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101. DAMP production by human islets under low oxygen and nutrients in the presence or absence of an immunoisolating-capsule and necrostatin-1

Author

Paredes-Juarez, Genaro A, Sahasrabudhe, Neha M, Tjoelker, Reina S, de Haan, Bart J, Engelse, Marten A, de Koning, Eelco J P, Faas, Marijke M, de Vos, Paul, Paredes-Juarez, Genaro A, Sahasrabudhe, Neha M, Tjoelker, Reina S, de Haan, Bart J, Engelse, Marten A, de Koning, Eelco J P, Faas, Marijke M, and de Vos, Paul

Abstract

In between the period of transplantation and revascularization, pancreatic islets are exposed to low-oxygen and low-nutrient conditions. In the present study we mimicked those conditions in vitro to study the involvement of different cell death processes, release of danger-associated molecular patterns (DAMP), and associated in vitro immune activation. Under low-oxygen and low-nutrient conditions, apoptosis, autophagy and necroptosis occur in human islets. Necroptosis is responsible for DAMP-release such as dsDNA, uric acid, and HMGB1. The sensors of the innate immune system able to recognize these DAMPs are mainly TLR, NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule MyD88, we were able to show that the islet-derived DAMPs signal mainly via TLR. Immunoisolation in immunoprotective membranes reduced DAMP release and immune activation via retention of the relative large DAMPs in the capsules. Another effective strategy was suppressing necroptosis using the inhibitor nec-1. Although the effect on cell-survival was minor, nec-1 was able to reduce the release of HMGB1 and its associated immune activation. Our data demonstrate that in the immediate post-transplant period islets release DAMPs that in vitro enhance responses of innate immune cells. DAMP release can be reduced in vitro by immunoisolation or intervention with nec-1.

Published
2015

102. DNA Methylation Landscapes of Human Fetal Development

Author

Slieker, Roderick C, Roost, Matthias S, van Iperen, Liesbeth, Suchiman, H Eka D, Tobi, Elmar W, Carlotti, Françoise, de Koning, Eelco J P, Slagboom, P Eline, Heijmans, Bastiaan T, Chuva de Sousa Lopes, Susana M, Slieker, Roderick C, Roost, Matthias S, van Iperen, Liesbeth, Suchiman, H Eka D, Tobi, Elmar W, Carlotti, Françoise, de Koning, Eelco J P, Slagboom, P Eline, Heijmans, Bastiaan T, and Chuva de Sousa Lopes, Susana M

Abstract

Remodelling the methylome is a hallmark of mammalian development and cell differentiation. However, current knowledge of DNA methylation dynamics in human tissue specification and organ development largely stems from the extrapolation of studies in vitro and animal models. Here, we report on the DNA methylation landscape using the 450k array of four human tissues (amnion, muscle, adrenal and pancreas) during the first and second trimester of gestation (9,18 and 22 weeks). We show that a tissue-specific signature, constituted by tissue-specific hypomethylated CpG sites, was already present at 9 weeks of gestation (W9). Furthermore, we report large-scale remodelling of DNA methylation from W9 to W22. Gain of DNA methylation preferentially occurred near genes involved in general developmental processes, whereas loss of DNA methylation mapped to genes with tissue-specific functions. Dynamic DNA methylation was associated with enhancers, but not promoters. Comparison of our data with external fetal adrenal, brain and liver revealed striking similarities in the trajectory of DNA methylation during fetal development. The analysis of gene expression data indicated that dynamic DNA methylation was associated with the progressive repression of developmental programs and the activation of genes involved in tissue-specific processes. The DNA methylation landscape of human fetal development provides insight into regulatory elements that guide tissue specification and lead to organ functionality.

