zhang, Yun; Jalili, Reza B; Kilani, Ruhangiz T; Elizei, Sanam Salimi; Farrokhi, Ali; Khosravi-Maharlooei, Mohsen; Warnock, Garth L; Ao, Ziliang; Marzban, Lucy; Ghahary, Aziz

    2016-09-01

    Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1β and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc. PMID:26743772

  10. Molecular mechanisms underlying the glucose-dependent transcription of the insulin and glucokinase genes in the pancreatic beta-cell

    OpenAIRE

    Moede, Tilo

    2002-01-01

    Background: Insulin is of vital importance in the maintenance of the glucose homeostasis in mammals. This necessitates a tight regulation of both insulin release and biosynthesis. Although pancreatic beta-cells secrete only a fraction of the stored insulin upon glucose stimulation, insulin biosynthesis starts immediately in order to replenish the insulin store. It is well documented that glucose exerts its immediate effects at the posttranscriptional and translational levels...

  11. Relationship between the level of fasting plasma glucose and beta cell functions in Chinese with or without diabetes

    Institute of Scientific and Technical Information of China (English)

    PANG Can; BAO Yu-qian; WANG Chen; LU Jun-xi; JIA Wei-ping; XIANG Kun-san

    2008-01-01

    Background Type 2 diabetes is a chronic disease characterized by a progressive loss of beta cell functions.However,the evaluation of beta cell functions is either expensive or inconvenient for clinical practice.We aimed to elucidate the association between the changes of insulin responsiveness and the fasting plasma glucose (FPG) during the development of diabetes.Methods A total of 1192 Chinese individuals with normal blood glucose or hyperglycemia were enrolled for the analysis.The early insulinogenic index (△I30/△G30),the area under the curve of insulin (AUC-I),and homeostasis model assessment were applied to evaluate the early phase secretion,total insulin secretion,and insulin resistance respectively.Polynomial regression analysis was performed to estimate the fluctuation of beta cell functions.Results The △I30/△G30 decreased much more rapidly than the AUC-I accompanying with the elevation of FPG.At the FPG of 110 mg/dl (a pre-diabetic stage),the △I30/△G30 lost 50% of its maximum while the AUC-I was still at a compensated normal level.The AUC-I exhibited abnormal and decreased gradually at the FPG of from 130 mg/dl to higher (overt diabetes),while the △I30/△G30 almost remained at 25% of its maximum value.When hyperglycemia continuously existed at >180 mg/dl,beth the △I30/△G30 and AUC-I were totally lost.Conclusion The increased fasting plasma glucose reflects progressive decompensation of beta cell functions,and could be used to guide the strategy of clinical treatments.

  12. The level of nitric oxide regulates lipocalin-2 expression under inflammatory condition in RINm5F beta-cells.

    Science.gov (United States)

    Chang, Seo-Yoon; Kim, Dong-Bin; Ko, Seung-Hyun; Jang, Hyun-Jong; Jo, Yang-Hyeok; Kim, Myung-Jun

    2016-07-15

    We previously reported that proinflammatory cytokines (interleukin-1β and interferon-γ) induced the expression of lipocalin-2 (LCN-2) together with inducible nitric oxide synthase (iNOS) in RINm5F beta-cells. Therefore, we examined the effect of nitric oxide (NO) on LCN-2 expression in cytokines-treated RINm5F beta-cells. Additionally, we observed the effect of LCN-2 on cell viability. First, we found the existence of LCN-2 receptor and the internalization of exogenous recombinant LCN-2 peptide in RINm5F and INS-1 beta-cells. Next, the effects of NO on LCN-2 expression were evaluated. Aminoguanidine, an iNOS inhibitor and iNOS gene silencing significantly inhibited cytokines-induced LCN-2 expression while sodium nitroprusside (SNP), an NO donor potentiated it. Luciferase reporter assay showed that transcription factor NF-κB was not involved in LCN-2 expression. Both LCN-2 mRNA and protein stability assays were conducted. SNP did not affect LCN-2 mRNA stability, however, it significantly reduced LCN-2 protein degradation. The LCN-2 protein degradation was significantly attenuated by MG132, a proteasome inhibitor. Finally, the effect of LCN-2 on cell viability was evaluated. LCN-2 peptide treatment and LCN-2 overexpression significantly reduced cell viability. FACS analysis showed that LCN-2 induced the apoptosis of the cells. Collectively, NO level affects LCN-2 expression via regulation of LCN-2 protein stability under inflammatory condition and LCN-2 may reduce beta-cell viability by promoting apoptosis. PMID:27233602

  13. Involvement of the autonomic nervous system in the in vivo memory to glucose of pancreatic beta cell in rats.

    OpenAIRE

    N'Guyen, J M; C. Magnan; Laury, M C; Thibault, C.; Leveteau, J; Gilbert, M.; Pénicaud, L.; Ktorza, A

    1994-01-01

    The fact that the potentiating effect of prolonged hyperglycemia on the subsequent insulin secretion is observed in vivo but not in vitro suggests the involvement of extrapancreatic factors in the in vivo memory of pancreatic beta cells to glucose. We have investigated the possible role of the autonomic nervous system. Rats were made hyperglycemic by a 48-h infusion with glucose (HG rats). At the end of glucose infusion as well as 6 h postinfusion, both parasympathetic and sympathetic nerve a...

  14. Glucagon-Like Peptide-1 Triggers Protective Pathways in Pancreatic Beta-Cells Exposed to Glycated Serum

    Directory of Open Access Journals (Sweden)

    Alessandra Puddu

    2013-01-01

    Full Text Available Advanced glycation end products (AGEs might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1, an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs, in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2, glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.

  15. Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes

    DEFF Research Database (Denmark)

    Røder, M E; Dinesen, B; Hartling, S G;

    1999-01-01

    OBJECTIVE: Type 2 diabetes is a heterogeneous disease in which both beta-cell dysfunction and insulin resistance are pathogenetic factors. Disproportionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnormality in type 2 diabetes whose mechanism is unknown. Increased demand due to...... obesity and/or insulin resistance may result in secretion of immature beta-cell granules with a higher content of intact proinsulin. RESEARCH DESIGN AND METHODS: We investigated the impact of obesity on beta-cell secretion in normal subjects and in type 2 diabetic patients by measuring intact proinsulin...... diabetic patients matched for fasting glucose (10.2 +/- 0.6 vs. 10.3 +/- 0.4 mmol/l) were compared with age- and BMI-matched lean (22.4 +/- 0.6 kg/m2) (LC) and obese (30.8 +/- 0.9 kg/m2) (OC) normal control subjects. RESULTS: Diabetic patients (LD vs. LC and OD vs. OC) had elevated fasting levels of intact...

  16. GeneSpeed Beta Cell: An Online Genomics Data Repository and Analysis Resource Tailored for the Islet Cell Biologist

    Directory of Open Access Journals (Sweden)

    Jan Jensen

    2008-09-01

    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.

  17. Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells.

    Science.gov (United States)

    Maulucci, Giuseppe; Daniel, Bareket; Cohen, Ofir; Avrahami, Yossef; Sasson, Shlomo

    2016-06-01

    proliferator-activated receptor δ (PPARδ) in vascular endothelial cells and insulin secreting beta cells, promote such adaptive responses to ameliorate detrimental effects of high glucose and diabetes-like conditions. In addition, due to the electrophilic nature of these reactive aldehydes they form covalent adducts with electronegative moieties in proteins, phosphatidylethanolamine and nucleotides. Normally these non-enzymatic modifications are maintained below the cytotoxic range due to efficient cellular neutralization processes of 4-hydroxyalkenals. The major neutralizing enzymes include fatty aldehyde dehydrogenase (FALDH), aldose reductase (AR) and alcohol dehydrogenase (ADH), which transform the aldehyde to the corresponding carboxylic acid or alcohols, respectively, or by biding to the thiol group in glutathione (GSH) by the action of glutathione-S-transferase (GST). This review describes the hormetic and cytotoxic roles of oxygen free radicals and 4-hydroxyalkenals in beta cells exposed to nutritional challenges and the cellular mechanisms they employ to maintain their level at functional range below the cytotoxic threshold. PMID:27012748

  18. To Abolish the One-Child Policy or Not?

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    In 1982 China endorsed the one-child policy as one of the country’s national policies.The policy came at a special historical moment when rapid population growth in preceding decades posed increasing challenges to the standards of people’s living,education,health care and employment,makingit extremelydifficult forthe coun-try to rid itself of poverty in the foreseeable future.A mong developing countries with huge populations,China was the only one to retain a low birth rate during part of the

  19. Design and optimization of beta-cell temperature sensor based on 63Ni–Si

    International Nuclear Information System (INIS)

    A theoretical study of the use of a beta-cell as a temperature sensor using MCNP4C Monte Carlo code is presented in this paper. Nickel-63 and silicon were selected as the beta source and semiconductor material, respectively. The maximum open-circuit voltage (VOC) is equal to 0.445 V with doping concentrations of NA=4×1018#/cm3 and ND=8×1019#/cm3 in the base and the emitter region, respectively, which, depending on the source activity, enables measurement in a wide range of temperature. The effects of the activity and its change over time on VOC were also studied. The results demonstrated that VOC exhibited smaller changes for higher activities. The temperature sensitivity of this sensor ranges from −2.42 mV/K to −3.41 mV/K for source activities from 100 mCi to 0.001 mCi, respectively, so the optimal activity can be determined according to the desired temperature range and sensitivity. - Highlights: • A silicon p–n junction using 63Ni is used as a temperature sensor. • The rate of electron–hole generation in silicon was simulated using Monte Carlo MCNP4c code. • The effects of the structural properties of the semiconductor, such as doping concentration and the thickness of the emitter, on the sensitivity and temperature range were studied. • The source thickness and the effect of the activity and its change over time on VOC were investigated at various temperatures

  20. Relationship Between Beta Cell Dysfunction and Severity of Disease Among Critically Ill Children: A STROBE-Compliant Prospective Observational Study.

    Science.gov (United States)

    Liu, Ping-Ping; Lu, Xiu-Lan; Xiao, Zheng-Hui; Qiu, Jun; Zhu, Yi-Min

    2016-05-01

    Although beta cell dysfunction has been proved to predict prognosis among humans and animals, its prediction on severity of disease remains unclear among children. The present study was aimed to examine the relationship between beta cell dysfunction and severity of disease among critically ill children.This prospective study included 1146 critically ill children, who were admitted to Pediatric Intensive Care Unit (PICU) of Hunan Children's Hospital from November 2011 to August 2013. Information on characteristics, laboratory tests, and prognostic outcomes was collected. Homeostasis model assessment (HOMA)-β, evaluating beta cell function, was used to divide all participants into 4 groups: HOMA-β = 100% (group I, n = 339), 80% ≤ HOMA-β ventilation (MV) and mortality. Logistic regression analysis was used to evaluate the risk of developing poor outcomes among patients in different HOMA-β groups, with group I as the reference group.Among 1146 children, incidence of HOMA-β < 100% was 70.41%. C-peptide and insulin declined with the decrement of HOMA-β (P < 0.01). C-reactive protein and procalcitonin levels, rather than white blood cell, were significantly different among 4 groups (P < 0.01). In addition, the worst SOFA score and the worst PRISMIII score increased with declined HOMA-β. For example, the worst SOFA score in group I, II, III, and IV was 1.55 ± 1.85, 1.71 ± 1.93, 1.92 ± 1.63, and 2.18 ± 1.77, respectively. Furthermore, patients with declined HOMA-β had higher risk of developing septic shock, MODS, MV, and mortality, even after adjusting age, gender, myocardial injury, and lung injury. For instance, compared with group I, the multivariate-adjusted odds ratio (95% confidence interval) for developing septic shock was 2.17 (0.59, 8.02), 2.94 (2.18, 6.46), and 2.76 (1.18, 6.46) among patients in group II, III, and IV, respectively.Beta cell dysfunction reflected the severity of disease among critically ill children

  1. Sulfonylurea receptor as a target for molecular imaging of pancreas beta cells with 99mTc-DTPA-glipizide

    International Nuclear Information System (INIS)

    This study was aimed to assess pancreas beta cell activity using 99mTc-diethyleneaminepentaacetic acid-glipizide (DTPA-GLP), a sulfonylurea receptor agent. The effect of DTPA-GLP on the blood glucose level in rats was also evaluated. DTPA dianhydride was conjugated with GLP in the presence of sodium amide, yielding 60%. Biodistribution and planar images were obtained at 30-120 min after injection of 99mTc-DTPA-GLP (1 mg/rat, 0.74 and 11.1 MBq per rat, respectively) in normal female Fischer 344 rats. The control group was given 99mTc-DTPA. To demonstrate pancreas beta cell uptake of 99mTc-DTPA-GLP via a receptor-mediated process, a group of rats was pretreated with streptozotocin (a beta cell toxin, 55 mg/kg, intravenous (i.v.)) and the images were acquired at immediately-65 min on day 5 post-treatment. The effect on the glucose levels after a single administration (ip) of DTPA-GLP was compared to glipizide (GLP) for up to 6 h. The structure of DTPA-GLP was confirmed by NMR, mass spectrometry and HPLC. Radiochemical purity assessed by ITLC was >96%. 99mTc-DTPA-GLP showed increased pancreas-to-muscle ratios, whereas 99mTc-DTPA showed decreased ratios at various time points. Pancreas could be visualized with 99mTc-DTPA-GLP in normal rat, however, 99mTc-DTPA has poor uptake suggesting the specificity of 99mTc-DTPA-GLP. Pancreas beta cell uptake could be blocked by pre-treatment with streptozotocin. DTPA-GLP showed an equal or better response in lowering the glucose levels compared to the existing GLP drug. It is feasible to use 99mTc-DTPA-GLP to assess pancreas beta cell receptor recognition. 99mTc-DTPA-GLP may be helpful in evaluating patients with diabetes, pancreatitis and pancreatic tumors. (author)

  2. Assessment on Functionality and Viability of Beta Cells Following Repetitive Dosage Administration of Ethanolic Extracts of Andrographis paniculata on Streptozotocin-induced Diabetic Rats.

    OpenAIRE

    Mohd Zaini, A; A Mariam; Amirin, S; Abdul Razak, K

    2010-01-01

    The study was done at the aim to assess the functionality and viability of the beta cells of the streptozotocin-induced diabetic rats model following repetitive dosage of administration of ethanolic extracts of Andrographis paniculata. Materials and Methods: The diabetic rats were treated with the extracts for fourteen days and at the dose given was 500 mg/kg twice daily. The assessments were made on fasting blood glucose, insulin, and immunohistochemical aspect of beta cells before and after...

  3. New approach to beta cell function screening by nitric oxide assessment of obese individuals at the population level

    Directory of Open Access Journals (Sweden)

    Chaim EA

    2012-05-01

    Full Text Available Elinton Adami Chaim, Renata Cristina GobatoUniversity of Campinas (UNICAMP, Faculty of Medical Sciences, Department of Surgery, Cidade Universitária Zeferino Vaz, Barão Geraldo, BrazilBackground: Approximately 27% of Americans today are obese, and this condition increases the prevalence of metabolic syndrome and diabetes. The UK Prospective Diabetes Study suggests that loss of beta cell function can begin at least 10 years before diagnosis, and mean beta cell function is already less than 50% at diagnosis. The aim of this research was to assess the possibility of detecting loss of beta cell function in obese patients by a novel approach involving nitric oxide assessment using a combination of technologies.Materials and methods: One hundred and fifteen obese patients (93 women, 22 men of mean age 39 (range 17–62 years, who were candidates for bariatric surgery were included in the study, and underwent laboratory tests, including fasting blood glucose, fasting insulin plasma, and examination with the Electro Sensor complex. The Electro Sensor complex offers a new way to assess nitric oxide production using five technologies managed by software, ie, the galvanic skin response, photoelectrical plethysmography, heart rate variability analysis, bioimpedance analysis, and blood pressure oscillometric measurements. The homeostasis model assessment 2% beta cell function (HOMA2% β algorithm was calculated from fasting blood glucose and fasting insulin plasma using free software provided by The University of Oxford Diabetes Trial Unit. The Electro Sensor complex percent beta (ESC% β algorithm was calculated from the Electro Sensor complex data and statistical neural network. Statistical analysis was performed to correlate ESC% β and HOMA2% β using the coefficient of correlation and Spearman's coefficient of rank correlation. Receiver-operating characteristic curves were also constructed to determine the specificity and sensitivity of ESC% β in

  4. The reprogrammed pancreatic progenitor-like intermediate state of hepatic cells is more susceptible to pancreatic beta cell differentiation.

    Science.gov (United States)

    Wang, Qiwei; Wang, Hai; Sun, Yu; Li, Shi-Wu; Donelan, William; Chang, Lung-Ji; Jin, Shouguang; Terada, Naohiro; Cheng, Henrique; Reeves, Westley H; Yang, Li-Jun

    2013-08-15

    Induced pluripotent stem cells (iPSCs) hold great promise for cell therapy. However, their low efficiency of lineage-specific differentiation and tumorigenesis severely hinder clinical translation. We hypothesized that reprogramming of somatic cells into lineage-specific progenitor cells might allow for large-scale expansion, avoiding the tumorigenesis inherent with iPSCs and simultaneously facilitating lineage-specific differentiation. Here we aimed at reprogramming rat hepatic WB cells, using four Yamanaka factors, into pancreatic progenitor cells (PPCs) or intermediate (IM) cells that have characteristics of PPCs. IM clones were selected based on their specific morphology and alkaline phosphatase activity and stably passaged under defined culture conditions. IM cells did not have iPSC properties, could be stably expanded in large quantity, and expressed all 14 genes that are used to define the PPC developmental stage. Directed differentiation of IM and WB cells by Pdx1-Ngn3-MafA (PNM) into pancreatic beta-like cells revealed that the IM cells are more susceptible to directed beta cell differentiation because of their open chromatin configuration, as demonstrated by expression of key pancreatic beta cell genes, secretion of insulin in response to glucose stimulation, and easy access to exogenous PNM proteins at the rat insulin 1 and Pdx1 promoters. This notion that IM cells are superior to their parental cells is further supported by the epigenetic demonstration of accessibility of Pdx1 and insulin 1 promoters. In conclusion, we have developed a strategy to derive and expand PPC cells from hepatic WB cells using conventional cell reprogramming. This proof-of-principal study may offer a novel, safe and effective way to generate autologous pancreatic beta cells for cell therapy of diabetes. PMID:23750005

  5. Arsenic exposure and calpain-10 polymorphisms impair the function of pancreatic beta-cells in humans: a pilot study of risk factors for T2DM.

    Directory of Open Access Journals (Sweden)

    Andrea Díaz-Villaseñor

    Full Text Available The incidence of type 2 diabetes mellitus (T2DM is increasing worldwide and diverse environmental and genetic risk factors are well recognized. Single nucleotide polymorphisms (SNPs in the calpain-10 gene (CAPN-10, which encodes a protein involved in the secretion and action of insulin, and chronic exposure to inorganic arsenic (iAs through drinking water have been independently associated with an increase in the risk for T2DM. In the present work we evaluated if CAPN-10 SNPs and iAs exposure jointly contribute to the outcome of T2DM. Insulin secretion (beta-cell function and insulin sensitivity were evaluated indirectly through validated indexes (HOMA2 in subjects with and without T2DM who have been exposed to a gradient of iAs in their drinking water in northern Mexico. The results were analyzed taking into account the presence of the risk factor SNPs SNP-43 and -44 in CAPN-10. Subjects with T2DM had significantly lower beta-cell function and insulin sensitivity. An inverse association was found between beta-cell function and iAs exposure, the association being more pronounced in subjects with T2DM. Subjects without T2DM who were carriers of the at-risk genotype SNP-43 or -44, also had significantly lower beta-cell function. The association of SNP-43 with beta-cell function was dependent on iAs exposure, age, gender and BMI, whereas the association with SNP-44 was independent of all of these factors. Chronic exposure to iAs seems to be a risk factor for T2DM in humans through the reduction of beta-cell function, with an enhanced effect seen in the presence of the at-risk genotype of SNP-43 in CAPN-10. Carriers of CAPN-10 SNP-44 have also shown reduced beta-cell function.

  6. Analysis of the noise-induced bursting-spiking transition in a pancreatic beta-cell model

    DEFF Research Database (Denmark)

    Aguirre, J.; Mosekilde, Erik; Sanjuan, M.A.F.

    2004-01-01

    A stochastic model of the electrophysiological behavior of the pancreatic beta cell is studied, as a paradigmatic example of a bursting biological cell embedded in a noisy environment. The analysis is focused on the distortion that a growing noise causes to the basic properties of the membrane...... potential signals, such as their periodic or chaotic nature, and their bursting or spiking behavior. We present effective computational tools to obtain as much information as possible from these signals, and we suggest that the methods could be applied to real time series. Finally, a universal dependence of...

  7. Pancreatic beta cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

    DEFF Research Database (Denmark)

    Malin, Steven K; Solomon, Thomas; Blaszczak, Alecia;

    2013-01-01

    composition (dual-energy x-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using VO2-heart rate derived linear-regression equations. Subjects expended 474.5±8.8 kcal/session (2372.5±44.1 kcal/week) during the intervention, and lost......While some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older, obese adults with prediabetes underwent a progressive 12-week supervised exercise...

  8. Characterization of stimulus-secretion coupling in the human pancreatic EndoC-βH1 beta cell line.

    Directory of Open Access Journals (Sweden)

    Lotta E Andersson

    Full Text Available Studies on beta cell metabolism are often conducted in rodent beta cell lines due to the lack of stable human beta cell lines. Recently, a human cell line, EndoC-βH1, was generated. Here we investigate stimulus-secretion coupling in this cell line, and compare it with that in the rat beta cell line, INS-1 832/13, and human islets.Cells were exposed to glucose and pyruvate. Insulin secretion and content (radioimmunoassay, gene expression (Gene Chip array, metabolite levels (GC/MS, respiration (Seahorse XF24 Extracellular Flux Analyzer, glucose utilization (radiometric, lactate release (enzymatic colorimetric, ATP levels (enzymatic bioluminescence and plasma membrane potential and cytoplasmic Ca2+ responses (microfluorometry were measured. Metabolite levels, respiration and insulin secretion were examined in human islets.Glucose increased insulin release, glucose utilization, raised ATP production and respiratory rates in both lines, and pyruvate increased insulin secretion and respiration. EndoC-βH1 cells exhibited higher insulin secretion, while plasma membrane depolarization was attenuated, and neither glucose nor pyruvate induced oscillations in intracellular calcium concentration or plasma membrane potential. Metabolite profiling revealed that glycolytic and TCA-cycle intermediate levels increased in response to glucose in both cell lines, but responses were weaker in EndoC-βH1 cells, similar to those observed in human islets. Respiration in EndoC-βH1 cells was more similar to that in human islets than in INS-1 832/13 cells.Functions associated with early stimulus-secretion coupling, with the exception of plasma membrane potential and Ca2+ oscillations, were similar in the two cell lines; insulin secretion, respiration and metabolite responses were similar in EndoC-βH1 cells and human islets. While both cell lines are suitable in vitro models, with the caveat of replicating key findings in isolated islets, EndoC-βH1 cells have the

  9. UPR in palmitate-treated pancreatic beta-cells is not affected by altering oxidation of the fatty acid

    OpenAIRE

    Sol E-ri; Sargsyan Ernest; Bergsten Peter

    2011-01-01

    Abstract Background Elevated levels of lipids are detrimental for beta-cell function and mass. One of the mechanisms of how fatty acids induce apoptosis is development of the unfolded protein response (UPR). It is still far from understood how fatty acids activate the UPR, however. Methods We examined how palmitate-induced activation of the UPR was affected by altering the metabolism of the fatty acid in insulin-secreting INS-1E and MIN6 cell lines and intact human islets. To increase oxidati...

  10. Abolishing Harrassment.

    Science.gov (United States)

    Bates, Percy; And Others

    1996-01-01

    Although society is more aware of sexual harassment than it was in the past, the problem is not disappearing. Many school children are afraid to talk about it for fear of reprisal and humiliation. The articles in this issue focus on harassment and the schools in the following papers: (1) "Harassment Revisited" (Percy Bates); (2) "Sexual…

  11. Abolishing GDP

    OpenAIRE

    Bergh, van den, H.

    2007-01-01

    Expectations and information about the growth of GDP per capita have a large influence on decisions made by private and public economic agents. It will be argued here that GDP (per capita) is far from a robust indicator of social welfare, and that its use as such must be regarded as a serious form of market and government failure. This article presents an update on the most important criticisms of GDP as an indicator of social welfare and economic progress. It further examines the nature and ...

  12. Abolishing GDP

    NARCIS (Netherlands)

    Bergh, van den Jeroen C.J.M.

    2007-01-01

    Expectations and information about the growth of GDP per capita have a large influence on decisions made by private and public economic agents. It will be argued here that GDP (per capita) is far from a robust indicator of social welfare, and that its use as such must be regarded as a serious form o

  13. Have We Overlooked the Importance of Serine/Threonine Protein Phosphatases in Pancreatic Beta-Cells? Role Played by Protein Phosphatase 2A in Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Esser V

    2005-07-01

    Full Text Available Genetic predisposition and environmental influences insidiously converge to cause glucose intolerance and hyperglycemia. Beta-cell compensates by secreting more insulin and when it fails, overt diabetes mellitus ensues. The need to understand the mechanisms involved in insulin secretion cannot be stressed enough. Phosphorylation of proteins plays an important role in regulating insulin secretion. In order to understand how a particular cellular process is regulated by protein phosphorylation the nature of the protein kinases and protein phosphatases involved and the mechanisms that determine when and where these enzymes are active should be investigated. While the actions of protein kinases have been intensely studied within the beta-cell, less emphasis has been placed on protein phosphatases even though they play an important regulatory role. This review focuses on the importance of protein phosphatase 2A in insulin secretion. Most of the present knowledge on protein phosphatase 2A originates from protein phosphatase inhibitor studies on islets and beta-cell lines. The ability of protein phosphatase 2A to change its activity in the presence of glucose and inhibitors provides clues to its role in regulating insulin secretion. An aggressive approach to elucidate the substrates and mechanisms of action of protein phosphatases is crucial to the understanding of phosphorylation events within the beta-cell. Characterizing protein phosphatase 2A within the beta-cell will certainly help us in understanding the mechanisms involved in insulin secretion and provide valuable information for drug development.

  14. Combined Optical Coherence and Fluorescence Microscopy to assess dynamics and specificity of pancreatic beta-cell tracers.

    Science.gov (United States)

    Berclaz, Corinne; Pache, Christophe; Bouwens, Arno; Szlag, Daniel; Lopez, Antonio; Joosten, Lieke; Ekim, Selen; Brom, Maarten; Gotthardt, Martin; Grapin-Botton, Anne; Lasser, Theo

    2015-01-01

    The identification of a beta-cell tracer is a major quest in diabetes research. However, since MRI, PET and SPECT cannot resolve individual islets, optical techniques are required to assess the specificity of these tracers. We propose to combine Optical Coherence Microscopy (OCM) with fluorescence detection in a single optical platform to facilitate these initial screening steps from cell culture up to living rodents. OCM can image islets and vascularization without any labeling. Thereby, it alleviates the need of both genetically modified mice to detect islets and injection of external dye to reveal vascularization. We characterized Cy5.5-exendin-3, an agonist of glucagon-like peptide 1 receptor (GLP1R), for which other imaging modalities have been used and can serve as a reference. Cultured cells transfected with GLP1R and incubated with Cy5.5-exendin-3 show full tracer internalization. We determined that a dose of 1 μg of Cy5.5-exendin-3 is sufficient to optically detect in vivo the tracer in islets with a high specificity. In a next step, time-lapse OCM imaging was used to monitor the rapid and specific tracer accumulation in murine islets and its persistence over hours. This optical platform represents a versatile toolbox for selecting beta-cell specific markers for diabetes research and future clinical diagnosis. PMID:25988507

  15. Insulin resistance and beta-cell function in different ethnic groups in Kenya: the role of abdominal fat distribution.

    Science.gov (United States)

    Christensen, D L; Faurholt-Jepsen, D; Faerch, K; Mwaniki, D L; Boit, M K; Kilonzo, B; Tetens, I; Friis, H; Borch-Johnsen, K

    2014-02-01

    Little is known about the pathophysiology of diabetes in Africans. Thus, we assessed whether insulin resistance and beta-cell function differed by ethnicity in Kenya and whether differences were modified by abdominal fat distribution. A cross-sectional study in 1,087 rural Luo (n = 361), Kamba (n = 378), and Maasai (n = 348) was conducted. All participants had a standard 75-g oral glucose tolerance test (OGTT). Venous blood samples were collected at 0, 30, and 120 min. Serum insulin was analysed at 0 and 30 min. From the OGTT, we assessed the homoeostasis model assessment of insulin resistance by computer model, early phase insulin secretion, and disposition index (DI) dividing insulin secretion by insulin resistance. Abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) thickness were carried out by ultrasonography. Linear regression analyses were done to assess ethnic differences in insulin indices. The Maasai had 32 and 17% higher insulin resistance than the Luo and Kamba, respectively (p Maasai compared to the Luo (p Maasai compared to the Luo and Kamba, respectively. Adjustments of SAT (range 0.1-7.1 cm) and VAT (range 1.5-14.2 cm) largely explained these inter-group differences with the Maasai having the highest combined abdominal fat accumulation. The Maasai had the highest insulin resistance and secretion, but the lowest relative beta-cell function compared to the Luo and Kamba. These differences were primarily explained by abdominal fat distribution. PMID:23563691

  16. Beta-cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Vølund, Aage;

    2005-01-01

    OBJECTIVE: To obtain a better understanding of the physiological aspects of glucose homeostasis in human immunodeficiency virus (HIV)-infected patients with lipodystrophy, we evaluated separately beta-cell function and insulin sensitivity after an oral glucose load. DESIGN: Beta-cell function was...... diabetes mellitus or impaired glucose tolerance. Prehepatic insulin secretion rates were estimated by deconvolution of C-peptide concentrations. A composite measure of insulin sensitivity was derived from the OGTT. RESULTS: Beta-cell secretory capacity (i.e. the rate of change in insulin secretion per unit...... change in glucose concentration) was similar in lipodystrophic and nonlipodystrophic patients (6.2 +/- 1.0 mU kg(-1) min(-1) mg(-1) dl vs. 5.4 +/- 0.4, P > 0.4), but insulin sensitivity was reduced by 61% in lipodystrophic patients (P < 0.004). The disposition index (insulin capacity multiplied with...

  17. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy;

    2010-01-01

    OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the...... expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed...... cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta...

