50 results on '"Mandrup-Poulsen, T."'
Search Results
2. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines
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Lundh, M., primary, Christensen, D. P., additional, Rasmussen, D. N., additional, Mascagni, P., additional, Dinarello, C. A., additional, Billestrup, N., additional, Grunnet, L. G., additional, and Mandrup-Poulsen, T., additional
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- 2010
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3. Multifactorial treatment increases endothelial progenitor cells in patients with type 2 diabetes
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Reinhard, H., primary, Jacobsen, P. Karl, additional, Lajer, M., additional, Pedersen, N., additional, Billestrup, N., additional, Mandrup-Poulsen, T., additional, Parving, H.-H., additional, and Rossing, P., additional
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- 2010
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4. The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation
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Kolb, H., primary and Mandrup-Poulsen, T., additional
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- 2009
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5. IL-1β-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells
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Jacobsen, M. L. B., primary, Rønn, S. G., additional, Bruun, C., additional, Larsen, C. M., additional, Eizirik, D. L., additional, Mandrup-Poulsen, T., additional, and Billestrup, N., additional
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- 2008
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6. Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
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Rønn, S. G., primary, Börjesson, A., additional, Bruun, C., additional, Heding, P. E., additional, Frobøse, H., additional, Mandrup-Poulsen, T., additional, Karlsen, A. E., additional, Rasschaert, J., additional, Sandler, S., additional, and Billestrup, N., additional
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- 2008
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7. Proliferation of sorted human and rat beta cells
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Parnaud, G., primary, Bosco, D., additional, Berney, T., additional, Pattou, F., additional, Kerr-Conte, J., additional, Donath, M. Y., additional, Bruun, C., additional, Mandrup-Poulsen, T., additional, Billestrup, N., additional, and Halban, P. A., additional
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- 2007
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8. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells
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Larsen, L., primary, Tonnesen, M., additional, Ronn, S. G., additional, Størling, J., additional, Jørgensen, S., additional, Mascagni, P., additional, Dinarello, C. A., additional, Billestrup, N., additional, and Mandrup-Poulsen, T., additional
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- 2007
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9. IL-1β-induced pro-apoptotic signalling is facilitated by NCAM/FGF receptor signalling and inhibited by the C3d ligand in the INS-1E rat beta cell line
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Petersen, L. G., primary, Størling, J., additional, Heding, P., additional, Li, S., additional, Berezin, V., additional, Saldeen, J., additional, Billestrup, N., additional, Bock, E., additional, and Mandrup-Poulsen, T., additional
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- 2006
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10. Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells
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Larsen, C. M., primary, Døssing, M. G., additional, Papa, S., additional, Franzoso, G., additional, Billestrup, N., additional, and Mandrup-Poulsen, T., additional
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- 2006
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11. Plasma cytokine levels in young and elderly twins: genes versus environment and relation to in vivo insulin action
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Grunnet, L., primary, Poulsen, P., additional, Klarlund Pedersen, B., additional, Mandrup-Poulsen, T., additional, and Vaag, A., additional
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- 2005
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12. Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells
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Larsen, L., primary, Størling, J., additional, Darville, M., additional, Eizirik, D. L., additional, Bonny, C., additional, Billestrup, N., additional, and Mandrup-Poulsen, T., additional
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- 2005
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13. Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt
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Størling, J., primary, Binzer, J., additional, Andersson, A. K., additional, Züllig, R. A., additional, Tonnesen, M., additional, Lehmann, R., additional, Spinas, G. A., additional, Sandler, S., additional, Billestrup, N., additional, and Mandrup-Poulsen, T., additional
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- 2005
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14. An immune origin of type 2 diabetes?
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Kolb, H., primary and Mandrup-Poulsen, T., additional
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- 2005
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15. Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes
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Hamid, Y. H., primary, Rose, C. S., additional, Urhammer, S. A., additional, Gl�mer, C., additional, Nols�e, R., additional, Kristiansen, O. P., additional, Mandrup-Poulsen, T., additional, Borch-Johnsen, K., additional, Jorgensen, T., additional, Hansen, T., additional, and Pedersen, O., additional
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- 2005
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16. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1?-mediated toxicity through inhibition of multiple nuclear factor-?B-regulated proapoptotic pathways
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Karlsen, A. E., primary, Heding, P. E., additional, Frob�se, H., additional, R�nn, S. G., additional, Kruh�ffer, M., additional, �rntoft, T. F., additional, Darville, M., additional, Eizirik, D. L., additional, Pociot, F., additional, Nerup, J., additional, Mandrup-Poulsen, T., additional, and Billestrup, N., additional
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- 2004
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17. Mutation analysis of suppressor of cytokine signalling 3, a candidate gene in Type 1 diabetes and insulin sensitivity
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Gylvin, T., primary, Nolsøe, R., additional, Hansen, T., additional, Nielsen, E. M. D., additional, Bergholdt, R., additional, Karlsen, A. E., additional, Billestrup, N., additional, Borch-Johnsen, K., additional, Pedersen, O., additional, Mandrup-Poulsen, T., additional, Nerup, J., additional, and Pociot, F., additional
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- 2004
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18. Complete mutation scan of the human Fas ligand gene: Linkage studies in Type I diabetes mellitus families
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Nolsøe, R. L., primary, Kristiansen, O. P., additional, Larsen, Z. M., additional, Johannesen, J., additional, Pociot, F., additional, and Mandrup-Poulsen, T., additional
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- 2002
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19. A choice of death - the signal-transduction of immune-mediated beta-cell apoptosis
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Eizirik, D. L., primary and Mandrup-Poulsen, T., additional
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- 2001
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20. TNFα and IFNγ potentiate IL-1β induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans
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Andersen, N. Aa., primary, Larsen, C. M., additional, and Mandrup-Poulsen, T., additional
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- 2000
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21. Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with Type I diabetes mellitus
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Nolsøe, R. L., primary, Kristiansen, O. P., additional, Sangthongpitag, K., additional, Larsen, Z. M., additional, Johannesen, J., additional, Karlsen, A. E., additional, Pociot, F., additional, Nerup, J., additional, Verge, C. F., additional, and Mandrup-Poulsen, T., additional
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- 2000
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22. The role of interleukin-1 in the pathogenesis of IDDM
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Mandrup-Poulsen, T., primary
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- 1996
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23. Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes.
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Pham, M., Kolb, H., Battelino, T., Ludvigsson, J., Pozzilli, P., Zivehe, F., Roden, M., Mandrup-Poulsen, T., and Schloot, N.
- Abstract
Aims/hypothesis: Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes. Methods: The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at −5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-β) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA and fasting blood glucose. Results: High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders ( p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-β and TGF-β were associated with lower fasting and stimulated C-peptide levels ( p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased ( p < 0.001) while those of IL-10 and TGF-β decreased ( p < 0.02) and IL-1RA and TGF-β remained unchanged. Conclusions/interpretation: The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function. [ABSTRACT FROM AUTHOR]
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- 2013
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24. Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats
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Zumsteg, U., primary, Reimers, J. I., additional, Pociot, F., additional, M�rch, L., additional, Helqvist, S., additional, Brendel, M., additional, Alejandro, R., additional, Mandrup-Poulsen, T., additional, Dinarello, C. A., additional, and Nerup, J., additional
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- 1993
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25. What are the types and cellular sources of free radicals in the pathogenesis of Type 1 (insulin-dependent) diabetes mellitus?
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Mandrup-Poulsen, T., primary
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- 1993
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26. Repetitive in vivo treatment with human recombinant interleukin-1? modifies Beta-cell function in normal rats
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Wogensen, L. D., primary, Reimers, J., additional, Nerup, J., additional, Kolb -Bachofen, V., additional, Kr�ncke, K. -D., additional, Almdal, T., additional, and Mandrup -Poulsen, T., additional
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- 1992
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27. The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation.
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Kolb, H. and Mandrup-Poulsen, T.
- Abstract
The recent major increase in the global incidence of type 2 diabetes suggests that most cases of this disease are caused by changes in environment and lifestyle. All major risk factors for type 2 diabetes (overnutrition, low dietary fibre, sedentary lifestyle, sleep deprivation and depression) have been found to induce local or systemic low-grade inflammation that is usually transient or milder in individuals not at risk for type 2 diabetes. By contrast, inflammatory responses to lifestyle factors are more pronounced and prolonged in individuals at risk of type 2 diabetes and appear to occur also in the pancreatic islets. Chronic low-grade inflammation will eventually lead to overt diabetes if counter-regulatory circuits to inflammation and metabolic stress are compromised because of a genetic and/or epigenetic predisposition. Hence, it is not the lifestyle change per se but a deficient counter-regulatory response in predisposed individuals which is crucial to disease pathogenesis. Novel approaches of intervention may target these deficient defence mechanisms. [ABSTRACT FROM AUTHOR]
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- 2010
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28. IL-1β-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells.
- Author
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Jacobsen, M., Rønn, S., Bruun, C., Larsen, C., Eizirik, D., Mandrup-Poulsen, T., and Billestrup, N.
- Abstract
Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1β and IFN-γ regulate the transcription of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1β- and IFN-γ-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine-induced Fas and chemokine expression in beta cells. Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas mRNA expression. The ability of SOCS-3 to influence the activity of cytokine-responsive Fas and Mcp-1 (also known as Ccl2) promoters was measured by reporter analysis. IL-1β induced a time-dependent increase in Mcp-1 and Mip-2 (also known as Cxcl2) mRNA expression after 6 h of stimulation in insulinoma (INS)-1 and neonatal rat islet cells. This induction was inhibited when Socs3 was expressed in the cells. In INS-1 cells, IL-1β + IFN-γ induced a tenfold and eightfold increase of Fas mRNA expression after 6 and 24 h, respectively. This induction was inhibited at both time-points when expression of Socs3 was induced. In promoter studies SOCS-3 significantly inhibited the cytokine-induced activity of Mcp-1 and Fas promoter constructs. SOCS-3 inhibits the expression of cytokine-induced chemokine and death-receptor Fas mRNA. [ABSTRACT FROM AUTHOR]
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- 2009
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29. Proliferation of sorted human and rat beta cells.
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Parnaud, G., Bosco, D., Berney, T., Pattou, F., Kerr-Conte, J., Donath, M., Bruun, C., Mandrup-Poulsen, T., Billestrup, N., and Halban, P.
- Abstract
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. Human beta cells were purified by FACS by virtue of their high zinc content using Newport Green, and excluding ductal and dead cells. Rat beta cells were sorted by autofluorescence or using the same method developed for human cells. Cells were plated on poly- l-lysine or ECMs from rat or human bladder carcinoma cells or bovine corneal ECM and incubated in the presence of BrdU with or without growth factors. The newly developed method for sorting human beta cells yields a population containing 91.4 ± 2.8% insulin-positive cells with a low level of spontaneous apoptosis and a robust secretory response to glucose. Beta cells from 8-week-old rats proliferated in culture and this was increased by ECM. Among growth factors, only human growth hormone (hGH) and the glucagon-like peptide-1 analogue liraglutide enhanced proliferation of rat beta cells, with a significant increase on both poly- l-lysine and ECM. By contrast, sorted adult human beta cells from 16 donors aged 48.9 ± 14.3 years (range 16–64 years) failed to replicate demonstrably in vitro regardless of the substratum or growth factors used. These findings indicate that, in our conditions, the fully differentiated human adult insulin-producing beta cell was unable to proliferate in vitro. This has important implications for any attempt to expand cells from pancreases of donors of this age group. By contrast, the rat beta cells used here were able to divide in vitro, and this was enhanced by ECM, hGH and liraglutide. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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30. Plasma cytokine levels in young and elderly twins: genes versus environment and relation to in vivo insulin action.