Published
2015

103. Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Author

Hoelen, Hanneke, Zaldumbide, Arnaud, van Leeuwen, Wouter F, Torfs, Ellen C W, Engelse, Marten A, Hassan, Chopie, Lebbink, Robert Jan, de Koning, Eelco J, Resssing, Maaike E, de Ru, Arnoud H, van Veelen, Peter A, Hoeben, Rob C, Roep, Bart O, Wiertz, Emmanuel J H J, Hoelen, Hanneke, Zaldumbide, Arnaud, van Leeuwen, Wouter F, Torfs, Ellen C W, Engelse, Marten A, Hassan, Chopie, Lebbink, Robert Jan, de Koning, Eelco J, Resssing, Maaike E, de Ru, Arnoud H, van Veelen, Peter A, Hoeben, Rob C, Roep, Bart O, and Wiertz, Emmanuel J H J

Abstract

Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T-cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D.

Published
2015

104. KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas

Author

Roost, Matthias S, van Iperen, Liesbeth, Ariyurek, Yavuz, Buermans, Henk P, Arindrarto, Wibowo, Devalla, Harsha D, Passier, Robert, Mummery, Christine L, Carlotti, Françoise, de Koning, Eelco J P, van Zwet, Erik W, Goeman, Jelle J, Chuva de Sousa Lopes, Susana M, Roost, Matthias S, van Iperen, Liesbeth, Ariyurek, Yavuz, Buermans, Henk P, Arindrarto, Wibowo, Devalla, Harsha D, Passier, Robert, Mummery, Christine L, Carlotti, Françoise, de Koning, Eelco J P, van Zwet, Erik W, Goeman, Jelle J, and Chuva de Sousa Lopes, Susana M

Abstract

Differentiated derivatives of human pluripotent stem cells in culture are generally phenotypically immature compared to their adult counterparts. Their identity is often difficult to determine with certainty because little is known about their human fetal equivalents in vivo. Cellular identity and signaling pathways directing differentiation are usually determined by extrapolating information from either human adult tissue or model organisms, assuming conservation with humans. To resolve this, we generated a collection of human fetal transcriptional profiles at different developmental stages. Moreover, we developed an algorithm, KeyGenes, which uses this dataset to quantify the extent to which next-generation sequencing or microarray data resemble specific cell or tissue types in the human fetus. Using KeyGenes combined with the human fetal atlas, we identified multiple cell and tissue samples unambiguously on a limited set of features. We thus provide a flexible and expandable platform to monitor and evaluate the efficiency of differentiation in vitro.

Published
2015

105. Thirty Years of Pancreas Transplantation at Leiden University Medical Center: Long-Term Follow-Up in a Large Eurotransplant Center

Author

Kopp, Wouter H, Verhagen, Merel J J, Blok, Joris J, Huurman, Volkert A L, de Fijter, Johan W, de Koning, Eelco J, Putter, Hein, Baranski, Andzrej G, Schaapherder, Alexander F M, Braat, Andries E, Ringers, Jan, Kopp, Wouter H, Verhagen, Merel J J, Blok, Joris J, Huurman, Volkert A L, de Fijter, Johan W, de Koning, Eelco J, Putter, Hein, Baranski, Andzrej G, Schaapherder, Alexander F M, Braat, Andries E, and Ringers, Jan

Abstract

BACKGROUND: An overview of 30 years of pancreas transplantation at a high volume center. Analysis of patient survival- and graft survival-associated risk factors.METHODS: All pancreas transplantations performed in our center from January 1, 1984, till December 31, 2012, were evaluated. Covariates influencing pancreas graft survival were analyzed using both univariate and multivariate analysis and Kaplan-Meier analysis.RESULTS: In the study period, 349 pancreas transplantations were performed. With the introduction of modern induction therapy in 1999, 5-year patient survival improved to 92.0% (P = 0.003). Five-year pancreas graft survival improved to 80.3% (P = 0.026). Pancreas graft survival was influenced by left or right donor kidney, transplant type, local origin of procurement team, pancreas cold ischemia time, recipient cerebrovascular disease. Pancreas donor risk index increased to 1.39 over the years and pancreas donor risk index 1.24 or higher is a risk factor for graft survival (P = 0.007).CONCLUSIONS: This study has shown excellent results in patient and pancreas graft survivals after 30 years of pancreas transplantation in a high volume center. Different donor, transplant, and recipient related risk factors influence pancreas graft survival. Even with higher risk pancreas donors, good results can be achieved.