  18. Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets

    DEFF Research Database (Denmark)

    Maedler, Kathrin; Størling, Joachim; Sturis, Jeppe;

    2004-01-01

    -regulated kinase (ERK) 1/2, an effect that was abrogated by 3 micromol/l NN414. Similarly, 1 micromol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 micromol/l of the l-type Ca(2+) channel blocker nimodipine prevented glucose- and IL-1beta-induced ERK activation, beta......Increasing evidence indicates that a progressive decrease in the functional beta-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, beta-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1beta...... and/or high-glucose-induced beta-cell production of IL-1beta. Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for...

  19. The Effects of an Abolishing Operation Intervention Component on Play Skills, Challenging Behavior, and Stereotypy

    Science.gov (United States)

    Lang, Russell; O'Reilly, Mark; Sigafoos, Jeff; Machalicek, Wendy; Rispoli, Mandy; Lancioni, Giulio E.; Aguilar, Jeannie; Fragale, Christina

    2010-01-01

    The purpose of this study was to reduce stereotypy and challenging behavior during play skills instruction by adding an abolishing operation component (AOC) to the intervention strategy. An alternating treatments design compared one condition in which participants were allowed to engage in stereotypy freely before beginning the play skills…

  20. Selective destruction of mouse islet beta cells by human T lymphocytes in a newly-established humanized type 1 diabetic model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yong, E-mail: yongzhao@uic.edu [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Guo, Chengshan; Hwang, David; Lin, Brian; Dingeldein, Michael; Mihailescu, Dan; Sam, Susan; Sidhwani, Seema [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Zhang, Yongkang [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Jain, Sumit [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Skidgel, Randal A. [Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Prabhakar, Bellur S. [Department of Immunology and Microbiology, University of Illinois at Chicago, Chicago, IL 60612 (United States); Mazzone, Theodore [Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612 (United States); Holterman, Mark J. [Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-09-03

    Research highlights: {yields} Establish a human immune-mediated type 1 diabetic model in NOD-scid IL2r{gamma}{sup null} mice. {yields} Using the irradiated diabetic NOD mouse spleen mononuclear cells as trigger. {yields} The islet {beta} cells were selectively destroyed by infiltrated human T cells. {yields} The model can facilitate translational research to find a cure for type 1 diabetes. -- Abstract: Type 1 diabetes (T1D) is caused by a T cell-mediated autoimmune response that leads to the loss of insulin-producing {beta} cells. The optimal preclinical testing of promising therapies would be aided by a humanized immune-mediated T1D model. We develop this model in NOD-scid IL2r{gamma}{sup null} mice. The selective destruction of pancreatic islet {beta} cells was mediated by human T lymphocytes after an initial trigger was supplied by the injection of irradiated spleen mononuclear cells (SMC) from diabetic nonobese diabetic (NOD) mice. This resulted in severe insulitis, a marked loss of total {beta}-cell mass, and other related phenotypes of T1D. The migration of human T cells to pancreatic islets was controlled by the {beta} cell-produced highly conserved chemokine stromal cell-derived factor 1 (SDF-1) and its receptor C-X-C chemokine receptor (CXCR) 4, as demonstrated by in vivo blocking experiments using antibody to CXCR4. The specificity of humanized T cell-mediated immune responses against islet {beta} cells was generated by the local inflammatory microenvironment in pancreatic islets including human CD4{sup +} T cell infiltration and clonal expansion, and the mouse islet {beta}-cell-derived CD1d-mediated human iNKT activation. The selective destruction of mouse islet {beta} cells by a human T cell-mediated immune response in this humanized T1D model can mimic those observed in T1D patients. This model can provide a valuable tool for translational research into T1D.

  1. Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice

    OpenAIRE

    Bailey, Kathleen A.; Savic, Daniel; Zielinski, Mark; Park, Soo-Young; Wang, Ling-Jia; Witkowski, Piotr; Brady, Matthew; Hara, Manami; Bell, Graeme I.; Nobrega, Marcelo A.

    2014-01-01

    Non-coding variation within TCF7L2 remains the strongest genetic determinant of type 2 diabetes risk in humans. A considerable effort has been placed in understanding the functional roles of TCF7L2 in pancreatic beta cells, despite evidence of TCF7L2 expression in various peripheral tissues important in glucose homeostasis. Here, we use a humanized mouse model overexpressing Tcf7l2, resulting in glucose intolerance, to infer the contribution of Tcf7l2 overexpression in beta cells and in other...

  2. Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation

    DEFF Research Database (Denmark)

    Ravnskjaer, Kim; Boergesen, Michael; Dalgaard, Louise T;

    2006-01-01

    mechanism underlying this transcriptional repression by glucose remains unclear. Here we report that glucose-induced repression of PPARalpha gene expression in INS-1E cells is independent of beta-cell excitation and insulin secretion but requires activation of protein phosphatase 2A in a process involving...... AMPKalpha1 using RNAi suppressed PPARalpha expression, thereby mimicking the effect of glucose. These results indicate that activation of protein phosphatase 2A and subsequent inactivation of AMPK is necessary for glucose repression of PPARalpha expression in pancreatic beta-cells....

  3. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

    DEFF Research Database (Denmark)

    Karlsen, Allan Ertman; Heding, P E; Frobøse, H;

    2004-01-01

    The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

  4. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

    DEFF Research Database (Denmark)

    Neve, Bernadette; Fernandez-Zapico, Martin E; Ashkenazi-Katalan, Vered; Dina, Christian; Hamid, Yasmin H; Joly, Erik; Vaillant, Emmanuel; Benmezroua, Yamina; Durand, Emmanuelle; Bakaher, Nicolas; Delannoy, Valerie; Vaxillaire, Martine; Cook, Tiffany; Dallinga-Thie, Geesje M; Jansen, Hans; Charles, Marie-Aline; Clément, Karine; Galan, Pilar; Hercberg, Serge; Helbecque, Nicole; Charpentier, Guillaume; Prentki, Marc; Hansen, Torben; Pedersen, Oluf; Urrutia, Raul; Melloul, Danielle; Froguel, Philippe

    2005-01-01

    KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first...... time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in...... beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1...

  5. Phantom bursting is highly sensitive to noise and unlikely to account for slow bursting in beta-cells

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram

    2007-01-01

    Pancreatic beta-cells show bursting electrical activity with a wide range of burst periods ranging from a few seconds, often seen in isolated cells, over tens of seconds (medium bursting), usually observed in intact islets, to several minutes. The phantom burster model [Bertram, R., Previte, J...... cells are subjected to stochastic fluctuations in plasma membrane currents, which are likely to disturb the bursting mechanism and transform medium bursters into spikers or very fast bursters. We present a polynomial, minimal, phantom burster model and show that noise modifies the plateau fraction and...... lowers the burst period dramatically in phantom bursters. It is therefore unlikely that slow bursting in single cells is driven by the slow phantom bursting mechanism, but could instead be driven by oscillations in glycolysis, which we show are stable to random ion channel fluctuations. Moreover, so...

  6. Strain-dependent differences in sensitivity of rat beta-cells to interleukin 1 beta in vitro and in vivo

    DEFF Research Database (Denmark)

    Reimers, J I; Andersen, H U; Mauricio, D;

    1996-01-01

    The aim of this study was to investigate whether strain-dependent differences in beta-cell sensitivity to interleukin (IL) 1 beta exist in vitro and in vivo and if so, whether these differences correlate to variations in IL-1 beta-induced islet inducible nitric oxide synthase (iNOS) mRNA expression....../CR) rats were resistant. Furthermore, IL-1 beta induced higher islet iNOS mRNA expression and nitric oxide production from WK/Mol islets compared with BN/CR islets. WK/Mol, WK/CR, BN/Mol, BN/CR, and Lewis-Scripps/Mol (LS/Mol) rats received one daily injection of recombinant human IL-1 beta (4.0 microg...

  7. Structural requirements for galanin interaction with receptors from pancreatic beta cells and from brain tissue of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Lagny-Pourmir, I.; Lorinet, A.M.; Yanaihara, N.; Laburthe, M. (Unite de Recherches sur la Differenciation et la Neuroendocrinologie de Cellules Digestives, Batiment INSERM, Villejuif (France))

    1989-07-01

    The binding activity of several galanin fragments and analogs was measured on specific receptors present in rat brain and the rat pancreatic beta cell line Rin m 5F. In both tissues it was observed that: (1) galanin(3-29), galanin(10-29) and (Ile2)-galanin were ineffective for inhibiting ({sup 125}I) galanin binding and (2) active peptides had the following rank order of potency: galanin(1-29) greater than (Ac-Trp2)-galanin(2-29) greater than galanin(2-29) greater than galanin(1-15) greater than (Phe2)-galanin greater than (Tyr2)-galanin. It was concluded that the N-terminal portion of galanin is very important for interaction with central or peripheral receptors. The aromatic amino acid in position 2 (Trp in native galanin) plays a crucial role.

  8. Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in beta-cell function

    DEFF Research Database (Denmark)

    Andersen, Ove; Haugaard, Steen B; Andersen, Ulrik B;

    2003-01-01

    exhibited impaired insulin secretion (P <.05). Our data suggest that fat redistribution independently of antiretroviral therapy is highly related to insulin resistance in HALS patients. Furthermore, in HALS patients, impaired glucose metabolism most likely relates to decreased NOGM and to defects in beta-cell...... =.006), whereas levels of basal and insulin-stimulated oxidative glucose metabolism (OGM) (2.4 v 2.3, P =.55, and 3.3 v 4.0, P =.064, respectively) were not significantly different between groups. Despite comparable total fat masses, dual energy x-ray absorptiometry (DEXA) scans showed that the...... percentage of limb fat (ie, peripheral-fat-mass/[peripheral-fat-mass + trunk-fat-mass]. 100%) was reduced in HALS patients (36% v 46%, P =.0002). Multiple linear regression analysis indicated that percentage of limb fat explained 53% of the variability of GDR and 45% of the variability of NOGM in HALS...

  9. Effects of Chinese medicine Tongxinluo on hyperglycemia and beta-cell damage in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    WANG Huai-qing; ZOU Jun-jie; ZHOU Xiang-hai; JI Li-nong; LIU Zhi-min

    2012-01-01

    Background Oxidative stress has been implicated in the onset and progression of diabetes.Tongxinluo is a traditional Chinese medicine with potent antioxidant properties.The aim of this study was to test the hypothesis that pretreatment with Tongxinluo has similar effects as melatonin on preventing hyperglycemia and beta-cell damage in a rat model of streptozotocin (STZ)-induced diabetes.Methods Forty male Sprague Dawley rats were randomly assigned to four groups (n=10 each):normal control (NC)group; STZ group (70 mg/kg,i.p.); Tongxinluo (1.0 g·kg-1·d-1) pretreated (TXL+STZ) group and melatonin (200μg·kg-1·d-1) pretreated (MLT+STZ) group.Tongxinluo and melatonin were administered by gavage beginning 8 days before STZ injection and continuing until the end of the study (15 days after STZ administration).Blood glucose levels and body weights, malondialdehyde (MDA),and reduced glutathione (GSH) levels were measured,and immunofluorescence studies were performed in all of the groups.Results Pretreatment with Tongxinluo,as with melatonin,attenuated severe hyperglycemia and weight loss induced by STZ.In pancreatic homogenates,MDA levels were significantly lower and GSH levels were significantly higher in Tongxinluo pretreated group and in melatonin pretreated group than those in STZ group.Values of insulin staining were significantly improved in Tongxinluo pretreated group and in melatonin pretreated group as compared with those in STZ group.Conclusions Tongxinluo,as melatonin,prevented hyperglycemia and beta-cell destruction induced by STZ in rats through reducing oxidative stress in pancreatic tissues.Tongxinluo may provide an alternative therapy for the prevention and treatment of diabetes.

  10. Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis

    Science.gov (United States)

    Fridlyand, Leonid E.; Philipson, Louis H.

    2016-01-01

    Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger

  11. 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

    NARCIS (Netherlands)

    Lundh, M.; Christensen, D.P.; Damgaard Nielsen, M.; Richardson, S.J.; Dahllof, M.S.; Skovgaard, T.; Berthelsen, J.; Dinarello, C.A.; Stevenazzi, A.; Mascagni, P.; Grunnet, L.G.; Morgan, N.G.; Mandrup-Poulsen, T.

    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 mediat

  12. The bimodal effect of interleukin 1 on rat pancreatic beta-cells--stimulation followed by inhibition--depends upon dose, duration of exposure, and ambient glucose concentration

    DEFF Research Database (Denmark)

    Spinas, G A; Palmer, J P; Mandrup-Poulsen, T;

    1988-01-01

    220% at 3.3 mmol/l glucose, but at 11 mmol/l glucose a 60% suppression was seen. On the basis of these data we suggest that interleukin 1's effect on beta-cells is bimodal: stimulation followed by inhibition. Increasing interleukin 1 dose and ambient glucose concentration shift this response to the...

  13. Pancreatic beta-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia V; Deacon, Carolyn F;

    2010-01-01

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...

  14. Differences in beta-cell function and insulin secretion in Black vs. White obese adolescents: Do incretin hormones play a role?

    Science.gov (United States)

    Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated beta-cell function and insulin hypersecretion, in response to intravenous (IV) glucose, compared with Whites. T...

  15. Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim / Mcl-1 imbalance.

    Directory of Open Access Journals (Sweden)

    Maikel L Colli

    2011-09-01

    Full Text Available The rise in type 1 diabetes (T1D incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA and a diabetogenic enterovirus (Coxsackievirus B5. Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1. Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.

  16. Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

    DEFF Research Database (Denmark)

    Størling, J; Binzer, J; Andersson, Annica; Züllig, R A; Tonnesen, M; Knudsen, René Lehmann Pulz; Spinas, G A; Sandler, S; Billestrup, N; Mandrup-Poulsen, Thomas

    2005-01-01

    Pro-inflammatory cytokines cause beta cell secretory dysfunction and apoptosis--a process implicated in the pathogenesis of type 1 diabetes. Cytokines induce the expression of inducible nitric oxide (NO) synthase (iNOS) leading to NO production. NO contributes to cytokine-induced apoptosis, but t...

  17. Cytosolic triglycerides and oxidative stress in central obesity : the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure?

    NARCIS (Netherlands)

    Bakker, SJL; IJzerman, RG; Teerlink, T; Westerhoff, HV; Gans, ROB; Heine, RJ

    2000-01-01

    Central obesity is increasingly recognized as a risk factor for atherosclerosis and type 2 diabetes mellitus. Here we present a hypothesis that may explain the excess atherosclerosis, endothelial dysfunction and progressive beta-cell failure. Central obesity is associated with increased cytosolic tr

  18. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Fisher, James P; Young, Colin N;

    2010-01-01

    Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebr...... abolished by glycopyrrolate (P <0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen....

  19. Why we must abolish nuclear weapons after the end of the Cold War

    International Nuclear Information System (INIS)

    The end of the Cold War has offered a great opportunity to reduce or even abolish nuclear weapons, but the international community seemed to lose interest in nuclear weapons issues. Today, however, there are a lot of other major menaces to the survival of the mankind: pollution, hunger, poverty, ethnic conflicts. So the nuclear weapons issue is merely one of the most pressing threats to survival

  20. Allosuppressor T lymphocytes abolish migration inhibition factor production in autoimmune thyroid disease: evidence from radiosensitivity experiments

    International Nuclear Information System (INIS)

    The ability of normal T lymphocytes to abolish the production of migration inhibition factor by antigen-sensitized T lymphocytes of Graves' disease (GD) and Hashimoto's thyroiditis (HT) in response to thyroid antigen has been studied by a modified migration inhibition factor test using isolated T lymphocytes alone. The production of migration inhibition factor was consistently abolished when normal T lymphocytes were mixed with GD or HT T lymphocytes in various ratios (1:9, 2:8, 5:5) as reported previously (Okita et al., 1980b). However, prior in-vitro irradiation (1000 rad) of the normal T lymphocytes resulted in loss of their ability to abolish migration inhibition factor production by the antigen-sensitized T lymphocytes of GD and HT. The effect is consistent with the radiosensitivity of suppressor T lymphocytes and indicates that the effect of normal T lymphocytes on GD and HT T lymphocytes is one of allosuppression. The results support the view that there is a defect in suppressor T cell function in GD and HT. (author)

  1. Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage

    Directory of Open Access Journals (Sweden)

    Mansouri Ahmed

    2011-08-01

    Full Text Available Abstract Background Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented. Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata. Hence in order to precise the functional link between both factors we performed a comparative analysis of Nkx2.2/Arx single- and double-mutants but also of Pax6-deficient animals. Results We show that most of the ghrelin+ cells emerging in pancreata of Nkx2.2- and Pax6-deficient mice, express the alpha-cell specifier Arx, but also additional beta-cell related genes. In Nkx2.2-deficient mice, Arx directly co-localizes with iAPP, PC1/3 and Pdx1 suggesting an Nkx2.2-dependent control of Arx in committed beta-cells. The combined loss of Nkx2.2 and Arx likewise results in the formation of a hyperplastic ghrelin+ cell population at the expense of mature alpha- and beta-cells. Surprisingly, such Nkx2.2-/-Arx- ghrelin+ cells also express the somatostatin hormone. Conclusions Our data indicate that Nkx2.2 acts by reinforcing the transcriptional networks initiated by Pax4 and Arx in early committed beta- and alpha-cell, respectively. Our analysis also suggests that one of the coupled functions of Nkx2.2 and Pax4 is to counteract Arx gene activity in early committed beta-cells.

  2. The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion.

    Directory of Open Access Journals (Sweden)

    Robert Spinnler

    Full Text Available AIMS/HYPOTHESIS: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt and its enzymatic product Nicotinamide mononucleotide (NMN, which has been associated with obesity and type 2 diabetes mellitus (T2DM directly influence beta-cell survival and function. METHODS: The effect of Nampt and NMN on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product NMN on insulin secretion were assessed by glucose stimulated insulin secretion in human islets. RESULTS: While stimulation of beta-cells with the cytokines IL-1β, TNFα and IFN-γ or palmitate significantly decreased viability, Nampt and NMN showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines. At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1 h incubation of human islets. CONCLUSION/INTERPRETATION: Nampt and NMN neither influenced beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion.

  3. Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes

    OpenAIRE

    Shields, Emily J.; Lam, Carol J.; Cox, Aaron R.; Rankin, Matthew M.; Van Winkle, Thomas J.; Hess, Rebecka S.; Kushner, Jake A.

    2015-01-01

    The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been prop...

  4. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    Directory of Open Access Journals (Sweden)

    Jurczyk A

    2013-12-01

    Full Text Available Agata Jurczyk,1 Philip diIorio,1 Dean Brostowin,1 Linda Leehy,1 Chaoxing Yang,1 Fumihiko Urano,2 David M Harlan,3 Leonard D Shultz,4 Dale L Greiner,1 Rita Bortell1 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Washington University School of Medicine, St Louis, MO, 3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 4The Jackson Laboratory, Bar Harbor, ME, USA Purpose: Dipeptidyl-peptidase-4 (DPP-4 inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Methods: Streptozotocin-induced diabetic NOD-scid IL2rγnull (NSG mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU incorporation. Results: Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Conclusion: Human islet-engrafted immunodeficient mice

  5. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes.

    Directory of Open Access Journals (Sweden)

    Yaiza Diaz-de-Durana

    Full Text Available Type-1 diabetes (T1D is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2 therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease

  6. Extracellular ATP stimulates exocytosis via localized Ca(2+) release from acidic stores in rat pancreatic beta cells.

    Science.gov (United States)

    Xie, Li; Zhang, Ming; Zhou, Wei; Wu, Zhengxing; Ding, Jiuping; Chen, Liangyi; Xu, Tao

    2006-04-01

    Three different methods, membrane capacitance (C(m)) measurement, amperometry and FM dye labeling were used to investigate the role of extracellular ATP in insulin secretion from rat pancreatic beta cells. We found that extracellular application of ATP mobilized intracellular Ca(2+) stores and synchronously triggered vigorous exocytosis. No influence of ATP on the readily releasable pool of vesicles was observed, which argues against a direct modulation of the secretory machinery at a level downstream of Ca(2+) elevation. The stimulatory effects of ATP were greatly reduced by intracellular perfusion of BAPTA but not EGTA, suggesting a close spatial association of fusion sites with intracellular Ca(2+) releasing sites. ATP-induced Ca(2+) transients and exocytosis were not blocked by thapsigargin (TG), by a ryanodine receptor antagonist or by dissipation of pH in acidic stores by monensin alone, but they were greatly attenuated by IP(3) receptor inhibition as well as ionomycin plus monensin, suggesting involvement of IP(3)-sensitive acidic Ca(2+) stores. Taken together, our data suggest that extracellular ATP triggers exocytosis by mobilizing spatially limited acidic Ca(2+) stores through IP(3) receptors. This mechanism may explain how insulin secretion from the pancreas is coordinated through diffusible ATP that is co-released with insulin. PMID:16536741

  7. Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity

    DEFF Research Database (Denmark)

    Bonfils, Linéa; Ellervik, Christina; Friedrich, Nele;

    2015-01-01

    Aims/hypothesis: Elevated serum ferritin levels are associated with an increased risk of type 2 diabetes, but the nature of this association remains elusive. The aim of this study was to test the hypothesis that an elevated fasting serum ferritin level is associated with an increased risk of type 2...... OGTT examinations. Results: The ORs for type 2 diabetes were 4.2 (95% CI 2.4, 7.2) for the highest vs the lowest quintile of serum ferritin, and 17 (95% CI 8.9, 33) for serum ferritin levels ≥97.5th percentile vs <20th percentile. Elevated serum ferritin levels were associated with elevated plasma...... glucose levels at 0, 30 and 120 min (p < 0.001), elevated serum insulin levels at 0 and 120 min (p = 0.02 and p < 0.001), decreased beta cell function estimated as the insulinogenic index and corrected insulin response (p < 0.001), and decreased insulin sensitivity estimated by the Matsuda index of...

  8. Mill, Gender Ideal and Gender Oppression: Do Feminists Need to Abolish Gender Roles?

    OpenAIRE

    Popa, Bogdan

    2011-01-01

    While feminist scholarship generally looks at Mill’s ambiguities as confusions or flaws, I suggest that Mill’s ambivalence has to be taken at face value by feminist theory.Many feminists – and particularly liberal feminists- feel that human beings cannot develop their true potential until they would live in a society where men and women have complete equality. One solution to this problem is to abolish gender roles, or to value social and legal norms because they promote gender neutrality. Be...

  9. Serine substitution for cysteine residues in levansucrase selectively abolishes levan forming activity.

    Science.gov (United States)

    Senthilkumar, Velusamy; Busby, Stephen J W; Gunasekaran, Paramasamy; Senthikumar, Velusamy; Bushby, Stephen J W

    2003-10-01

    Levansucrase is responsible for levan formation during sucrose fermentation of Zymomonas mobilis, and this decreases the efficiency of ethanol production. As thiol modifying agents decrease levan formation, a role for cysteine residues in levansucrase activity has been examined using derivatives of Z. mobilis levansucrase that carry serine substitutions of cysteine at positions 121, 151 or 244. These substitutions abolished the levan forming activity of levansucrase whilst only halving its activity in sucrose hydrolysis. Thus, polymerase and hydrolase activities of Z. mobilis levansucrase are separate and have different requirements for the enzyme's cysteine residues. PMID:14584923

  10. Abolished synthesis of cholic acid reduces atherosclerotic development in apolipoprotein E knockout mice[S

    OpenAIRE

    Slätis, Katharina; Gåfvels, Mats; Kannisto, Kristina; Ovchinnikova, Olga; Paulsson-Berne, Gabrielle; Parini, Paolo; Jiang, Zhao-Yan; Eggertsen, Gösta

    2010-01-01

    To investigate the effects of abolished cholic acid (CA) synthesis in the ApoE knockout model [apolipoprotein E (apoE) KO],a double-knockout (DKO) mouse model was created by crossbreeding Cyp8b1 knockout mice (Cyp8b1 KO), unable to synthesize the primary bile acid CA, with apoE KO mice. After 5 months of cholesterol feeding, the development of atherosclerotic plaques in the proximal aorta was 50% less in the DKO mice compared with the apoE KO mice. This effect was associated with reduced inte...

  11. Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells

    DEFF Research Database (Denmark)

    Ortis, F; Pirot, P; Naamane, N; Kreins, A Y; Rasschaert, J; Moore, F; Théâtre, E; Verhaeghe, C; Magnusson, N E; Chariot, A; Orntoft, T F; Eizirik, D L

    2008-01-01

    AIMS/HYPOTHESIS: IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN......: Blocking NF-kappaB activation protected beta cells against IL-1beta + IFNgamma- or TNFalpha + IFNgamma-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-alpha- or IL-1beta-induced beta cell death, in line with the observations that cytokines induced the expression of the anti...

  12. GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim.

    OpenAIRE

    Nogueira, Tatiane C; Paula, Flavia M; Olatz Villate; Colli, Maikel L.; Moura, Rodrigo F.; Daniel A Cunha; Lorella Marselli; Piero Marchetti; Miriam Cnop; Cécile Julier; Eizirik, Decio L.

    2013-01-01

    Mutations in human Gli-similar (GLIS) 3 protein cause neonatal diabetes. The GLIS3 gene region has also been identified as a susceptibility risk locus for both type 1 and type 2 diabetes. GLIS3 plays a role in the generation of pancreatic beta cells and in insulin gene expression, but there is no information on the role of this gene on beta cell viability and/or susceptibility to immune- and metabolic-induced stress. GLIS3 knockdown (KD) in INS-1E cells, primary FACS-purified rat beta cells, ...

  13. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming; Holst, Jens Juul; Storgaard, Heidi; Fenger, Mogens; Iversen, Johan; Madsbad, Sten

    2005-01-01

    glucose metabolism, lipid metabolism and beta-cell function in lipodystrophic HIV-infected patients. METHODS: [3-3H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO......), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio...... of limb to trunk fat (RLF; > 34%, P < 0.001), hepatic insulin sensitivity (> 40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free...

  14. Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass

    DEFF Research Database (Denmark)

    Larsen, Marianne Olholm; Rolin, Bidda; Ribel, Ulla; Wilken, Michael; Deacon, Carolyn F; Svendsen, Ove; Gotfredsen, Carsten F; Carr, Richard David

    2003-01-01

    for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect...... levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral......; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass....

  15. Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

    DEFF Research Database (Denmark)

    Frigerio, F; Brun, T; Bartley, C;

    2009-01-01

    upregulation preserved glucose-stimulated insulin secretion, essentially by increasing the response at a stimulatory concentration of glucose (15 mmol/l), a protection we also observed in human islets. The protective effect was associated with restored glucose oxidation rate and upregulation of the anaplerotic......AIMS/HYPOTHESIS: Pancreatic beta cells chronically exposed to fatty acids may lose specific functions and even undergo apoptosis. Generally, lipotoxicity is triggered by saturated fatty acids, whereas unsaturated fatty acids induce lipodysfunction, the latter being characterised by elevated basal...... insulin release and impaired glucose responses. The peroxisome proliferator-activated receptor alpha (PPARalpha) has been proposed to play a protective role in this process, although the cellular mechanisms involved are unclear. METHODS: We modulated PPARalpha production in INS-1E beta cells and...

  16. Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes.

    Directory of Open Access Journals (Sweden)

    Emily J Shields

    Full Text Available The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated β-cell destruction. It remains unclear to what extent β-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in β-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of β-cells. Very few β-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme β-cell deficiency in both new and longstanding disease. The β-cell predominant composition of canine islets and the near-total absence of β-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, β-cell loss underlies the pathophysiology of canine diabetes.

  17. Intrathecal noradrenaline restores 5-methoxy-N,N-dimethyltryptamine induced antinociception abolished by intrathecal 6-hydroxydopamine.

    Science.gov (United States)

    Minor, B G; Persson, M L; Post, C; Jonsson, G; Archer, T

    1988-01-01

    Intrathecal administration of 6-hydroxydopamine (6-OHDA) abolished the antinociceptive effects of acute administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 1 mg/kg, s.c.) in the hot-plate, tail-flick and shock titration tests of nociception. The antinociceptive effects of 5-MeODMT, abolished by the prior intrathecal 6-OHDA treatment, were restored by intrathecal administration (2 or 1 microgram) of noradrenaline (NA), immediately prior to 5-MeODMT, in all three tests of nociception. Biochemical analysis confirmed severe NA depletions (95 percent loss) in the lumbar and thoracic regions of the spinal and much lesser dopamine depletions (25-35 percent loss). Intrathecal 5,7-dihydroxytryptamine (5,7-DHT) attenuated 5-MeODMT induced antinociception in the tail-flick test and combined NA + 5-MeODMT induced antinociception in the hot-plate and tail-flick tests. Intrathecal administration of 5,7-DHT caused a severe depletion of 5-hydroxytryptamine in the lumbar region of the spinal cord. The present findings demonstrate further the modulatory role of NA upon serotonergic systems in nociception and indicate the necessity of NA availability for induction of 5-MeODMT analgesia. PMID:3133452

  18. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    International Nuclear Information System (INIS)

    Highlights: •PET images showed high uptake of 68Ga-DOTA-octreotide in the normal pancreas. •68Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of 68Ga-DOTA-octreotide was decreased in the diabetic rats. •68Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with 68Gallium (68Ga). After intravenous injection of 68Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that 68Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of 68Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with 68Ga-DOTA-octreotide could be a potential tool for evaluating BCM

  19. Improved pancreatic beta-cell function in type 2 diabetic patients after lifestyle-induced weight loss is related to glucose-dependent insulinotropic polypeptide

    DEFF Research Database (Denmark)

    Solomon, Thomas; Haus, Jacob M; Kelly, Karen R; Rocco, Michael; Kashyap, Sangeeta R; Kirwan, John P

    2010-01-01

    Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in beta-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion...... in type 2 diabetes have also not been examined but may involve the incretin axis....

  20. Parameters Measuring Beta-Cell Function Are Only Valuable in Diabetic Subjects with Low Body Mass Index, High Blood Glucose Level, or Long-Standing Diabetes

    OpenAIRE

    Lee, Seung Won; Lee, Sangheun; Kim, Se Hwa; Kim, Tae Ho; Kang, Byung Soo; Yoo, Seung Hoon; Lee, Min Kyung; Koh, Won Jun; Kang, Won Sik; Kim, Hyeong Jin

    2011-01-01

    Purpose The aim of this study was to identify the most precise and clinically practicable parameters that predict future oral hypoglycemic agent (OHA) failure in patients with type 2 diabetes, and to determine whether these parameters are valuable in various subgroups. Materials and Methods We took fasting blood samples from 231 patients for laboratory data and standard breakfast tests for evaluation of pancreatic beta-cell function. Hemoglobin A1c (HbA1c) levels were tested, and we collected...