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Grunnet, L., Poulsen, P., Klarlund Pedersen, B., Mandrup-Poulsen, T., and Vaag, A.
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BIOCHEMISTRY ,BLOOD plasma ,BIRTH weight ,INSULIN resistance ,HYPOGLYCEMIC agents ,GLYCOGENOLYSIS ,TWINS ,GENETICS - Abstract
Aims/hypothesis: We studied the impact of genetic versus pre- and postnatal environmental factors on the plasma levels of IL6, TNF and the soluble TNF receptor superfamily, member 1A (TNFRSF1A, previously known as TNF receptor type1 [TNFR1]). Materials and methods: Using the hyperinsulinaemic—euglycaemic clamp, we assessed the association between cytokine levels and both peripheral insulin sensitivity and hepatic glucose production. Fasting plasma IL6, TNF and soluble TNFRSF1A levels were measured using ELISA in 55 young and 43 elderly twinpairs. Results: Plasma IL6 and TNF were influenced by genetic factors in young and elderly twins respectively, while no significant impact of genetics was found for soluble TNFRSF1A. Significant intra-twin pair correlations between birthweight and both IL6 and soluble TNFRSF1A levels were found. In addition to the effect of birthweight on IL6, age and fat % also significantly influenced IL6 levels, whereas soluble TNFRSF1A levels were significantly influenced by zygosity, age, fat % and sex. Plasma soluble TNFRSF1A was associated with higher plasma NEFA and to some extent with reduced insulin sensitivity. Plasma IL6 was associated positively with basal NEFA. TNF level was not associated with in vivo glucose or fat metabolism after correction for known confounders. Conclusions/interpretation: Plasma IL6 and soluble TNFRSF1A are influenced by the intrauterine environment. We found some evidence of a genetic component for TNF and IL6 in young and elderly twins respectively. Plasma IL6 may influence basal lipolysis, but neither plasma TNF nor IL6 levels are independently associated with hepatic or peripheral insulin action. Nevertheless, plasma soluble TNFRSF1A may play some role in the control of insulin action. [ABSTRACT FROM AUTHOR]
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- 2006
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31. Assessment of precision, concordance, specificity, and sensitivity of islet cell antibody measurement in 41 assays
- Author
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Bonifacio, E., primary, Boitard, C., additional, Gleichmann, H., additional, Shattock, M. A., additional, Molenaar, J. L., additional, Bottazzo, G. F., additional, Assa, S., additional, Arnaiz-Villena, A., additional, Barbosa, J., additional, Betterle, C., additional, Beutner, E., additional, Bright, G., additional, Chapel, H., additional, Codina, M., additional, Dawkins, R., additional, Deitsch, E., additional, Di Mario, U., additional, Eisenbarth, G., additional, Elliot, R., additional, Gomis de Barbara, R., additional, Hanafusa, T., additional, Harrison, L., additional, Helmke, K., additional, Howard, C., additional, Veld, P.In't, additional, Kawathara, D., additional, Kobayashi, T., additional, Landin, M., additional, Lernmark, Å., additional, Maclaren, N., additional, Mandrup-Poulsen, T., additional, Manna, R., additional, Miettinen, A., additional, Palmer, J., additional, Panczel, P., additional, Peter, J., additional, Pirich, K., additional, Quenette, L., additional, Reeves, G., additional, Reinauer, K., additional, Scherbaum, W., additional, Scott-Morgan, L., additional, Vergani, D., additional, and Vialettes, B., additional
- Published
- 1990
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32. Functional and morphological effects of interleukin-1? on the perfused rat pancreas
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Wogensen, L. D., primary, Kolb-Bachofen, V., additional, Christensen, P., additional, Dinarello, C. A., additional, Mandrup-Poulsen, T., additional, Martin, S., additional, and Nerup, J., additional
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- 1990
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33. IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis T. Sparre et al.: Proteome analysis of BB rat islets.
- Author
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Sparre, T., Christensen, U. Bjerre, Larsen, P. Mose, Fey, S. J., Wrzesinski, K., Roepstorff, P., Mandrup-Poulsen, T., Pociot, F., Karlsen, A. E., and Nerup, J.
- Subjects
GENETICS of diabetes ,DIABETES ,PEPTIDES ,INTERLEUKINS ,ISLANDS of Langerhans ,PROTEIN synthesis - Abstract
Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is characterized by selective destruction of the insulin producing beta cells. Interleukin-1β (IL-1β) modulates the beta-cell function, protein synthesis, energy production and causes apoptosis. We have previously shown changes in the expression of 82 out of 1 815 protein spots detected by two dimensional gel electrophoresis in IL-1β exposed diabetes prone Bio Breeding (BB-DP) rat islets of Langerhans in vitro. The aim of this study was to identify the proteins in these 82 spots by mass spectrometry and compare these changes with those seen in IL-1β exposed Wistar Furth (WF) rat islets. Methods. The 82 protein spots, that changed expression after IL-1β exposure, were all re-identified on preparative gels of 200 000 neonatal WF rat islets, cut out and subjected to mass spectrometry for identification. Results. Forty-five different proteins were identified from 51 spots and grouped according to function: (i) energy transduction and redox potentials; (ii) glycolytic and Krebs cycle enzymes; (iii) protein, DNA and RNA synthesis, chaperoning and protein folding; (iv) signal transduction, regulation, differentiation and apoptosis; (v) cellular defence; and (vi) other functions. Comparison of IL-1β exposed BB-DP and WF islets showed common changes in 14 proteins and several proteins influencing similar pathways, suggesting that similar routes in the two strains lead to beta-cell destruction. Conclusion/interpretation. We demonstrate that proteome analysis is a powerful tool to identify proteins and pathways in BB-DP rat islets exposed to IL-1β. [ABSTRACT FROM AUTHOR]
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- 2002
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34. Repetitive in vivo treatment with human recombinant interleukin-1 β modifies Beta-cell function in normal rats.
- Author
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Wogensen, L., Reimers, J., Nerup, J., Kolb -Bachofen, V., Kröncke, K., Almdal, T., and Mandrup -Poulsen, T.
- Abstract
It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 μg of recombinant human interleukin-1 β per kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either untreated or pre-treated with 4 μg/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal injections of 4 μg/kg interleukin-1 on blood glucose, glucose tolerance, plasma levels of insulin, glucagon and corticosterone, pancreatic insulin content and pancreatic ultrastructure; and (c) blood glucose and plasma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at which time point the inhibitory effect of short-term interleukin-1 exposure on insulin secretion reaches its nadir in vitro. A single injection of 4 μg/kg of interleukin-1 caused a slight, but significant lowering of blood glucose 2 h after interleukin-1 injection with no significant changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 μg/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance. Blood glucose levels significantly increased time-dependently 4-10 h after the third and fifth injection of interleukin-1, and diabetic values (blood glucose >11.0 mmol/l) were observed 6 and 10 h after the fifth injection of interleukin-1. Ten hours after the fifth injection of interleukin-1, diabetic blood glucose levels were observed together with a 50% reduction in plasma insulin concentration. Ultrastructural examination showed no signs of Betacell lysis. In conclusion, interleukin-1 has bimodal effects on glucose homeostasis in vivo, a slight lowering of the blood glucose followed by impaired glucose tolerance and later by diabetic blood glucose levels. Two hours after the last of five daily injections of interleukin-1 impaired glucose tolerance is primarily caused by a state of insulin resistance, whereas diabetic blood glucose levels are associated with inhibition of insulin secretion. Thus, interleukin-1 causes a diabetic state in normal animals, but it remains to be demonstrated that administration of interleukin-1 to normal animals leads to permanent diabetes due to Beta-cell destruction. [ABSTRACT FROM AUTHOR]
- Published
- 1992
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35. Insulin autoantibodies are associated with islet cell antibodies; their relation to insulin antibodies and B-cell function in diabetic children.
- Author
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Ludvigsson, J., Binder, C., and Mandrup-Poulsen, T.
- Abstract
Blood was drawn from 74 children, 3-16 years old, at diagnosis of Type 1 (insulin-dependent) diabetes and before the first insulin injection. Insulin autoantibodies were detected with a polyethylen-glycol-method in 27/74 (36.4%) and with an immuno-electrophoretic method in 6/74 (8.1%). Islet cell cytoplasmic antibodies detected by indirect immuno-fluorescence were found in 49/74 patients (66.2%), who included as many as 23 of the 27 patients with insulin autoantibodies determined with the polyethylen-glycol-method ( p<0.01). The proportion of insulin autoantibody-positive patients who developed insulin antibodies during the first 9 months of insulin treatment was not significantly greater (51.8%) than that of insulin autoantibody-negative patients (44.6%), but patients with both islet cell antibodies and insulin autoantibodies at diagnosis produced more insulin antibodies during the first 9 months ( p<0.05). There was no difference in fasting or meal stimulated serum C-peptide after 3, 9 or 18 months as related to occurrence of insulin autoantibodies and/or islet cell antibodies. The correlation between insulin autoantibodies and islet cell antibodies indicates that both types of autoantibodies reflect the same immunological process, although the lack of correlation to C-peptide may indicate that they play a minor causal role. In addition, the results show that patients with an active autoimmune process evidently tend to produce more insulin antibodies during the first months of insulin treatment, but the islet cell antibodies and insulin autoantibodies-positive patients had at least as good residual B-cell function as patients without autoantibodies at diagnosis. If insulin antibodies produced as a response to exogenous insulin do have a negative effect on B-cell function our present results suggest that such mechanisms are of minor importance. [ABSTRACT FROM AUTHOR]
- Published
- 1988
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36. Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans.
- Author
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Spinas, G., Hansen, B., Linde, S., Kastern, W., Mølvig, J., Mandrup-Poulsen, T., Dinarello, C., Nielsen, J., and Nerup, J.
- Abstract
Human crude and recombinant interleukin 1 (IL-1) was found to dose- and time-dependently affect the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Incubation of rat islets with either 0.5 U/ml or 5 U/ml of crude IL-1 for 1 h had no detectable effect on (pro)insulin biosynthesis. After 24 hours of exposure 0.5 U/ml of crude or 0.6 ng/ml of recombinant IL-1 (beta) increased the (pro)insulin biosynthesis by 42% and 58%, respectively, whereas a 10-fold greater concentration of IL-1 decreased the (pro)insulin biosynthesis by 74% and 89%, respectively. The increase in (pro)insulin biosynthesis was accompanied by an increase in total protein biosynthesis indicating a nonspecific stimulatory action of low IL-1 concentrations. In contrast, high IL-1 concentrations caused a more selective decrease of the (pro)insulin biosynthesis when compared to the total protein biosynthesis. In addition, low IL-1 concentrations were found to increase and high concentrations to decrease the relative levels of pre-proinsulin mRNA suggesting that IL-1 may act both at a pre- and post-translational level of insulin biosynthesis. [ABSTRACT FROM AUTHOR]
- Published
- 1987
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37. Affinity-purified human Interleukin I is cytotoxic to isolated islets of Langerhans.
- Author
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Mandrup-Poulsen, T., Bendtzen, K., Nerup, J., Dinarello, C., Svenson, M., and Nielsen, J.