Published
2015

106. Targeting development of incretin-producing cells increases insulin secretion

Author

Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Petersen, Natalia, Reimann, Frank, van Es, Johan H, van den Berg, Bernard M, Kroone, Chantal, Pais, Ramona, Jansen, Erik, Clevers, Hans, Gribble, Fiona M, de Koning, Eelco J P, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, Child Health, Petersen, Natalia, Reimann, Frank, van Es, Johan H, van den Berg, Bernard M, Kroone, Chantal, Pais, Ramona, Jansen, Erik, Clevers, Hans, Gribble, Fiona M, and de Koning, Eelco J P

Published
2015

107. KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas

Author

Hubrecht Institute with UMC, Regenerative Medicine and Stem Cells, Roost, Matthias S., Van Iperen, Liesbeth, Ariyurek, Yavuz, Buermans, Henk P., Arindrarto, Wibowo, Devalla, Harsha D., Passier, Robert, Mummery, Christine L., Carlotti, Françoise, De Koning, Eelco J P, Van Zwet, Erik W., Goeman, Jelle J., Chuva De Sousa Lopes, Susana M., Hubrecht Institute with UMC, Regenerative Medicine and Stem Cells, Roost, Matthias S., Van Iperen, Liesbeth, Ariyurek, Yavuz, Buermans, Henk P., Arindrarto, Wibowo, Devalla, Harsha D., Passier, Robert, Mummery, Christine L., Carlotti, Françoise, De Koning, Eelco J P, Van Zwet, Erik W., Goeman, Jelle J., and Chuva De Sousa Lopes, Susana M.

Published
2015

108. DNA Methylation Landscapes of Human Fetal Development

Author

Hubrecht Institute with UMC, Regenerative Medicine and Stem Cells, Slieker, Roderick C., Roost, Matthias S., van Iperen, Liesbeth, Suchiman, H. Eka D, Tobi, Elmar W., Carlotti, Françoise, de Koning, Eelco J P, Slagboom, P. Eline, Heijmans, Bastiaan T., Chuva de Sousa Lopes, Susana M., Hubrecht Institute with UMC, Regenerative Medicine and Stem Cells, Slieker, Roderick C., Roost, Matthias S., van Iperen, Liesbeth, Suchiman, H. Eka D, Tobi, Elmar W., Carlotti, Françoise, de Koning, Eelco J P, Slagboom, P. Eline, Heijmans, Bastiaan T., and Chuva de Sousa Lopes, Susana M.

Published
2015

109. Structure-Guided Design of Selective Epac1 and Epac2 Agonists

Author

Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, CMM Groep Bos, Schwede, Frank, Bertinetti, Daniela, Langerijs, Carianne N., Hadders, Michael A., Wienk, Hans, Ellenbroek, Johanne H., de Koning, Eelco J P, Bos, Johannes L., Herberg, Friedrich W., Genieser, Hans Gottfried, Janssen, Richard A J, Rehmann, Holger, Hubrecht Institute with UMC, CMM Sectie Molecular Cancer Research, Cancer, CMM Groep Bos, Schwede, Frank, Bertinetti, Daniela, Langerijs, Carianne N., Hadders, Michael A., Wienk, Hans, Ellenbroek, Johanne H., de Koning, Eelco J P, Bos, Johannes L., Herberg, Friedrich W., Genieser, Hans Gottfried, Janssen, Richard A J, and Rehmann, Holger

Published
2015

110. Cytokine and chemokine production by human pancreatic islets upon enterovirus infection

Author

Schulte, Barbara M, Lanke, Kjerstin H W, Piganelli, Jon D, Kers-Rebel, Esther D, Bottino, Rita, Trucco, Massimo, Huijbens, Richard J F, Radstake, Timothy R D J, Engelse, Marten A, de Koning, Eelco J P, Galama, Jochem M, Adema, Gosse J, van Kuppeveld, Frank J M, LS Virologie, and LS Virologie