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

    Directory of Open Access Journals (Sweden)

    Nan Sook Lee

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

  2. Activation of PPAR{delta} up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic {beta}-cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Jun; Jiang, Li; Lue, Qingguo; Ke, Linqiu [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China); Li, Xiaoyu [State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, Sichuan 610041 (China); Tong, Nanwei, E-mail: buddyjun@hotmail.com [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China)

    2010-01-15

    Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic {beta}-cells. After HIT-T15 cells (a {beta}-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR{delta}), we found that administration of GW increased the expression of PPAR{delta} mRNA. GW-induced activation of PPAR{delta} up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR{delta} plays an important role in protecting pancreatic {beta}-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

  3. Beta-cell function is associated with metabolic syndrome in Mexican subjects

    Directory of Open Access Journals (Sweden)

    Blanca G Baez-Duarte

    2010-08-01

    Full Text Available Blanca G Baez-Duarte1,3, María Del Carmen Sánchez-Guillén3†, Ricardo Pérez-Fuentes2,3, Irma Zamora-Ginez1,3, Bertha Alicia Leon-Chavez1, Cristina Revilla-Monsalve4, Sergio Islas-Andrade41Posgrado en Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, México; 2Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, México; 3Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Atlixco, Puebla, México; 4Multidiciplinary Research Group on Diabetes (José Sánchez-Corona, Fernando Guerrero-Romero, Martha Rodriguez-Moran, Agustin Madero, Jorge Escobedo-de-la-Peña, Silvia Flores-Martinez, Esperanza, Martinez-Abundis, Manuel Gonzalez-Ortiz, Alberto Rascon-Pacheco, Margarita Torres-Tamayo, Instituto Mexicano del Seguro Social, México, Distrito Federal, México; †María Del Carmen Sánchez-Guillén passed away on 27 November 2009.Aims: The clinical diagnosis of metabolic syndrome does not find any parameters to evaluate the insulin sensitivity (IS or β-cell function. The evaluation of these parameters would detect early risk of developing metabolic syndrome. The aim of this study is to determine the relationship between β-cell function and presence of metabolic syndrome in Mexican subjects.Material and methods: This study is part of the Mexican Survey on the Prevention of Diabetes (MexDiab Study with headquarters in the city of Puebla, Mexico. The study comprised of 444 subjects of both genders, aged between 18 and 60 years and allocated into two study groups: (1 control group of individuals at metabolic balance without metabolic syndrome and (2 group composed of subjects with metabolic syndrome and diagnosed according to the criteria of the Third Report of the National Cholesterol Education Program Expert Panel on Defection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Anthropometric, biochemical, and clinical assessments were carried out.Results: Average age of the

  4. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice

    OpenAIRE

    Mustroph, M.L.; Merritt, J R; Holloway, A.L.; Pinardo, H.; Miller, D S; Kilby, C.N.; Bucko, P.; Wyer, A.; Rhodes, J S

    2014-01-01

    Recent evidence suggests wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesized to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without ...

  5. Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function.

    Directory of Open Access Journals (Sweden)

    Harald Staiger

    Full Text Available BACKGROUND: Very recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs covering 100% of common genetic variation (minor allele frequency > 0.05 within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638. In a subgroup (N = 513, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301, glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p < 0.0001 and reduced OGTT- and IVGTT-induced insulin release (p < or = 0.0007 and p < or = 0.01, respectively. By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p < or = 0.0002, respectively. Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p < or = 0.0021. None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion. CONCLUSIONS/SIGNIFICANCE: In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on beta-cell

  6. Lipodystrophy in human immunodeficiency virus patients impairs insulin action and induces defects in beta-cell function.

    Science.gov (United States)

    Andersen, Ove; Haugaard, Steen B; Andersen, Ulrik B; Friis-Møller, Nina; Storgaard, Heidi; Vølund, Aage; Nielsen, Jens Ole; Iversen, Johan; Madsbad, Sten

    2003-10-01

    The pathophysiology of insulin resistance in human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is not fully clarified. We investigated 18 men with HALS and 18 HIV-positive males without lipodystrophy (control subjects). Duration and modality of antiretroviral therapy were similar between study groups. A hyperinsulinemic euglycemic clamp showed an impaired glucose disposal rate (GDR) in HALS patients (5.6 v 8.3 mg glucose/min. kg(FFM), P =.0006). As demonstrated by indirect calorimetry, HALS patients showed an impaired nonoxidative glucose metabolism (NOGM, 2.2 v 4.2, P =.006), whereas levels of basal and insulin-stimulated oxidative glucose metabolism (OGM) (2.4 v 2.3, P =.55, and 3.3 v 4.0, P =.064, respectively) were not significantly different between groups. Despite comparable total fat masses, dual energy x-ray absorptiometry (DEXA) scans showed that the percentage of limb fat (ie, peripheral-fat-mass/[peripheral-fat-mass + trunk-fat-mass]. 100%) was reduced in HALS patients (36% v 46%, P =.0002). Multiple linear regression analysis indicated that percentage of limb fat explained 53% of the variability of GDR and 45% of the variability of NOGM in HALS patients. In HALS patients, leg fat mass correlated positively with NOGM (r =.51, P <.05), whereas abdominal fat mass and NOGM did not correlate (P =.91). Analyzing the relationship between first phase insulin secretion and insulin sensitivity, 6 HALS patients compared with none of the control subjects exhibited impaired insulin secretion (P <.05). Our data suggest that fat redistribution independently of antiretroviral therapy is highly related to insulin resistance in HALS patients. Furthermore, in HALS patients, impaired glucose metabolism most likely relates to decreased NOGM and to defects in beta-cell function. PMID:14564688

  7. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells

    DEFF Research Database (Denmark)

    Cardozo, Alessandra K; Ortis, Fernanda; Storling, Joachim;

    2005-01-01

    , beta-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER Ca(2+) depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol......Cytokines and free radicals are mediators of beta-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1beta (IL-1beta) + gamma-interferon (IFN-gamma) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic beta-cells. We have previously shown, by...... microarray analysis of primary beta-cells, that IL-1beta + IFN-gamma decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump Ca(2+) ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress-related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding...

  8. Islamic movement and human rights: Pertubuhan Jamaah Islah Malaysia’s involvement in the “Abolish Internal Security Act Movement,” 2000-2012

    Directory of Open Access Journals (Sweden)

    Maszlee Malik

    2014-12-01

    Full Text Available Human rights has been acknowledged as one of the essential characteristics of good governance. Abuse of human rights is strongly associated with bad governance, which is believed by many to be a serious impediment to development and sustainable growth. Despite the active participations of Islamic movements in many parts of the political world, very little is known of their involvement in advocating human rights issues as part of their struggle for power. Nevertheless, as an Islamic movement and an Islamic revivalism actor in Malaysia, Pertubuhan Jamaah Islah Malaysia (JIM has shown otherwise. JIM has resembled a different attitude towards the issue of human rights that they believe as an integrated and pertinent composition of good governance. By scrutinising their political activities and discourse since 2000, it becomes clear that JIM has been actively engaged in good governance and human rights issues, especially those that relate to the political rights of citizens through its involvement in the Abolish Internal Security Act (ISA Movement (Gerakan Mansuhkan ISA. This paper examines JIM’s involvement in human rights issues with a special focus on its active and leading role in calling for the abolishment of the Internal Security Act (ISA.

  9. Recent advances in the Okamoto model: the CD38-cyclic ADP-ribose signal system and the regenerating gene protein (Reg)-Reg receptor system in beta-cells.

    Science.gov (United States)

    Okamoto, Hiroshi; Takasawa, Shin

    2002-12-01

    Twenty years ago, we first proposed our hypothesis on beta-cell damage and its prevention (the Okamoto model), according to which poly(ADP-ribose) synthetase/polymerase (PARP) activation is critically involved in the consumption of NAD(+), leading to energy depletion and cell death by necrosis. Recently, the model was reconfirmed by results using PARP knockout mice and has been recognized as providing the basis for necrotic death of various cells and tissues. Based on the model, we proposed two signal systems in beta-cells: one is the CD38-cyclic ADP-ribose (cADPR) signal system for insulin secretion, and the other is the regenerating gene protein (Reg)-Reg receptor system for beta-cell regeneration. The physiological and pathological significance of the two signal systems in a variety of cells and tissues as well as in pancreatic beta-cells has recently been recognized. Here, we describe the Okamoto model and its descendents, the CD38-cADPR signal system and the Reg-Reg receptor system, focusing on recent advances and how their significance came to light. Because PARP is involved in Reg gene transcription to induce beta-cell regeneration, and the PARP activation reduces the cellular NAD(+) to decrease the formation of cADPR (a second messenger for insulin secretion) and further to cause necrotic beta-cell death, PARP and its inhibitors have key roles in the induction of beta-cell regeneration, the maintenance of insulin secretion, and the prevention of beta-cell death. PMID:12475791

  10. Abolished ventilation and perfusion of lung caused by blood clot in the left main bronchus

    DEFF Research Database (Denmark)

    Afzelius, P; Bergmann, A; Henriksen, J H

    2015-01-01

    It is generally assumed that the lungs possess arterial autoregulation associated with bronchial obstruction. A patient with pneumonia and congestive heart failure unexpectedly developed frequent haemoptysis. High-resolution CT and diagnostic CT were performed as well as ventilation/perfusion (V....../Q) scintigraphy with single-photon emission CT (SPECT)/CT. V/Q SPECT/CT demonstrated abolished ventilation due to obstruction of the left main bronchus and markedly reduced perfusion of the entire left lung, a condition that was completely reversed after removal of a blood clot. We present the first pictorially...... documented case of hypoxia-induced pulmonary vasoconstriction and flow shift in a main pulmonary artery due to a complete intrinsic obstruction of the ipsilateral main bronchus. The condition is reversible, contingent on being relieved within a few days....

  11. Indonesia’s Regional Anti-Corruption Courts: Should They Be Abolished?

    Directory of Open Access Journals (Sweden)

    Simon Butt

    2012-05-01

    Full Text Available Indonesia’s regional anti-corruption courts have been criticised in recent times for perceived impropriety and for acquitting defendants. Senior jurists and politicians have called for these courts to be abolished or recentralised. This article suggests that neither abolition nor recentralisation is prudent and that these criticisms might not be supported by available case statistics. In any event, this article argues, acquittal rates are very poor indicators of judicial performance. Indeed, acquittals might be legally correct, or even necessary, in some cases. More resources should be allocated to these courts, and to the Corruption Eradication Commission so that it can investigate and prosecute more cases in Indonesia’s regions.

  12. Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Fisher, James P; Young, Colin N; Hartwich, Doreen; Ogoh, Shigehiko; Raven, Peter B; Fadel, Paul J; Secher, Niels H

    2010-01-01

    Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral......) (P <0.01) and cardiac output by approximately 40% (P <0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate...... abolished by glycopyrrolate (P <0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen....

  13. The influence of maternal islet beta-cell autoantibodies in conjunction with gestational hyperglycemia on neonatal outcomes.

    Directory of Open Access Journals (Sweden)

    Zhe Li

    Full Text Available To determine the predictive value of the presence of maternal islet beta-cell autoantibodies with respect to neonatal outcomes.A total of 311 pregnant women with abnormal 75 g oral glucose tolerance test (OGTT results were enrolled in this study. Maternal glutamic acid decarboxylase autoantibodies (GADA, islet cell autoantibodies (ICA and insulin autoantibodies (IAA were tested in fasting blood both on the day following the routine OGTT and before delivery. The birth weight, Apgar score, blood glucose and outcomes of each neonate were later evaluated and recorded.1. In this study, 33.9% of the pregnant women with gestational hyperglycemia had detectable levels of one or more types of anti-islet cell antibodies in the third trimester. The proportion of women who produced GADA and/or ICA was significantly higher in the group of women with gestational hyperglycemia than in the control group (P<0.05. The groups similarly differed in the proportion of women who tested positive for any anti-islet cell antibody (P<0.05. 2. Of the patients in our study, those who produced GADA exhibited an increase in uterine and umbilical arterial pulsatility indexes (PIs during the third trimesters compared with the control group (P˂0.05. Additionally, an increased frequency of fetal growth restriction (FGR was observed in the infants of women who produced IAA during pregnancy compared with those without autoantibodies (P˂0.05. 3. The rate of newborn admission to the neonatal intensive care unit (NICU was significantly associated with the presence of maternal ICA during the third trimester (OR, 6.36; 95% CI, 1.22-33.26. 4. The incidence of neonatal asphyxia was associated with the presence of maternal GADA in both the second (OR, 10.44; 95% CI, 1.46-74.92 and the third (OR, 8.33; 95% CI, 1.45-47.82 trimesters.Approximately one-third of the women with gestational hyperglycemia produced anti-islet cell antibodies. The incidence of FGR was higher in women with

  14. Improvement of cellulose catabolism in Clostridium cellulolyticum by sporulation abolishment and carbon alleviation

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yongchao [ORNL; Xu, Tao [University of Oklahoma, Norman; Tschaplinski, Timothy J [ORNL; Engle, Nancy L [ORNL; Graham, David E [ORNL; He, Zhili [University of Oklahoma, Norman; Zhou, Jizhong [University of Oklahoma, Norman

    2014-01-01

    Background Clostridium cellulolyticum can degrade lignocellulosic biomass, and ferment the soluble sugars to produce valuable chemicals such as lactate, acetate, ethanol and hydrogen. However, the cellulose utilization efficiency of C. cellulolyticum still remains very low, impeding its application in consolidated bioprocessing for biofuels production. In this study, two metabolic engineering strategies were exploited to improve cellulose utilization efficiency, including sporulation abolishment and carbon overload alleviation. Results The spo0A gene at locus Ccel_1894, which encodes a master sporulation regulator was inactivated. The spo0A mutant abolished the sporulation ability. In a high concentration of cellulose (50 g/l), the performance of the spo0A mutant increased dramatically in terms of maximum growth, final concentrations of three major metabolic products, and cellulose catabolism. The microarray and gas chromatography mass spectrometry (GC-MS) analyses showed that the valine, leucine and isoleucine biosynthesis pathways were up-regulated in the spo0A mutant. Based on this information, a partial isobutanol producing pathway modified from valine biosynthesis was introduced into C. cellulolyticum strains to further increase cellulose consumption by alleviating excessive carbon load. The introduction of this synthetic pathway to the wild-type strain improved cellulose consumption from 17.6 g/l to 28.7 g/l with a production of 0.42 g/l isobutanol in the 50 g/l cellulose medium. However, the spo0A mutant strain did not appreciably benefit from introduction of this synthetic pathway and the cellulose utilization efficiency did not further increase. A technical highlight in this study was that an in vivo promoter strength evaluation protocol was developed using anaerobic fluorescent protein and flow cytometry for C. cellulolyticum. Conclusions In this study, we inactivated the spo0A gene and introduced a heterologous synthetic pathway to manipulate the stress

  15. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    Energy Technology Data Exchange (ETDEWEB)

    Puddu, A., E-mail: alep100@hotmail.com [University of Genova, Department of Internal Medicine and Medical Specialties, Viale Benedetto XV, 16132 Genova (Italy); Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L. [University of Genova, Department of Internal Medicine and Medical Specialties, Viale Benedetto XV, 16132 Genova (Italy)

    2010-07-30

    Research highlights: {yields} GLP-1 prevents AGEs-induced cell death. {yields} GLP-1 prevents AGEs-induced oxidative stress. {yields} GLP-1 ameliorated AGEs-induced cell dysfunction. {yields} GLP-1 attenuates AGEs-induced RAGE increment. {yields} GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  16. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    International Nuclear Information System (INIS)

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  17. Carriers of loss-of-function mutations in EXT display impaired pancreatic beta-cell reserve due to smaller pancreas volume.

    Directory of Open Access Journals (Sweden)

    Sophie J Bernelot Moens

    Full Text Available Exotosin (EXT proteins are involved in the chain elongation step of heparan sulfate (HS biosynthesis, which is intricately involved in organ development. Loss of function mutations (LOF in EXT1 and EXT2 result in hereditary exostoses (HME. Interestingly, HS plays a role in pancreas development and beta-cell function, and genetic variations in EXT2 are associated with an increased risk for type 2 diabetes mellitus. We hypothesized that loss of function of EXT1 or EXT2 in subjects with hereditary multiple exostoses (HME affects pancreatic insulin secretion capacity and development. We performed an oral glucose tolerance test (OGTT followed by hyperglycemic clamps to investigate first-phase glucose-stimulated insulin secretion (GSIS in HME patients and age and gender matched non-affected relatives. Pancreas volume was assessed with magnetic resonance imaging (MRI. OGTT did not reveal significant differences in glucose disposal, but there was a markedly lower GSIS in HME subjects during hyperglycemic clamp (iAUC HME: 0.72 [0.46-1.16] vs. controls 1.53 [0.69-3.36] nmol·l-1·min-1, p<0.05. Maximal insulin response following arginine challenge was also significantly attenuated (iAUC HME: 7.14 [4.22-10.5] vs. controls 10.2 [7.91-12.70] nmol·l-1·min-1 p<0.05, indicative of an impaired beta-cell reserve. MRI revealed a significantly smaller pancreatic volume in HME subjects (HME: 72.0±15.8 vs. controls 96.5±26.0 cm3 p = 0.04. In conclusion, loss of function of EXT proteins may affect beta-cell mass and insulin secretion capacity in humans, and render subjects at a higher risk of developing type 2 diabetes when exposed to environmental risk factors.

  18. cPLA2alpha-evoked formation of arachidonic acid and lysophospholipids is required for exocytosis in mouse pancreatic beta-cells

    DEFF Research Database (Denmark)

    Juhl, Kirstine; Høy, Marianne; Olsen, Hervør L;

    2003-01-01

    Using capacitance measurements, we investigated the effects of intracellularly applied recombinant human cytosolic phospholipase A2 (cPLA2alpha) and its lipolytic products arachidonic acid and lysophosphatidylcholine on Ca2+-dependent exocytosis in single mouse pancreatic beta-cells. cPLA2alpha...... dose dependently (EC50 = 86 nM) stimulated depolarization-evoked exocytosis by 450% without affecting the whole cell Ca2+ current or cytoplasmic Ca2+ levels. The stimulatory effect involved priming of secretory granules as reflected by an increase in the size of the readily releasable pool of granules...

  19. Beta-cell dysfunction and low insulin clearance in insulin-resistant human immunodeficiency virus (HIV)-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Vølund, Aage; Hansen, Birgitte Rønde; Iversen, Johan; Andersen, Ulrik B; Nielsen, Jens Ole; Madsbad, Sten

    2005-01-01

    investigated during an oral glucose tolerance test (OGTT) (75 g, 180 min) in 16 lipodystrophic HIV-infected patients and in 15 age- and weight-matched nonlipodystrophic HIV-infected patients. All participants were sedentary Caucasian males, who were on highly active antiretroviral therapy with no history of...... and diabetes mellitus (63%vs. 20%, P < 0.05). CONCLUSIONS: Our data support the concept that impaired glucose tolerance in lipodystrophic HIV-infected patients relates to a failure of the beta-cells to fully compensate for decrements in insulin sensitivity despite simultaneous reduction in insulin...

  20. Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling

    DEFF Research Database (Denmark)

    Gromada, J; Bokvist, K; Ding, W G; Holst, J J; Nielsen, Jens Høiriis; Rorsman, P

    1998-01-01

    The effect of glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide] on membrane potential, whole-cell ATP-sensitive potassium channel (K[ATP]) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human beta-cells. GLP-1(7-36) amide induced membrane...... depolarization that was associated with inhibition of whole-cell K(ATP) current. In addition, GLP-1(7-36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca......2+ channels. More importantly, GLP-1(7-36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when the...

  1. A mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder.

    Science.gov (United States)

    Wang, Yuexia; Lichter-Konecki, Uta; Anyane-Yeboa, Kwame; Shaw, Jessica E; Lu, Jonathan T; Östlund, Cecilia; Shin, Ji-Yeon; Clark, Lorraine N; Gundersen, Gregg G; Nagy, Peter L; Worman, Howard J

    2016-05-15

    In 1994 in the Journal of Cell Science, Hennekes and Nigg reported that changing valine to arginine at the endoproteolytic cleavage site in chicken prelamin A abolishes its conversion to lamin A. The consequences of this mutation in an organism have remained unknown. We now report that the corresponding mutation in a human subject leads to accumulation of prelamin A and causes a progeroid disorder. Next generation sequencing of the subject and her parents' exomes identified a de novo mutation in the lamin A/C gene (LMNA) that resulted in a leucine to arginine amino acid substitution at residue 647 in prelamin A. The subject's fibroblasts accumulated prelamin A, a farnesylated protein, which led to an increased percentage of cultured cells with morphologically abnormal nuclei. Treatment with a protein farnesyltransferase inhibitor improved abnormal nuclear morphology. This case demonstrates that accumulation of prelamin A, independent of the loss of function of ZMPSTE24 metallopeptidase that catalyzes processing of prelamin A, can cause a progeroid disorder and that a cell biology assay could be used in precision medicine to identify a potential therapy. PMID:27034136

  2. Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

    International Nuclear Information System (INIS)

    Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of [6-3H]- and [U-14C]glucose. Compared with noninfected rats, infected animals were hyperthermic and showed increased rates of glucose appearance, clearance, and recycling as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol (β-blocker) and phentolamine (α-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection

  3. Virtual lesions of the IFG abolish response facilitation for biological and non-biological cues

    Directory of Open Access Journals (Sweden)

    Roger D Newman-Norlund

    2010-03-01

    Full Text Available Humans are faster to perform a given action following observation of that same action. Converging evidence suggests that the human mirror neuron system (MNS plays an important role in this phenomenon. However, the specificity of the neural mechanisms governing this effect remain controversial. Specialist theories of imitation suggest that biological cues are maximally capable of eliciting imitative facilitation. Generalist models, on the other hand, posit a broader role for the MNS in linking visual stimuli with appropriate responses. In the present study, we investigated the validity of these two theoretical approaches by disrupting the left and right inferior frontal gyrus (IFG during the preparation of congruent (imitative and incongruent (complementary actions cued by either biological (hand or non-biological (static dot stimuli. Delivery of TMS over IFG abolished imitative response facilitation. Critically, this effect was identical whether actions were cued by biological or non-biological stimuli. This finding argues against theories of imitation in which biological stimuli are treated preferentially and stresses the notion of the IFG as a vital center of general perception-action coupling in the human brain.

  4. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

    Science.gov (United States)

    Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

    2015-01-01

    Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. PMID:25393660

  5. The relationship between node degree and dissipation rate in networks of diffusively coupled oscillators and its significance for pancreatic beta cells.

    Science.gov (United States)

    Gosak, Marko; Stožer, Andraž; Markovič, Rene; Dolenšek, Jurij; Marhl, Marko; Rupnik, Marjan Slak; Perc, Matjaž

    2015-07-01

    Self-sustained oscillatory dynamics is a motion along a stable limit cycle in the phase space, and it arises in a wide variety of mechanical, electrical, and biological systems. Typically, oscillations are due to a balance between energy dissipation and generation. Their stability depends on the properties of the attractor, in particular, its dissipative characteristics, which in turn determine the flexibility of a given dynamical system. In a network of oscillators, the coupling additionally contributes to the dissipation, and hence affects the robustness of the oscillatory solution. Here, we therefore investigate how a heterogeneous network structure affects the dissipation rate of individual oscillators. First, we show that in a network of diffusively coupled oscillators, the dissipation is a linearly decreasing function of the node degree, and we demonstrate this numerically by calculating the average divergence of coupled Hopf oscillators. Subsequently, we use recordings of intracellular calcium dynamics in pancreatic beta cells in mouse acute tissue slices and the corresponding functional connectivity networks for an experimental verification of the presented theory. We use methods of nonlinear time series analysis to reconstruct the phase space and calculate the sum of Lyapunov exponents. Our analysis reveals a clear tendency of cells with a higher degree, that is, more interconnected cells, having more negative values of divergence, thus confirming our theoretical predictions. We discuss these findings in the context of energetic aspects of signaling in beta cells and potential risks for pathological changes in the tissue. PMID:26232966

  6. Proteomic screening of glucose-responsive and glucose non-reponsive MIN-6 beta cells reveals differential expression of protein involved in protein folding, secretion and oxidative stress

    DEFF Research Database (Denmark)

    Dowling, P.; O´Driscoll, L.; O´Sullivan, F.;

    2006-01-01

    The glucose-sensitive insulin-secretion (GSIS) phenotype is relatively unstable in long-term culture of beta cells. The purpose of this study was to investigate relative changes in the proteome between glucose-responsive (low passage) and glucose non-responsive (high passage) murine MIN-6...... pancreatic beta cells. The 2D-DIGE and subsequent DeCyder analysis detected 3351 protein spots in the pH range of 4-7. Comparing MIN-6(H) to MIN-6(L) and using a threshold of 1.2-fold, the number of proteins with a decrease in expression level was 152 (4.5%), similar was 3140 (93.7%) and increased 59 (1...... protein 29 (ERp29); 78-kDa glucose-related protein, (GRP78); 94-kDa glucose-related protein (GRP94); protein disulphide isomerase; carbonyl reductase 3; peroxidoxin 4 and superoxide dismutase 1. These results suggest that non-GSIS MIN-6 cells do not have the same ability/capacity of glucose-responsive MIN...

  7. Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism.

    Science.gov (United States)

    Ahrén, Bo; Foley, James E

    2016-05-01

    Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism. PMID:26894277

  8. Caffeine Abolishes the Ultraviolet-Induced REV3 Translesion Replication Pathway in Mouse Cells

    Directory of Open Access Journals (Sweden)

    Kouichi Yamada

    2011-11-01

    Full Text Available When a replicative DNA polymerase stalls upon encountering a photoproduct on the template strand, it is relieved by other low-processivity polymerase(s, which insert nucleotide(s opposite the lesion. Using an alkaline sucrose density gradient sedimentation technique, we previously classified this process termed UV-induced translesion replication (UV-TLS into two types. In human cancer cells or xeroderma pigmentosum variant (XP-V cells, UV-TLS was inhibited by caffeine or proteasome inhibitors. However, in normal human cells, the process was insensitive to these reagents. Reportedly, in yeast or mammalian cells, REV3 protein (a catalytic subunit of DNA polymerase ζ is predominantly involved in the former type of TLS. Here, we studied UV-TLS in fibroblasts derived from the Rev3-knockout mouse embryo (Rev3KO-MEF. In the wild-type MEF, UV-TLS was slow (similar to that of human cancer cells or XP-V cells, and was abolished by caffeine or MG-262. In 2 cell lines of Rev3KO-MEF (Rev3−/− p53−/−, UV-TLS was not observed. In p53KO-MEF, which is a strict control for Rev3KO-MEF, the UV-TLS response was similar to that of the wild-type. Introduction of the Rev3 expression plasmid into Rev3KO-MEF restored the UV-TLS response in selected stable transformants. In some transformants, viability to UV was the same as that in the wild-type, and the death rate was increased by caffeine. Our findings indicate that REV3 is predominantly involved in UV-TLS in mouse cells, and that the REV3 translesion pathway is suppressed by caffeine or proteasome inhibitors.

  9. Glycogen overload by postexercise insulin administration abolished the exercise-induced increase in GLUT4 protein.

    Science.gov (United States)

    Chou, Chia-Hau; Tsai, Yin-Lan; Hou, Chien-Wen; Lee, Hsing-Hao; Chang, Wei-Hsiang; Lin, Tzi-Wen; Hsu, Tung-Hsiung; Huang, Yi-Jen; Kuo, Chia-Hua

    2005-12-01

    To elucidate the role of muscle glycogen storage on regulation of GLUT4 protein expression and whole-body glucose tolerance, muscle glycogen level was manipulated by exercise and insulin administration. Sixty Sprague-Dawley rats were evenly separated into three groups: control (CON), immediately after exercise (EX0), and 16 h after exercise (EX16). Rats from each group were further divided into two groups: saline- and insulin-injected. The 2-day exercise protocol consisted of 2 bouts of 3-h swimming with 45-min rest for each day, which effectively depleted glycogen in both red gastrocnemius (RG) and plantaris muscles. EX0 rats were sacrificed immediately after the last bout of exercise on second day. CON and EX16 rats were intubated with 1 g/kg glucose solution following exercise and recovery for 16 h before muscle tissue collection. Insulin (0.5 microU/kg) or saline was injected daily at the time when glucose was intubated. Insulin injection elevated muscle glycogen levels substantially in both muscles above saline-injected group at CON and EX16. With previous day insulin injection, EX0 preserved greater amount of postexercise glycogen above their saline-injected control. In the saline-injected rats, EX16 significantly increased GLUT4 protein level above CON, concurrent with muscle glycogen supercompensation. Insulin injection for EX16 rats significantly enhanced muscle glycogen level above their saline-injected control, but the increases in muscle GLUT4 protein and whole-body glucose tolerance were attenuated. In conclusion, the new finding of the study was that glycogen overload by postexercise insulin administration significantly abolished the exercise-induced increases in GLUT4 protein and glucose tolerance. PMID:16319996

  10. Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble

    DEFF Research Database (Denmark)

    Christgau, S; Schierbeck, H; Aanstoot, H J;

    1991-01-01

    The 64-kDa pancreatic beta-cell autoantigen, which is a target of autoantibodies associated with early as well as progressive stages of beta-cell destruction, resulting in insulin-dependent diabetes (IDDM) in humans, has been identified as the gamma-aminobutyric acid-synthesizing enzyme glutamic...... compartment and hydrophobicity. A major portion of GAD64 is hydrophobic and firmly membrane-anchored and can only be released from membrane fractions by detergent. A second portion is hydrophobic but soluble or of a low membrane avidity, and a third minor portion is soluble and hydrophilic. All the GAD64...

  11. Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality.

    OpenAIRE

    Dalu, A; Rao, P S; Mehendale, H M

    1998-01-01

    We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride (CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the underlying cause of resistance. The objective of the current study was to investigate if the antimitotic effect of colchicine (CLC) abolishes this resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell division....

  12. A Paradoxical Effect of Presession Attention on Stereotypy: Antecedent Attention as an Establishing, Not an Abolishing, Operation

    OpenAIRE

    Roantree, Christina F; Kennedy, Craig H

    2006-01-01

    Previous studies have shown that presession attention for problem behavior can serve as an abolishing operation when attention functions as a positive reinforcer. In the current study, we show that the stereotypy of a child with severe disabilities was undifferentiated during standard analogue functional analysis conditions. However, when noncontingent presession attention was provided, stereotypy occurred for social attention as a positive reinforcer, suggesting that the antecedent manipulat...