- Abstract
Addition of highly purified human Interleukin-1 to the culture medium of isolated rat islets of Langerhans for 6 days led to 88% inhibition of glucose-induced insulin-release, reduction of islet contents of insulin and glucagon to 31% and 8% respectively, and disintegration of the islets. These effects were dose-dependent and reproducible when using three different Interleukin-1 preparations. Highly purified human Interleukin-2, Lymphotoxin, Leucocyte Migration Inhibitory Factor and Macrophage Migration Inhibitory Factor were ineffective. These findings suggest that Interleukin-1 may play an important role in the molecular mechanisms underlying autoimmune B-cell destruction leading to Type 1 (insulin-dependent) diabetes mellitus. [ABSTRACT FROM AUTHOR]
- Published
- 1986
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38. Increased reduction in fasting C-peptide is associated with islet cell antibodies in Type 1 (insulin-dependent) diabetic patients.
- Author
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Marner, B., Agner, T., Binder, C., Lernmark, Å., Nerup, J., Mandrup-Poulsen, T., and Walldorff, S.
- Abstract
A cohort of 82 patients with Type 1 (insulin-dependent) diabetes was followed prospectively for 24 months, and 54 of them for 30 months, to study the relationship between fasting levels of immunoreactive C-peptide and titres of islet cell antibodies. After diagnosis, fasting C-peptide rose temporarily for 1-6 months of insulin therapy and declined continuously thereafter. While islet cell antibodies were present among 55% of the newly diagnosed patients, only 31% remained positive at 30 months. Their antibody titres decreased from 1∶81 at diagnosis to 1∶3. Only 3 patients (4%) who were islet cell antibody negative at diagnosis became positive later. The median C-peptide values among the persistently islet cell antibody positive patients decreased from 0.11 pmol/ml at 18 months, to 0.09 pmol/ml at 24 months, to 0.06 pmol/ml at 30 months compared to 0.18 ( p=0.04), 0.15 ( p=0.05) and 0.16 ( p< 0.003) pmol/ml, respectively, for the islet cell antibody negative patients. The median slope for the latter was −0.09 compared to −0.19 for the islet cell antibody positive patients ( p=0.01). These differences were reflected in increasing dosages of insulin, since patients remaining antibody-positive for 30 months were given 1.3-1.4 times more insulin ( p=0.01-0.004) than the antibody negative patients. This study demonstrates that islet cell antibodies may be a useful marker for predicting an increased rate by which endogenous B cell function is lost in Type 1 diabetes. [ABSTRACT FROM AUTHOR]
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- 1985
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39. Insulin-gene flanking sequences, diabetes mellitus and atherosclerosis: a review.
- Author
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Mandrup-Poulsen, T., Owerbach, D., Nerup, J., Johansen, K., Ingerslev, J., and Tybjærg Hansen, A.
- Abstract
A highly polymorphic locus flanking the human insulin gene contains two major size classes of DNA restriction fragments, which segregate in families as stable genetic elements. The L-allele, i.e. fragments with an average size of about 600 base-pairs seems to be a weak genetic marker for Type 1 (insulin-dependent) diabetes mellitus, whereas the Uallele, i. e. fragments of an average size of about 2500 basepairs hitherto has been associated with Type 2 (non-insulin-dependent) diabetes mellitus and diabetic hypertriglyceridaemia. The most recent reports on this subject do not confirm an association between the U-allele and Type 2 diabetes. Our own studies indicate that the U-allele is a fairly strong marker for the development of atherosclerosis (relative risk for U-carriers 3.36). The putative functions of the polymorphic region in atherogenesis and the relation of this region to other genetic markers for atherosclerosis are not known. [ABSTRACT FROM AUTHOR]
- Published
- 1985
- Full Text
- View/download PDF
40. 35th Annual Meeting of the European Association for the Study of Diabetes
- Author
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Melander, A., Olsson, J., Lindberg, G., Salzman, A., Howard, T., Stang, P., Lydick, E., Emslie-Smith, A., Boyle, D. I. R., Evans, J. M. M., Macdonald, T. M., Bain, J., Sullivan, F., Juhl, C., Pørksen, N., Sturis, J., Hollingdal, M., Pincus, S., Veldhuis, J., Dejgaard, A., Schmitz, O., Kristensen, J. S., Frandsen, K. B., Bayer, Th., Müller, P., Dunning, B. E., Paladini, S., Gutierrez, C., Deacon, R., Valentin, M., Grunberger, G., Weston, W. M., Patwardhan, R., Rappaport, E. B., Sargeant, L. A., Wareham, N. J., Khaw, K. T., Zethelius, Björn, Lithell, Hans, Hales, C. Nicholas, Berne, Christian, Lakka, H.-M., Oksanen, L., Tuomainen, T.-P., Kontula, K., Salonen, J. T., Dekker, J. M., de Boks, P., de Vegt, F., Stehouwer, C. D. A., Nijpels, G., Bouter, L. M., Heine, R. J., Bruno, G., Cavallo-Perin, P., Bargero, G., D’Errico, N., Borra, M., Macchia, G., Pagano, G., Newton, R. W., Ruta, D. A., New, J. P., Wallace, C., Roxburgh, M. A., Young, R. J., Vaughan, N. J. A., Elliott, P., Brennan, G., Devers, M., MacAlpine, R., Steinke, D., Lawson, D. H., Decallonne, B., Casteels, K., Gysemans, C., Bouillon, R., Mathieu, C., Linn, Thomas, Strate, Christine, Schneider, Kerstin, Funda, D. P., Jirsa, M., Kozáková, H., Kaas, A., Kofronová, O., Tlaskalová-Hogenová, H., Buschard, K., Wanka, H., Hartmann, A., Kuttler, B., Rasmussen, S. B., Sørensen, T. S., Markholst, H., Petersen, J. S., Karounos, D., Dyrberg, T., Mabley, J. G., Haskó, G., Szabó, C., Seissler, J., Nguyen, T. B. T., Steinbrenner, H., Scherbaum, W. A., Cipriani, R., Gabriele, A., Sensi, M., Guidobaldi, L., Pantellini, F., Cerrito, M. G., Scarpa, S., Di Mario, U., Morano, S., Ceolotto, G., Iori, E., Baritono, E., Del Prato, S., Semplicini, A., Trevisan, R., Zerbini, G., Meregalli, G., Asnaghi, V., Tentori, F., Maestroni, A., Mangili, R., Marescotti, C., Vedovato, M., Tiengo, A., Tadjieva, J., Mankovsky, B. N., Van Aken, S., Raes, A., Vande Walle, J., Matthys, D., Craen, M., Hansen, H. P., Lund, S. S., Rossing, P., Jensen, T., Parving, H.-H., Andersen, S., Tarnow, L., Hansen, B. V., Trautner, C., Haastert, B., Ennenbach, N., Willich, S., Tabák, Á. Gy., Orchard, T. J., Spranger, J., Preissner, K. T., Schatz, H., Pfeiffer, A., Cantón, A., Burgos, R., Hernández, C., Lecube, A., Mesa, J., Segura, R. M., Mateo, C., Simó, R., Fathallah, L., Greene, D. A., Obrosova, I., Gilbert, R. E., Kelly, D. J., Cox, A. J., Berka-Wilkinson, J. L., Taylor, H. R., Panagiotopoulos, S., Lee, V., Jerums, G., Cooper, M. E., Hitman, G. A., Aganna, E., Ogunkolade, W. B., Rema, M., Deepa, R., Shanthi-Rani, C. S., Barakat, K., Kumarajeewa, T. R., Cassell, P. G., McDermott, M. F., Mohan, V., Ways, K., Bursell, S., Devries, T., Woodworth, J., Alatorre, C., King, G., Aiello, L. P., Karisen, A. E., Pavlovic, D., Nielsen, K., Jensen, J., Andersen, H. U., Pociot, F., Mandrup-Poulsen, T., Eizirik, D. L., Nerup, J., Lortz, S., Tiedge, M., Lenzen, S., Lally, F. J., Bone, A. J., Darville, M. I., Ho, Y.-S., Sternesjö, J., Sandler, S., Chen, M.-C., Schuit, F., Pipeleers, D. G., Merezak, S., Hardikar, A., Hoet, J. J., Remacle, C., Reusens, B., Bréant, B., Garofano, A., Czernichow, P., Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Nakano, R., Komeda, K., Eto, K., Tobe, K., Kimura, S., Kadowaki, T., Ide, T., Murakami, K., Tsunoda, M., Mochizuki, T., Ozanne, S. E., Nave, B. T., Wang, C. L., Dorling, M. W., Petry, C. J., Koopmans, S. J., van der Bent, C., Que, I., Radder, J. K., Sebokova, E., Sana, A. K., Klimes, I., Ruderman, N., Morviducci, L., Pastore, L., Morelli, S., Sagratella, E., Zorretta, D., Buongiomo, A., Tamburrano, G., Giaccari, A., Martinenghi, Sabina, De Angelis, Gabriella Cusella, Ravasi, Flavio, Bifari, Francesco, Bordignon, Claudio, Falqui, Luca, Kessler, A., Dransfeld, O., Sasson, S., Tomas, E., Zorzano, A., Eckel, J., Thorsby, P., Rosenfalck, A. M., Kjems, L., Hanssen, K. F., Madsbad, S., Birkeland, K. I., Hamilton-Wessler, M., Markussen, J., Bergman, R. N., Melki, V., Hanaire-Broutin, H., Bessières-Lacombe, S., Tauber, J.