Subjects
Chemokine, viruses, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Coronacrisis-Taverne, Coxsackievirus Infections, medicine.disease_cause, Proinflammatory cytokine, Islets of Langerhans, Poverty-related infectious diseases Infection and autoimmunity [N4i 3], Interferon, Immune Regulation [NCMLS 2], Diabetes Mellitus, Internal Medicine, medicine, Humans, Macrophage inflammatory protein, biology, Pancreatic islets, Translational research Immune Regulation [ONCOL 3], virus diseases, Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1], Infection and autoimmunity Auto-immunity, transplantation and immunotherapy [NCMLS 1], Enterovirus B, Human, Diabetes Mellitus, Type 1, Cytokine, medicine.anatomical_structure, Islet Studies, Immunology, biology.protein, Cytokines, Enterovirus, Tumor necrosis factor alpha, Chemokines, Enterovirus B, Type 1, Human, medicine.drug
Abstract

Contains fulltext : 110765.pdf (Publisher’s version ) (Open Access) Enteroviruses of the human enterovirus B species (HEV-Bs) (e.g., coxsackie B viruses [CVBs] and echoviruses) have been implicated as environmental factors that trigger/accelerate type 1 diabetes, but the underlying mechanism remains elusive. The aim of this study was to gain insight into the cytokines and chemokines that are produced by human pancreatic islets upon infection with CVBs. To this end, we studied the response of human islets of Langerhans upon mock or CVB3 infection. Using quantitative PCR, we showed that upon CVB3 infection, transcription of interferon (IFN), IFN-stimulated genes, and inflammatory genes was induced. Analysis of secreted cytokines and chemokines by Luminex technology confirmed production and secretion of proinflammatory cytokines (e.g., interleukin [IL]-6 and tumor necrosis factor-alpha) as well as various chemotactic proteins, such as IFN-gamma-induced protein 10, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and IL-8. Infection with other HEV-Bs induced similar responses, yet their extent depended on replication efficiency. Ultra violet-inactivated CVB3 did not induce any response, suggesting that virus replication is a prerequisite for antiviral responses. Our data represent the first comprehensive overview of inflammatory mediators that are secreted by human islets of Langerhans upon CVB infection and may shed light on the role of enteroviruses in type 1 diabetes pathogenesis. 01 augustus 2012

Published
2012

111. β-Cell Generation: Can Rodent Studies Be Translated to Humans?

Author

Carlotti, Françoise, Zaldumbide, Arnaud, Ellenbroek, Johanne H., Spijker, H. Siebe, Hoeben, Rob C., and de Koning, Eelco J.

Subjects
Article Subject
Abstract

β-cell replacement by allogeneic islet transplantation is a promising approach for patients with type 1 diabetes, but the shortage of organ donors requires new sources of β cells. Islet regeneration in vivo and generation of β-cells ex vivo followed by transplantation represent attractive therapeutic alternatives to restore the β-cell mass. In this paper, we discuss different postnatal cell types that have been envisaged as potential sources for future β-cell replacement therapy. The ultimate goal being translation to the clinic, a particular attention is given to the discrepancies between findings from studies performed in rodents (both ex vivo on primary cells and in vivo on animal models), when compared with clinical data and studies performed on human cells.