  13. Abolished thermal and mechanical antinociception but retained visceral chemical antinociception induced by butorphanol in μ-opioid receptor knockout mice

    OpenAIRE

    Ide, Soichiro; Minami, Masabumi; Ishihara, Kumatoshi; Uhl, George R; Satoh, Masamichi; Sora, Ichiro; Ikeda, Kazutaka

    2008-01-01

    Butorphanol is hypothesized to induce analgesia via opioid pathways, although the precise mechanisms for its effects remain unknown. In this study, we investigated the role of the μ-opioid receptor (MOP) in thermal, mechanical, and visceral chemical antinociception induced by butorphanol using MOP knockout (KO) mice. Butorphanol-induced thermal antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice com...

  14. Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Dela, Flemming;

    2005-01-01

    ), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naive to antiretroviral therapy (NAIVE) respectively). beta-cell function was evaluated by an intravenous glucose tolerance test. RESULTS: Compared with NONLIPO and NAIVE separately, LIPO displayed markedly reduced ratio...... of limb to trunk fat (RLF; > 34%, P < 0.001), hepatic insulin sensitivity (> 40%, P < 0.03), incremental glucose disposal (>50%, P < 0.001) and incremental exogenous glucose storage (>50%, P < 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P < 0.01), increased clamp free...... fatty acids (P < 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P < 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r = 0.69), incremental glucose disposal (r = 0.71) and incremental exogenous glucose storage (r = 0.40), all...

  15. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes

    DEFF Research Database (Denmark)

    Greenbaum, Carla J; Mandrup-Poulsen, Thomas; McGee, Paula Friedenberg;

    2008-01-01

    OBJECTIVE: Beta-cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study...... Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS: In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects...... completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS: Among individuals with up to 4 years' duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were...

  16. Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods

    DEFF Research Database (Denmark)

    Kjems, L L; Vølund, A; Madsbad, Sten

    2001-01-01

    AIMS/HYPOTHESIS: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. METHODS: Eight control...... subjects and eight Type II diabetic patients underwent an intravenous glucose tolerance test with tolbutamide and an intravenous bolus injection of C-peptide to assess C-peptide kinetics. Insulin secretion rates were determined by the Eaton deconvolution (reference method), the Insulin SECretion method...... first-phase insulin response (r = 0.78). The two-compartment combined model failed to provide reliable estimates of insulin secretion in three of the control subjects and in two patients with Type II diabetes. The four methods were accurate with respect to mean basal and first-phase secretion response...

  17. Unprotected daily sun exposure is differently associated with central adiposity and beta-cell dysfunction by gender: The Korean national health and nutrition examination survey (KNHANES) V

    International Nuclear Information System (INIS)

    Background: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results: The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure. - Highlights: • Sun exposure for more than 5 h per day is associated with diabetes risk. • Insulin resistance associated with visceral adiposity may play a role in women. • Insulin secretory defect may explain diabetes risk in men

  18. Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia.

    Directory of Open Access Journals (Sweden)

    Angeles Mondragon

    Full Text Available Glucagon-like peptide-1 (GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4 inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.C57BL6 mice were maintained for 131 days on a normal diet (ND or a diet comprising 60% fat (HFD before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.Whereas liraglutide (200 µg/kg and exendin-4 (10 µg/kg treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

  19. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.

    Directory of Open Access Journals (Sweden)

    Inês Barroso

    2003-10-01

    Full Text Available Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT cohort in the United Kingdom. Polymorphisms in five of 15 genes (33% encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor, KCNJ11 (KIR6.2, SLC2A2 (GLUT2, HNF4A (HNF4alpha, and INS (insulin-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

  20. Candidate Gene Association Study in Type 2 Diabetes Indicates a Role for Genes Involved in beta-Cell Function as Well as Insulin Action

    Directory of Open Access Journals (Sweden)

    Barroso Ines

    2003-01-01

    Full Text Available Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT cohort in the United Kingdom. Polymorphisms in five of 15 genes (33% encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor, KCNJ11 (KIR6.2, SLC2A2 (GLUT2, HNF4A (HNF4alpha, and INS (insulin-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

  1. Cooperation between HMGA1, PDX-1, and MafA is Essential for Glucose-Induced Insulin Transcription in Pancreatic Beta Cells

    Science.gov (United States)

    Arcidiacono, Biagio; Iiritano, Stefania; Chiefari, Eusebio; Brunetti, Francesco S.; Gu, Guoqiang; Foti, Daniela Patrizia; Brunetti, Antonio

    2014-01-01

    The high-mobility group AT-hook 1 (HMGA1) protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called “enhanceosomes” on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS) gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production. PMID:25628604

  2. Cooperation between HMGA1, PDX-1 and MafA is essential for glucose-induced insulin transcription in pancreatic beta cells

    Directory of Open Access Journals (Sweden)

    Biagio eArcidiacono

    2015-01-01

    Full Text Available The high-mobility group AT-hook 1 (HMGA1 protein is a nuclear architectural factor that can organize chromatin structures. It regulates gene expression by controlling the formation of stereospecific multiprotein complexes called enhanceosomes on the AT-rich regions of target gene promoters. Previously, we reported that defects in HMGA1 caused decreased insulin receptor expression and increased susceptibility to type 2 diabetes mellitus in humans and mice. Interestingly, mice with disrupted HMGA1 gene had significantly smaller islets and decreased insulin content in their pancreata, suggesting that HMGA1 may have a direct role in insulin transcription and secretion. Herein, we investigate the regulatory roles of HMGA1 in insulin transcription. We provide evidence that HMGA1 physically interacts with PDX-1 and MafA, two critical transcription factors for insulin gene expression and beta-cell function, both in vitro and in vivo. We then show that the overexpression of HMGA1 significantly improves the transactivating activity of PDX-1 and MafA on human and mouse insulin promoters, while HMGA1 knockdown considerably decreased this transactivating activity. Lastly, we demonstrate that high glucose stimulus significantly increases the binding of HMGA1 to the insulin (INS gene promoter, suggesting that HMGA1 may act as a glucose-sensitive element controlling the transcription of the INS gene. Together, our findings provide evidence that HMGA1, by regulating PDX-1- and MafA-induced transactivation of the INS gene promoter, plays a critical role in pancreatic beta-cell function and insulin production.

  3. Unprotected daily sun exposure is differently associated with central adiposity and beta-cell dysfunction by gender: The Korean national health and nutrition examination survey (KNHANES) V

    Energy Technology Data Exchange (ETDEWEB)

    Ohn, Jung Hun [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Kwon, In Ho [Department of Dermatology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong (Korea, Republic of); Park, Juri; Ryu, Ohk Hyun; Lee, Seong Jin; Kim, Doo-Man; Ihm, Sung-Hee; Choi, Moon-Gi; Yoo, Hyung Joon [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Hong, Eun-Gyoung, E-mail: hegletter@hallym.or.kr [Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon (Korea, Republic of)

    2014-08-15

    Background: Ultraviolet irradiation by sun exposure has been associated with both harms and benefits to metabolic health. Objective: The objective of this study was to determine whether unprotected daily sun exposure is associated with the prevalence of diabetes and explore the underlying mechanism. Methods: We analyzed the Korean National Health and Nutrition Survey V from 2010 to 2011. Participants 19–60 years of age were asked about the average amount of time they had been exposed to direct sunlight per day since the age of 19. We categorized participants into three groups with different levels of lifetime daily sun exposure and explored the association of sun exposure with the prevalence of diabetes. Results: The risk of diabetes was higher in subjects with more than 5 h of unprotected sun exposure per day, with an odds ratio of 2.39 (95% CI 1.75–3.25), compared to those with less than 2 h of sun exposure, and the association remained significant after adjusting for diabetes risk factors. Long-term sun exposure was associated with increased central obesity and the possibility of an increase in visceral adiposity, especially among women, and with decrease in beta cell function and peripheral adiposity or percent body fat in men. Conclusions: Our study provides a cutoff for upper limit of sun exposure and suggests unprotected daily sun exposure for more than 5 h should be avoided to prevent diabetes. Increased central adiposity and decreased beta cell function were observed in women and men, respectively, who had long-term unprotected daily sun exposure. - Highlights: • Sun exposure for more than 5 h per day is associated with diabetes risk. • Insulin resistance associated with visceral adiposity may play a role in women. • Insulin secretory defect may explain diabetes risk in men.

  4. Ca2+-dependent dephosphorylation of kinesin heavy chain on beta-granules in pancreatic beta-cells. Implications for regulated beta-granule transport and insulin exocytosis

    Science.gov (United States)

    Donelan, Matthew J.; Morfini, Gerardo; Julyan, Richard; Sommers, Scott; Hays, Lori; Kajio, Hiroshi; Briaud, Isabelle; Easom, Richard A.; Molkentin, Jeffery D.; Brady, Scott T.; Rhodes, Christopher J.

    2002-01-01

    The specific biochemical steps required for glucose-regulated insulin exocytosis from beta-cells are not well defined. Elevation of glucose leads to increases in cytosolic [Ca2+]i and biphasic release of insulin from both a readily releasable and a storage pool of beta-granules. The effect of elevated [Ca2+]i on phosphorylation of isolated beta-granule membrane proteins was evaluated, and the phosphorylation of four proteins was found to be altered by [Ca2+]i. One (a 18/20-kDa doublet) was a Ca2+-dependent increase in phosphorylation, and, surprisingly, three others (138, 42, and 36 kDa) were Ca2+-dependent dephosphorylations. The 138-kDa beta-granule phosphoprotein was found to be kinesin heavy chain (KHC). At low levels of [Ca2+]i KHC was phosphorylated by casein kinase 2, but KHC was rapidly dephosphorylated by protein phosphatase 2B beta (PP2Bbeta) as [Ca2+]i increased. Inhibitors of PP2B specifically reduced the second, microtubule-dependent, phase of insulin secretion, suggesting that dephosphorylation of KHC was required for transport of beta-granules from the storage pool to replenish the readily releasable pool of beta-granules. This is distinct from synaptic vesicle exocytosis, because neurotransmitter release from synaptosomes did not require a Ca2+-dependent KHC dephosphorylation. These results suggest a novel mechanism for regulating KHC function and beta-granule transport in beta-cells that is mediated by casein kinase 2 and PP2B. They also implicate a novel regulatory role for PP2B/calcineurin in the control of insulin secretion downstream of a rise in [Ca2+]i.

  5. Leg vasoconstriction during head-up tilt in patients with autonomic failure is not abolished

    NARCIS (Netherlands)

    Groothuis, J.T.; Thijssen, D.H.J.; Lenders, J.W.M.; Deinum, J.; Hopman, M.T.E.

    2011-01-01

    Maintaining blood pressure during orthostatic challenges is primarily achieved by baroreceptor-mediated activation of the sympathetic nervous system, which can be divided into preganglionic and postganglionic parts. Despite their preganglionic autonomic failure, spinal cord-injured individuals demon

  6. Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice

    NARCIS (Netherlands)

    Kruit, J. K.; Kremer, P. H. C.; Dai, L.; Tang, R.; Ruddle, P.; de Haan, W.; Brunham, L. R.; Verchere, C. B.; Hayden, M. R.

    2010-01-01

    Cellular cholesterol accumulation is an emerging mechanism for beta cell dysfunction in type 2 diabetes. Absence of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) results in increased islet cholesterol and impaired insulin secretion, indicating that impaired cholesterol effl

  7. Circulating Levels of MicroRNA from Children with Newly Diagnosed Type 1 Diabetes and Healthy Controls: Evidence That miR-25 Associates to Residual Beta-Cell Function and Glycaemic Control during Disease Progression

    DEFF Research Database (Denmark)

    Nielsen, L. B.; Wang, C.; Sorensen, K.;

    2012-01-01

    This study aims to identify key miRNAs in circulation, which predict ongoing beta-cell destruction and regeneration in children with newly diagnosed Type 1 Diabetes (T1D). We compared expression level of sera miRNAs from new onset T1D children and age-matched healthy controls and related the miRN...

  8. Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats.

    Science.gov (United States)

    Dasinger, John Henry; Intapad, Suttira; Rudsenske, Benjamin R; Davis, Gwendolyn K; Newsome, Ashley D; Alexander, Barbara T

    2016-06-01

    Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity, indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, SC for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin-converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin-angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats. PMID:27113045

  9. The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons

    Science.gov (United States)

    Sorenson, E. M.; Gallagher, J. P.

    1993-01-01

    Previous intracellular recordings have demonstrated that dorsolateral septal nucleus (DLSN) neurons express a novel nicotinic receptor which produces a direct membrane hyperpolarization when activated by nicotinic agonists. Activation of the classical excitatory nicotinic receptors has been shown to require a disulfide bond involving the cysteines at positions 192 and 193 of the alpha subunits of the receptor. Reduction of this cystine bond with dithiothreitol (DTT) abolishes agonist activation of excitatory nicotinic receptors. We have now examined whether DTT treatment of the inhibitory nicotinic receptor on DLSN neurons also abolishes the inhibitory nicotinic response. We find that the inhibitory response persists after treatment of the neurons with 1 mM DTT, even if the reduction is followed by alkylation of the receptor with bromoacetylcholine to prevent possible reformation of disulfide bonds. This result suggests that the agonist binding site on the inhibitory nicotinic receptor does not require an intact disulfide bond, similar to the bond on the alpha subunit of the excitatory nicotinic receptor, for agonist activation of the receptor. Some of these results have been previously reported in abstract form.

  10. Monkey׳s short-term auditory memory nearly abolished by combined removal of the rostral superior temporal gyrus and rhinal cortices.

    Science.gov (United States)

    Fritz, Jonathan B; Malloy, Megan; Mishkin, Mortimer; Saunders, Richard C

    2016-06-01

    While monkeys easily acquire the rules for performing visual and tactile delayed matching-to-sample, a method for testing recognition memory, they have extraordinary difficulty acquiring a similar rule in audition. Another striking difference between the modalities is that whereas bilateral ablation of the rhinal cortex (RhC) leads to profound impairment in visual and tactile recognition, the same lesion has no detectable effect on auditory recognition memory (Fritz et al., 2005). In our previous study, a mild impairment in auditory memory was obtained following bilateral ablation of the entire medial temporal lobe (MTL), including the RhC, and an equally mild effect was observed after bilateral ablation of the auditory cortical areas in the rostral superior temporal gyrus (rSTG). In order to test the hypothesis that each of these mild impairments was due to partial disconnection of acoustic input to a common target (e.g., the ventromedial prefrontal cortex), in the current study we examined the effects of a more complete auditory disconnection of this common target by combining the removals of both the rSTG and the MTL. We found that the combined lesion led to forgetting thresholds (performance at 75% accuracy) that fell precipitously from the normal retention duration of ~30 to 40s to a duration of ~1 to 2s, thus nearly abolishing auditory recognition memory, and leaving behind only a residual echoic memory. This article is part of a Special Issue entitled SI: Auditory working memory. PMID:26707975

  11. Adipose Tissue-Derived Mesenchymal Stem Cells Exert In Vitro Immunomodulatory and Beta Cell Protective Functions in Streptozotocin-Induced Diabetic Mice Model

    Directory of Open Access Journals (Sweden)

    Hossein Rahavi

    2015-01-01

    Full Text Available Regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs might be applied for type 1 diabetes mellitus (T1DM treatment. Thus, we proposed in vitro assessment of adipose tissue-derived MSCs (AT-MSCs immunomodulation on autoimmune response along with beta cell protection in streptozotocin- (STZ- induced diabetic C57BL/6 mice model. MSCs were extracted from abdominal adipose tissue of normal mice and cultured to proliferate. Diabetic mice were prepared by administration of multiple low-doses of streptozotocin. Pancreatic islets were isolated from normal mice and splenocytes prepared from normal and diabetic mice. Proliferation, cytokine production, and insulin secretion assays were performed in coculture experiments. AT-MSCs inhibited splenocytes proliferative response to specific (islet lysate and nonspecific (PHA triggers in a dose-dependent manner (P<0.05. Decreased production of proinflammatory cytokines, such as IFN-γ, IL-2, and IL-17, and increased secretion of regulatory cytokines such as TGF-β, IL-4, IL-10, and IL-13 by stimulated splenocytes were also shown in response to islet lysate or PHA stimulants (P<0.05. Finally, we demonstrated that AT-MSCs could effectively sustain viability as well as insulin secretion potential of pancreatic islets in the presence of reactive splenocytes (P<0.05. In conclusion, it seems that MSCs may provide a new horizon for T1DM cell therapy and islet transplantation in the future.

  12. The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Fisker, S; Hilsted, J;

    1999-01-01

    The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment...... with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study.......7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin...

  13. Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection

    DEFF Research Database (Denmark)

    Ekholm, E; Shaat, N; Holst, Jens Juul

    2012-01-01

    The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from...... eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P <0.......01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703...

  14. The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells

    DEFF Research Database (Denmark)

    Emanuelli, Brice; Glondu, Murielle; Filloux, Chantal;

    2004-01-01

    ) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as...... an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and...... reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta...

  15. The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Chamutal Gur

    Full Text Available NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice is prominent. We have recently demonstrated that in type 1 diabetes (T1D NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

  16. Ubiquitin fold modifier 1 (UFM1 and its target UFBP1 protect pancreatic beta cells from ER stress-induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Katleen Lemaire

    Full Text Available UFM1 is a member of the ubiquitin like protein family. While the enzymatic cascade of UFM1 conjugation has been elucidated in recent years, the biological function remains largely unknown. In this report we demonstrate that the recently identified C20orf116, which we name UFM1-binding protein 1 containing a PCI domain (UFBP1, and CDK5RAP3 interact with UFM1. Components of the UFM1 conjugation pathway (UFM1, UFBP1, UFL1 and CDK5RAP3 are highly expressed in pancreatic islets of Langerhans and some other secretory tissues. Co-localization of UFM1 with UFBP1 in the endoplasmic reticulum (ER depends on UFBP1. We demonstrate that ER stress, which is common in secretory cells, induces expression of Ufm1, Ufbp1 and Ufl1 in the beta-cell line INS-1E. siRNA-mediated Ufm1 or Ufbp1 knockdown enhances apoptosis upon ER stress. Silencing the E3 enzyme UFL1, results in similar outcomes, suggesting that UFM1-UFBP1 conjugation is required to prevent ER stress-induced apoptosis. Together, our data suggest that UFM1-UFBP1 participate in preventing ER stress-induced apoptosis in protein secretory cells.

  17. 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

    investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. RESULTS: Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of......-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1a, Il1ß, Tnfa or Cxcl2. HDAC3 knock-down reduced nuclear factor ¿B binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent......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...

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

    DEFF Research Database (Denmark)

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

    1993-01-01

    We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in...... phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to...... derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to...

  19. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    Energy Technology Data Exchange (ETDEWEB)

    Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)

    2013-12-06

    Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

  20. Variation within the PPARG gene is associated with residual beta-cell function and glycemic control in children and adolescents during the first year of clinical type 1 diabetes

    DEFF Research Database (Denmark)

    Porksen, S.; Nielsen, L.B.; Mortensen, H.B.;

    2008-01-01

    the PPARG gene in relation to residual beta-cell function and glycemic control in newly diagnosed T1D. Design: Prospective, non-interventional, 12-month follow-up study, conducted in 18 centers in 15 countries. Patients: Two hundred and fifty-seven children and adolescents (aged < 16 yr) with newly...... in the PPARG locus may influence disease progression during the first year after the presentation of T1D Udgivelsesdato: 2008/8...

  1. Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation.

    OpenAIRE

    Bollheimer, L. C.; Skelly, R H; Chester, M W; McGarry, J D; Rhodes, C. J.

    1998-01-01

    The pancreatic beta cell normally maintains a stable balance among insulin secretion, insulin production, and insulin degradation to keep optimal intracellular stores of the hormone. Elevated levels of FFA markedly enhance insulin secretion; however, the effects of FFA on insulin production and intracellular stores remain unclear. In this study, twofold elevation in total circulating FFA effected by infusion of lard oil and heparin into rats for 6 h under normoglycemic conditions resulted in ...

  2. Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus.

    Science.gov (United States)

    Kryvalap, Yury; Lo, Chi-Wen; Manuylova, Ekaterina; Baldzizhar, Raman; Jospe, Nicholas; Czyzyk, Jan

    2016-01-01

    Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ∼80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans. PMID:26578518

  3. Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells

    Directory of Open Access Journals (Sweden)

    Young-Hye You

    2011-04-01

    Full Text Available BackgroundA limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.MethodsAdult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.ResultsThe adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.ConclusionThese data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.

  4. Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study

    OpenAIRE

    Weijian Ke; Liehua Liu; Juan Liu; Ailing Chen; Wanping Deng; Pengyuan Zhang; Xiaopei Cao; Zhihong Liao; Haipeng Xiao; Jianbin Liu; Yanbing Li

    2015-01-01

    The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 wee...

  5. Spinal and locus coeruleus noradrenergic lesions abolish the analgesic effects of 5-methoxy-N,N-dimethyltryptamine.

    Science.gov (United States)

    Danysz, W; Jonsson, G; Minor, B G; Post, C; Archer, T

    1986-07-01

    Two experiments were performed on Sprague-Dawley rats to study the effects of noradrenaline and 5-hydroxytryptamine depletion upon the antinociceptive effects of acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) administration. 6-Hydroxydopamine-induced lesions following microinjections to either the locus coeruleus or the spinal cord (lumbar) abolished completely 5-MeODMT-induced analgesia in the tail-flick, hot-plate, and shock titration tests whereas 5,7-dihydroxytryptamine-induced lesions of the nucleus raphe magnus and the lumbar spinal cord attenuated 5-MeODMT analgesia in the tail-flick and shock titration tests. Thus, the experiments serve to demonstrate an important interaction between descending noradrenergic and serotonergic pathways, possibly at a spinal locus. PMID:3015120

  6. Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells

    International Nuclear Information System (INIS)

    Heparanase facilitates the invasion and metastasis of cancer cells, and is over-expressed in many kinds of malignancies. Our studies indicated that heparanase was frequently expressed in advanced gastric cancers. The aim of this study is to determine whether silencing of heparanase expression can abolish the malignant characteristics of gastric cancer cells. Three heparanase-specific small interfering RNA (siRNAs) were designed, synthesized, and transfected into cultured gastric cancer cell line SGC-7901. Heparanase expression was measured by RT-PCR, real-time quantitative PCR and Western blot. Cell proliferation was detected by MTT colorimetry and colony formation assay. The in vitro invasion and metastasis of cancer cells were measured by cell adhesion assay, scratch assay and matrigel invasion assay. The angiogenesis capabilities of cancer cells were measured by tube formation of endothelial cells. Transfection of siRNA against 1496-1514 bp of encoding regions resulted in reduced expression of heparanase, which started at 24 hrs and lasted for 120 hrs post-transfection. The siRNA-mediated silencing of heparanase suppressed the cellular proliferation of SGC-7901 cells. In addition, the in vitro invasion and metastasis of cancer cells were attenuated after knock-down of heparanase. Moreover, transfection of heparanase-specific siRNA attenuated the in vitro angiogenesis of cancer cells in a dose-dependent manner. These results demonstrated that gene silencing of heparanase can efficiently abolish the proliferation, invasion, metastasis and angiogenesis of human gastric cancer cells in vitro, suggesting that heparanase-specific siRNA is of potential values as a novel therapeutic agent for human gastric cancer

  7. Research Advances on Acupuncture-moxibustion for Improving Pancreatic Beta-cell Function%针灸改善胰岛β细胞功能研究进展

    Institute of Scientific and Technical Information of China (English)

    庞晓英; 孙志

    2014-01-01

    2型糖尿病( T2DM)是临床常见多发病,严重危害人们的身体健康。胰岛β细胞功能障碍是T2 DM发生发展的中心环节。针灸治疗T2 DM有较好疗效,可以有效改善胰岛β细胞功能。笔者查阅了近15年针灸治疗糖尿病的相关文献资料,从实验研究和临床研究两方面对针灸改善胰岛β细胞功能的研究进行综述。%The type 2 diabetes mellitus ( T2DM) is a clinical common and frequently -occurring disease .It is seriously detrimental to people ’ s health.The dysfunction of pancreatic beta -cells is central to the occurrence and development of T2DM.Acupuncture -moxibustion treatment for T2DM obtains an curative effect.It can effectively protect the pancreatic beta -cells.We have consulted pertinent literatures of last 15 years, and will review researches on acupuncture -moxibustion for improving pancreatic beta -cell function from two sides of experimental and clinical researches .

  8. Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Weijian Ke

    2016-01-01

    Full Text Available The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM. Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group or CSII in combination with liraglutide (CSII + Lira group for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA indices, and acute insulin response (AIR were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0 versus 2 (3 days, P=0.039. HbA1c at the end of study was comparable between two groups (6.3±0.7% versus 6.0±0.5%, for CSII alone group and CSII + Lira group, resp., P=0.325. The increment of AIR was higher in CSII + Lira group (177.58 (351.57 μU·min/mL versus 58.15 (51.30 μU·min/mL, P<0.001. However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy.

  9. Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study

    Science.gov (United States)

    Ke, Weijian; Liu, Liehua; Liu, Juan; Chen, Ailing; Deng, Wanping; Zhang, Pengyuan; Cao, Xiaopei; Liao, Zhihong; Xiao, Haipeng; Liu, Jianbin; Li, Yanbing

    2016-01-01

    The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA) indices, and acute insulin response (AIR) were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0) versus 2 (3) days, P = 0.039). HbA1c at the end of study was comparable between two groups (6.3 ± 0.7% versus 6.0 ± 0.5%, for CSII alone group and CSII + Lira group, resp., P = 0.325). The increment of AIR was higher in CSII + Lira group (177.58 (351.57) μU·min/mL versus 58.15 (51.30) μU·min/mL, P < 0.001). However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy. PMID:26640805

  10. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion.

    Directory of Open Access Journals (Sweden)

    Yuko Nakagawa

    Full Text Available BACKGROUND: Sweet taste receptor is expressed in the taste buds and enteroendocrine cells acting as a sugar sensor. We investigated the expression and function of the sweet taste receptor in MIN6 cells and mouse islets. METHODOLOGY/PRINCIPAL FINDINGS: The expression of the sweet taste receptor was determined by RT-PCR and immunohistochemistry. Changes in cytoplasmic Ca(2+ ([Ca(2+](c and cAMP ([cAMP](c were monitored in MIN6 cells using fura-2 and Epac1-camps. Activation of protein kinase C was monitored by measuring translocation of MARCKS-GFP. Insulin was measured by radioimmunoassay. mRNA for T1R2, T1R3, and gustducin was expressed in MIN6 cells. In these cells, artificial sweeteners such as sucralose, succharin, and acesulfame-K increased insulin secretion and augmented secretion induced by glucose. Sucralose increased biphasic increase in [Ca(2+](c. The second sustained phase was blocked by removal of extracellular calcium and addition of nifedipine. An inhibitor of inositol(1, 4, 5-trisphophate receptor, 2-aminoethoxydiphenyl borate, blocked both phases of [Ca(2+](c response. The effect of sucralose on [Ca(2+](c was inhibited by gurmarin, an inhibitor of the sweet taste receptor, but not affected by a G(q inhibitor. Sucralose also induced sustained elevation of [cAMP](c, which was only partially inhibited by removal of extracellular calcium and nifedipine. Finally, mouse islets expressed T1R2 and T1R3, and artificial sweeteners stimulated insulin secretion. CONCLUSIONS: Sweet taste receptor is expressed in beta-cells, and activation of this receptor induces insulin secretion by Ca(2+ and cAMP-dependent mechanisms.

  11. MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise

    Directory of Open Access Journals (Sweden)

    Siobhán Bacon

    2015-06-01

    Full Text Available MicroRNA (miRNA are a class of non-coding, 19–25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic form of diabetes; HNF1A-MODY. miR-224 is a novel miRNA in the field of diabetes. We sought to explore the role of miR-224 as a potential biomarker in diabetes, and whether such diabetes-associated-miRNA can also be detected in the urine of patients. Absolute levels of miR-224 and miR-103 were determined in the urine of n = 144 individuals including carriers of a HNF1A mutation, participants with type 1 diabetes mellitus (T1DM, type 2 diabetes mellitus (T2DM and normal controls. Expression levels were correlated with clinical and biochemical parameters. miR-224 was significantly elevated in the urine of carriers of a HNF1A mutation and participants with T1DM. miR-103 was highly expressed in urine across all diabetes cohorts when compared to controls. For both miR-224 and-103, we found a significant correlation between serum and urine levels (p < 0.01. We demonstrate that miRNA can be readily detected in the urine independent of clinical indices of renal dysfunction. We surmise that the differential expression levels of miR-224 in both HNF1A-MODY mutation carriers and T1DM may be an attempt to compensate for beta-cell demise.

  12. Co-culture of neural crest stem cells (NCSC and insulin producing beta-TC6 cells results in cadherin junctions and protection against cytokine-induced beta-cell death.

    Directory of Open Access Journals (Sweden)

    Anongnad Ngamjariyawat

    Full Text Available PURPOSE: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death. PROCEDURES: Beta-TC6 and NCSC cells were cultured either alone or together, and either with or without cell culture inserts. The cultures were then exposed to the pro-inflammatory cytokines IL-1β and IFN-γ for 48 hours followed by analysis of cell death rates (flow cytometry, nitrite production (Griess reagent, protein localization (immunofluorescence and protein phosphorylation (flow cytometry. RESULTS: We observed that beta-TC6 cells co-cultured with NCSCs were protected against cytokine-induced cell death, but not when separated by cell culture inserts. This occurred in parallel with (i augmented production of nitrite from beta-TC6 cells, indicating that increased cell survival allows a sustained production of nitric oxide; (ii NCSC-derived laminin production; (iii decreased phospho-FAK staining in beta-TC6 cell focal adhesions, and (iv decreased beta-TC6 cell phosphorylation of ERK(T202/Y204, FAK(Y397 and FAK(Y576. Furthermore, co-culture also resulted in cadherin and beta-catenin accumulations at the NCSC/beta-TC6 cell junctions. Finally, the gap junction inhibitor carbenoxolone did not affect cytokine-induced beta-cell death during co-culture with NCSCs. CONCLUSION: In summary, direct contacts, but not soluble factors, promote improved beta-TC6 viability when co-cultured with NCSCs. We hypothesize that cadherin junctions between NCSC and beta-TC6 cells promote powerful signals that maintain beta-cell

  13. Legislature Abolishes Agricultural Tax

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

      China's 2,600-year-old agricultural tax will be rescinded as of Jan. 1,2006, after China's top legislature voted on December 27 to adopt a motion on the regulations revoking the agricultural tax.……

  14. Diminished but Not Abolished Effect of Two His351 Mutants of Anthrax Edema Factor in a Murine Model

    Directory of Open Access Journals (Sweden)

    Taoran Zhao

    2016-02-01

    Full Text Available Edema toxin (ET, which is composed of a potent adenylate cyclase (AC, edema factor (EF, and protective antigen (PA, is one of the major toxicity factors of Bacillus anthracis. In this study, we introduced mutations in full-length EF to generate alanine EF(H351A and arginine EF(H351R variants. In vitro activity analysis displayed that the adenylyl cyclase activity of both the mutants was significantly diminished compared with the wild-type EF. When the native and mutant toxins were administered subcutaneously in a mouse footpad edema model, severe acute swelling was evoked by wild-type ET, while the symptoms induced by mutant toxins were very minor. Systemic administration of these EF variants caused non-lethal hepatotoxicity. In addition, EF(H351R exhibited slightly higher activity in causing more severe edema than EF(H351A. Our findings demonstrate that the toxicity of ET is not abolished by substitution of EF residue His351 by alanine or arginine. These results also indicate the potential of the mouse footpad edema model as a sensitive method for evaluating both ET toxicity and the efficacy of candidate therapeutic agents.