-P., Home, P. D., Lindholm, A., Riis, A., Rosenstock, J., Schwartz, S., Clark, C., Edwards, M., Donley, D., Swift, P., Mortensen, H. B., Lynggaard, H., Hougaard, P., Cull, C. A., Neil, H. A. W., Frighi, V., Manley, S. E., Holman, R. R., Turner, R. C., Steiner, G., Davis, W. A., Weeraratna, T., Bruce, D. G., Davis, T. M. E., Vergès, B., Duvillard, L., Pont, F., Florentin, E., Gambert, Ph., Benko, B., Ljubić, S., Turk, Z., Granić, M., März, W., Wollschläger, H., Klein, G., Neiss, A., Wehling, M., Huxtable, S. J., Saker, P. J., Walker, M., Frayling, T. M., Levy, J. C., O’Rahilly, S., Hattersley, A. T., McCarthy, M. I., Orecchio, A., Giacchini, A., Dominici, R., Canettieri, G., Trinti, B., Zani, M., Andreoli, M., Sciacchitano, S., de Silva, A. M., Whitecross, K., Pasco, J., Kotowicz, M., Nicholson, G., Zimmet, P., Boyko, E. J., Collier, G. R., Frittitta, L., Pizzuti, A., Argiolas, A., Graci, S., Goldfine, I. D., Bozzali, M., Ercolino, T., Costanzo, B., Iacoviello, L., Tassi, V., Trischitta, V., Wauters, M., Rankinen, T., Mertens, I., Chagnon, M., Bouchard, C., Van Gaal, L., Sivenius, K., Valve, R., Hakkarainen, V., Niskanen, L., Laakso, M., Uusitupa, M., Beridze, N., Japaridze, M., Kurashvili, R., Dundua, M., Kebuladze, G., Kazakhashvili, N., Offley-Shore, B., Thomas, B., Ghebremeskel, K., Crawford, M., Lowy, C., Eriksson, Ulf J., Martin Simán, C., Wisse, Bert, Gittenberger-de Groot, Adriana C., Wentzel, P., Eriksson, U. J., Wender-Ożegowska, E., Drews, K., Biczysko, R., Bronisz, A., Rość, D., Graczykowska-Koczorowska, A., Kotschy, M., Sokup, A., Kohnert, K. D., Besch, W., Strese, J., Frick, U., Zander, E., Kemer, W., Škrha, J., Kvasnička, J., Kalvodová, B., Hilgertová, J., Schatteman, K., Goossens, F., Scharpé, S., De Leeuw, I., Hendriks, D., Legakis, I. N., Panayiotou, D., Mountokalakis, Th. D., Enderle, M. D., Beckmann, P., Balletshofer, B., Rittig, K., Maerker, E., Volk, A., Meisner, C., Jacob, S., Matthaei, S., Häring, H. U., Rett, K., Ueda, K., Nakagawa, T., Shimajiri, Y., Kokawa, M., Matsumoto, E., Sasaki, H., Sanke, T., Nanjo, K., McKinnon, Caroline M., Macfarlane, Wendy M., Docherty, Kevin, Furukawa, N., Shirotani, T., Kishikawa, H., Kaneko, K., Araki, E., Shichiri, M., Prentki, M., Roduit, R., Susini, S., Buteau, J., Ejrnæs, A. M., Andersen, N. Aa., Osterhoff, M., Möhlig, M., Ortmann, J., Bikashaghi, F., Mayer, C., Bikashagi, F., Ackermans, M. T., Pereira Arias, A. M., Bisschop, P. H. L. T., Endert, E., Sauerwein, H. P., Romijn, J. A., Gastaldelli, A., Baldi, S., Pettiti, M., Natali, A., Frascerra, S., Camastra, S., Toschi, E., Ferrannini, E., Stingl, H., Krssak, M., Bischof, M. G., Krebs, M., Fürnsinn, C., Nowotny, P., Waldhäusl, W., Roden, M., Neeft, M., Meijer, A. J., Båvenholm, P., Pigon, J., Efendic, S., Kästenbauer, T., Sauseng, S., Sokol, G., Auinger, M., Irsigler, K., Abbott, C. A., Carrington, A. L., Faragher, B., Kulkarni, J., Van Ross, E. R. E., Boulton, A. J. M., Armstrong, D. G., Hadi, S., Nguyen, H. C., Harkless, L. B., Jirkovská, A., Kasalicky, P., Hosová, J., Skibova, J., Uccioli, L., Caselli, A., Giacomozzi, C., Macellari, V., Giurato, L., Lardieri, L., Menzinger, G., Pham, H. T., Rosenblum, B. I., Lyons, T. E., Giurini, J. M., Smakowski, P., Chrzan, J. S., Habershaw, G. M., Veves, A., Foster, A. M., Bates, M., Doxford, M., Edmonds, M. E., Kecha, O., Winkler, R., Martens, H., Collette, J., Lefèbvre, P. J., Greiner, D., Geenen, V., Atlan-Gepner, C., Naspetti, M., Valéro, R., Barad, M., Lepault, F., Vialettes, B., Naquet, P., de Galan, B., Netea, M. G., Hancu, N., Smits, P., Van der Meer, J. W. M., Osterbye, T., Jørgensen, K. H., Tranum-Jensen, J., Fredman, P., Høy, M., Bokvist, K., Olsen, H. L., Horn, T., Gromada, J., Laub, R., Lohmann, T., Hahn, H. J., Adler, T., Emmrich, F., Rabuazzo, A. M., Lupi, R., Dotta, F., Patanè, G., Marselli, L., Realacci, M., Piro, S., Del Guerra, S., Santangelo, C., Navalesi, R., Purrello, F., Marchetti, P., de Vos, P., Visser, L., de Haan, B. J., Klok, P., van Schilfgaarde, R., Poppema, S., Juang, J.-H., Kuo, C.-H., Hsu, B. R.-S., Nacher, V., Pérez, M., Biarnés, M., Raurell, M., Soler, J., Montanya, E., Ritzel, R., Maubach, J., Büsing, M., Becker, T., Klempnauer, J., Hücking, K., Schmiegel, W. H., Nauck, M. A., Bouček, P., Saudek, F., Adamec, M., Kožitarová, R., Jedináková, T., Vlasáková, Z., Skibová, J., Bartoš, V., Maffi, P., Bertuzzi, F., Aldrighetti, L., Taglietti, M. V., Castelnuovo, A., Pozza, G., Di Carlo, V., Secchi, A., Renier, G., Mamputu, J.-C., Gillespie, J. S., McMaster, D., Mercer, C., Trimble, E. R., Lecomte, M., Véricel, E., Paget, C., Ruggiero, D., Lagarde, M., Wiernsperger, N., Pricci, F., Leto, G., Amadio, L., Cordone, S., Iacobini, C., Catalano, S., Violi, F., Rotella, C. M., Pugliese, G., Zicari, A., Gradini, R., Sale, P., Pala, L., Cresci, B., Giannini, S., Manuelli, C., Dahlfors, G., Arnqvist, H. J., Gonelle-Gispert, C., Halnan, P. A., Sadoul, K., Wolter, S., Lang, J., Niwa, T., Yu, W., Hidaka, H., Senda, T., Niki, I., Fukasawa, T., Renstrom, E., Barg, S., Seward, E., Rorsman, P., Rutter, G. A., Molinete, M., Lilla, V., Ravazzola, M., Halban, P. A., Efanov, A. M., Bertorello, A. M., Zaitsev, S. V., Zwiller, J., Berggren, P.-O., MŞengül, A., Salman, F., Sargrn, M., Özer, E., Karşidaǧ, K., Salman, S., Gedik, S., Satman, İ., Dinççaǧ, N., Yılmaz, M. T., Lloyd, A., Hopkinson, P. K., Testa, M. A., Blonde, L., Turner, R. R., Hayes, J., Simonson, D. C., van der Ven, N. C. W., Lubach, C. H. C., Snoek, F. J., Mollema, E. D., van der Ploeg, H. M., Danne, T., Hoey, H., McGee, H., Fitzgerald, H., Lernmark, B., Thernlund, G., Fredin, K., Hägglöf, B., Lugari, R., Dell’Anna, C., Ugolotti, D., Dei Cas, A., Barilli, A. L., Sard, L., Marani, B., Iotti, M., Zandomeneghi, R., Gnudi, A., Kjems, L. L., Volund, Aa., Toft-Nielsen, M., Damholt, M. B., Hilsted, L., Hughes, T. E., Krarup, T., Holst, J. J., Young, A., Gottlieb, A., Fineman, M., Kolterman, O., Cancelas, J., García-Martínez, J. A., Villanueva-Peñacarrillo, M. L., Valverde, I., Malaisse, W. J., Filipsson, K., Ahrén, B., Balkan, B., Kwasnik, L., Battle, B., Li, X., Egan, J. M., Clocquet, A. R., Elahi, D., Petrella, E., Pricket, K., Petersen, K. F., Sullivan, J. T., Amatruda, J. M., Livingston, J. N., Shulman, G. I., Freyse, E.-J., Knospe, S., Glund, K., Demuth, H.-U., Walker, D., Malik, R. A., Reljanovic, M., Barada, A., Milicevic, Z., Tack, Cees J., Goldstein, David S., Van Huysen, C., Stevens, M. J., Cao, X., Sundkvist, G., Dahlin, L.-B., Eriksson, K.-F., Rosén, I., Lattimer, S. A., Sima, A. A. F., Sullivan, K., Shaw, J. E., de Courten, M. P., Zimmet, P. Z., Gourdy, P., Ruidavets, J. B., Arveiler, D., Amouyel, Ph., Bingham, A., Tauber, J. P., Lam, K. S. L., Wat, N. M. S., Lam, T. H., Janus, E. D., de Pablos, P., Rodriguez, F., Martínez, J., Sánchez, V., Santana, C., García, I., Macías, A., Levin, K., Hother-Nielsen, O., Henriksen, J. E., Beck-Nielsen, H., Brechtel, K., Machann, J., Koch, M., Nielsen, M., Löblein, K., Becker, R., Denignger, M., Renn, W., Machicao, F., Claussen, C. D., Schick, F., Diraison, F., Moulin, P., Beylot, M., Thams, P., Capito, K., Eliasson, Lena, Barg, Sebastian, Göpel, Sven, Kanno, Takahiro, Renström, Erik, Meda, P., Charollais, A., Gjnovci, A., Calabrese, A., Wonkam, A., Caton, D., Wisznievski, L., Serre, V., Cogne, F., Bauquis, J., Bosco, D., Huarte, J., Herrera, P., Gotfredsen, C. F., Vessby, B., Manuel y Keenoy, B., Engelen, W., Vertommen, J., Schrans, S., Louheranta, A., Lindström, J., Tuomilehto, J., Segal, K. R., Heymsfield, S., Hauptman, J., Boldrin, M., Lucas, C., Pandolfi, A., Cetrullo, D., Polishchuck, R., Alberta, M., Pellegrini, G., Calafiore, A., Vitacolonna, E., Capani, F., Consoli, A., Halleux, C. M., Gillot, E. F., Brichard, S. M., Van der Planken, M., Corthouts, B., Peiffer, F., Scholten, D., Walke, M., Assert, R., Pirags, V., Pedula, K. L., Hillier, T. A., Brown, J. B., Santini, S. A., Marra, G., Cotroneo, P., Manto, A., Di Leo, M. A. S., Di Gregorio, S., Tordi, A., Pitocco, D., Ruotolo, V., Ghirlanda, G., Temelkova-Kurktschiev, T., Schaper, F., Koehler, C., Henkel, E., Hanefeld, M., Mancini, L., Citterio, F., Cotroneo, A., Ceroone, S., Castagneto, M., Rajbhandari, S. M., Dent, M. T., Plater, M. E., Harris, N. D., Tesfaye, S., Ward, J. D., Dupuy, O., Mayaudon, H., Lecoules, S., Bauduceau, B., Palou, M., Farret, O., Molinié, C., Antonelli-Incalzi, R., Fuso, L., Giordano, A., Calcagni, M. L., Todaro, L., Basso, S., Tramaglino, L. M., Troncone, L., Pistelli, R., Guillot, R., Bringuier, A., Porokhov, B., Guillausseau, P. J., Feldmann, G., Zivanic, S., Cizmic, M., Dragojevic, R., Vanovic, M., Borghouts, L. B., van Kranenburg, G. P. J., Schaart, G., Keizer, H. A., Niess, A. M., Dickuth, H. H., Lutz, O., Barbe, P., Calazel-Fournier, C., Hernandez, G., Saint-Martin, F., Galitzky, J., Gonçalves, A. A., da Silva, E. C., Brito, I. J. L., da Silva, C. A., Lawrence, N. J., Kousta, E., Mulnier, H., Penny, A., Millauer, B., Johnston, D. G., Robinson, S., Perriello, G., Pimenta, W., Pampanelli, S., Lucidi, P., Lepore, M., Porcellati, F., Cordoni, M. C., De Feo, P., Bolli, G. B., Sjöstrand, M., Holmäng, A., Lönnroth, P., Hauer, B., Grauer, P., Artzner, S., Lang, R., Stumvoll, M., Monti, L. D., Piatti, P. M., Gemone, F., Valsecchi, G., Magni, M., Barbieri, E., Setola, E., Sandoli, E. P., Galli-Kienle, M., Pontiroli, A. E., Nichols, Gregory A., Brown, Jonathan B., Salzsieder, E., Boltz, H., Ramirez, J. C., Rutscher, A., Fischer, U., Koenig, Ch., Friske, M., Schramm, W., Landgraf, R., Bachmann, W., Bangemann, M., Groeneveld, G., Edvell, Anders, Lindström, Per, Tsiotra, P., Koukourava, A., Raptis, S. A., Tsigos, C., Boutou, E., Triandaffilopoulou, A., Egido, E. M., Rodríguez-Gallardo, J., Gutiérrez, E., García, P., Silvestre, R. A., Marco, J., Khan, Akhtar, Ling, Zong-Chao, Ahren, Bo, Efendic, Suad, Bünting, C., Du, X., Zhi Sui, G., Rösen, P., Koschinsky, T., Kearney, T. M., Sharp, P. S., Lapolla, A., Fedele, D., Martano, L., Garbeglio, M., Seraglia, R., Favretto, D., Traldi, P., Meerwaldt, R., Smit, A. J., Links, Th. P., v. Roon, A. M., Graaf, R., Gans, R. O. B., Deynelİ, O., Ersöz, H. Ö., Gogas, D., Fak, A. S., Akalin, S., Veglio, M., Sivieri, R., Chinaglia, A., Scaglione, L., Le, T., Wong, N., Detrano, R., Charles, M. A., Colhoun, H. M., Francis, D. P., Rubens, M., Underwood, S. R., Fuller, J. H., Knudsen, E., Sato, A., Nielsen, F. S., Bonora, E., Kiechl, S., Willeit, J., Oberhollenzer, F., Egger, G., Bonadonna, R., Muggeo, M., Festa, A., D’Agostino, R., Howard, G., Mykkänen, L., Tracy, R. P., Haffner, S. M., Poulsen, P., Vach, K., Ijzerman, R. G., Bakker, S. J. L., Truster, J., Crowther, N. J., Cameron, N., Gray, I. P., Chaillous, L., Carel, J. C., Thivolet, C., Boitard, C., Charbonnel, B., Saï, P., Decochez, K., Keymeulen, B., Somers, G., Dorchy, H., Rottiers, R., Winnock, F., ver Elst, K., Weets, I., Pipeleers, D., Gorus, F., Seebaum, S., Schumm-Draeger, P.