  15. Diminished but Not Abolished Effect of Two His351 Mutants of Anthrax Edema Factor in a Murine Model.

    Science.gov (United States)

    Zhao, Taoran; Zhao, Xinghui; Liu, Ju; Meng, Yingying; Feng, Yingying; Fang, Ting; Zhang, Jinlong; Yang, Xiuxu; Li, Jianmin; Xu, Junjie; Chen, Wei

    2016-02-01

    Edema toxin (ET), which is composed of a potent adenylate cyclase (AC), edema factor (EF), and protective antigen (PA), is one of the major toxicity factors of Bacillus anthracis. In this study, we introduced mutations in full-length EF to generate alanine EF(H351A) and arginine EF(H351R) variants. In vitro activity analysis displayed that the adenylyl cyclase activity of both the mutants was significantly diminished compared with the wild-type EF. When the native and mutant toxins were administered subcutaneously in a mouse footpad edema model, severe acute swelling was evoked by wild-type ET, while the symptoms induced by mutant toxins were very minor. Systemic administration of these EF variants caused non-lethal hepatotoxicity. In addition, EF(H351R) exhibited slightly higher activity in causing more severe edema than EF(H351A). Our findings demonstrate that the toxicity of ET is not abolished by substitution of EF residue His351 by alanine or arginine. These results also indicate the potential of the mouse footpad edema model as a sensitive method for evaluating both ET toxicity and the efficacy of candidate therapeutic agents. PMID:26848687

  16. Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet.

    Science.gov (United States)

    Mashhedi, Haider; Blouin, Marie-José; Zakikhani, Mahvash; David, Stéphanie; Zhao, Yunhua; Bazile, Miguel; Birman, Elena; Algire, Carolyn; Aliaga, Antonio; Bedell, Barry J; Pollak, Michael

    2011-08-15

    Insulin regulates glucose uptake by normal tissues. Although there is evidence that certain cancers are growth-stimulated by insulin, the possibility that insulin influences tumor glucose uptake as assessed by ( 18) F-2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography (FDG-PET) has not been studied in detail. We present a model of diet-induced hyperinsulinemia associated with increased insulin receptor activation in neoplastic tissue and with increased tumor FDG-PET image intensity. Metformin abolished the diet-induced increases in serum insulin level, tumor insulin receptor activation and tumor FDG uptake associated with the high energy diet but had no effect on these measurements in mice on a control diet. These findings provide the first functional imaging correlate of the well-known adverse effect of caloric excess on cancer outcome. They demonstrate that, for a subset of neoplasms, diet and insulin are variables that affect tumor FDG uptake and have implications for design of clinical trials of metformin as an antineoplastic agent. PMID:21811094

  17. The Yeast Prion [SWI+] Abolishes Multicellular Growth by Triggering Conformational Changes of Multiple Regulators Required for Flocculin Gene Expression

    Directory of Open Access Journals (Sweden)

    Zhiqiang Du

    2015-12-01

    Full Text Available Although transcription factors are prevalent among yeast prion proteins, the role of prion-mediated transcriptional regulation remains elusive. Here, we show that the yeast prion [SWI+] abolishes flocculin (FLO gene expression and results in a complete loss of multicellularity. Further investigation demonstrates that besides Swi1, multiple other proteins essential for FLO expression, including Mss11, Sap30, and Msn1 also undergo conformational changes and become inactivated in [SWI+] cells. Moreover, the asparagine-rich region of Mss11 can exist as prion-like aggregates specifically in [SWI+] cells, which are SDS resistant, heritable, and curable, but become metastable after separation from [SWI+]. Our findings thus reveal a prion-mediated mechanism through which multiple regulators in a biological pathway can be inactivated. In combination with the partial loss-of-function phenotypes of [SWI+] cells on non-glucose sugar utilization, our data therefore demonstrate that a prion can influence distinct traits differently through multi-level regulations, providing insights into the biological roles of prions.

  18. Beta-cell dysfunction is the primary contributor to the early postpartum diabetes among Chinese women with history of gestational diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    CAO Xiao-pei; XIAO Hai-peng; CHEN Song-jin; ZHAN Yan-feng; XIU Ling-ling; WANG Zi-lian

    2008-01-01

    Background Women with a history of gestational diabetes mellitus(GDM)are at higher risk of future development of diabetes. This study investigated the risk factors associated with early postpartum abnormal glucose regulation (AGR) among Chinese women with a history of GDM. Methods A total of 186 women with a history of GDM were screened for early postpartum AGR at 6-8 weeks after delivery. Those with AGR were given lifestyle intervention therapy and reevaluated in 6-12 months. The demographic, anthropometric, prenatal and delivery data were recorded. The plasma high-sensitivity C-reactive protein (HsCRP)and lipid concentration were measured, and insulin secretion were analyzed. Insulinogenic index △ins30'/△BG30', the homeostasis model assessment index(HOMA)-B, and HOMA-IR were calculated. Multiple regression analysis was performed to identify the risk factors. Results of the GDM women 28. O%(52/186)had AGR at 6-8 weeks after delivery;45. 2% (17/40) of these AGR women reminded abnormal after 6-12 month lifestyle intervention. Compared to the women who reverted to normal, women with consistent AGR showed significantly lower fasting insulin concentration, lower △ins30'/△BG30'as well aslower HOMA-B. No significant differences in age, body mass index(BMI), waist circumference, blood pressure, lipid level, HsCRP and HOMA-IR were observed between the two groups. Pre-pregnancy BMI>25 kg/m2. fasting glucose level≥5. 6 mmol/L and/or 75 g oral glucose tolerance test (OGTT)2 hours glucose level≥11. 1 mmol/L during pregnancy were predictors for the AGR at 6-8 weeks after delivery. △ins30'/△BG30≤1.05 was a significant risk contributor to the consistent early postpartum AGR. Conclusion There is a high incidence of early postpartum AGR among Chinese woman with prior GDM. Beta-cell dysfunction, rather than insulin resistance or inflammation, is the predominant contributor to the early onset and consistent AGR after delivery.

  19. 胰岛β细胞放射性核素分子显像研究进展%Research progress of radionuclide molecular imaging in pancreatic beta cells

    Institute of Scientific and Technical Information of China (English)

    刘帅; 张一帆

    2013-01-01

    Diabetes is a common disease that poses great threat to human health. At present, insulin replacement therapy remains the main treatment. In recent years, pancreatic beta cell transplantation has demonstrated potential prospect in treatment of type 1 diabetes, however, it is an important issue in clinical application on the non-invasive monitoring of in vivo pancreatic beta cell transplantation. Radionuclide molecular imaging technology, which has been developing rapidly with high sensitivity and specificity, has been widely applied in monitoring pancreatic beta cell transplantation, and has demonstrated favorable prospect in application.%糖尿病是严重威胁人类健康的常见病和多发病,胰岛素替代治疗是其主要的治疗手段.近年来,胰岛β细胞移植治疗1型糖尿病展示出潜在的应用前景,但如何在活体条件下无创地进行胰岛β细胞移植的监测,是目前临床应用所面临的重要问题.放射性核素分子显像技术近年来得到了快速发展,具有灵敏度高、特异性强等特点,在胰岛β细胞移植监测方面得到了广泛应用,展示了良好的应用前景.

  20. Gestational Diabetes Mellitus Worsens the Profile of Cardiometabolic Risk Markers and Decrease Indexes of Beta-Cell Function Independently of Insulin Resistance in Nondiabetic Women with a Parental History of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Alina Sokup

    2014-01-01

    Full Text Available Background. Women with a history of both parental type 2 diabetes (pt2DM and previous gestational diabetes (pGDM represent a group at high risk of cardiovascular events. We hypothesized that pGDM changes cardiometabolic risk markers levels as well as theirs associations with glucose indices in nondiabetic pt2DM women. Methods. Anthropometric parameters, glucose regulation (OGTT, insulin resistance (HOMA-IR, beta-cell function, lipid levels, parameters of endothelial dysfunction, and inflammation were evaluated in 55 women with pt2DM, 40 with both pt2DM and pGDM 2–24 months postpartum, and 35 controls. Results. Prediabetes was diagnosed more frequently in women with both pt2DM and pGDM in comparison with women with only pt2DM (10 versus 8, P=0.04. The pGDM group had higher LDL-cholesterol, sICAM-1, tPa Ag, fibrinogen, and lower beta-cell function after adjustment for HOMA-IR, in comparison with pt2DM group. In pt2DM group postchallenge glucose correlated independently with hsCRP and in pGDM group fasting glucose with HOMA-IR. Conclusions. pGDM exerts a combined effect on cardiometabolic risk markers in women with pt2DM. In these women higher LDL-cholesterol, fibrinogen, sICAM-1, tPa Ag levels and decreased beta cell function are associated with pGDM independently of HOMA-IR index value. Fasting glucose is an important cardiometabolic risk marker and is independently associated with HOMA-IR.

  1. NR2B antagonist CP-101,606 abolishes pitch-mediated deviance detection in awake rats

    Directory of Open Access Journals (Sweden)

    Siva eDigavalli

    2014-08-01

    Full Text Available Schizophrenia patients exhibit a decreased ability to detect change in their auditory environment as measured by auditory event related potentials such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence link NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detection. We recorded event related potentials from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30 mg/kg and a highly selective NR2B antagonist, CP-101,606 (10 or 30 mg/kg on deviance detection. Ketamine attenuated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant’s N1 amplitude and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia.

  2. Does enriched acoustic environment in humans abolish chronic tinnitus clinically and electrophysiologically? A double blind placebo controlled study.

    Science.gov (United States)

    Vanneste, Sven; van Dongen, Marijn; De Vree, Bjorn; Hiseni, Senad; van der Velden, Eddy; Strydis, Christos; Joos, Kathleen; Norena, Arnaud; Serdijn, Wouter; De Ridder, Dirk

    2013-02-01

    Animal research has shown that loss of normal acoustic stimulation can increase spontaneous firing in the central auditory system and induce cortical map plasticity. Enriched acoustic environment after noise trauma prevents map plasticity and abolishes neural signs of tinnitus. In humans, the tinnitus spectrum overlaps with the area of hearing loss. Based on these findings it can be hypothesized that stimulating the auditory system by presenting music compensating specifically for the hearing loss might also suppress chronic tinnitus. To verify this hypothesis, a study was conducted in three groups of tinnitus patients. One group listened just to unmodified music (i.e. active control group), one group listened to music spectrally tailored to compensate for their hearing loss, and a third group received music tailored to overcompensate for their hearing loss, associated with one (in presbycusis) or two notches (in audiometric dip) at the edge of hearing loss. Our data indicate that applying overcompensation to the hearing loss worsens the patients' tinnitus loudness, the tinnitus annoyance and their depressive feelings. No significant effects were obtained for the control group or for the compensation group. These clinical findings were associated with an increase in current density within the left dorsal anterior cingulate cortex in the alpha2 frequency band and within the left pregenual anterior cingulate cortex in beta1 and beta2 frequency band. In addition, a region of interest analysis also demonstrated an associated increase in gamma band activity in the auditory cortex after overcompensation in comparison to baseline measurements. This was, however, not the case for the control or the compensation groups. In conclusion, music therapy compensating for hearing loss is not beneficial in suppressing tinnitus, and overcompensating hearing loss actually worsens tinnitus, both clinically and electrophysiologically. PMID:23104014

  3. The antiestrogens tamoxifen and fulvestrant abolish estrogenic impacts of 17α-ethinylestradiol on male calling behavior of Xenopus laevis.

    Science.gov (United States)

    Hoffmann, Frauke; Kloas, Werner

    2012-01-01

    Various synthetic chemicals released to the environment can interfere with the endocrine system of vertebrates. Many of these endocrine disrupting compounds (EDCs) exhibit estrogenic activity and can interfere with sexual development and reproductive physiology. More recently, also chemicals with different modes of action (MOAs), such as antiestrogenic, androgenic and antiandrogenic EDCs, have been shown to be present in the environment. However, to date EDC-research primarily focuses on exposure to EDCs with just one MOA, while studies examining the effects of simultaneous exposure to EDCs with different MOAs are rare, although they would reflect more real, natural exposure situations. In the present study the combined effects of estrogenic and antiestrogenic EDCs were assessed by analyzing the calling behavior of short-term exposed male Xenopus laevis. The estrogenic 17α-ethinylestradiol (EE2), and the antiestrogenic EDCs tamoxifen (TAM) and fulvestrant (ICI) were used as model substances. As previously demonstrated, sole EE2 exposure (10-10 M) resulted in significant alterations of the male calling behavior, including altered temporal and spectral parameters of the advertisement calls. Sole TAM (10-7 M, 10-8 M, 10-10 M) or ICI (10-7 M) exposure, on the other hand, did not affect any of the measured parameters. If frogs were co-exposed to EE2 (10-10 M) and TAM (10-7 M) the effects of EE2 on some parameters were abolished, but co-exposure to EE2 and ICI (10-7 M) neutralized all estrogenic effects. Thus, although EDCs with antiestrogenic MOA might not exhibit any effects per se, they can alter the estrogenic effects of EE2. Our observations demonstrate that there is need to further investigate the combined effects of EDCs with various, not only opposing, MOAs as this would reflect realistic wildlife situations. PMID:23028589

  4. Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14

    International Nuclear Information System (INIS)

    Recent evidence indicates that methyl jasmonate (MJ), a plant stress hormone, exhibits anti-cancer activity on human cancer cells. The aim of this study is to determine whether sub-cytotoxic MJ can abolish the migration, invasion and angiogenesis gastric cancer cells. Human gastric cancer cell lines SGC-7901 and MKN-45 were treated with diverse concentrations of MJ. Cell viability, proliferation, migration, invasion and angiogenesis capabilities of cancer cells were measured by MTT colorimetry, EdU incorporation, scratch assay, matrigel invasion assay, and tube formation assay. Gene expression was detected by western blot and real-time quantitative RT-PCR. Binding of transcription factor on gene promoter was detected by chromatin immunoprecipitation. Sub-cytotoxic (0.05 to 0.2 mM) MJ attenuated the migration, invasion and angiogenesis, but not the cell viability or proliferation, of gastric cancer cells in a time- and dose-dependent manner, with down-regulation of matrix metalloproteinase 14 (MMP-14) and its downstream gene vascular endothelial growth factor. Restoration of MMP-14 expression rescued the SGC-7901 and MKN-45 cells from sub-cytotoxic MJ-inhibited migration, invasion and angiogenesis. In addition, sub-cytotoxic MJ decreased the specificity protein 1 (Sp1) expression and binding on MMP-14 promoter, while restoration of Sp1 expression rescued the cancer cells from sub-cytotoxic MJ-mediated defects in MMP-14 expression, migration, invasion and angiogenesis. Sub-cytotoxic MJ attenuates the MMP-14 expression via decreasing the Sp1 expression and binding on MMP-14 promoter, thus inhibiting the migration, invasion and angiogenesis of gastric cancer cells

  5. H2O2-Activated Mitochondrial Phospholipase iPLA2 gamma Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-Protein-Coupled Receptor GPR40, and Regulates Insulin Secretion in Pancreatic beta-Cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Jan; Dlasková, Andrea; Zelenka, Jaroslav; Jabůrek, Martin; Ježek, Petr

    2015-01-01

    Roč. 23, č. 12 (2015), s. 958-972. ISSN 1523-0864 R&D Projects: GA ČR(CZ) GPP303/11/P320; GA ČR(CZ) GA13-02033S; GA ČR(CZ) GA13-06666S; GA ČR GA15-02051S Institutional support: RVO:67985823 Keywords : mitochondrial phospholipase iPLA2 gamma * uncoupling protein UCP2 * G-protein coupled receptor - 40 * glucose -stimulated insulin secretion * pancreatic beta cells Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 7.407, year: 2014

  6. Frequency Of Pancreatic Beta-Cell Autoimmunity Markers In Patients With Autoimmune Thyroid Disease Frecuencia de marcadores de autoinmunidad beta pancreática en pacientes con enfermedad tiroidea autoinmune

    Directory of Open Access Journals (Sweden)

    María E. Primo

    2008-02-01

    Full Text Available A total of 305 ambulatory patients recruited at the Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, with autoimmune thyroid disease (AITD were studied to search for associations between autoimmune thyroid disease and presence of serum markers of autoimmune diabetes mellitus. Screening for markers of pancreatic beta-cell autoimmunity was performed by radioligand binding assays (RBA as follows: autoantibodies to glutamic acid decarboxylase (GADA and proinsulin (PAA were determined in all sera, whereas autoantibodies to protein tyrosine phosphatase (IA-2A and insulin (IAA were additionally measured in 200 sera randomly selected from the total collection. In addition, every GADA positive serum among the remaining 105 sera was systematically tested for the presence of IA-2A and IAA. In the cohort of 305 AITD patients 22 (7.2% were previously diagnosed as type 1, type 2 or insulin-requiring type 2 diabetics. Ten of these patients presented serum marker positivity specific for β-cell autoantigens and 12 were marker negative. On the other hand, considering the majority of non-diabetic AITD patients (n=283, β-cell marker positivity was detected in 17 individuals (6.0%. The prevalence of autoimmune diabetes markers was much higher in the studied population than in the general population utilized as a control group, and GADA was the most frequent marker.Se investigó la asociación entre enfermedad tiroidea autoinmune y la presencia de marcadores séricos de diabetes mellitus en 305 pacientes ambulatorios con enfermedad tiroidea autoinmune reclutados en la División Endocrinología. La búsqueda de marcadores de autoinmunidad contra las células beta pancreáticas se realizó por la técnica de unión de radioligandos (RBA como se detalla a continuación: se determinaron autoanticuerpos contra la decarboxilasa del ácido glutámico (GADA y proinsulina (PAA en todos los sueros, mientras que los anticuerpos contra la prote

  7. Inhibition of IkappaB kinase alpha (IKKα) or IKKbeta (IKKβ) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy

    International Nuclear Information System (INIS)

    Research highlights: → Independent inhibition of Foxo, IKKα and IKKβ activities does not alter muscle fiber size in weight bearing muscles. → Inhibition of Foxo activity plus IKKα or IKKβ activities increases muscle fiber size. → Independent inhibition of Foxo and IKKβ activities attenuates cast immobilization-induced muscle fiber atrophy. → Disuse muscle fiber atrophy is abolished by inhibition of Foxo activity plus IKKα or IKKβ activities. -- Abstract: Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor κB (NF-κB) and forkhead box O (Foxo). There is clear evidence that both NF-κB and Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-κB activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKKα and IKKβ), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKKα-EGFP, d.n. IKKβ-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKKα-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKKβ-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting

  8. D-saccharic acid-1,4-lactone ameliorates alloxan-induced diabetes mellitus and oxidative stress in rats through inhibiting pancreatic beta-cells from apoptosis via mitochondrial dependent pathway

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharya, Semantee [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Manna, Prasenjit [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India); Gachhui, Ratan [Department of Life Sciences and Biotechnology, Jadavpur University, 188, Raja S C Mullick Road, Kolkata 700 032 (India); Sil, Parames C., E-mail: parames@bosemain.boseinst.ac.in [Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054 (India)

    2011-12-15

    Oxidative stress plays a vital role in diabetic complications. To suppress the oxidative stress mediated damage in diabetic pathophysiology, a special focus has been given on naturally occurring antioxidants present in normal diet. D-saccharic acid 1,4-lactone (DSL), a derivative of D-glucaric acid, is present in many dietary plants and is known for its detoxifying and antioxidant properties. The aim of the present study was to evaluate the beneficial role of DSL against alloxan (ALX) induced diabetes in the pancreas tissue of Swiss albino rats. A dose-dependent study for DSL (20-120 mg/kg body weight) was carried out to find the effective dose of the compound in ALX-induced diabetic rats. ALX exposure elevated the blood glucose, glycosylated Hb, decreased the plasma insulin and disturbed the intra-cellular antioxidant machineries whereas oral administration of DSL at a dose of 80 mg/kg body weight restored these alterations close to normal. Investigating the mechanism of the protective activity of DSL we observed that it prevented the pancreatic {beta}-cell apoptosis via mitochondria-dependent pathway. Results showed decreased mitochondrial membrane potential, enhanced cytochrome c release in the cytosol and reciprocal regulation of Bcl-2 family proteins in the diabetic rats. These events were also found to be associated with increased level of Apaf-1, caspase 9, and caspase 3 that ultimately led to pancreatic {beta}-cell apoptosis. DSL treatment, however, counteracted these changes. In conclusion, DSL possesses the capability of ameliorating the oxidative stress in ALX-induced diabetes and thus could be a promising approach in lessening diabetic complications. Highlights: Black-Right-Pointing-Pointer Oxidative stress is suggested as a key event in the pathogenesis of diabetes. Black-Right-Pointing-Pointer D-saccharic acid 1,4-lactone (DSL) reduces the alloxan-induced diabetes mellitus. Black-Right-Pointing-Pointer DSL normalizes cellular antioxidant machineries

  9. Multinational study in children and adolescents with newly diagnosed type 1 diabetes: association of age, ketoacidosis, HLA status, and autoantibodies on residual beta-cell function and glycemic control 12 months after diagnosis

    DEFF Research Database (Denmark)

    Mortensen, H.B.; Swift, P.G.F.; Holl, R.W.;

    2010-01-01

    Objective: To identify predictors of residual beta-cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D). Subjects and Methods: Clinical information and blood samples were collected from 275 children. HbA1c, antibodies, HLA typing and mixed meal......-stimulated C-peptide levels 1, 6, and 12 months after diagnosis were analyzed centrally. Results: Mean age at diagnosis was 9.1 yr. DKA with standard bicarbonate cell function 1 (p = 0.004) and 12 months (p = 0.0003) after diagnosis. At 12...... months, the decline in stimulated C-peptide levels compared with the levels at 1 month was 69% in the youngest age group and 50% in patients 10 yr and above (p

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

    DEFF Research Database (Denmark)

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

    1992-01-01

    Synthetic peptides representing unique sequences in rat proinsulin C-peptide I and II were used to generate highly specific antisera, which, when applied on sections of normal rat pancreas, confirm a homogeneous coexpression of the two C-peptides in all islet beta-cells. Insulin gene expression is...... insulin-producing cells showed highly differential expression at the cellular level of the three proinsulin C-peptide immunoreactivities, as follows: C-peptide I greater than human C-peptide greater than C-peptide II. The fractions of cells expressing human C-peptide and C-peptide II decreased in time and...... species of proinsulin-C-peptide immunoreactivity but still at high levels. However, rat C-peptide II and human C-peptide were often colocalized, even in later passages. In situ hybridization studies combined with the immunocytochemical data suggest that the differential expression occurs at the level of...

  11. Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice.

    Directory of Open Access Journals (Sweden)

    Wendy W J Unger

    Full Text Available Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP. HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies.

  12. 咖啡因对链尿霉素诱发大鼠β-细胞损伤的保护作用%Protective effect of caffeine on streptozotocin - induced beta - cell damage in rats

    Institute of Scientific and Technical Information of China (English)

    梁艳; 陈充抒; 梁莉

    2011-01-01

    目的 探讨咖啡因对链尿霉素(streptozotocin,STZ)诱导大鼠β-细胞损伤的影响.方法 Wistar大鼠皮下注射生理盐水(对照组)或咖啡因(治疗组).15 min后,大鼠再皮下给柠檬酸缓冲或STZ(65 mg/kg).注射后第3天对大鼠进行口服葡萄糖耐量试验(OGTT).OGTT后第3天分离胰腺测定其中胰岛素水平.结果 STZ处理的大鼠,与对照组比较,在OGTT测试所有时间点都明显增加血浆葡萄糖水平.预先给咖啡因可明显减低ST2的升高血糖作用.STZ处理还可明显减少血浆胰岛素的浓度,但预先给咖啡因任何剂量不能逆转血浆胰岛素降低的作用.与对照组比较,STZ处理可明显降低胰腺中胰岛素水平.此作用也能被咖啡因所逆转.结论 此研究结果表明咖啡因对STZ损伤大鼠胰岛β-细胞,具有一定的保护效应.但要了解咖啡因对2型糖尿病患者β-细胞是否有保护效果尚需进一步研究.%Objective To investigate the effect of caffeine on pancreatic beta - cell damage in rats using the diabetogenic a-gent streptozotocin (STZ). Methods Wistar rats were given intraperitoneal injections of saline or caffeine(10,50 or 100 mg/kg). After 15 min, the rats were injected with a citrate buffer or 65 mg/kg STZ. Three days after injection, an oral glucose tolerance test(OG-TT)was performed on the rats. Furthermore, three days after the OG'IT, the pancreas was isolated and homogenized, followed by determination of the insulin content. Results STZ treatment significantly increased the plasma glucose level, compared with the control throughout the OGTT,which was significantly reduced by caffeine pretreatment at each dose. STZ treatment significantly decreased the plasma insulin level, which, however, was not recovered by caffeine pretre at merit. Pancreatic insulin content was significantly reduced by STZ treatment, compared with the control, which was significangly recovered by caffeine pretreatment. Conclusions Caffeine pro

  13. 骨形态发生蛋白7对胰岛素分泌的影响及机制研究%Bone morphorgenetic protein 7 improves insulin secretion from mouse pancreatic beta cell line MIN6

    Institute of Scientific and Technical Information of China (English)

    姜友昭; 曾俊; 陈兵

    2012-01-01

    Objective To determine the effect of bone morphorgenetic protein 7 ( BMP7) on insulin secretion in pancreatic beta cells. Methods The expression of three type I receptors of BMP7 , BMPR1 A, BMPR1B and ACVR1A, was detected by Western blotting in mouse pancreatic beta cell line MIN6. Then the MIN6 cells were treated respectively by PBS (control), low-, medium- and high-dose of rhBMP7 (final concentration of rhBMP7 was 10, 50, and 100 ng/ml). Then the insulin level of the culture media was detected by ELISA and the intracellular concentration of calcium was determined by laser confocal microscopy. Results BMPR1A, BMPR1B and ACVR1A were all expressed in the MIN6 cells. The insulin concentration of PBS, low-, medium- and high-dose rhBMP7 treatment was 0.42 ±0. 11, 0.63 ±0.22, 0.82+0.0.19 and 1.24 ±0. 26 ng/(ml ·μxg) , respectively. The insulin concentration of rhBMP7 treatment groups was significantly higher than that of the control (all P 0. 05). Conclusion BMP7 enhances insulin secretion significantly in pancreatic beta cells, which may be due to its regulation of calcium-independent exocytosis.%目的 探讨骨形态发生蛋白7(bone morphorgenetic protein 7,BMP7)对胰岛细胞胰岛素分泌的影响.方法 Westem blot检测小鼠胰岛细胞株MIN6中3种BMP7的Ⅰ型受体BMPR1A、BMPR 1B、ACVR1A的表达情况.将MIN6细胞分为4组:PBS对照组,重组人BMP7( rhBMP7)低、中、高剂量组(rhBMP7终浓度分别为10、50、100 ng/ml),每组设5个复孔.ELISA检测各组细胞培养基中的胰岛素分泌情况.激光共聚焦显微镜检测细胞内钙离子浓度变化.结果 BMPR1A、BMPR1B、ACVR1A均表达于MIN6细胞.PBS对照组及rhBMP7低、中、高剂量组的胰岛素浓度分别为(0.42±0.11)、(0.63±0.22)、(0.82±0.19)、( 1.24 -±0.26) ng/(ml· μg).与对照组相比,rhBMP7低、中、高剂量组的胰岛素分泌均明显增加(P<0.05).PBS对照组及rhBMP7低、中、高剂量组的细胞内钙离子浓度增加分别为(3.5

  14. Characterization of FKGK18 as inhibitor of group VIA Ca2+-independent phospholipase A2 (iPLA2β: candidate drug for preventing beta-cell apoptosis and diabetes.

    Directory of Open Access Journals (Sweden)

    Tomader Ali

    Full Text Available Ongoing studies suggest an important role for iPLA2β in a multitude of biological processes and it has been implicated in neurodegenerative, skeletal and vascular smooth muscle disorders, bone formation, and cardiac arrhythmias. Thus, identifying an iPLA2βinhibitor that can be reliably and safely used in vivo is warranted. Currently, the mechanism-based inhibitor bromoenol lactone (BEL is the most widely used to discern the role of iPLA2β in biological processes. While BEL is recognized as a more potent inhibitor of iPLA2 than of cPLA2 or sPLA2, leading to its designation as a "specific" inhibitor of iPLA2, it has been shown to also inhibit non-PLA2 enzymes. A potential complication of its use is that while the S and R enantiomers of BEL exhibit preference for cytosol-associated iPLA2β and membrane-associated iPLA2γ, respectively, the selectivity is only 10-fold for both. In addition, BEL is unstable in solution, promotes irreversible inhibition, and may be cytotoxic, making BEL not amenable for in vivo use. Recently, a fluoroketone (FK-based compound (FKGK18 was described as a potent inhibitor of iPLA2β. Here we characterized its inhibitory profile in beta-cells and find that FKGK18: (a inhibits iPLA2β with a greater potency (100-fold than iPLA2γ, (b inhibition of iPLA2β is reversible, (c is an ineffective inhibitor of α-chymotrypsin, and (d inhibits previously described outcomes of iPLA2β activation including (i glucose-stimulated insulin secretion, (ii arachidonic acid hydrolysis; as reflected by PGE2 release from human islets, (iii ER stress-induced neutral sphingomyelinase 2 expression, and (iv ER stress-induced beta-cell apoptosis. These findings suggest that FKGK18 is similar to BEL in its ability to inhibit iPLA2β. Because, in contrast to BEL, it is reversible and not a non-specific inhibitor of proteases, it is suggested that FKGK18 is more ideal for ex vivo and in vivo assessments of iPLA2β role in biological functions.

  15. Abolished ventilation and perfusion of lung caused by blood clot in the left main bronchus: auto-downregulation of pulmonary arterial blood supply.