-M., Petzoldt, R., Federlin, K., Bonnevie-Nielsen, V., Martensen, P. M., Justesen, J., Worsaa, A., Karlsson, Maria, Sederholm, Sofia, Ludvigsson, Johnny, Bélicar, P., Dale, C., Vague, Ph., Alessis, C., Lassmann-Vague, V., Bode, B. W., Gross, T. M., Ghegan, M., Steed, R. D., Davidson, P. C., Ordoñez, A., Rubio, J. L., Sulleiro, J. M., Buendía, J. P., Zamora, J., Castillo, M., Schaupp, L., Ellmerer, M., Brunner, G. A., Sendlhofer, G., Schlack, Ch., Skrabal, F., Wach, P., Pieber, T. R., Heinemann, L., Krämer, U., Klötzer, H. M., Hermann, M., Cosgrove, K. E., Chapman, J. C., Shepherd, R. M., McIntyre, S., Butler, P. C., Dunne, M. J., Brekardin, E., Dörschner, H., Schwanstecher, C., Schwanstecher, M., Uhde, I., Emmanouilidou, E., Teschemacher, A. G., Pouli, A. E., Gylfe, E., Tengholm, A., Hellman, B., Perfetti, R., Aggarwal, S., Müller, Günter, Welte, Stefan, Wied, Susanne, Valverde, A. M., Mur, C., Kahn, C. R., Benito, M., Rondinone, C. M., Peterson, T., Laviola, L., Belsanti, G., Logoluso, F., Napoli, R., Davalli, A. M., Weir, G. C., Giorgino, R., Giorgino, F., Flesch, S., Hompesch, B., Rave, K., Susanto, F., Kühn-Velten, W. N., Heise, T., Rendell, M., Dole, J., Esper, R. 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C., Hirtz, C., Deville de Périère, D., Meoni, C., Falqui, L., Arcelloni, C., Paroni, R., Folli, F., Barry, R., Turner, N. C., Tadayyon, M., Arch, J. R., Sutti, F., Perego, L., Baglioni, S., Otte, A., Socci, C., Raffaele, H. S., Stumpf, E., Aalto, Y., Otonkoski, T., Knuutila, S., Andersson, L. C., Berra, C., Furlan, R., Coppelli, A., Tellini, C., Bordignon, C., Rouiller, D. G., Lister, C. A., Moore, G. B. T., Piercy, V., Newman, M., Chapman, H., Smith, S. A., Anastasi, E., Bulotta, A., Tiberti, C., Ponte, E., Liddi, R., Taruscio, D., Falchi, M., Annerén, C., Welsh, M., Bernard, C., Ilic, C., Guilbert, V., Palgi, J., Korbutt, G. S., Rayat, G. R., Rajotte, R. V., Kieffer, T. J., Karlsson, Ella, Sandler, Stellan, Boujendar, S., Huotari, M.-A., Miettinen, P. J., Keski-Oja, J., Breda, E., Pacini, G., Vilsbøll, T., Toft-Nielsen, M.-B., Dinesen, B., Corssmit, E. P. M., Qvigstad, E., Mostad, I. L., Bjerve, K., Ann, C. W., Kume, M., Hiramatsu, M., Taniguchi, J., Saito, Y., Kawasaki, Y., Kanazawa, M., Notoya, Y., Hayashi, T., Djemli, A., Gallice, P., Coste, T., Jannot, M. F., Dufayet, D., Raccah, D., Vague, P., Sattar, S., Basak, R. C., Hasan, Z., Ali, L., Nikulina, M. A., Karlsen, A. E., Hong, T. P., Andersen, N. A., Puren, A. J., Fantuzzi, G., Dinarello, C. A., Gysemans, C. A., Sparre, T., Fey, S., Larsen, P. M., Andersson, A. K., John, N. E., Fey, S. J., Mose Larsen, P., Frigerio, S., Ghayur, T., Holländer, G. A., Zumsteg, U., Pinach, S., Monge, L., Grassi, G., Pasquero, P., Ruiu, G., Dall’Omo, A., Carta, Q., Hadjivassiliou, V., Dunger, A. M., Green, M. H. L., Rasilainen, S., Roivainen, M., Ylipaasto, P., Bouwens, L., Hovi, T., Sekine, N., Takahashi, K., Ishikawa, T., Okazaki, T., Fujita, T., Elliott, J., Scarpello, J. H. B., Conroy, S., Byrne, P., Newsholme, P., Harrison, M., Greenl, I. C., Kaya, F., Süsleyici, B., Öztürk, M., Eisner, M., Guldbakke, B., Karpenko, N., Brizgalova, G., Alesina, M., Røder, M. E., Schwartz, R. S., Prigeon, R., Kahn, S. E., Kendereški, A., Micić, D., Šumarac, M., Macut, Dj., Zonć, S., Čolić, M., Cvijović, G., Gligorović, P., Courtney, C. H., Atkinson, A. B., Ennis, C., Sheridan, B., Bell, P. M., Jolly, M., Amin, R., Godsland, I., Horvoka, R., Anyaoku, V., Lawrence, N., Krasova, N., Sergienko, L., Mingrone, G., Plat, L., Balasse, E. O., Zykova, T., Jenssen, T., Strelkova, A., Zykova, S., Tipisova, E., Féry, F., Wijenaike, A. N., Watt, P. W., Jung, R. T., Bolton-Smith, C., Rennie, M. J., Ludvik, B., Aigmueller, Th., Waldhaeusl, W., Courtois, P., Bource, F., Guenat, E., Philippe, J., Jéquier, E., Tappy, L., Benny, Santosa, Grönemeyer, Dietrich, Aygen, Sitke, Scholz, Nicole, Busch, Martin, Tauveron, I., Rochon, C., Dejax, C., Benoit, P., Capitan, P., Bayle, G., Prugnaud, J., Fabricio, A., Champredon, C., Thieblot, P., Grizard, J., Nielsen, M. F., Nyholm, B., Chandramouli, V., Schumann, W. C., Landau, B. R., Rizza, R. A., Mitrakou, A., Meyer, C., Tolias, A., Platanisiotis, D., Vlachos, L., Gerich, J., Wajngot, A., Sprangers, F., Jellema, W. T., Lopuhaä, C. E., van Lieshout, J. J., van der Zee, J. S., Mithieux, G., Croset, M., Zitoun, C., Hurot, J. M., Rajas, F., Montano, S., Willem, R., Verbruggen, I., Grue-Sørensen, G., Björkling, F., Watson, N. D., Burns, S. P., Murphy, H. C., Iles, R. A., Cohen, R. D., Rooney, K., Swan, V., Phuyal, J., Millar, J., Bryson, J., Denyer, G., Caterson, I., Thompson, C., Gaster, M., Handberg, Aa., Schrøder, H. D., Alzaid, A., Sobki, S., Thye-Rønn, P., Alford, F., Christopher, M., Gras, F., Brunmair, B., Neschen, S., Py, G., Lambert, K., Raynaud, E., Mercier, J., Tsuchihashi, K., Sumida, Y., Fujimoto, H., Nakamura, M., Miyata, E., Furuta, M., Katsuki, A., Ito, K., Sasaki, R., Hori, Y., Yano, Y., Adachi, Y., Lauritz, J., Eriksson, J. W., Burén, J., Zhao, L. J., Li, Z.-C., Kullin, M., Karlsson, F. A., Redondo, A., Puente, J., Clemente, F., González, N., Moberg, E., Amer, P., Hagström-Toft, E., Bolinder, J., Björnholm, M., Krook, A., Galuska, D., Myers, M., Zierath, J. R., Wallberg-Henriksson, H., Niklasson, M., Strindberg, L., Sternberg, F., Hebeda, S., Kratzer, W., Salgado, M. I., Hoss, U., Kalatz, B., Lohmann, S., Fussgänger, R., Khomazjuk, A. I., Ncscheret, A. P., Gonchar, I. V., Quinones-Galvan, A., Sironi, A. M., Cominacini, L., Nagai, Y., Yamashita, H., Takamura, T., Kobayashi, K., Szanto, I., Peth, J. A., Kinnick, T. R., Youngblood, E. B., Tritschler, H. J., Henriksen, E. J., Gašperíková, D., Rufo, C., Teran-Garcia, M., Nakamura, M. T., Clarke, S. D., Pye, S., Zhang, Z., Radziuk, J., Guignot, L., Bell, K. S., Lim-Fraser, M., Cooney, G., Kraegen, E. W., Takayama, S., Legare, D. J., Macedo, M. P., Lautt, W. W., Bradley, B., Barron, P., Davies, J., Ader, M., Richey, J. M., Ait El Mkadem, S., Macari, F., Renard, E., Méchaly, I., Brun, J. F., Cros, G., Bringer, J., del Aguila, L. F., Krishnan, R. K., Farrell, P. A., Ulbrecht, J., Correll, P. H., Kirwan, J. P., Mei, J., Rahn-Landström, T., Brindley, D., Manganiello, V., Degerman, E., Ziv, E., Shafrir, E., Kaiman, R., Galer, S., Bar-On, H., Gerő, L., Földes, K., Janssen, J., Járay, J., Perner, F., Haap, M., Houdali, B., Schmit, M. B., Dietze, G. J., Perrini, S., Natalicchio, A., Montrone, C., de Robertis, O., De Pergola, G., Strack, V., Kellerer, M., Kausch, C., Condorelli, G., Beguinot, F., Häring, H.-U., Song, X. M., Chibalin, A. V., Ryder, J. W., Jiang, X. J., Alessi, D. R., Hennige, A. M., Metzinger, E., Seipke, G., Trüb, T., Hey, A., Sørensen, A. R., Schäffer, L., Drejer, K., Kurtzhals, P., Hansen, B. F., Matozaki, T., Noguchi, T., Yamao, T., Takada, T., Ochi, F., Takeda, H., Inagaki, K., Hosoka, T., Kasuga, M., Schürt, M., Meier, M., Drenckhan, M., Meyer, M., Aries, S. P., Klein, H. H., Telting, D., van der Zon, G. C. M., Dorrestijn, J., Maassen, J. A., Clapham, J. C., Holder, J. C., Tomlinson, K. M., Pickavance, L., Buckingham, R., Wilding, J., Jacinto, S. M., Harrold, J., Ljung, B., Kjellstedt, A., Thalén, P., Widdowson, P., Williams, G., Oakes, N., Aoki, K., Saito, T., Satoh, S., Mukasa, K., Kaneshiro, M., Kawasaki, S., Hoshino, K., Okamura, A., Sekihara, H., Smith, U., Johansson, A., Nilsson, E., Olausson, T., Nakazawa, T., Suzuki, M., Martinez, J., Murado, P., Azal, Ö., Yönem, A., Çakır, B., Polat, Z., Kutlu, M., Çorakçı, A., Bayraktar, M., Gürlek, A., Koray, Z., Damian, M. S., Linn, T., Laube, H., Arzner, S., Meißner, H.-P., Giunti, S., Comune, M., Cassader, M., Conte, M. R., Sacchi, C., Musso, G., Mecca, F., Depetris, N., Gambino, R., Perin, P. Cavallo, Kawakami, S., Sandqvist, M., Jansson, P.-A., Šindelka, G., Widimský, J., Haas, T., Prázný, M., Mari, A., Nolan, J. J., Uusitupa, M. I. J., Karşıdağ, K., Hacıhanefioğlu, B., Dinççağ, N., Drivsholm, T., Palacios, R. T., Vølund, A., Pedersen, Oluf B., Letiexhe, M. R., Scheen, A. J., Quiñones Galvan, A., Simeoni, M., Basu, A., Uosukainen, A., Mäkimattila, S., Schlenzka, A., Adler, A. I., Levy, J., Stevens, R., Matthews, D., Holman, R., Boland, B. J., Jeanjean, M., Hermans, M. P., Maudoigt, C., Tonglet, R., Robert, A., Quiñones-Galvan, A., Cini, G., Galetta, F., Sanna, G., Gernone, F., Janssen, M. J., Gonera, R. K., Wolffenbuttel, B. H. R., de Leeuw, P. W., Schaper, N. C., Molęda, P., Kuczerowski, R., Czech, A., Tatoń, J., Taddei, S., Patiag, D., Qu, X., Wilkes, M., Gray, S., Seale, J. P., Donnelly, R., Campión, J., Maestro, B., Dávila, N., Carranza, M. C., Calle, C., Hales, C. N., Fernández-Real, J. M., Grasa, M., Pugeat, M., Barret, C., Ricart, W., Lindmark, S., Olsson, T., Tufvesson, M., Loeblein, K., Mehnert, B., Haering, H. U., Rave, Klaus, Heise, Tim, Clauson, Per, Hirschberger, Sabine, Heinemann, Lutz, Claret, M., Nadal, B., Truc, A., Rossi, L., Hildebrand, P., Ketterer, S., Beglinger, C., Keller, U., Gyr, K., Parvin, S., Overkamp, D., Vayreda, M., González-Huix, F., G-Huix, F., Zavaroni, I., Gasparini, P., Massironi, P., Zuccarelli, A., Delsignore, R., Reaven, G. M., Sheu, W. H. H., Lee, W. J., Chen, Y.-T., Iraklianou, S., Tournis, S., Volonakis, I., Spylopoulou, M., Bilianou, E., Melidonis, A., Foussas, S., Güler, Serdar, çakir, Bekir, Demi̇rbaş, Berrin, Gürsoy, Gül, Serter, Rüştü, Aral, Yalçin, Morton, G., Lee, S., Fahey, R., de Silva, A., Cai, X. J., Buckingham, R. E., Arch, J. R. S., Wilson, S., Clausen, J. T., Kristensen, P., Nielsen, P. F., Wulff, B. S., Thim, L., Holness, M. J., Sugden, M. C., Fryer, L. G. D., Munns, M. J., Mannucci, E., Ognibene, A., Cremasco, F., Bardini, G., Mencucci, A., Ciani, S., Pierazzuoli, E., Tsuchihashil, K., Rigalleau, V., Delafaye, C., Baillet, L., Vergnot, V., Brunou, P., Gatta, B., Gin, H., Felber, J. P., Munger, R., Assimacopoulos, F., Bobbioni, E., Golay, A., Wilken, M., Larsen, F. S., Buckley, D., Molina, L. M., Marquez, L., Arbeo, A., Hernandez, C., Kofod, H., Damholt, A. B., Buchan, A., Márquez, L., Luque, M. A., Sarti, L., Sutton, P. J., Behle, K., Heimesaat, M. M., Hüfner, M., Gravholt, Claus Højbjerg, Mølier, Niels, Christiansen, Jens Sandahl, Schmitz, Ole, Deacon, C. F., Brock, B., Knudsen, L. B., Agersø, H., Huusfeldt, P. O., Kelly, C. M. N., Brunn, C., Schioos, J., Sewing, S., Lemansky, P., Wawro, S., Mest, H. J., Taguchi, T., Motoshima, H., Yoshizato, K., Guenifi, Amel, Henriksson, M., Johansson, J., Shafqat, J., Tally, M., Wahren, J., Jömvall, H., Ekberg, K., Rigler, R., Pramanik, A., Kratz, G., Johansson, B.-L., Uhlén, M., Jörnvall, H., Forst, T., Dufayet De La Tour, D., Kunt, T., Pfützner, A., Goitom, K., Pohlmann, T., Schneider, S., Johansson, B. L., Löbig, M., Engelbach, M., Beyer, J., Ekman, Bertil, Nyström, Fredrik, Arnqvist, Hans J., Halvatsiotis, P. G., Meek, S., Bigelow, M., Nair, K. S., Maghsoudi, S., Fisker, S., Vølund, A. A., Jörgensen, J. O. L., Christiansen, J. S., Hilsted, J., Mazerkina, N. A., Tiulpakov, A. N., Gorelyshev, S. K., Peterkova, V. A., Macut, D. J., Dieguez, C., Casanueva, F. F., Catalina, P. F., Mallo, F., Andrade, A., García-Mayor, R. V. G., Popova, V. V., ter Maaten, J. C., Popp-Snijders, C., Madsen, L., Ukropec, J., Bergene, E., Rnstan, A. C., Berge, R., Arner, P., Wahl, G., Häring, H., Bryson, J. M., Curtis, S. E., Caterson, I. D., Winzell, M. Sörhede, Svensson, H., Ahnén, B., Holm, C., Phillips, C., Madigan, C., Owens, D., Collins, P., Johnson, A., Tomkin, G. H., Cabezas, M. Castro, van Oostrom, A. J. H. H. M., Erkelens, D. W., Summers, L. K. M., Fielding, B. A., Ilic, V., Clark, M. L., Frayn, K. N., Pietzsch, J., Julius, U., Nitzsche, S., Fischer, S., Lindgren, C., Amrot-Fors, L., Hoffmann, M. M., Luft, D., Schmülling, R.-M., D’Adamo, M., Leonetti, F., Paoloni, A., Ribaudo, M. C., Basso, M. S., Elmore, U., Restuccia, A., Sbraccia, P., Emilsson, V., O’Dowd, J., Heyman, R., Cawthorne, M. A., Pelikánová, T., Kazdová, L., Žák, A., Chvojková, Š., Özer, E. M., Kadıoğlu, P., Korugan, Ü., Hatemi, H., Rivellese, A. A., Dullaart, R. P. F., Riemens, S. C., Sluiter, W. J., van Tol, A., Farnier, M., Megnien, S., Turpin, G., Stulp, B. K., Brambilla, P., Brunelli, A., Riva, M. C., Manzoni, P., de Poli, S., Riboni, S., Stolk, R. P., Meijer, R., Wink, O., Zelissen, P. M. J., van Gils, A. P. G., Grobbee, D. E., Vilarrasa, N., Gimenez, O., Lopez, L., Insa, R., Fdez Castañer, M., Cabrera-Rode, E., Perich, P., Diaz-Horta, O., Molina, G., Fernández Castañer, M., López, L., Jiménez, O., Boltaña, A., Ampudia-Blasco, F. J., Martínez, I., Civera, M., Ascaso, J. F., Carmena, R., Ahmed, K., Luzio, S., Furmaniak, V., Owens, D. R., Dionadji, Mbainguinam, Mbaissouroum, Mouanodji, Anderson, J., Garg, S., MacKenzie, T., Shephard, M., Peery, B., Chase, H., Holstein, A., Thießen, E., Kaufmann, N., Egberts, E.-H., Lutgers, H. L., Hullegie, L. M., Hoogenberg, K., Wientjes, K. J., Schoonen, A. J., Wientjes, K. J. C., Schoonen, A. J. M., Weitgasser, R., Gappmayer, B., Pichler, M., Sapin, R., Friess, P., Eskes, S. A., de Vries, J. H., Pouwer, F., van Ballegooie, E., Spijker, A. J., Jeng, L., Winsett, J., Tubiana-Rufi, N., Munz-Licha, G., Polak, M., Sheehan, J., Ulchaker, M., Toeller, M., Üstün, A., Yilmaz, M. T., Aparicio, M., Peyron, E., Rizkalla, S. W., Taverna, M., Guerre-Millo, M., Chevalier, A., Pacher, N., Slama, G., Gorshunska, M., Buyken, A. E., Heitkamp, G., Kabir, M., Oppert, J. M., Wursch, P., Bruzzo, F., Rahman, M. H., Fatima, K., Ahmed, S., Mondal, H. N., Yilmaz, M., Öztok, U., Karakoç, A., Çakır, N., Düzgün, E., Yetkin, İ., Arslan, M., Şardaş, S., Wilding, John, Géloën, A., Baret, G., Dalmaz, Y., Peyronnet, J., Clémenceau, B., Martignat, L., Lalain, S., Gouin, E., Kenda-Ropson, N., Miller, A. O. A., You, S., Aguilera, E., Recasens, M., Flores, L., Ricart, M. J., Fernández-Cruz, L., Esmatjes, E., Crenier, L., Noël, C., Le Moine, A., Mahy, M., Danguy, A., Kiss, R., Goldman, M., Bracci, C., De Haan, B., Nilsson, K., Deschamps, J. Y., Glagoličová, A., Smrčková, I., Dieterle, C., Illner, W. D., Land, W., Feldmeier, H., Scheuer, R., Lalli, C., Di Loreto, C., Ellringmann, U., Balks, H. J., v. zur Mühlen, A., Dengler, R., Weissenborn, K., Rasmussen, B. M., Ørskov, L., Watson, J., Owen, G., Barrett, G., Ingleby, J., Weiss, M., Deary, I., Cavan, D., Kerr, D., Bruneiii, A., Cuce’, A., Elsing, H. G., Kühne, D., Quinn, N. D., Warner, D. P., Buysschaert, M., Jamal, R., O’Brien, T., Latare, P., Mullen, J., Rein, A., Wargo, M., Parkes, J. L., Ginsberg, B., Sotiropoulos, A., Peppas, Th. A., Kotsini, V., Apostolou, O., Bousboulas, S., Michailidis, E., Sawala, M., Pappas, S., Nilsson, P. M., Nilsson, J. Å., Berglund, G., Molins, T., Esteban, J. I., Genescà, J., Paris, I., Haufroid, V., Selvais, Ph., Petit, J. M., Duong, M., Grappin, M., Guiguet, M., Rudoni, S., Portier, H., Brun, J. M., Bagg, W., Plank, L., Drury, P. L., Sharpe, N., Braatvedt, G. D., Carrascosa, J. M., Molero, J. C., Fermίn, Y., Andrés, A., Satrústegui, J., Rietzsch, H., Patzak, A., Schwanebeck, U., Simpson, H., Robertson-Mackay, F., Montegriffo, E., Fox, C., Chiasson, J.-L., Josse, R. G., Dorman, J. M., Gerstein, H. C., Lau, D., Leiter, L. A., Maheux, P., Meneilly, G. 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G., Manti, R., Gallo, M., Molinar Hin, A., Brignardello, E., Boccuzzi, G., Li, Shanfang, Xiang, Kunsan, Zhang, Rugeng, Shangguan, Xinhong, Wu, Jianrong, Donnan, P. T., Broomhall, J., Hunter, K., Morris, A. D., Ioannidis, G., Peppa, M., Rontogianni, E., Kallifronas, M., Lekatsas, I., Chrysanthopoulou, G., Anthopoulos, L., Kesse, M., Thalassinos, N., Neves, C., Medina, J. L., Lopes, F., Yılmaz, M., Güvener, N., Güvener, M., Kocagöz, T., Böke, E., Paşaoglu, I., Bascil Tutuncu, N., Oto, A., Karvonen, M. K., Koulu, M., Pesonen, U., Mercuri, M., Rauramaa, R., Rutter, M. K., Kestevan, P., McComb, J. M., Marshall, S. M., Sobieska, M., Wiktorowicz, K., Kanters, S. D. J. M., Banga, J. D., Algra, A., Frijns, C. J. M., Beutler, J. J., Fijnheer, R., Nicoloff, G., Baydanoff, S., Stanimirova, N., Petrova, Ch., Lario, S., Campistol, J. M., Cases, A., Clària, J., Iñigo, P., Esmatjcs, E., Sármán, B., Tóth, M., Kocsis, I., Somogyi, A., Bumbure, A., Jachimowicz, K., Samson, J., Tomasiak, M., Sobol, A., Stańczyk, L., Watala, C., Stradina, P., Wiśniewska-Jarosińska, M., Marciniak, D., Więcławska, B., Watała, C., Golański, J., Zinnat, R., Mahmud, I., Büyükasik, Yahya, Demiroğlu, H., Szczepanik, A., Skowroński, M., Murawska, A., Meeking, D. R., Allard, S., Munday, J., Chowienczyk, P., Shaw, K. M., Cummings, M. H., Šimková, R., Jirsa, M., Hadoke, P. W. F., McIntyre, C. A., Jones, G. C., Williams, B. C., Elliott, A. I., McKnight, J. A., Pernow, J., Bombonato, G. C., Finucci, G. F., Zotta, L., Senses, V., Ozyazgan, S., Ince, E., Tunçdemir, M., Oztürk, M., Sultuybek, G., Akkan, A. G., Özyazgan, S., Unlücerci, Y., Bekpınar, S., Meyer, M. F., Lee, B. C., Shore, A. C., Humphreys, J. M., Tooke, J. E., Dell’Omo, G., Giovannitti, G., Caricato, F., Mariani, M., Pedrinelli, R., Kiviet-Boehm, C., Schwelling, V., Matthäei, S., Pfohl, M., McInerney, D., Itoh, H., Ohno, T., Katoh, N., Baumgartner-Parzer, S., Artwohl, M., Graier, W., Ludwig, C., Tachi, Y., Bannai, C., Shinohara, M., Shimpuku, H., Ohura, K., Bertacca, A., Sasvári, M., Szaleczki, E., Pusztai, P., Boes, U., Klaus, E., Dittrich, P., Wagner, Z., Wittmann, I., Pótó, L., Wagner, L., Mazák, I., Nagy, J., Feletto, F., Taboga, C., Tonutti, L., Lizzio, S., Russo, A., Selmo, V., Ceriello, A., Lekakis, J., Papamichael, C. M., Stamatelopoulos, K., Stamatelopoulos, S., Yillar, D. O., Gay, M., Lillaz, E., Passaro, A., Vanini, A., Calzoni, F., D’Elia, K., Carantoni, M., Zuliani, G., Fellin, R., Solini, A., Chwatko, G., Bald, E., Dramais, A.-S., Wallemacq, P. E., Vandeleene, B., Ciaria, M. V., Ariano, M., Strom, R., Gibney, J., Weiss, U., Turner, B., O’Gorman, P., Watts, G., Powrie, J., Crook, M., Shaw, K., and Cummings, M.