    Science.gov (United States)

    Afzelius, P; Bergmann, A; Henriksen, J H

    2015-01-01

    It is generally assumed that the lungs possess arterial autoregulation associated with bronchial obstruction. A patient with pneumonia and congestive heart failure unexpectedly developed frequent haemoptysis. High-resolution CT and diagnostic CT were performed as well as ventilation/perfusion (V/Q) scintigraphy with single-photon emission CT (SPECT)/CT. V/Q SPECT/CT demonstrated abolished ventilation due to obstruction of the left main bronchus and markedly reduced perfusion of the entire left lung, a condition that was completely reversed after removal of a blood clot. We present the first pictorially documented case of hypoxia-induced pulmonary vasoconstriction and flow shift in a main pulmonary artery due to a complete intrinsic obstruction of the ipsilateral main bronchus. The condition is reversible, contingent on being relieved within a few days. PMID:26374773

  16. On Theory of Abolishment of Coerced Apology%“被迫的赔礼道歉”应被废除

    Institute of Scientific and Technical Information of China (English)

    孙尊航

    2014-01-01

    At present, Tort Liability Law stipulates that "Apology" can be divided into two types: "Voluntary Apology" and "Coerced Apology". Although the latter is affirmed by scholars, from the perspective of theory of legislation, it should be abolished. The reasons are as follows: (1) legislatures only need to have"Voluntary Apology"; (2)"Coerced Apology" is abolished in principle in United States, British, Canada, Columbia, France, Germany, Austria, Japan and Taiwan. (3) "Coerced Apology" can neither reduces or eliminates the plaintiff's anger, nor helps the defendant turn over a new leaf. The plaintiff can receive pensions for comfort.%目前,《侵权责任法》规定的“赔礼道歉”,可分为“自愿的赔礼道歉”和“被迫的赔礼道歉”。后者虽然目前为部分学者所肯定,但从立法论的角度来看应被废除。其理由是:(1)立法机关其实只希望拥有“自愿的赔礼道歉”。(2)美国、英国、加拿大哥伦比亚省、法国、德国、奥地利、日本、我国台湾地区原则上禁止强迫赔礼道歉。(3)“被迫的赔礼道歉”既不能减少或消除原告的愤怒,又无助于被告改过迁善,且原告可以获得慰抚金。

  17. Ekstrak Air Tapak Dara Menurunkan Kadar Gula dan Meningkatkan Jumlah Sel Beta Pankreas Kelinci Hiperglikemia (THE WATER EXTRACT OF TAPAK DARA DECREASES BLOOD GLUCOSE CONCENTRATION AND INCREASES INSULIN PRODUCTION BY PANCREATIC BETA-CELLS ON HYPERGLYCEMIC

    Directory of Open Access Journals (Sweden)

    Srikayati Widyastuti

    2012-03-01

    Full Text Available The present study was carried out to investigate the effects of tapak dara (Catharanthus roseus onblood glucose level and insulin profile in hyperglicemic rabbits. Fifeteen local male rabbits were used forthis study. The rabbits were randomly divided into five groups. Group 1 (K-, a control negative group;group 2 (K+, a control positive hipergliccemia; group 3 (KT1 and group 4 (KT2, were groups hiperglicemiaand treated with water extract of tapak dara doses 1 and 2 g/kg bw, respectively; and group 5 (KO, a grouphiperglicemia that treated with glibenclamide 2 mg/kg bw. The result showed water extract of tapak daradose 1 g/kgbw could not decrease the blood glucose level in hyperglycemic rabbits, while dose 2 g/kg bwcould decline blood glucose level in rabbits. This decline had no significantly difference compared withglibenclamide treatment (P> 0.05. Immunohistchemistry result indicated that water extract of tapakdara could stimulate beta cells pancreas to produce insulin.

  18. Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology

    Science.gov (United States)

    Beer, Nicola L.; Gloyn, Anna L.

    2016-01-01

    Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes. Such models facilitate investigation of diabetes-associated genomic perturbations in a physiologically representative cell context and allow the role of both developmental and adult islet dysfunction in T2D pathogenesis to be investigated. Accordingly, we interrogate the role that patient-derived induced pluripotent stem cell models are playing in understanding cellular dysfunction in monogenic diabetes, and how site-specific nucleases such as the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system are helping to confirm genes crucial to human endocrine pancreas development. We also highlight the novel biology gleaned in the absence of patient lines, including an ability to model the whole phenotypic spectrum of diabetes phenotypes occurring both in utero and in adult cells, interrogating the non-coding ‘islet regulome’ for disease-causing perturbations, and understanding the role of other islet cell types in aberrant glycaemia. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type. PMID:27508066

  19. Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Nicola L. Beer

    2016-07-01

    Full Text Available Type 2 diabetes (T2D is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes. Such models facilitate investigation of diabetes-associated genomic perturbations in a physiologically representative cell context and allow the role of both developmental and adult islet dysfunction in T2D pathogenesis to be investigated. Accordingly, we interrogate the role that patient-derived induced pluripotent stem cell models are playing in understanding cellular dysfunction in monogenic diabetes, and how site-specific nucleases such as the clustered regularly interspaced short palindromic repeats (CRISPR-Cas9 system are helping to confirm genes crucial to human endocrine pancreas development. We also highlight the novel biology gleaned in the absence of patient lines, including an ability to model the whole phenotypic spectrum of diabetes phenotypes occurring both in utero and in adult cells, interrogating the non-coding ‘islet regulome’ for disease-causing perturbations, and understanding the role of other islet cell types in aberrant glycaemia. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type.

  20. 重症儿童高血糖与胰腺β细胞功能障碍的研究%Relationship between hyperglycemia and pancreatic beta cell dysfunction in critically ill children

    Institute of Scientific and Technical Information of China (English)

    刘萍萍; 祝益民; 肖政辉; 张新萍; 仇君; 卢秀兰

    2014-01-01

    Objective To analyse the relationship between insulin resistance and the pancreatic beta cell dysfunction in critically ill children with hyperglycemia,to investigate the relationship between the pancreas injury and pancreatic beta cells dysfunction.Methods Seven hundred and thirty-six critically ill children admitted in PICU of Hunan Children's Hospital from Nov 2012 to Mar 2013 were reviewed and analyzed.According to the maximum intravenous blood glucose within 24 h after admission,they were divided into severely elevated group (blood glucose ≥11.1 mmol/L,n =67),slightly elevated group(blood glucose 6.1 ~ 11.1 mmol/L,n =361) and control group (blood glucose ≤ 6.1 mmo/L,n =308).Serum insulin,C peptide,serum amylase,lipase,urinary amylase,HOMA-β,HOMA-IR were compared among 3 groups.According to the severity of sepsis,they were divided into non-sepsis group (n =414),sepsis group (n =237),severe sepsis group (n =64),septic shock group (n =21).Blood glucose,serum insulin,C peptide,HOMA-βand HOMA-IR were compared among 4 groups.Results (l)The levels of insulin,C peptide,blood amylase,lipase and urine amylase were gradually increased with elevated blood sugar(rs =0.235,P < 0.05;C =0.142,P < 0.05 ; rs =0.142,P < 0.05 ; rs =0.119,P < 0.05 ; r.s =0.093,P < 0.05).The differences among 3 groups were significant (P < 0.05).The levels of serum amylase (IU/L) [102.81 (10.48-191.69)],lipase(U/L) [69.75(10.67-121.85)] were higher than upper limit of normal in severely elevated group.HOMA-β fell to 18.75% in severely elevated group.The level of HOMA-β was decreased with the increase of blood sugar level (rs =-0.108,P < 0.05).The level of HOMA-IR was increased with the elevated blood sugar level(rs =0.455,P < 0.05).(2) The levels of blood glucose,insulin,C peptide and HOMA-β were significantly different among 4 groups of non-sepsis,sepsis,severe sepsis and septic shock group (P < 0.05),HOMA-IR showed no significant difference among 4 groups (P > 0

  1. 唐代御史台狱置废探析%On the establishment and abolishment of the procuratorate jails in Tang dynasty

    Institute of Scientific and Technical Information of China (English)

    唐华全; 王旭

    2013-01-01

    The procuratorate jail is not initially established from the Tang dynasty , but since the Northern dynasties .Emperor Li Shimin sets up the procuratorate jails in 648 in order to strengthen the im-perial power and punish crimes .Emperor Li Longji abolishes the procuratorate jail in 726 in order to cen-tralize the power ,and effectively reduce natural disasters .But the procuratorate jail is indispensable ,so it is restored soon .%在御史台设置监狱并非始于唐代,唐代的御史台狱乃承袭北朝而来。唐太宗贞观二十二年,为了加强皇权,惩治百官犯罪,设置了御史台狱。唐玄宗开元十四年,为了使御史台内部权力得以集中,同时也是出于罢狱减灾的考虑,御史台狱一度被罢废。但御史台狱在唐代监狱体系中已不可或缺,故台狱罢废后不久,御史台又复置狱禁囚,此后直至唐末相沿未改。

  2. Withaferin A abolishes the stem cell factor-stimulated pigmentation of human epidermal equivalents by interrupting the auto-phosphorylation of c-KIT in human melanocytes.

    Science.gov (United States)

    Terazawa, Shuko; Nakajima, Hiroaki; Fukasawa, Katsunori; Imokawa, Genji

    2015-01-01

    We characterized the mechanism(s) underlying the abrogating effect of withaferin A (WFA) on the stem cell factor (SCF)-stimulated pigmentation of human epidermal equivalents (HEEs). Increased gene and protein expression levels of tyrosinase, tyrosinase-related protein1, dopachrome tautomerase, PMEL17, c-KIT and their targeted transcription factor, microphthalmia-associated transcription factor (MITF) were significantly reversed at days 7 and 10, respectively, by treatment with WFA. In WFA-treated normal human melanocytes (NHMs), there was a marked deficiency in the SCF-stimulated series of phosphorylations of c-KIT, Shc, Raf-1, MEK, ERK, MITF and CREB. Treatment with dithiothreitol (DTT) distinctly abolished the suppressive effect of WFA on the SCF-stimulated phosphorylation of c-KIT in NHMs. On the other hand, even after incubation at 4 °C for 2 h with 5 nM SCF, followed by the removal of unbound SCF by washing and then raising the temperature to 37 °C to start the signaling reaction, c-KIT was distinctly phosphorylated to a similar extent by incubation for 15 min with SCF only or with SCF + WFA. These findings indicate that WFA attenuates the SCF-induced activation of c-KIT in NHMs by interrupting the auto-phosphorylation of c-KIT through DTT-suppressible Michael addition thioalkylation reactions without interrupting the binding of SCF to the c-KIT receptor. PMID:25376854

  3. Changing a conserved amino acid in R2R3-MYB transcription repressors results in cytoplasmic accumulation and abolishes their repressive activity in Arabidopsis.

    Science.gov (United States)

    Zhou, Meiliang; Sun, Zhanmin; Wang, Chenglong; Zhang, Xinquan; Tang, Yixiong; Zhu, Xuemei; Shao, Jirong; Wu, Yanmin

    2015-10-01

    Sub-group 4 R2R3-type MYB transcription factors, including MYB3, MYB4, MYB7 and MYB32, act as repressors in phenylpropanoid metabolism. These proteins contain the conserved MYB domain and the ethylene-responsive element binding factor-associated amphiphilic repression (EAR) repression domain. Additionally, MYB4, MYB7 and MYB32 possess a putative zinc-finger domain and a conserved GY/FDFLGL motif in their C-termini. The protein 'sensitive to ABA and drought 2' (SAD2) recognizes the nuclear pore complex, which then transports the SAD2-MYB4 complex into the nucleus. Here, we show that the conserved GY/FDFLGL motif contributes to the interaction between MYB factors and SAD2. The Asp → Asn mutation in the GY/FDFLGL motif abolishes the interaction between MYB transcription factors and SAD2, and therefore they cannot be transported into the nucleus and cannot repress their target genes. We found that MYB4(D261N) loses the capacity to repress expression of the cinnamate 4-hydroxylase (C4H) gene and biosynthesis of sinapoyl malate. Our results indicate conservation among MYB transcription factors in terms of their interaction with SAD2. Therefore, the Asp → Asn mutation may be used to engineer transcription factors. PMID:26332741

  4. Antibodies against Tityus discrepans venom do not abolish the effect of Tityus serrulatus venom on the rat sodium and potassium channels.

    Science.gov (United States)

    Borges, A; Tsushima, R G; Backx, P H

    1999-06-01

    Anti-(Tityus serrulatus + Tityus bahiensis) and anti-Tityus discrepans venom polyclonal antisera were used to investigate whether antigenic differences exist between the venoms of the Brazilian T. serrulatus and the Venezuelan T. discrepans scorpions. Both antisera recognised the toxin-containing electrophoretic fractions of their cognate venoms and also those from Tityus zulianus and Tityus trinitatis venoms on Western blots. The anti-T. discrepans antiserum reacted only weakly with T. serrulatus toxic polypeptides. The effect of T. serrulatus alpha- or beta-toxins on rat skeletal muscle Na+ channels expressed in Xenopus laevis oocytes was abolished by pre-incubating the venom with anti-(T. serrulatus + T. bahiensis) serum but not with anti-T. discrepans serum. Nor did the Brazilian or the Venezuelan sera prevent the reduction in K+ currents by T. serrulatus venom in X. laevis oocytes expressing the rat brain delayed rectifying Shaker K+ channel (Kv1.2). These results indicate that toxins from T. serrulatus and T. discrepans venoms, which primarily target mammalian Na+ channels, are antigenically distinct, although they probably share common epitopes. Our results also suggest that Na+ channel-active toxins are the immunodominant antigens of the T. serrulatus venom. PMID:10340827

  5. Serum levels of pancreatic stone protein (PSP/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY carriers from the third decade of life onward

    Directory of Open Access Journals (Sweden)

    Bacon Siobhan

    2012-07-01

    Full Text Available Abstract Background Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A result in the commonest type of maturity onset diabetes of the young (MODY. HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis. Methods We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY, and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed. Results PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37 subjects compared to controls (n = 60 (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008. PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02. Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02 with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes. Conclusion Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over

  6. Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

    LENUS (Irish Health Repository)

    Bacon, Siobhan

    2012-07-18

    AbstractBackgroundMutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein\\/regenerating (PSP\\/reg) gene in surviving neighbour cells, and that PSP\\/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP\\/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.MethodsWe analysed serum PSP\\/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.ResultsPSP\\/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng\\/ml, IQR = 10.61-17.87 ng\\/ml versus median = 10.72 ng\\/ml, IQR = 8.94-12.54 ng\\/ml, p = 0.0008). PSP\\/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP\\/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP\\/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP\\/reg1A compared to controls, however this was independent of the duration of diabetes.ConclusionOur data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and

  7. Toward beta cell replacement for diabetes

    OpenAIRE

    Johannesson, Bjarki; Sui, Lina; Freytes, Donald O.; Creusot, Remi J.; Egli, Dieter

    2015-01-01

    The discovery of insulin more than 90 years ago introduced a life-saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserve...

  8. 再论嫖宿幼女罪之存废%Reanalysis of Reserving or Abolishing Crime of Prostituting Girls under the Age of 1 4

    Institute of Scientific and Technical Information of China (English)

    黄明儒; 向夏厅

    2014-01-01

    关于嫖宿幼女罪的论争,保留论者对嫖宿幼女罪合理性的论证理由不够充分,因为该罪名在立法目的、条文设置、司法实践与效益对比诸方面均存在缺陷,并且无法通过解释论进行解决。从短期来看,在没有相关司法解释或者立法修改时,司法上应该废弃嫖宿幼女罪的适用,将相关行为纳入相关犯罪条目进行规制;从长期着眼,应该坚持平等保护幼女合法权益的基本刑事政策,彻底废除嫖宿幼女罪罪名。%Those who are for reserving the crime of prostituting girls under the age of 14 don't give enough argu-ment.The crime has several defects in legislative purpose,provision's setting,juridical practice,benefit imbal-ance and etc.What's worse,these defects can't be settled by theory of interpretation.For the short term,the crime of prostituting girls under the age of 14 shall be ceased to apply in justice,and relative behaviors shall be regulated by means of being involved in relative crime until relative judicial interpretation or legislation amendment come out.For the long term,we should keep the basic criminal policies which equally protect the legal rights and benefits of girls under the age of 14,and abolish the crime of prostituting girls under the age of 14 completely.

  9. Conditional knockout of TMEM16A/anoctamin1 abolishes the calcium-activated chloride current in mouse vomeronasal sensory neurons.

    Science.gov (United States)

    Amjad, Asma; Hernandez-Clavijo, Andres; Pifferi, Simone; Maurya, Devendra Kumar; Boccaccio, Anna; Franzot, Jessica; Rock, Jason; Menini, Anna

    2015-04-01

    Pheromones are substances released from animals that, when detected by the vomeronasal organ of other individuals of the same species, affect their physiology and behavior. Pheromone binding to receptors on microvilli on the dendritic knobs of vomeronasal sensory neurons activates a second messenger cascade to produce an increase in intracellular Ca(2+) concentration. Here, we used whole-cell and inside-out patch-clamp analysis to provide a functional characterization of currents activated by Ca(2+) in isolated mouse vomeronasal sensory neurons in the absence of intracellular K(+). In whole-cell recordings, the average current in 1.5 µM Ca(2+) and symmetrical Cl(-) was -382 pA at -100 mV. Ion substitution experiments and partial blockade by commonly used Cl(-) channel blockers indicated that Ca(2+) activates mainly anionic currents in these neurons. Recordings from inside-out patches from dendritic knobs of mouse vomeronasal sensory neurons confirmed the presence of Ca(2+)-activated Cl(-) channels in the knobs and/or microvilli. We compared the electrophysiological properties of the native currents with those mediated by heterologously expressed TMEM16A/anoctamin1 or TMEM16B/anoctamin2 Ca(2+)-activated Cl(-) channels, which are coexpressed in microvilli of mouse vomeronasal sensory neurons, and found a closer resemblance to those of TMEM16A. We used the Cre-loxP system to selectively knock out TMEM16A in cells expressing the olfactory marker protein, which is found in mature vomeronasal sensory neurons. Immunohistochemistry confirmed the specific ablation of TMEM16A in vomeronasal neurons. Ca(2+)-activated currents were abolished in vomeronasal sensory neurons of TMEM16A conditional knockout mice, demonstrating that TMEM16A is an essential component of Ca(2+)-activated Cl(-) currents in mouse vomeronasal sensory neurons. PMID:25779870

  10. Mutation of Serine 32 to Threonine in Peroxiredoxin 6 Preserves Its Structure and Enzymatic Function but Abolishes Its Trafficking to Lamellar Bodies.

    Science.gov (United States)

    Sorokina, Elena M; Dodia, Chandra; Zhou, Suiping; Tao, Jian-Qin; Gao, Ling; Raabe, Tobias; Feinstein, Sheldon I; Fisher, Aron B

    2016-04-22

    Peroxiredoxin 6 (Prdx6), a bifunctional protein with phospholipase A2 (aiPLA2) and GSH peroxidase activities, protects lungs from oxidative stress and participates in lung surfactant phospholipid turnover. Prdx6 has been localized to both cytosol and lamellar bodies (LB) in lung epithelium, and its organellar targeting sequence has been identified. We propose that Prdx6 LB targeting facilitates its role in the metabolism of lung surfactant phosphatidylcholine (PC). Ser-32 has been identified as the active site in Prdx6 for aiPLA2 activity, and this activity was abolished by the mutation of serine 32 to alanine (S32A). However, aiPLA2 activity was unaffected by mutation of serine 32 in Prdx6 to threonine (S32T). Prdx6 protein expression and aiPLA2 activity were normal in the whole lung of a "knock-in" mouse model carrying an S32T mutation in the Prdx6 gene but were absent from isolated LB. Analyses by proximity ligation assay in lung sections demonstrated the inability of S32T Prdx6 to bind to the chaperone protein, 14-3-3ϵ, that is required for LB targeting. The content of total phospholipid, PC, and disaturated PC in lung tissue homogenate, bronchoalveolar lavage fluid, and lung LB was increased significantly in Prdx6-S32T mutant lungs, whereas degradation of internalized [(3)H]dipalmitoyl-PC was significantly decreased. Thus, Thr can substitute for Ser for the enzymatic activities of Prdx6 but not for its targeting to LB. These results confirm an important role for LB Prdx6 in the degradation and remodeling of lung surfactant phosphatidylcholine. PMID:26921317

  11. Osmanli Devletinin İkilemi: Gedik İhdası ya da İlgası The Dilemma Of The Ottoman State: Establishing New Gediks Or Abolishing Them

    Directory of Open Access Journals (Sweden)

    Miyase KOYUNCU

    2013-07-01

    Full Text Available This study aims to analyse the Ottoman state's dilemma on establishing new gediks or abolishing them in late eighteenth and early nineteenth centuries. This study is limited to Ottoman capital city, Istanbul which presented many examples of gediks. Selim III was the first sultan being aware of inflationary effect of gedik in commodity prices. Even if he aimed to abolish the gedik as a monopolistic right of artisans which was gradually interfering into the right of proprietorship, in practise state created confusion itself sometimes by forbidding new gediks and sometimes by giving permission to establishment of gediks. He also tried to put a limit on the inheritance of this right but not the inheritance of tools and equipment. As a traditional reformist, Selim III tried to preserve existing order and put an end new establishments, in practise he gave discordant desicions. Mahmud II's all attempts on gediks seem to find financial support for his reforms. While he was trying to give "order" to institution of gedik by gathering all of them under the framework of vakıfs and admitting limitations in some crafts/trades, he also opened the way of unrestricted gediks on field of new fashions. In order to understand the state's manner and artisans' attitude to developments concerning the institution of gedik which has been regarded as a constituent element of the Ottoman guild system, the origin of the word gedik, its meaning in artisans' world, the artisans' approach to the development of gedik rights concerning the social and economic conditions in Ottoman capital city are discussed throughout the study. Besides, in this study it is argued that gedik was not only an innovation imposed by the Ottoman ruling men but it was also an instrument of the artisans for preserving their livelihood. As a conclusion, the paper discusses the problem of abolishment process of gedik institution after Tanzimat era. Bu çalışma, Osmanlı Devleti'nin on sekizinci y

  12. 酮替芬对2型糖尿病大鼠胰岛β细胞氧化应激的影响%Effect of ketotifen on oxidative stress of pancreatic beta cells of type 2 diabetic rats

    Institute of Scientific and Technical Information of China (English)

    陈咨苗; 倪连松; 王美荣; 潘亮亮; 胡万里

    2013-01-01

    OBJECTIVE To investigate the effect and mechanism of ketotifen on oxidative stress of pancreatic beta cells in streptozotocin-induced type 2 diabetic rats.METHODS Male SD rats were fed with high-carbon hydrate-fat diet 6 weeks and ip given STZ to induce a type 2 diabetes model.Rats of ketotifen group were given ketotifen 0.09 mg· kg-1 for 8 weeks.The fasting blood glucose (FBG),free fatty acid (FFA),triglyceride(TG) and low density lipoprotein cholesterin (LDL-C),interleukin-6(IL-6)and tumor necrosis factor-alpha (TNF-α) were analyzed,the content of malondialdehyde(MDA) and the activity of superoxide dismutase (SOD) in pancreatic tissue were measured,the activities of cytochrome C oxidase (CCO) and succinate dehydrogenase (SDH) in pancreatic cells mitochondria were tested,Histomorphology were observed by transmission electron microscope.RESULTS Compared with normal control group,FBG levels in diabetic rats significantly increased (P < 0.01),FFA,TG and LDL-C levels in diabetic rats increased(P <0.05),IL-6 and TNF-α levels in diabetic rats increased(P <0.05),the content of MDA increased while the activites of SOD,CCO and SDH decreased (P < 0.05).Compared with model group,ketotifen 0.09 mg·kg-1 suppressed serum glucose in diabetic rats to (15.9 ± 1.9)mmol·L-1,and reduced FFA,TG and LDL-C levels to 0.71 ±0.15,2.36 ±0.40 and (.56 ± 0.30) mmol· L-1.Ketotifen 0.09 mg· kg-1 could significantly decrease IL-6 and TNF-α levels to (33.84 ± 3.82)ng· L-1 and (1.12 ± 0.27) μg· L-1,reduced M DA content to (0.87 ± 0.20) μmol· g-1,and increased theactivitesofSOD,CCO and SDH to (31.34 ±2.59)kU·g-1,(15.87±1.64)mmol·g-1 and (4.92±0.50) kU· g-1.Transmission electron microscope observation showed that beta cells morphological structure were improved by ketotifen.CONCLUSION Ketotifen has protective effects on pancreatic beta cells by reduction of inflammation medium and free fatty acid leves,alleviation of oxidative stress and improvement of islet cell

  13. Motorcycle Parts

    Science.gov (United States)

    1993-01-01

    An article in NASA Tech Briefs describing a vacuum bagging process for forming composite parts helped a small Oklahoma Company to improve its manufacturing process. President of Performance Extremes, Larry Ortega, and his partners make motorcycle parts from carbon/epoxy to reduce weight. Using vacuum bags, parts have a better surface and fewer voids inside. When heat used in the vacuum bag process caused deformation upon cooling, a solution found in another tech brief solved the problem. A metal plate inside the vacuum bag made for more even heat transfer. A third article described a simple procedure for repairing loose connector pins, which the company has also utilized.

  14. Inhibition of IkappaB kinase alpha (IKK{alpha}) or IKKbeta (IKK{beta}) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Reed, S.A. [Department of Physical Therapy, University of Florida, 101 S. Newell Drive, Gainesville, FL 32610 (United States); Senf, S.M. [Department of Applied Physiology and Kinesiology, University of Florida, 25 Stadium Road, Gainesville, FL 32610 (United States); Cornwell, E.W.; Kandarian, S.C. [Department of Health Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215 (United States); Judge, A.R., E-mail: arjudge@phhp.ufl.edu [Department of Physical Therapy, University of Florida, 101 S. Newell Drive, Gainesville, FL 32610 (United States)

    2011-02-18

    Research highlights: {yields} Independent inhibition of Foxo, IKK{alpha} and IKK{beta} activities does not alter muscle fiber size in weight bearing muscles. {yields} Inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities increases muscle fiber size. {yields} Independent inhibition of Foxo and IKK{beta} activities attenuates cast immobilization-induced muscle fiber atrophy. {yields} Disuse muscle fiber atrophy is abolished by inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities. -- Abstract: Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor {kappa}B (NF-{kappa}B) and forkhead box O (Foxo). There is clear evidence that both NF-{kappa}B and Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-{kappa}B activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKK{alpha} and IKK{beta}), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKK{alpha}-EGFP, d.n. IKK{beta}-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKK{alpha}-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKK{beta}-EGFP and d.n. Foxo-DsRed inhibited the immobilization

  15. Part two

    DEFF Research Database (Denmark)

    Nielsen, Mads Pagh; Kær, Søren Knudsen; Korsgaard, Anders

    2008-01-01

    A novel micro combined heat and power system and a dynamic model thereof were presented in part one of the publication. In the following, the control system and dynamic performance of the system are presented. The model is subjected to a measured consumption pattern of 25 Danish single family hou...

  16. Balsamic Vinegar Improves High Fat-Induced Beta Cell Dysfunction via Beta Cell ABCA1

    Directory of Open Access Journals (Sweden)

    Hannah Seok

    2012-08-01

    Full Text Available BackgroundThe aim of this study was to investigate the effects of balsamic vinegar on β-cell dysfunction.MethodsIn this study, 28-week-old Otsuka Long-Evans Tokushima Fatty (OLETF rats were fed a normal chow diet or a high-fat diet (HFD and were provided with tap water or dilute balsamic vinegar for 4 weeks. Oral glucose tolerance tests and histopathological analyses were performed thereafter.ResultsIn rats fed both the both chow diet and the HFD, the rats given balsamic vinegar showed increased insulin staining in islets compared with tap water administered rats. Balsamic vinegar administration also increased β-cell ATP-binding cassette transporter subfamily A member 1 (ABCA1 expression in islets and decreased cholesterol levels.ConclusionThese findings provide the first evidence for an anti-diabetic effect of balsamic vinegar through improvement of β-cell function via increasing β-cell ABCA1 expression.

  17. A physiological increase of insulin in the olfactory bulb decreases detection of a learned aversive odor and abolishes food odor-induced sniffing behavior in rats.

    Directory of Open Access Journals (Sweden)

    Pascaline Aimé

    Full Text Available Insulin is involved in multiple regulatory mechanisms, including body weight and food intake, and plays a critical role in metabolic disorders such as obesity and diabetes. An increasing body of evidence indicates that insulin is also involved in the modulation of olfactory function. The olfactory bulb (OB contains the highest level of insulin and insulin receptors (IRs in the brain. However, a role for insulin in odor detection and sniffing behavior remains to be elucidated. Using a behavioral paradigm based on conditioned olfactory aversion (COA to isoamyl-acetate odor, we demonstrated that an intracerebroventricular (ICV injection of 14 mU insulin acutely decreased olfactory detection of fasted rats to the level observed in satiated animals. In addition, whereas fasted animals demonstrated an increase in respiratory frequency upon food odor detection, this effect was absent in fasted animals receiving a 14 mU insulin ICV injection as well as in satiated animals. In parallel, we showed that the OB and plasma insulin levels were increased in satiated rats compared to fasted rats, and that a 14 mU insulin ICV injection elevated the OB insulin level of fasted rats to that of satiated rats. We further quantified insulin receptors (IRs distribution and showed that IRs are preferentially expressed in the caudal and lateral parts of the main OB, with the highest labeling found in the mitral cells, the main OB projection neurons. Together, these data suggest that insulin acts on the OB network to modulate olfactory processing and demonstrate that olfactory function is under the control of signals involved in energy homeostasis regulation and feeding behaviors.

  18. Pinealectomy abolishes circadian behavior and interferes with circadian clock gene oscillations in brain and liver but not retina in a migratory songbird.

    Science.gov (United States)

    Trivedi, Amit Kumar; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod

    2016-03-15

    In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings. PMID:26801391

  19. “消灭哲学”与“扬弃哲学”之辩及其意义%Significance of Debate on“Abolish philosophy” and “Transcend philosophy”

    Institute of Scientific and Technical Information of China (English)

    彭玉峰

    2014-01-01

    马克思在其早期著作中多次提出要“消灭哲学”,这是马克思主义哲学的研究者必须给出解释的问题。对此,俞吾金教授认为,这句话的中文翻译有误,马克思的原义是要扬弃哲学。根据马克思相关文本的中译文和英译文,从“消灭哲学”的出场语境出发,得出结论,“消灭哲学”的翻译无误。但是马克思原义是要消灭具有意识形态特征的那种哲学而并非所有哲学。俞吾金教授所提出的翻译问题具有重要的现实意义,它提醒人们将马克思的格言放入特定的文本语境中来理解,而不是脱离语境任意的引用。%In his early works, Marx talked about“abolish philosophy” several times, of which researchers of Marxist philosophy must explain.Professor Yu Wujin claims that the translation of the phrase is wrong , which should be interpreted as“transcend philosophy”.This paper , according to the Chinese version and the English ver-sion of Marx’ s relative works, on the base of context of“abolish philosophy”,conclude that the translation of“auf-heben” to“abolish” is right.However , Marx meant to abolish philosophy as ideology but not all philosophies.The appeal of Professor Yu Wujin has a realistic significance , which remind us to comprehend Marx ’ s maxim upon its context but not to cite it arbitrarily.