- Published
- 1999
- Full Text
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41. Repetitive in vivo treatment with human recombinant interleukin-1βmodifies Beta-cell function in normal rats
- Author
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Wogensen, L., Reimers, J., Nerup, J., Kolb -Bachofen, V., Kröncke, K., Almdal, T., and Mandrup -Poulsen, T.
- Abstract
It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 μg of recombinant human interleukin-1βper kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either untreated or pre-treated with 4 μg/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal injections of 4 μg/kg interleukin-1 on blood glucose, glucose tolerance, plasma levels of insulin, glucagon and corticosterone, pancreatic insulin content and pancreatic ultrastructure; and (c) blood glucose and plasma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at which time point the inhibitory effect of short-term interleukin-1 exposure on insulin secretion reaches its nadir in vitro. A single injection of 4 μg/kg of interleukin-1 caused a slight, but significant lowering of blood glucose 2 h after interleukin-1 injection with no significant changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 μg/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance. Blood glucose levels significantly increased time-dependently 4–10 h after the third and fifth injection of interleukin-1, and diabetic values (blood glucose >11.0 mmol/l) were observed 6 and 10 h after the fifth injection of interleukin-1. Ten hours after the fifth injection of interleukin-1, diabetic blood glucose levels were observed together with a 50% reduction in plasma insulin concentration. Ultrastructural examination showed no signs of Betacell lysis. In conclusion, interleukin-1 has bimodal effects on glucose homeostasis in vivo, a slight lowering of the blood glucose followed by impaired glucose tolerance and later by diabetic blood glucose levels. Two hours after the last of five daily injections of interleukin-1 impaired glucose tolerance is primarily caused by a state of insulin resistance, whereas diabetic blood glucose levels are associated with inhibition of insulin secretion. Thus, interleukin-1 causes a diabetic state in normal animals, but it remains to be demonstrated that administration of interleukin-1 to normal animals leads to permanent diabetes due to Beta-cell destruction.
- Published
- 1992
- Full Text
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42. Erratum: Diabetologia (2001) 44: 2115–2133.
- Author
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Eizirik, D. L. and Mandrup-Poulsen, T.
- Subjects
PERIODICALS - Abstract
Presents a correction on a choice of death, the signal-transduction of immune-mediated beta-cell apoptosis published in the 2000 issue of "Diabetologia."
- Published
- 2002
- Full Text
- View/download PDF
43. No direct effect of SGLT2 activity on glucagon secretion.
- Author
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Kuhre RE, Ghiasi SM, Adriaenssens AE, Wewer Albrechtsen NJ, Andersen DB, Aivazidis A, Chen L, Mandrup-Poulsen T, Ørskov C, Gribble FM, Reimann F, Wierup N, Tyrberg B, and Holst JJ
- Subjects
- Animals, Blotting, Western, Chickens, Female, Glucagon metabolism, Immunohistochemistry, Insulin metabolism, Male, Mice, Rats, Rats, Wistar, Sodium-Glucose Transporter 1 genetics, Sodium-Glucose Transporter 1 metabolism, Sodium-Glucose Transporter 2 genetics, Somatostatin metabolism, Islets of Langerhans metabolism, Pancreas metabolism, Sodium-Glucose Transporter 2 metabolism
- Abstract
Aims/hypothesis: Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting., Methods: We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets., Results: Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells., Conclusions/interpretation: Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects.
- Published
- 2019
- Full Text
- View/download PDF
44. Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice.
- Author
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Besançon A, Goncalves T, Valette F, Dahllöf MS, Mandrup-Poulsen T, Chatenoud L, and You S
- Subjects
- Administration, Oral, Animals, Antibodies, Monoclonal, Humanized therapeutic use, Cells, Cultured, Diabetes Mellitus, Type 1 metabolism, Female, Flow Cytometry, Histone Deacetylase Inhibitors blood, Insulin-Secreting Cells drug effects, Interferon-gamma blood, Interleukin-10 blood, Interleukin-1beta blood, Interleukin-6 blood, Male, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Tumor Necrosis Factor-alpha blood, Diabetes Mellitus, Type 1 drug therapy, Histone Deacetylase Inhibitors therapeutic use, Immunotherapy methods, Insulin-Secreting Cells metabolism, T-Lymphocytes physiology
- Abstract
Aim/hypothesis: Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity., Methods: NOD mice transgenic for the human CD3ε (also known as CD3E) chain (NOD-huCD3ε) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 μg/day, 5 days, i.v.) or a combination of both drugs. Disease remission, metabolic profiles and autoreactive T cell responses were analysed in treated mice., Results: We demonstrated that givinostat synergised with otelixizumab to induce durable remission of diabetes in 80% of recently diabetic NOD-huCD3ε mice. Remission was obtained in only 47% of mice treated with otelixizumab alone. Oral givinostat monotherapy did not reverse established diabetes but reduced the in situ production of inflammatory cytokines (IL-1β, IL-6, TNF-α). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3ε mice; the mice recovered the capacity to appropriately produce insulin, control hyperglycaemia and sustain glucose tolerance. Finally, diabetes remission induced by the combination therapy was associated with a significant reduction of insulitis and autoantigen-specific CD8
+ T cell responses., Conclusions/interpretation: HDACi and low-dose CD3 antibodies synergised to abrogate in situ inflammation and thereby improved pancreatic beta cell survival and metabolic function leading to long-lasting diabetes remission. These results support the therapeutic potential of protocols combining these two drugs, both in clinical development, to restore self-tolerance and insulin independence in type 1 diabetes.- Published
- 2018
- Full Text
- View/download PDF
45. Inhibition of beta cell growth and function by bone morphogenetic proteins.
- Author
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Bruun C, Christensen GL, Jacobsen ML, Kanstrup MB, Jensen PR, Fjordvang H, Mandrup-Poulsen T, and Billestrup N
- Subjects
- Animals, Cells, Cultured, Insulin metabolism, Insulin-Secreting Cells physiology, Mice, Rats, Signal Transduction drug effects, Apoptosis drug effects, Bone Morphogenetic Protein 2 pharmacology, Bone Morphogenetic Protein 4 pharmacology, Cell Proliferation drug effects, Gene Expression drug effects, Insulin-Secreting Cells drug effects
- Abstract
Aims/hypothesis: Impairment of beta cell mass and function is evident in both type 1 and type 2 diabetes. In healthy physiological conditions pancreatic beta cells adapt to the body's increasing insulin requirements by proliferation and improved function. We hypothesised that during the development of diabetes, there is an increase in the expression of inhibitory factors that prevent the beta cells from adapting to the increased need for insulin. We evaluated the effects of bone morphogenetic protein (BMP) 2 and -4 on beta cells., Methods: The effects of BMP2 and -4 on beta cell proliferation, apoptosis, gene expression and insulin release were studied in isolated islets of Langerhans from rats, mice and humans. The expression of BMPs was analysed by immunocytochemistry and real-time PCR. The role of endogenous BMP was investigated using a soluble and neutralising form of the BMP receptor 1A., Results: BMP2 and -4 were found to inhibit basal as well as growth factor-stimulated proliferation of primary beta cells from rats and mice. Bmp2 and Bmp4 mRNA and protein were expressed in islets and regulated by inflammatory cytokines. Neutralisation of endogenous BMP activity resulted in enhanced proliferation of rodent beta cells. The expression of Id mRNAs was induced by BMP4 in rat and human islets. Finally, glucose-induced insulin secretion was significantly impaired in rodent and human islets pre-treated with BMP4, and inhibition of BMP activity resulted in enhanced insulin release., Conclusions/interpretation: These data show that BMP2 and -4 exert inhibitory actions on beta cells in vitro and suggest that BMPs exert regulatory roles of beta cell growth and function.
- Published
- 2014
- Full Text
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46. Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor kappaB-mediated gene expression in insulin-producing INS-1E cells.
- Author
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Larsen L, Størling J, Darville M, Eizirik DL, Bonny C, Billestrup N, and Mandrup-Poulsen T
- Subjects
- Animals, Apoptosis genetics, Blotting, Western, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Flavonoids pharmacology, Humans, Imidazoles pharmacology, Insulin Secretion, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, Interleukin-1 pharmacology, MAP Kinase Kinase 4 antagonists & inhibitors, MAP Kinase Kinase 4 physiology, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases physiology, Nitric Oxide Synthase Type II biosynthesis, Phosphorylation, Pyridines pharmacology, Rats, Serine analysis, Synaptotagmin I chemistry, Synaptotagmin I physiology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases physiology, Extracellular Signal-Regulated MAP Kinases physiology, Gene Expression drug effects, Gene Expression physiology, Insulin metabolism, Insulin-Secreting Cells physiology, Interleukin-1 physiology, NF-kappa B physiology, Nitric Oxide Synthase Type II genetics
- Abstract
Aims/hypothesis: The beta cell destruction and insulin deficiency that characterises type 1 diabetes mellitus is partially mediated by cytokines, such as IL-1beta, and by nitric oxide (NO)-dependent and -independent effector mechanisms. IL-1beta activates mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK), and the nuclear factor kappa B (NFkappaB) pathway. Both pathways are required for expression of the gene encoding inducible nitric oxide synthase (iNOS) and for IL-1beta-mediated beta cell death. The molecular mechanisms by which these two pathways regulate beta cell Nos2 expression are currently unknown. Therefore, the aim of this study was to clarify the putative crosstalk between MAPK and NFkappaB activation in beta cells., Materials and Methods: The MAPKs ERK, p38 and JNK were inhibited by SB203580, PD98059 or Tat-JNK binding domain or by cells overexpressing the JNK binding domain. The effects of MAPK inhibition on IL-1beta-induced iNOS production and kappa B inhibitor protein (IkappaB) degradation were examined by western blotting. NFkappaB DNA binding was investigated by electrophoretic mobility shift assay, while NFkappaB-induced gene transcription was evaluated by gene reporter assays., Results: Inhibition of the MAPKs did not affect IkappaB degradation or NFkappaB DNA binding. However, inhibition of ERK reduced NFkappaB-mediated Nos2 expression; serine 276 phosphorylation of the p65 unit of the NFkappaB complex seemed critical, as evaluated by amino acid mutation analysis., Conclusions/interpretation: ERK activity is required for NFkappaB-mediated transcription of Nos2 in insulin-producing INS-1E cells, indicating that ERK regulates Nos2 expression by increasing the transactivating capacity of NFkappaB. This may involve phosphorylation of Ser276 on p65 by an as yet unidentified kinase.
- Published
- 2005
- Full Text
- View/download PDF
47. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways.
- Author
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Karlsen AE, Heding PE, Frobøse H, Rønn SG, Kruhøffer M, Orntoft TF, Darville M, Eizirik DL, Pociot F, Nerup J, Mandrup-Poulsen T, and Billestrup N
- Subjects
- Animals, Base Sequence, Cell Line, DNA Primers, Gene Expression Regulation, Nitric Oxide metabolism, Oligonucleotide Array Sequence Analysis, Rats, Repressor Proteins genetics, Signal Transduction drug effects, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins, Transcription Factors genetics, Apoptosis drug effects, Interleukin-1 toxicity, NF-kappa B physiology, Repressor Proteins physiology, Signal Transduction physiology, Transcription Factors physiology
- Abstract
Aims/hypothesis: 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., Methods: The effect of SOCS-3 expression on the global gene-expression profile following IL-1beta exposure was microarray-analysed using a rat beta cell line (INS-1) with inducible SOCS-3 expression. Subsequently, functional analyses were performed., Results: Eighty-two known genes and several expressed sequence tags (ESTs) changed expression level 2.5-fold or more in response to IL-1beta alone. Following 6 h of IL-1beta exposure, 23 transcripts were up-regulated. Of these, several, including all eight transcripts relating to immune/inflammatory response pathways, were suppressed by SOCS-3. Following 24 h of IL-1beta exposure, secondary response genes were detected, affecting metabolism, energy generation, protein synthesis and degradation, growth arrest, and apoptosis. The majority of these changes were prevented by SOCS-3 expression. Multiple IL-1beta-induced NF-kappaB-dependent proapoptotic early response genes were inhibited by SOCS-3 expression, suggesting that SOCS-3 inhibits NF-kappaB-mediated signalling. These observations were experimentally confirmed in functional analyses., Conclusions/interpretation: This study suggests that there is an unexpected cross-talk between the SOCS/IFN and the IL-1beta pathways of signalling in pancreatic beta cells, which could lead to a novel perspective of blocking two important proapoptotic pathways in pancreatic beta cells by influencing a single signalling molecule, namely SOCS-3.
- Published
- 2004
- Full Text
- View/download PDF
48. On the pathogenesis of IDDM.
- Author
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Nerup J, Mandrup-Poulsen T, Helqvist S, Andersen HU, Pociot F, Reimers JI, Cuartero BG, Karlsen AE, Bjerre U, and Lorenzen T
- Subjects
- Animals, Denmark, Diabetes Mellitus, Type 1 etiology, Europe, History, 20th Century, Humans, Interleukin-1 physiology, Islets of Langerhans physiopathology, Islets of Langerhans ultrastructure, Models, Biological, Nitric Oxide toxicity, Receptors, Interleukin-1 physiology, Societies, Medical, Superoxides toxicity, Awards and Prizes, Diabetes Mellitus history, Diabetes Mellitus, Type 1 physiopathology, Islets of Langerhans pathology
- Abstract
A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2- and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.
- Published
- 1994
- Full Text
- View/download PDF
49. Repetitive in vivo treatment with human recombinant interleukin-1 beta modifies beta-cell function in normal rats.
- Author
-
Wogensen LD, Reimers J, Nerup J, Kolb-Bachofen V, Kröncke KD, Almdal T, and Mandrup-Poulsen T
- Subjects
- Animals, Blood Glucose metabolism, Body Weight drug effects, Corticosterone blood, Glucagon blood, Glucagon metabolism, Insulin blood, Insulin metabolism, Insulin Secretion, Islets of Langerhans drug effects, Islets of Langerhans ultrastructure, Male, Microscopy, Electron, Organ Size drug effects, Rats, Rats, Inbred WKY, Reference Values, Interleukin-1 pharmacology, Islets of Langerhans physiology, Recombinant Proteins pharmacology
- Abstract
It is unknown whether interleukin-1 exerts a bimodal effect on Beta-cell function in vivo, and whether interleukin-1 has a diabetogenic action in normal animals. We therefore studied: (a) acute effects 2 h after an intraperitoneal bolus injection of 4 micrograms of recombinant human interleukin-1 beta per kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either untreated or pre-treated with 4 micrograms/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal injections of 4 micrograms/kg interleukin-1 on blood glucose, glucose tolerance, plasma levels of insulin, glucagon and corticosterone, pancreatic insulin content and pancreatic ultrastructure; and (c) blood glucose and plasma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at which time point the inhibitory effect of short-term interleukin-1 exposure on insulin secretion reaches its nadir in vitro. A single injection of 4 micrograms/kg of interleukin-1 caused a slight, but significant lowering of blood glucose 2 h after interleukin-1 injection with no significant changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 micrograms/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
- Full Text
- View/download PDF
50. Functional and morphological effects of interleukin-1 beta on the perfused rat pancreas.
- Author
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Wogensen LD, Kolb-Bachofen V, Christensen P, Dinarello CA, Mandrup-Poulsen T, Martin S, and Nerup J
- Subjects
- Animals, Dinoprostone metabolism, Glucose pharmacology, In Vitro Techniques, Insulin Secretion, Islets of Langerhans drug effects, Islets of Langerhans ultrastructure, Kinetics, Male, Microscopy, Electron, Perfusion, Rats, Rats, Inbred Strains, Recombinant Proteins pharmacology, Glucagon metabolism, Insulin metabolism, Interleukin-1 pharmacology, Islets of Langerhans metabolism
- Abstract
We recently reported a potentiating effect of recombinant human interleukin-1 beta on glucose-stimulated insulin release from the isolated perfused pancreas. With the aim of determining whether the stimulatory effect of recombinant interleukin-1 beta on the B cell in the intact gland was modulated by varying the concentration, time of exposure to recombinant interleukin-1 beta or B-cell activity, and to elucidate a possible mechanism of action, we measured in the perfused rat pancreas the release of insulin, glucagon and/or prostaglandin E2 according to the following three different protocols: (1) perfusion with 20 ng/ml of recombinant interleukin-1 beta for 92 min at 5 and 20 mmol/l D-glucose (2) perfusion with varying concentrations of recombinant interleukin-1 beta ranging from 0.1 x 10(-3) ng/ml to 100 ng/ml at 5 and 20 mmol/l D-glucose (3) perfusion with 20 ng/ml of recombinant interleukin-1 beta at 5, 11 or 20 mmol/l D-glucose. Furthermore, in a separate set of experiments we examined the influence of the cytokine on the morphology of the endocrine pancreas. Interleukin-1 beta stimulated insulin secretion at 11 and 20 mmol/l D-glucose and potentiated first as well as second phase insulin release in a dose-dependent fashion, with decreasing effect at higher concentrations. Glucagon secretion was also stimulated by recombinant interleukin-1 beta, irrespective of increasing glucose (5, 11, 20 mmol/l) and insulin concentrations. The potentiating effect of recombinant interleukin-1 beta on insulin secretion was evident even after discontinued perfusion with the cytokine, suggesting a priming effect on B-cell function.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
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