  20. Improved effect of acupuncture on insulin expression of islet beta cells in type 2 diabetes rats%针刺提高2型糖尿病模型大鼠胰岛β细胞胰岛素的表达

    Institute of Scientific and Technical Information of China (English)

    孙志; 马丽; 韩海荣; 张作记; 孔令斌

    2012-01-01

    BACKGROUND: Acupuncture for type 2 diabetes has obtained good clinical effects. OBJECTIVE: To observe the effect of acupuncture on insulin expression of islet beta cells in type 2 diabetes rats. METHODS: The diabetes model rats were randomly divided into acupuncture, rosiglitazone, model and normal control groups. Acupoints of Zusanli, Neiting and Yishu were selected in the acupuncture group for needling. Rosiglitazone (0.2 mg/kg) were given intragastrically in the rosiglitazone group. Double distilled water (2 mL/kg) was given intragastrically in the model group once daily for 4 consecutive weeks. RESULTS AND CONCLUSION: (T) Blood glucose level of the acupuncture group was significantly lowerthan that of the model and rosiglitazone groups (P < 0.05). (2) Blood lipid: Cholesterol and triglyceride of the acupuncture group were significantly lowerthan those of the model group (P < 0.05), and high-density lipoprotein cholesterol of the acupuncture group was significantly higher than that of the model group (P < 0.01). The above three indicators between the acupuncture and rosiglitazone groups had no significant difference. (3) The insulin expression of islet beta cells in the acupuncture group was significantly higher than that of the model and rosiglitazone groups (P < 0.05). @ Morphology of islet: Islet structure was incomplete and damaged, and the staining of insulin was poor in the model and rosiglitazone groups. Islet structure tended to be complete, and staining of insulin was visible in the acupuncture group. It is indicated that acupuncture can significantly increase the insulin expression and improve the function of islet beta cells in type 2 diabetes rats.%背景:针刺治疗2型糖尿病具有很好的疗效.目的:观察针刺对2型糖尿病模型大鼠胰岛β细胞胰岛素表达的影响.方法:将糖尿病模型大鼠按随机化原则分为针刺组、西药组、模型组,同时设置正常对照组.针刺组大鼠取足三里、内庭和胰俞穴

  1. University fee should not be abolished

    Institute of Scientific and Technical Information of China (English)

    谢凯

    2011-01-01

    @@ University Education is a quasi-public good, which guarantees that the university fee possesses the properties of quasi-price mechanism.Equivalently, university fee is a window into the price, with the function of price mechanism, however, as far as some aspects are concerned; university charges system has about flaws and failure to coordinate with the whole market demand.Consequently, in order to improve the efficiency, the universities should make the full use of the lever effect of price mechanism on university fee system.In the condition of market economy, this paper is targeted to explore the possibilities on maintaining university fees safely enough through the investigation on rudimental research of the properties of public goods and the externalities analysis, and signaling and separating equilibrium.

  2. Regional impacts of abolishing direct payments

    DEFF Research Database (Denmark)

    Uthes, Sandra; Priorr, Annette; Zander, Peter;

    2011-01-01

    The direct payment system of the Common Agricultural Policy (CAP) provides income transfers to European farmers. Recently, several countries including England and Sweden have advocated the elimination of direct payments after 2013. The extent to which an elimination of direct payments would affect...

  3. Should 'Anti-Corruption' Accounts Be Abolished?

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    The "account against corruption" originated in Ningbo, Zhejiang Province. At the beginning of 2000, after Xu Yunhong, former Secretary of the Ningbo Municipal Committee of the Communist Party of China, and some other top officials were arrested on corruption charges, the municipal government set up China's

  4. Manhattan project II: Abolishing nuclear weapons

    International Nuclear Information System (INIS)

    Most people seem to think that the era of nuclear danger is over, that it ended along with the Cold War. Whatever residual problems remain in terms of proliferation or possible terrorism, they believe, are being dealt urgently and adequately by their national leaders. Unfortunately, they are wrong on both counts. Although the risk of nuclear war between the NATO and former Warsaw Pact powers has virtually vanished, the chance that some nuclear weapons will kill many people, may be higher than before. The elimination of nuclear weapons, meaning rejection of terrorism, must be accomplished by multilateral collaboration. To recover fundamental moral bearings, as well as to preserve life and civilization, the USA, Russia, Great Britain, France, China, India and Pakistan must cease to be terrorist states

  5. Steroids Update, Part 1 and Part 2.

    Science.gov (United States)

    Miller, Calvin; Duda, Marty

    1986-01-01

    Part 1 of this two-part article describes the views of a physician who believes that athletes who want to take steroids are best protected by receiving a prescription and monitoring. Part 2 discusses the more general view of physicians that steroids should not be prescribed but perhaps should be monitored. (MT)

  6. 嫖宿幼女罪存与废之立法选择%Legislative Choice of Reserving or Abolishing the Crime of Prostituting Girls under the Age of 1 4

    Institute of Scientific and Technical Information of China (English)

    刘飞; 温建辉

    2014-01-01

    The crime of prostituting girls under the age of 14 in Chinese Criminal Law are overlapped with other similar crimes in the legislation,and the legal punishment setting is not reasonable,which causes controversy on its judicial application,and raises the discussion about reserving or abolishing the crime of prostituting girls under the age of 14.It is necessary to reserve the crime of prostituting girls under the age of 14 in China's Criminal Law. The existing controversy on the judicial application should be solved by the perfection of legislation.%我国刑法中的嫖宿幼女罪在立法上与其他相近罪名存在重叠现象,法定刑设置不甚合理,导致司法适用上存在争议,并引起嫖宿幼女罪存与废的讨论。我国刑法中有必要保留嫖宿幼女罪,在司法适用中存在的争议应当依赖立法完善予以解决。

  7. Rev1, Rev3, or Rev7 siRNA Abolishes Ultraviolet Light-Induced Translesion Replication in HeLa Cells: A Comprehensive Study Using Alkaline Sucrose Density Gradient Sedimentation

    Directory of Open Access Journals (Sweden)

    Jun Takezawa

    2010-01-01

    Full Text Available When a replicative DNA polymerase stalls upon encountering a lesion on the template strand, it is relieved by other low-processivity polymerase(s, which insert nucleotide(s opposite the lesion, extend by a few nucleotides, and dissociate from the 3′-OH. The replicative polymerase then resumes DNA synthesis. This process, termed translesion replication (TLS or replicative bypass, may involve at least five different polymerases in mammals, although the participating polymerases and their roles have not been entirely characterized. Using siRNAs originally designed and an alkaline sucrose density gradient sedimentation technique, we verified the involvement of several polymerases in ultraviolet (UV light-induced TLS in HeLa cells. First, siRNAs to Rev3 or Rev7 largely abolished UV-TLS, suggesting that these 2 gene products, which comprise Polζ, play a main role in mutagenic TLS. Second, Rev1-targeted siRNA also abrogated UV-TLS, indicating that Rev1 is also indispensable to mutagenic TLS. Third, Polη-targeted siRNA also prevented TLS to a greater extent than our expectations. Forth, although siRNA to Polι had no detectable effect, that to Polκ delayed UV-TLS. To our knowledge, this is the first study reporting apparent evidence for the participation of Polκ in UV-TLS.

  8. Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin may alter LH release patterns by abolishing sex differences in GABA/glutamate cell number and modifying the transcriptome of the male anteroventral periventricular nucleus.

    Science.gov (United States)

    Del Pino Sans, Javier; Clements, Kelsey J; Suvorov, Alexander; Krishnan, Sudha; Adams, Hillary L; Petersen, Sandra L

    2016-08-01

    Developmental exposure to arylhydrocarbon receptor (AhR) ligands abolishes sex differences in a wide range of neural structures and functions. A well-studied example is the anteroventral periventricular nucleus (AVPV), a structure that controls sex-specific luteinizing hormone (LH) release. In the male, testosterone (T) secreted by the developing testes defeminizes LH release mechanisms; conversely, perinatal AhR activation by 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) blocks defeminization. To better understand developmental mechanisms altered by TCDD exposure, we first verified that neonatal TCDD exposure in male rats prevented the loss of AVPV GABA/glutamate neurons that are critical for female-typical LH surge release. We then used whole genome arrays and quantitative real-time polymerase chain reaction (QPCR) to compare AVPV transcriptomes of males treated neonatally with TCDD or vehicle. Our bioinformatics analyses showed that TCDD enriched gene sets important for neuron development, synaptic transmission, ion homeostasis, and cholesterol biosynthesis. In addition, upstream regulatory analysis suggests that both estrogen receptors (ER) and androgen receptors (AR) regulate genes targeted by TCDD. Of the 23 mRNAs found to be changed by TCDD at least 2-fold (pbrain. These findings provide new insights into how TCDD may interfere with defeminization of LH release patterns. PMID:27185484

  9. 论授益行政行为的废止--基于《德国行政程序法》第49条的分析%On abolishment of beneficial administrative action--Based on the article 49 of the German Administrative Procedure Act

    Institute of Scientific and Technical Information of China (English)

    李垒

    2014-01-01

    The topic of abolishment about beneficial administrative action has been specially provided in article 49 of the German Administrative Act. Generally, administrative organs don’t abolish beneficial administrative action for the sake of trust protection as well as the law of stability. But under some statutory conditions, administrative organs can also abolish beneficial administrative action and the private party’s reliance compensation must be considered at the same time. In the respect for effect of abolishment about beneficial administrative action, the effectiveness of abolishment usually happens to the future but not retroactive. However, there are some exceptions in some cases. The German act about abolishment of the beneficial administration has provided the beneficial revelation to our country both in the field of legislative language about abolishment of beneficial administrative action and about the application in specific content.%关于授益行政行为的废止,《德国行政程序法》第49条有专门规定。对于合法的授益行政行为,出于信赖保护以及法安定性的考虑,行政机关原则上不得废止,但特定情形下,也可废止,并对相对人的信赖损失予以补偿。至于废止生效的时点,一般仅限于废止行为作出之时,除非行政机关选择溯及至某一较迟的时点。德国的授益行政行为废止制度,无论是在废止的立法用语方面,还是在具体的授益行政行为废止内容方面,都对我国立法提供了有益的启示。

  10. STUDY ON THE CORRELATION OF SERUM TRACE ELEMENTS AND PANCREATIC BETA CELL FUNCTION AND INSULIN SENSITIVITY IN INDIVIDUALS WITH IMPAIRED FASTING GLUCOSE%空腹血糖受损人群血清微量元素与胰岛β细胞功能及胰岛素敏感性的相关性研究

    Institute of Scientific and Technical Information of China (English)

    李小霞; 赵燚; 靳雅男; 樊学敏; 廖沙; 张毓洪

    2015-01-01

    目的:探讨空腹血清受损(ISF)人群血清微量元素Cu、Zn、Se含量和Cu/Zn比与胰岛β细胞功能及胰岛素敏感性之间的相关性。方法采用整群抽样结合系统抽样方法对在宁夏回族自治区吴忠市和固原市抽取的1267名25~74岁农村居民进行问卷调查和体格检查,并测定有关生化指标及血清中微量元素含量;采用 HOMA-2模型计算胰岛β细胞功能参数(%β)、胰岛素敏感性参数(%S)和胰岛素抵抗参数(IR)。结果共1267例研究对象,其中约55%(n=698)为 NGT人群,约45%(n=569)为 IFG人群。NGT与 IFG组间微量元素的差异无统计学意义;NGT与IFG组比较,IFG组的%β、%S明显降低(P<0.001),IR增加(P<0.05);多元线性结果表明,Cu、Zn、Cu/Zn、腰臀比(WHR)与%β存在相关性。结论与NGT组比较,IFG组出现明显的%β和%S降低,IR增加;Cu、Zn、Cu/Zn、%Objective To test if there are differences in serum zinc, copper, selenium concentrations and Cu/Zn ratio between normal glucose tolerance (NGT) and impaired fasting glucose (IFG) groups; and if these parameters are associated with pancreatic beta cell function and insulin sensitivity. Methods One thousand two hundred and sixty seven rural residents aged 25 to 74 were selected from four villages in Guyuan and Wuzhong cities in Ningxia Province by stratified cluster sampling combined with systematic sampling. Questionnaire survey, physical examination and the biochemical tests were carried out and the levels of serum trace elements were measured. Beta cell function (%β), insulin sensitivity (%S) and insulin resistance (IR) were calculated for NGT and IFG participants using the Homeostasis Model Assessment (HOMA-2) calculator. Results Approximately 55% (n=698) were NGT; 45% (n=569) were IFG. Serum trace elements were not significantly different between NGT and IFG groups. However, HOMA-2 parameters were significantly different between

  11. Part C and Part D Compliance Actions

    Data.gov (United States)

    U.S. Department of Health & Human Services — This page includes results from CMSs Past Performance Review. The report called Spring 2014 Past Performance Review Outlier Results lists MA organizations and Part...

  12. Effects of cannabinoid-1 receptor on pancreatic beta-cell function in obese rats%大麻素受体1激动剂和抑制剂对肥胖大鼠胰岛β细胞功能的影响

    Institute of Scientific and Technical Information of China (English)

    樊大贝; 秦贵军; 余勤; 贾贺堂; 马晓君; 闫晓洁

    2009-01-01

    目的 研究大麻素受体1对肥胖大鼠胰岛β细胞功能的影响.方法 30只8周龄清洁级健康雄性SD大鼠,体质最150~200 g,采用数字表法随机分至正常对照组(n=6)和肥胖组(n=24).正常对照组给予普通鼠饲料喂养,肥胖组给予高脂鼠饲料喂养.8周后,与正常对照组比较,肥胖纽大鼠体质量增加36%,总胆固醇增加52%,提示24只肥胖大鼠制作成功.肥胖大鼠以数字表法随机分至生理盐水组(n=8)、WIN55212-2组(n=8)、AM251组(n=8).测定大鼠体质量、血脂、胰岛素、胰岛素原等指标,采用高葡萄糖钳央试验评价胰岛β细胞功能和胰岛素敏感性.采用LSD检验进行统计学分析.结果 腹腔注射药物2周后,生理盐水组、WIN55212-2组体质量、血脂、卒腹血糖、C肽、胰岛素、胰岛素原、胰岛素原/C肽、胰岛素原/胰岛素、胰岛素10~90 min分泌量及胰岛素最大分泌量均高于正常对照组(P<0.05),WIN55212-2组上述指标均高于生理盐水组(P<0.05),AM251组上述指标均低于生理盐水组和WIN55212-2组(P<0.05).生理盐水组、WIN55212-2组胰岛素0~10 min分泌量、匍萄糖输注率低于正常对照组(P<0.05),WIN55212-2组胰岛素0~10 min分泌量、葡萄糖输注率低于生理盐水组(P<0.05).AM251组胰岛素0~10 min分泌量、葡萄糖输注率高于生理盐水组和WIN55212-2组(P<0.05).结论 大麻素受体1受体激动可增加肥胖大鼠体质量,升高血脂水平,加重胰岛素抵抗和胰岛β细胞功能减退,抑制大麻素受体1可逆转此效应.%Objective To investigate the effects of cannabinoind-1 receptor (CB1R) on pancreatic beta-cell function in obese rats. Methods A total of 30 male 8-week healthy SD rats were randomly assigned to the control group (n=6) or obesity group (n=24). After 8 weeks' intervention, 24 obese rats were randomly divided into the saline group (n=8), WIN55212-2 injection group (n=8) and AM251 injection group (n=8). The body weight

  13. Drug Coverage (Part D)

    Science.gov (United States)

    ... plans Ways to pay Part A & Part B premiums Costs at a glance What Medicare Covers Is ... File a complaint Identity theft: protect yourself Phone numbers & websites Privacy practices Contact Medicare The page could ...

  14. The effect of noise on beta-cell burst period

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram; Sørensen, Mads Peter

    2006-01-01

    on numerical simulations. We show here how the application of two recent methods allows an analytic treatment of the stochastic effects on the location of the saddle-node and homoclinic bifurcations, which determine the burst period. Thus, the stochastic system can be analyzed similarly to the...... isolated and coupled cells has been suggested to be due to stochastic fluctuations of the plasma membrane ions channels, which are supposed to have a stronger effect on single cells than on cells situated in clusters (the channel sharing hypothesis). This effect of noise has previously been studied based...

  15. Present and future cell therapies for pancreatic beta cell replenishment

    OpenAIRE

    Domínguez-Bendala, Juan; Ricordi, Camillo

    2012-01-01

    If only at a small scale, islet transplantation has successfully addressed what ought to be the primary endpoint of any cell therapy: the functional replenishment of damaged tissue in patients. After years of less-than-optimal approaches to immunosuppression, recent advances consistently yield long-term graft survival rates comparable to those of whole pancreas transplantation. Limited organ availability is the main hurdle that stands in the way of the widespread clinical utilization of this ...

  16. Role of topology in complex functional networks of beta cells.

    Science.gov (United States)

    Cherubini, Christian; Filippi, Simonetta; Gizzi, Alessio; Loppini, Alessandro

    2015-10-01

    The activity of pancreatic β cells can be described by biological networks of coupled nonlinear oscillators that, via electrochemical synchronization, release insulin in response to augmented glucose levels. In this work, we analyze the emergent behavior of regular and percolated β-cells clusters through a stochastic mathematical model where "functional" networks arise. We show that the emergence and robustness of the synchronized dynamics depend both on intrinsic and extrinsic parameters. In particular, cellular noise level, glucose concentration, network spatial architecture, and cell-to-cell coupling strength are the key factors for the generation of a rhythmic and robust activity. Their role in the functional network topology associated with β-cells clusters is analyzed and discussed. PMID:26565267

  17. Adhesion of Pancreatic Beta Cells to Biopolymer Films

    OpenAIRE

    Williams, S. Janette; Wang, Qun; MacGregor, Ronal R.; Siahaan, Teruna J.; Stehno-Bittel, Lisa; Berkland, Cory

    2009-01-01

    Dramatic reversal of Type 1 diabetes in patients receiving pancreatic islet transplants continues to prompt vigorous research concerning the basic mechanisms underlying patient turnaround. At the most fundamental level, transplanted islets must maintain viability and function in vitro and in vivo and should be protected from host immune rejection. Our previous reports showed enhancement of islet viability and insulin secretion per tissue mass for small islets (125 µm), thus, demonstrating the...

  18. Incretin hormones and beta cell function in chronic pancreatitis

    DEFF Research Database (Denmark)

    Knop, Filip Krag

    2010-01-01

    insufficiency, with and without pancreatic enzyme supplementation (PES), we observed preserved incretin responses as compared to matched healthy subjects; and, further, that PES increased postprandial incretin responses in these patients. This suggests not only that the secretion of incretin hormones is....... It is unknown whether the incretin defect is a primary event leading to T2DM or arises as a consequence of the diabetic state. To investigate this we studied patients with chronic pancreatitis (CP). Over time, CP leads to secondary diabetes mellitus (DM). If patients with CP and secondary DM exhibit...... is preserved independently of the endocrine status of patients with CP, the incretin defect could represent a primary pathogenetic defect. Three protocols have been employed to investigate this. In a study investigating postprandial incretin responses in 8 patients with CP and exocrine pancreatic...

  19. High affinity binding of the heat-stable protein kinase inhibitor to the catalytic subunit of cAMP-dependent protein kinase is selectively abolished by mutation of Arg133.

    Science.gov (United States)

    Wen, W; Taylor, S S

    1994-03-18

    The two classes of physiological inhibitors of the catalytic subunit of cAMP-dependent protein kinase are the regulatory subunits and the heat-stable protein kinase inhibitors (PKIs), and both share a common mechanism of inhibition. Each has a similar inhibitor site that resembles a peptide substrate, and this occupies the P-3 to P+1 portion of the peptide recognition site. However, in addition to this consensus site, each inhibitor requires a peripheral binding site to achieve high affinity binding. Arg134 and Arg133 lie on the surface of the catalytic subunit with Arg133 coming close to the amphipathic helix of PKI(5-24) (Knighton, D. R., Zheng, J., Ten Eyck, L. F., Xuong, N.-h., Taylor, S. S., and Sowadski, J. M. (1991) Science 253, 414-420). Replacement of Arg134 and Arg133 with Ala selectively abolishes the high affinity binding of PKI. Replacement of Arg133 alone is sufficient to give the same phenotype. In the presence of MgATP, the Kd,app, is increased from < 0.2 to 105 nM and, in the absence of ATP, the Kd is too large to be reliably measured. Based on the crystal structure, Arg133 hydrogen bonds to the P-7 backbone carbonyl of PKI(5-24). However, more importantly, it also contributes to the hydrophobicity of the P-11 binding site in the C.PKI(5-24) complex. We predict that it is the perturbation of this hydrophobic pocket that accounts for the effects of this mutation. In the absence of peptide, Arg133 may help to stabilize Glu230, a buried carboxylate that binds to the P-2 Arg in the crystal structure of C.PKI(5-24). Replacement of Arg133 and Arg134 with Ala has little effect on catalysis using a heptapeptide substrate and has no effect on the inhibition of the catalytic subunit by the regulatory subunit. The results thus demonstrate that these two inhibitor proteins that both bind to the catalytic subunit with a high affinity utilize different sites on the enzyme to achieve tight binding. The gamma isoform of the catalytic subunit is insensitive to

  20. Part Machinability Evaluation System

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    In the early design period, estimation of the part or the whole product machinability is useful to consider the function and process request of the product at the same time so as to globally optimize the design decision. This paper presents a part machinability evaluation system, discusses the general restrictions of part machinability, and realizes the inspection of these restrictions with the relation between tool scan space and part model. During the system development, the expansibility and understandability were considered, and an independent restriction algorithm library and a general function library were set up. Additionally, the system has an interpreter and a knowledge manager.

  1. Controlled parts management

    International Nuclear Information System (INIS)

    The Controlled Parts Management (CPM) system is based on industry standard practices for managing inventory. CPM is designed to record the movement of any type of inventory in a defined region referred to as an Account or SubAccount. The system is used to track the receiving, processing, storing and transfer of inventory parts. CPM provides information on parts, quantity and the exact location of the inventory. CPM is a barcode-based-part tracking system currently used to track controlled parts that are used in the R and D and testing of weapons; this tracking helps maintain the part pedigree that is required for certification of a weapon or weapon test. CPM includes bar code data collection software programmed into portable bar code readers for automating physical inventory services and remote transaction capture. CPM interfaces to other Engineering systems and supports a 'material content' of a weapons test through the test Bill of Materials and assignment of a unique inventory part in CPM. Additional functionality includes the ability to group or join parts, logically or physically and temporary or permanent, to represent discrete parts, containers, subassemblies and assemblies, and groupings.

  2. 胰岛素泵治疗对控制新诊2型糖尿病血糖及改善β细胞功能的作用研究%Study on the Role of Insulin Pump Therapy in Blood Glucose Control and Beta Cell Function Improvement of Newly Diagnosed Type 2 Diabetes Mellitus

    Institute of Scientific and Technical Information of China (English)

    张云林

    2014-01-01

    /L) on (6 .3 ± 3 .9)d after CSII .Compared with before treatment ,FPG , 2hPG ,HbA1c ,TC ,TG ,LDL-C and FFA of patients 2 weeks after CSII were markedly decreased ,but HDL-C was ob-viously increased( P < 0 .01 ,P < 0 .05) ,and the recovery of beta cell function was more significant ( P < 0 .05) .[Conclusion]Short-term intensive insulin therapy can achieve long-term control of blood sugar in newly diagnosed T2DM patients with severe hyperglycemia ,and improve beta cell function ,and especially recover the first phase insulin secretion , which may be the mechanism of the alleviation of patients .

  3. Walrus parts collection notes

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The attached field diary notes provide documentation of walrus parts collection activities which occurred in the Nome and surrounding area during the periods of May...

  4. Workshop 96. Part III

    International Nuclear Information System (INIS)

    Part III of the proceedings contain 155 contributions in various fields of science and technology including nuclear engineering, environmental science, and biomedical engineering. Out of these, 10 were selected to be inputted in INIS. (P.A.)

  5. 替米沙坦对2型糖尿病合并高血压患者胰岛β细胞功能影响的临床观察%The Effects of Telmisartan to the Function of Beta Cell of Islet in Human New Diagnosis of Type 2 Diabetes and Hypertension

    Institute of Scientific and Technical Information of China (English)

    黄爽; 周强; 顾学林; 胡晓琼; 肖建香

    2012-01-01

    Objective: To investigate the effects of Telmisartan to the beta cell of islet in people diagnosis with type 2 diabetes combine hypertension. Methods: 70 people diagnosis with diabetes and combine mild to moderate hypertension people were divided into two groups: the telmisartan group and the amlodipine group, 35 people in each group. The base control blood glucose were given in both of the groups , in telmisartan group the telmisartan were given to control the blood pressure; the amlodipine group the amlodipine were given to control the blood pressure. The blood pressure and fasting blood glucose were observed in two weeks. The observation time is 12 weeks, before and after observation time, the HbAlc, insulin levels, glucose level after two hours after glucose challenge were detected. Calculated steady-state model according to HOMA β-cell function index (HOMA-β) and insulin resistance index (HOMA-IR). ResultS:In lower the blood pressure, there were no significantly difference between the two groups, including the SBP and DBP, P>0.05. Compared to the amlodipine group, the telmisartan improved the insulin secretion and the HOMA-βbut decreased the HOMA-IR. Conclusions:Telmisartan may make more significant improvement in patients with diabetes and high blood pressure β-cell function, with improvement in blood pressure as well as the function of islet cells.%目的:观察替米沙坦对糖尿病合并高血压患者胰岛β细胞功能的影响,探索血管紧张素Ⅱ阻断剂降压以外的胰岛功能修复作用.方法:70例糖尿病合并轻、中度高血压的患者随机分为替米沙坦治疗组和氨氯地平治疗组,每组35例患者;替米沙坦治疗组在控制血糖的治疗上给予替米沙坦进行降压治疗;氨氯地平治疗组在控制血糖的治疗上给予氨氯地平进行降压治疗;两组的观察周期均12周,每2周观察1次血压、空腹血糖、并记录低血糖及其它不良反应.治疗前后测糖

  6. Matrix comparison, Part 2

    DEFF Research Database (Denmark)

    Schneider, Jesper Wiborg; Borlund, Pia

    2007-01-01

    The present two-part article introduces matrix comparison as a formal means for evaluation purposes in informetric studies such as cocitation analysis. In the first part, the motivation behind introducing matrix comparison to informetric studies, as well as two important issues influencing such...... comparisons, matrix generation, and the composition of proximity measures, are introduced and discussed. In this second part, the authors introduce and thoroughly demonstrate two related matrix comparison techniques the Mantel test and Procrustes analysis, respectively. These techniques can compare and...... evaluate the degree of monotonicity between different proximity measures or their ordination results. In common with these techniques is the application of permutation procedures to test hypotheses about matrix resemblances. The choice of technique is related to the validation at hand. In the case of the...

  7. PHP The Good Parts

    CERN Document Server

    MacIntyre, Peter

    2010-01-01

    Get past all the hype about PHP and dig into the real power of this language. This book explores the most useful features of PHP and how they can speed up the web development process, and explains why the most commonly used PHP elements are often misused or misapplied. You'll learn which parts add strength to object-oriented programming, and how to use certain features to integrate your application with databases. Written by a longtime member of the PHP community, PHP: The Good Parts is ideal for new PHP programmers, as well as web developers switching from other languages. Become familiar w

  8. Plutonium microstructures. Part 1

    International Nuclear Information System (INIS)

    This report is the first of three parts in which Los Alamos and Lawrence Livermore National Laboratory metallographers exhibit a consolidated set of illustrations of inclusions that are seen in plutonium metal as a consequence of inherent and tramp impurities, alloy additions, and thermal or mechanical treatments. This part includes illustrations of nonmetallic and intermetallic inclusions characteristic of major impurity elements as an aid to identifying unknowns. It also describes historical aspects of the increased purity of laboratory plutonium samples, and it gives the composition of the etchant solutions and describes the etching procedure used in the preparation of each illustrated sample. 25 figures

  9. Workshop 95. Part I

    International Nuclear Information System (INIS)

    The proceedings of the seminar contain more than 420 contributions divided into 21 areas of interest. In Part I, 144 contributions are presented from the following fields: mathematics, physics, chemistry, engineering informatics and cybernetics, computer art, and fluid mechanics. For input in INIS, 15 contributions were selected from the physics section and 1 from the chemistry section. (J.B.)

  10. Workshop 93. Part A

    International Nuclear Information System (INIS)

    The aim of the seminar was to present and discuss the latest results obtained in research at the Czech Technical University and collaborating institutions. Part A of the Proceedings contains 99 contributions from the following fields: physical electronics and optics, mathematics, informatics and cybernetics, and materials engineering. Two contributions were selected for INIS. (J.B.)

  11. Workshop 96. Part II

    International Nuclear Information System (INIS)

    Part II of the seminar proceedings contains contributions in various areas of science and technology, among them materials science in mechanical engineering, materials science in electrical, chemical and civil engineering, and electronics, measuring and communication engineering. In those areas, 6 contributions have been selected for INIS. (P.A.)

  12. MIRD methodology. Part 1

    International Nuclear Information System (INIS)

    This lecture develops the MIRD (Medical Internal Radiation Dose) methodology for the evaluation of the internal dose due to the administration of radiopharmaceuticals. In this first part, the basic concepts and the main equations are presented. The ICRP Dosimetric System is also explained. (author)

  13. Part E: Evolutionary Computation

    DEFF Research Database (Denmark)

    2015-01-01

    Part E, Evolutionary Computation, edited by Professors Frank Neumann, Carsten Witt, Peter Merz, Carlos A. Coello Coello, Oliver Schütze, Thomas Bartz-Beielstein, Jörn Mehnen, and Günther Raidl, concerns the third fundamental element of what is traditionally being considered to be the core of Comp...

  14. Basic Electricity. Part 3.

    Science.gov (United States)

    Kilmer, Donald C.

    Third (part 3) in a set of four guides designed for the student interested in a vocation in electrical work, this guide includes four units: Unit VI--Ohm's Law, covering six lessons (voltage, current-flow and resistance, the Ohm's Law formula, formula for finding voltage, formula for finding resistance); Unit VII--Voltages, covering five lessons…

  15. Music with changing parts

    OpenAIRE

    Tullett, Barrie

    2013-01-01

    Part of an ongoing investigation into the music of Philip Glass, the books seek to visualise the soundscape of a particlaur Glasswork -- Each of these nine limited edition concertina books has a different series of images taken from a greater whole.

  16. Rockets -- Part II.

    Science.gov (United States)

    Leitner, Alfred

    1982-01-01

    If two rockets are identical except that one engine burns in one-tenth the time of the other (total impulse and initial fuel mass of the two engines being the same), which rocket will rise higher? Why? The answer to this question (part 1 response in v20 n6, p410, Sep 1982) is provided. (Author/JN)

  17. Auto Part Boom

    Institute of Scientific and Technical Information of China (English)

    WANG PEI

    2006-01-01

    @@ "Facing a very good market space at the present time,no matter domestic or overseas,we are increasing all the resources we can to expand our production capacity,"says Xu Peng,sales manager of a major Chinese private auto parts company."However,there are still many external conditions restricting the expansion."

  18. Son: Part Two

    Directory of Open Access Journals (Sweden)

    Jennifer Higgie

    2005-03-01

    Full Text Available It is 1842. Two Englishman set out on a Grand Tour of Europe and the Middle East. One is a young, gifted artist; the other a Gentleman. By the time they return to England, the artist has become a devotee of the Egyptian god Osiris. One night, after dining together in a small inn in Cobham, he violently murders his beloved father, believing him to be an imposter. Why? Son is a novel inspired by the life of Richard Dadd, one of the greatest Victorian painters and inmate of Bethlem Hospital - more commonly known as Bedlam. Part one of Son was published in PORTAL vol. 1, no. 2, in July 2004. This is the second and concluding part of the novel.

  19. Concern for older parts

    International Nuclear Information System (INIS)

    For the last half decade, regulatory expectations of the procurement process for nuclear commercial-grade safety-related materials have increase. The changes have been driven by concern for fraudulent or misrepresented parts and the loss of original equipment manufacturers. The industry responded to these concerns by developing improved procurement programs that changed how parts were specified and received and provided for verification of attributes that were critical to the successful performance of safety functions(s). Like its counterparts, Duquesne Light Company (DLCo), Beaver Valley power station began applying these enhanced requirements to procurements initiated after January 1, 1990, in response to the Nuclear Management and Resources Council initiative on dedication. Procurements prior to this data were not subject to the new requirements

  20. Workshop 93. Part B

    International Nuclear Information System (INIS)

    The aim of the seminar was to present and discuss the latest results obtained in research at the Czech Technical University and collaborating institutions. Part B of the Proceedings contains 109 contributions from the following fields: physics; medical engineering; fluid mechanics, environmental engineering, and structural mechanics. Fourteen contributions dealing with nuclear physics, plasma physics, quantum physics, nuclear chemistry, and computational physics were selected for INIS. (J.B.)

  1. Just Perfect, Part 2

    Science.gov (United States)

    Scott, Paul

    2007-01-01

    In "Just Perfect: Part 1," the author defined a perfect number N to be one for which the sum of the divisors d (1 less than or equal to d less than N) is N. He gave the first few perfect numbers, starting with those known by the early Greeks. In this article, the author provides an extended list of perfect numbers, with some comments about their…

  2. Parts without a whole?

    OpenAIRE

    Schmiedgen, Jan; Rhinow, Holger; Köppen, Eva; Meinel, Christoph

    2015-01-01

    This explorative study gives a descriptive overview of what organizations do and experience when they say they practice design thinking. It looks at how the concept has been appropriated in organizations and also describes patterns of design thinking adoption. The authors use a mixed-method research design fed by two sources: questionnaire data and semi-structured personal expert interviews. The study proceeds in six parts: (1) design thinking¹s entry points into organizations; (2) understand...

  3. Workshop 96. Part I

    International Nuclear Information System (INIS)

    The proceedings of the seminar contain nearly 500 contributions divided into 22 fields of science and technology. In Part I, 167 contributions are presented in the following areas: mathematics, physics, chemistry, engineering informatics and cybernetics, computers, and fluid mechanics. For input in INIS, 19 contributions were selected from the Physics section, 2 from the Mathematics section, and 4 from the Chemistry section. (P.A.)

  4. Measurement of cylindrical parts

    Science.gov (United States)

    Knight, Paul Douglas, Jr.

    The form of cylindrical parts has been traditionally evaluated using stylus-based mechanical instruments. The Tropel Corporation has developed a grazing incidence interferometer (GII) for the measurement of cylindrical parts. The repeatability of this instrument due to various instrument uncertainties was measured. Differing instrument configurations that produce the same systematic error were determined to produce a zonal calibration method for determining systematic error over the full range of the instrument, given knowledge of the error in a single zone. The effect of the aperture stop on the response of the imaging system to axially sinusoidal artifacts was simulated. Diamond-turned axially sinusoidal artifacts, with amplitude of order1 um and spatial wavelength of order10 mm, were measured to test the axial response of the interferometer. The modulation transfer function of the instrument's imaging system, measured using a knife edge test, predicts the response observed with the sinusoidal artifacts. A diffraction analysis predicts that the measured axial form is modified by a second order envelope function with phase that varies with the relative position of the imaging system focal plane and part position. A compensation method is proposed for this effect. A comparison of roundness measurements by both a traditional stylus-based instrument and the GII was performed demonstrating that the roundness measurements of the two instruments are equivalent when the measurements are properly corrected for the differing effects of surface finish.

  5. R806 (part 1)

    CERN Multimedia

    1976-01-01

    R806 was designed by the BNL-CERN-Syracuse-Yale Collaboration (Bill Willis spokesman) to study large transverse momentum phenomena, and installed in intersection 8 of the ISR. The main detectors were Lithium foil transition radiation detectors to identify electrons and liquid argon calorimeters to measure the energy of the electrons and photons (among the first such calorimeters to be used in an experiment). In part 1 there were two modules, top and bottom of the horizontal beam pipe; the black vertical pipe contains the cryogenics (LN2 and Lar) and is connected to the two modules with the horizontal piping.

  6. Java The Good Parts

    CERN Document Server

    Waldo, Jim

    2010-01-01

    What if you could condense Java down to its very best features and build better applications with that simpler version? In this book, veteran Sun Labs engineer Jim Waldo reveals which parts of Java are most useful, and why those features make Java among the best programming languages available. Every language eventually builds up crud, Java included. The core language has become increasingly large and complex, and the libraries associated with it have grown even more. Learn how to take advantage of Java's best features by working with an example application throughout the book. You may not l

  7. Invisible parts of attractors

    International Nuclear Information System (INIS)

    This paper deals with attractors of generic dynamical systems. We introduce the notion of ε-invisible set, which is an open set of the phase space in which almost all orbits spend on average a fraction of time no greater than ε. For extraordinarily small values of ε (say, smaller than 2−100), these are large neighbourhoods of some parts of the attractors in the phase space which an observer virtually never sees when following a generic orbit. For any n ≥ 100, we construct a set Qn in the space of skew products over a solenoid with the fibre a circle having the following properties. Any map from Qn is a structurally stable diffeomorphism; the Lipschitz constants of the map and its inverse are no greater than L (where L is a universal constant that does not depend on n, say L n has a 2−n-invisible part of its attractor, whose size is comparable to that of the whole attractor. The set Qn is a ball of radius O(n−2) in the space of skew products with the C1 metric. It consists of structurally stable skew products. Small perturbations of these skew products in the space of all diffeomorphisms still have attractors with the same properties. Thus for all such perturbations, a sizable portion of the attractor is almost never visited by generic orbits and is practically never seen by the observer

  8. Mapping sequences by parts

    Directory of Open Access Journals (Sweden)

    Guziolowski Carito

    2007-09-01

    Full Text Available Abstract Background: We present the N-map method, a pairwise and asymmetrical approach which allows us to compare sequences by taking into account evolutionary events that produce shuffled, reversed or repeated elements. Basically, the optimal N-map of a sequence s over a sequence t is the best way of partitioning the first sequence into N parts and placing them, possibly complementary reversed, over the second sequence in order to maximize the sum of their gapless alignment scores. Results: We introduce an algorithm computing an optimal N-map with time complexity O (|s| × |t| × N using O (|s| × |t| × N memory space. Among all the numbers of parts taken in a reasonable range, we select the value N for which the optimal N-map has the most significant score. To evaluate this significance, we study the empirical distributions of the scores of optimal N-maps and show that they can be approximated by normal distributions with a reasonable accuracy. We test the functionality of the approach over random sequences on which we apply artificial evolutionary events. Practical Application: The method is illustrated with four case studies of pairs of sequences involving non-standard evolutionary events.

  9. 16 CFR Figure 2 to Part 1511 - Small Parts Gage

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Small Parts Gage 2 Figure 2 to Part 1511 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FEDERAL HAZARDOUS SUBSTANCES ACT REGULATIONS REQUIREMENTS FOR PACIFIERS Pt.1511, Fig. 2 Figure 2 to Part 1511—Small Parts Gage EC03OC91.069...

  10. Son: Part One

    Directory of Open Access Journals (Sweden)

    Jennifer Higgie

    2004-08-01

    Full Text Available It is 1842. Two Englishman set out on a Grand Tour of Europe and the Middle East. One is a young, gifted artist; the other a Gentleman. By the time they return to England, the artist has become a devotee of the Egyptian god Osiris. One night, after dining together in a small inn in Cobham, he violently murders his beloved father, believing him to be an imposter. Why? Son is a novel inspired by the life of Richard Dadd, one of the greatest Victorian painters and inmate of Bethlem Hospital - more commonly known as Bedlam. Part Two of Son will be published in Portal vol. 2, no. 1, January 2005.

  11. Multiple part feeding

    DEFF Research Database (Denmark)

    Hvilshøj, Mads; Bøgh, Simon; Nielsen, Oluf Skov;

    2012-01-01

    Purpose - The purpose of this paper is to present experience from a real-world demonstration of autonomous industrial mobile manipulation (AIMM) based on the mobile manipulator "Little Helper" performing multiple part feeding at the pump manufacturer Grundfos A/S. Design/methodology/approach - The...... necessary AIMM technologies exist at a mature level - the reason that no mobile manipulators have yet been implemented in industrial environments, is that research in the right applications have not been carried out. We propose a pragmatic approach consisting of: a commercial-off-the-shelf (COTS) mobile....... Originality/value - The paper presents a full-scale demonstration of a state-of-the-art COTS autonomous mobile manipulator system with particular focus on industrial utilization and application....

  12. Part 2: Applications. Introduction

    Energy Technology Data Exchange (ETDEWEB)

    Mok, G.C. [Lawrence Livermore National Lab., CA (United States). Fission Energy and Systems Safety Program; Chung, H.H. [Argonne National Lab., IL (United States). Reactor Engineering Division

    1995-12-01

    As pointed out in the introduction of Part 1, the isolation strategy can be used to effectively decouple a structure from its environment and thus the structure can be protected from damaging seismic loads or unwanted vibrations and noises from the environment. The method has been used for solving vibration and shock problems in machinery and equipment for many years, but its application to the protection of structures from seismic loadings is relatively recent. Owing to the current interest generated by the Northridge and Kobe earthquakes, all but one of the papers in this publication deal with seismic isolation. The authors preview the papers in this section on the following applications of seismic isolation to: buildings, civil structures, industrial facilities, and nuclear plants.

  13. Part 2: Applications. Introduction

    International Nuclear Information System (INIS)

    As pointed out in the introduction of Part 1, the isolation strategy can be used to effectively decouple a structure from its environment and thus the structure can be protected from damaging seismic loads or unwanted vibrations and noises from the environment. The method has been used for solving vibration and shock problems in machinery and equipment for many years, but its application to the protection of structures from seismic loadings is relatively recent. Owing to the current interest generated by the Northridge and Kobe earthquakes, all but one of the papers in this publication deal with seismic isolation. The authors preview the papers in this section on the following applications of seismic isolation to: buildings, civil structures, industrial facilities, and nuclear plants

  14. Orienting Parts with Shape Variation

    NARCIS (Netherlands)

    Panahi, F.; Davoodi, Mansoor; van der Stappen, A.F.

    2015-01-01

    Industrial parts are manufactured to tolerances as no production process is capable of delivering perfectly identical parts. It is unacceptable that a plan for a manipulation task that was determined on the basis of a CAD model of a part fails on some manufactured instance of that part, and therefor

  15. Part Objects and Their Location

    DEFF Research Database (Denmark)

    Madsen, Ole Lehrmann; Møller-Pedersen, Birger

    1992-01-01

    The notion of location of part objects is introduced, yielding a reference to the containing object. Combined with locally defined objects and classes (block structure), singularly defined part objects, and references to part objects, it is a powerful language mechanism for defining objects...... with different aspects or roles. The use of part objects for inheritance of code is also explored....

  16. Fuel cycle math - part one

    International Nuclear Information System (INIS)

    This article is Part One of a two-part article that reviews some of the numbers associated with the nuclear fuel cycle. The contents of Part One include: composition of the element uranium, considering atomic mass and weight-percent of the isotopes; uranium in the ground, including ore grades; mining, with dilution factors and recovery rates; ore sorting, including concentration factors; and uranium recovery. No financial information is presented in either Part One or Part Two

  17. Procedural Safeguards under Part H: How Judicial Interpretations of Part B May Affect Part H.

    Science.gov (United States)

    Turnbull, H. Rutherford, III; Turnbull, Ann P.

    1991-01-01

    This article compares and contrasts provisions for procedural safeguards and due process hearings under 2 sections of Public Law 99-457: Part B, dealing with children ages 3-5, and Part H, dealing with infants and toddlers. Potential problems under Part H are pointed out and suggestions are made for implementing Part H safeguards without conflict.…

  18. Medicare Utilization for Part B

    Data.gov (United States)

    U.S. Department of Health & Human Services — This link takes you to the Medicare utilization statistics for Part B (Supplementary Medical Insurance SMI) which includes the Medicare Part B Physician and...

  19. Development of Aircraft Sandwich Parts

    Directory of Open Access Journals (Sweden)

    J. Křena

    2000-01-01

    Full Text Available The presented paper shows the design and development process of sandwich parts. A spoiler plate and a main landing gear door are developed. Sandwich parts are made of C/E composite facings and a foam core. FE models have been used for optimization of structures. Emphasis has been placed on deformations of parts under a few load cases. Experimental tests have been used for a verification of structure parts loaded by concentrated forces.

  20. Exploring Water Pollution. Part II

    Science.gov (United States)

    Rillo, Thomas J.

    1975-01-01

    This is part two of a three part article related to the science activity of exploring environmental problems. Part one dealt with background information for the classroom teacher. Presented here is a suggested lesson plan on water pollution. Objectives, important concepts and instructional procedures are suggested. (EB)

  1. Should the Death Penalty Be Abolished For Corruption?

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Chinese officials who had committed economic crimes began to flee overseas between the late 1980s and early 1990s. Although China has signed extradition treaties with 25 countries, including Thailand, Belarus, Russia and South Korea since 1993, it has not final-

  2. Estrogen Abolishes Latent Inhibition in Ovariectomized Female Rats

    Science.gov (United States)

    Nofrey, Barbara S.; Ben-Shahar, Osnat M.; Brake, Wayne G.

    2008-01-01

    Estrogen is frequently prescribed as a method of birth control and as hormone replacement therapy for post-menopausal women with varied effects on cognition. Here the effects of estrogen on attention were examined using the latent inhibition (LI) behavioral paradigm. Ovariectomized (OVX) female rats were given either estrogen benzoate (EB, 10 or…

  3. Social experience does not abolish cultural diversity in eye movements

    Directory of Open Access Journals (Sweden)

    David J Kelly

    2011-05-01

    Full Text Available Adults from Eastern (e.g., China and Western (e.g., USA cultural groups display pronounced differences in a range of visual processing tasks. For example, the eye movement strategies used for information extraction during a variety of face processing tasks (e.g., identification and facial expressions of emotion categorization differs across cultural groups. Currently, many of the differences reported in previous studies have asserted that culture itself is responsible for shaping the way we process visual information, yet this has never been directly investigated. In the current study, we assessed the relative contribution of genetic and cultural factors by testing face processing in a population of British Born Chinese (BBC adults using face recognition and expression classification tasks. Contrary to predictions made by the cultural differences framework, the majority of BBC adults deployed ‘Eastern’ eye movement strategies, while approximately 25% of participants displayed ‘Western’ strategies. Furthermore, the cultural eye movement strategies used by individuals were consistent across recognition and expression tasks. These findings suggest that ‘culture’ alone cannot straightforwardly account for diversity in eye movement patterns. Instead a more complex understanding of how the environment and individual experiences can influence the mechanisms that govern visual processing is required.

  4. Inactivation of Efflux Pumps Abolishes Bacterial Biofilm Formation▿

    OpenAIRE

    Kvist, Malin; Hancock, Viktoria; Klemm, Per

    2008-01-01

    Bacterial biofilms cause numerous problems in health care and industry; notably, biofilms are associated with a large number of infections. Biofilm-dwelling bacteria are particularly resistant to antibiotics, making it hard to eradicate biofilm-associated infections. Bacteria rely on efflux pumps to get rid of toxic substances. We discovered that efflux pumps are highly active in bacterial biofilms, thus making efflux pumps attractive targets for antibiofilm measures. A number of efflux pump ...

  5. Social experience does not abolish cultural diversity in eye movements.

    OpenAIRE

    David J. Kelly1*, Rachael E. Jack2, Sébastien Miellet2, Emanuele De Luca2,; Kay Foreman2 and Roberto Caldara3*; 1 Department of Psychology, Royal Holloway, Egham, UK; 2 Department of Psychology and Centre for Cognitive Neuroimaging, University; of Glasgow, Glasgow, UK; 4 . Department of Psychology, University of Fribourg, Switzerland

    2011-01-01

    Adults from Eastern (e.g., China) and Western (e.g., USA) cultural groups display pronounced differences in a range of visual processing tasks. For example, the eye movement strategies used for information extraction during a variety of face processing tasks (e.g., identification and facial expressions of emotion categorization) differs across cultural groups. Currently, many of the differences reported in previous studies have asserted that culture itself is responsible for shaping the...

  6. Should We Abolish Chapter 11? Evidence from Canada.

    OpenAIRE

    Fisher, Timothy C G; Martel, Jocelyn

    1999-01-01

    Chapter 11 has been severely criticized over the last decade. Some American jurists arguing in favor of revising Chapter 11 have raised the possibility that the Canadian reorganization system might be a good alternative. This article examines data on firms undergoing reorganization under the Canadian bankruptcy system and argues that there are fruitful lessons to be learned from the Canadian experience with court-supervised reorganization. Canadian reorganization plans have very high rates of...

  7. Automotive stamped part fatigue design

    OpenAIRE

    Caudoux Mélanie; Facchinetti Matteo Luca; Raynal Renaud

    2014-01-01

    Fatigue design of automotive axle parts is of prior concern because of these are high safety parts and they are expected to drive the overall vehicle mass reduction. In this framework, the stamping process is widely used to form axle parts, before assembling them by welding. Consequently, the mechanical and physical characteristics of the blank sheet are modified, having a strong influence on the fatigue behavior. In this paper, we address the consequences of the stamped process on the fatigu...

  8. Water Pollution: Part I, Municipal Wastewaters; Part II, Industrial Wastewaters.

    Science.gov (United States)

    Fowler, K. E. M.

    This publication is an annotated bibliography of municipal and industrial wastewater literature. This publication consists of two parts plus appendices. Part one is entitled Municipal Wastewaters and includes publications in such areas as health effects of polluted waters, federal policy and legislation, biology and chemistry of polluted water,…

  9. Staircase and Fractional Part Functions

    Science.gov (United States)

    Amram, Meirav; Dagan, Miriam; Ioshpe, Michael; Satianov, Pavel

    2016-01-01

    The staircase and fractional part functions are basic examples of real functions. They can be applied in several parts of mathematics, such as analysis, number theory, formulas for primes, and so on; in computer programming, the floor and ceiling functions are provided by a significant number of programming languages--they have some basic uses in…

  10. The Majorana Parts Tracking Database

    Energy Technology Data Exchange (ETDEWEB)

    Abgrall, N.; Aguayo, E.; Avignone, F. T.; Barabash, A. S.; Bertrand, F. E.; Brudanin, V.; Busch, M.; Byram, D.; Caldwell, A. S.; Chan, Y-D.; Christofferson, C. D.; Combs, D. C.; Cuesta, C.; Detwiler, J. A.; Doe, P. J.; Efremenko, Yu.; Egorov, V.; Ejiri, H.; Elliott, S. R.; Esterline, J.; Fast, J. E.; Finnerty, P.; Fraenkle, F. M.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, V. E.; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J. Diaz; Leviner, L. E.; Loach, J. C.; MacMullin, J.; Martin, R. D.; Meijer, S. J.; Mertens, S.; Miller, M. L.; Mizouni, L.; Nomachi, M.; Orrell, J. L.; O׳Shaughnessy, C.; Overman, N. R.; Petersburg, R.; Phillips, D. G.; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Soin, A.; Suriano, A. M.; Tedeschi, D.; Thompson, J.; Timkin, V.; Tornow, W.; Trimble, J. E.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Young, A. R.; Yu, C. -H.; Yumatov, V.; Zhitnikov, I.

    2015-04-01

    The MAJORANA DEMONSTRATOR is an ultra-low background physics experiment searching for the neutrinoless double beta decay of 76Ge. The MAJORANA Parts Tracking Database is used to record the history of components used in the construction of the DEMONSTRATOR. Transportation, storage, and processes undergone by parts such as machining or cleaning are linked to part records. Tracking parts provides a great logistics benefit and an important quality assurance reference during construction. In addition, the location history of parts provides an estimate of their exposure to cosmic radiation. A web application for data entry and a radiation exposure calculator have been developed as tools for achieving the extreme radiopurity required for this rare decay search.

  11. The MAJORANA Parts Tracking Database

    International Nuclear Information System (INIS)

    The MAJORANA DEMONSTRATOR is an ultra-low background physics experiment searching for the neutrinoless double beta decay of 76Ge. The MAJORANA Parts Tracking Database is used to record the history of components used in the construction of the DEMONSTRATOR. The tracking implementation takes a novel approach based on the schema-free database technology CouchDB. Transportation, storage, and processes undergone by parts such as machining or cleaning are linked to part records. Tracking parts provide a great logistics benefit and an important quality assurance reference during construction. In addition, the location history of parts provides an estimate of their exposure to cosmic radiation. A web application for data entry and a radiation exposure calculator have been developed as tools for achieving the extreme radio-purity required for this rare decay search

  12. The MAJORANA Parts Tracking Database

    Energy Technology Data Exchange (ETDEWEB)

    Abgrall, N. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Aguayo, E. [Pacific Northwest National Laboratory, Richland, WA (United States); Avignone, F.T. [Department of Physics and Astronomy, University of South Carolina, Columbia, SC (United States); Oak Ridge National Laboratory, Oak Ridge, TN (United States); Barabash, A.S. [Institute for Theoretical and Experimental Physics, Moscow (Russian Federation); Bertrand, F.E. [Oak Ridge National Laboratory, Oak Ridge, TN (United States); Brudanin, V. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Busch, M. [Department of Physics, Duke University, Durham, NC (United States); Triangle Universities Nuclear Laboratory, Durham, NC (United States); Byram, D. [Department of Physics, University of South Dakota, Vermillion, SD (United States); Caldwell, A.S. [South Dakota School of Mines and Technology, Rapid City, SD (United States); Chan, Y-D. [Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Christofferson, C.D. [South Dakota School of Mines and Technology, Rapid City, SD (United States); Combs, D.C. [Department of Physics, North Carolina State University, Raleigh, NC (United States); Triangle Universities Nuclear Laboratory, Durham, NC (United States); Cuesta, C.; Detwiler, J.A.; Doe, P.J. [Center for Experimental Nuclear Physics and Astrophysics, and Department of Physics, University of Washington, Seattle, WA (United States); Efremenko, Yu. [Department of Physics and Astronomy, University of Tennessee, Knoxville, TN (United States); Egorov, V. [Joint Institute for Nuclear Research, Dubna (Russian Federation); Ejiri, H. [Research Center for Nuclear Physics and Department of Physics, Osaka University, Ibaraki, Osaka (Japan); Elliott, S.R. [Los Alamos National Laboratory, Los Alamos, NM (United States); and others

    2015-04-11

    The MAJORANA DEMONSTRATOR is an ultra-low background physics experiment searching for the neutrinoless double beta decay of {sup 76}Ge. The MAJORANA Parts Tracking Database is used to record the history of components used in the construction of the DEMONSTRATOR. The tracking implementation takes a novel approach based on the schema-free database technology CouchDB. Transportation, storage, and processes undergone by parts such as machining or cleaning are linked to part records. Tracking parts provide a great logistics benefit and an important quality assurance reference during construction. In addition, the location history of parts provides an estimate of their exposure to cosmic radiation. A web application for data entry and a radiation exposure calculator have been developed as tools for achieving the extreme radio-purity required for this rare decay search.

  13. The Majorana Parts Tracking Database

    CERN Document Server

    Abgrall, N; Avignone, F T; Bertrand, F E; Brudanin, V; Busch, M; Byram, D; Caldwell, A S; Chan, Y-D; Christofferson, C D; Combs, D C; Cuesta, C; Detwiler, J A; Doe, P J; Efremenko, Yu; Egorov, V; Ejiri, H; Elliott, S R; Esterline, J; Fast, J E; Finnerty, P; Fraenkle, F M; Galindo-Uribarri, A; Giovanetti, G K; Goett, J; Green, M P; Gruszko, J; Guiseppe, V E; Gusev, K; Hallin, A L; Hazama, R; Hegai, A; Henning, R; Hoppe, E W; Howard, S; Howe, M A; Keeter, K J; Kidd, M F; Kochetov, O; Kouzes, R T; LaFerriere, B D; Leon, J Diaz; Leviner, L E; Loach, J C; MacMullin, J; Martin, R D; Meijer, S J; Mertens, S; Miller, M L; Mizouni, L; Nomachi, M; Orrell, J L; O'Shaughnessy, C; Overman, N R; Petersburg, R; Phillips, D G; Poon, A W P; Pushkin, K; Radford, D C; Rager, J; Rielage, K; Robertson, R G H; Romero-Romero, E; Ronquest, M C; Shanks, B; Shima, T; Shirchenko, M; Snavely, K J; Snyder, N; Soin, A; Suriano, A M; Tedeschi, D; Thompson, J; Timkin, V; Tornow, W; Trimble, J E; Varner, R L; Vasilyev, S; Vetter, K; Vorren, K; White, B R; Wilkerson, J F; Wiseman, C; Xu, W; Yakushev, E; Young, A R; Yu, C -H; Zhitnikov, I

    2015-01-01

    The Majorana Demonstrator is an ultra-low background physics experiment searching for the neutrinoless double beta decay of $^{76}$Ge. The Majorana Parts Tracking Database is used to record the history of components used in the construction of the Demonstrator. The tracking implementation takes a novel approach based on the schema-free database technology CouchDB. Transportation, storage, and processes undergone by parts such as machining or cleaning are linked to part records. Tracking parts provides a great logistics benefit and an important quality assurance reference during construction. In addition, the location history of parts provides an estimate of their exposure to cosmic radiation. A web application for data entry and a radiation exposure calculator have been developed as tools for achieving the extreme radio-purity required for this rare decay search.

  14. Měkkýši zrušené Státní přírodní rezervace Loucké rybníky (Slezsko, Česká republika Molluscs of the abolished reserve of the Loucké Rybníky ponds (Silesia, Czech Republic

    Directory of Open Access Journals (Sweden)

    Jiří Kupka

    2011-11-01

    Full Text Available The Loucké Rybníky ponds State Nature Reserve was established in 1954 and due to negative effects of mining activities it was abolished in 1979. This article presents results of malacological survey in the Loucké Rybníky ponds (Karviná-Louky, Czech Republic conducted in 2006 and 2007. The samples were collected at seven locations which match with sites sampled in 1954 and 1978; the location of sites were detected based on original schematic maps showing their position. The research was focused on aquatic species, terrestrial mollusc were collected only marginally. In 2006 and 2007, 38 mollusc species were found (35 gastropods and 3 bivalves, which include 17 species of aquatic molluscs and 21 terrestrial. Based on comparison with the data collected in 1954 and 1978 we conclude that the total destruction of aquatic habitats was irreversible and lead to changes in the species composition. Several rare and endangered species have extinct at this site and the total species richness of aquatic species decided from 29 to 17.

  15. Juhan Parts lubab investeerida teedesse / Juhan Parts ; interv. Tanel Raig

    Index Scriptorium Estoniae

    Parts, Juhan, 1966-

    2007-01-01

    Ilmunud ka: Delovõje Vedomosti 17. okt. lk. 13. Majandusminister Juhan Parts arutleb lahendamist vajavate küsimuste ja prioriteetsete investeeringute üle transpordisektoris. Lisa: Juhan Partsi kuus kuud ministrina

  16. Otvetshajet Juhan Parts, premjer-ministr / Juhan Parts

    Index Scriptorium Estoniae

    Parts, Juhan, 1966-

    2005-01-01

    Peaminister Juhan Parts selgitab Res Publica ja valitsuse korruptsioonivastast poliitikat ning loodab, et justiitsminister Ken-Marti Vaheri pakutud strateegia võitluses korruptsiooniga ei saa koalitsiooni lagunemise põhjuseks

  17. Parts hindab oma valitsust "kolmega" / Juhan Parts ; interv. Toomas Sildam

    Index Scriptorium Estoniae

    Parts, Juhan, 1966-

    2005-01-01

    Peaminister Juhan Parts vastab küsimustele, mis puudutavad uue valitsuskoalitsiooni moodustamist. Peaminister peab oluliseks, et uus valitsus tekiks kiiresti, ning on nõus ise uue valitsuse kokku panema

  18. part of an IBM computer

    CERN Multimedia

    1985-01-01

    Part of the IBM computer that was used for physics simulations in preparation for experiments at LEP. When installed in 1985, it was considered to be very powerful. Nowadays, a PC can outperform it by a factor of ten.

  19. Medicare Part D Program Analysis

    Data.gov (United States)

    U.S. Department of Health & Human Services — This page contains information on Part D program analysis performed by CMS. These reports will also be used to better identify, evaluate and measure the effects of...

  20. World Auto Parts Market Thriving

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ In a global market with increased competition, the global auto industrial chain in some regions of Europe, the U.S. and Japan is transforming into a new relationship between the auto parts producers and complete vehicle producers.