Published
2011
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112. DNA Methylation Landscapes of Human Fetal Development

Author

Slieker, Roderick C., primary, Roost, Matthias S., additional, van Iperen, Liesbeth, additional, Suchiman, H. Eka D., additional, Tobi, Elmar W., additional, Carlotti, Françoise, additional, de Koning, Eelco J. P., additional, Slagboom, P. Eline, additional, Heijmans, Bastiaan T., additional, and Chuva de Sousa Lopes, Susana M., additional

Published
2015
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114. Thirty Years of Pancreas Transplantation at Leiden University Medical Center

Author

Kopp, Wouter H., primary, Verhagen, Merel J. J., additional, Blok, Joris J., additional, Huurman, Volkert A. L., additional, de Fijter, Johan W., additional, de Koning, Eelco J., additional, Putter, Hein, additional, Baranski, Andzrej G., additional, Schaapherder, Alexander F. M., additional, Braat, Andries E., additional, and Ringers, Jan, additional

Published
2015
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115. Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Author

Hoelen, Hanneke, primary, Zaldumbide, Arnaud, additional, van Leeuwen, Wouter F., additional, Torfs, Ellen C. W., additional, Engelse, Marten A., additional, Hassan, Chopie, additional, Lebbink, Robert Jan, additional, de Koning, Eelco J., additional, Resssing, Maaike E., additional, de Ru, Arnoud H., additional, van Veelen, Peter A., additional, Hoeben, Rob C., additional, Roep, Bart O., additional, and Wiertz, Emmanuel J. H. J., additional

Published
2015
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117. Islet Amyloidosis in Transgenic Mouse Isolated Islets is Progressive, Largely Extracellular and Proportional to Beta Cell Secretion

Author

MACARTHUR, DIANE L, DE KONING, EELCO J, HIGHAM, CLAIRE E, MORRIS, JOHN F, VERBEEK, SJIEF, and CLARK, ANNE

Subjects
Diabetes -- Research, Health
Abstract

Islet amyloid forms in human pancreatic islets in Type 2 (non-insulin dependent) diabetes from islet amyloid polypeptide (IAPP)/amylin by an unknown mechanism and progressively replaces endocrine cells over periods of [...]

Published
1999

118. Generation of L cells in mouse and human small intestine organoids

Author

Petersen, Natalia, Reimann, Frank, Bartfeld, Sina, Farin, Henner F, Ringnalda, Femke C, Vries, Robert G J, van den Brink, Stieneke, Clevers, Hans, Gribble, Fiona M, de Koning, Eelco J P, Petersen, Natalia, Reimann, Frank, Bartfeld, Sina, Farin, Henner F, Ringnalda, Femke C, Vries, Robert G J, van den Brink, Stieneke, Clevers, Hans, Gribble, Fiona M, and de Koning, Eelco J P

Abstract

Upon a nutrient challenge, L cells produce glucagon-like peptide 1 (GLP-1), a powerful stimulant of insulin release. Strategies to augment endogenous GLP-1 production include promoting L-cell differentiation and increasing L-cell number. Here we present a novel in vitro platform to generate functional L cells from three-dimensional cultures of mouse and human intestinal crypts. We show that short-chain fatty acids selectively increase the number of L cells, resulting in an elevation of GLP-1 release. This is accompanied by the upregulation of transcription factors associated with the endocrine lineage of intestinal stem cell development. Thus, our platform allows us to study and modulate the development of L cells in mouse and human crypts as a potential basis for novel therapeutic strategies in patients with type 2 diabetes.

Published
2014

119. Increased vimentin in human α- and ß-cells in type 2 diabetes.

Author

Roefs, Maaike M., Carlotti, Françoise, Jones, Katherine, Wills, Hannah, Hamilton, Alexander, Verschoor, Michael, Durkin, Joanna M. Williams, Garcia-Perez, Laura, Brereton, Melissa F., McCulloch, Laura, Engelse, Marten A., Johnson, Paul R. V., Hansen, Barbara C., Docherty, Kevin, de Koning, Eelco J. P., and Clark, Anne

Subjects
TYPE 2 diabetes treatment, ISLANDS of Langerhans, CELL transformation, IMMUNOHISTOCHEMISTRY, MORPHOMETRICS
Abstract

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of ß-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and ß cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (ß-cells) in the human ND group (1.43% total α-cells, 0.98% total ß-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% ß-cells; P < 0.05). Vimentin-positive ß-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive ß-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and ß-cell dysfunction in T2DM. [ABSTRACT FROM AUTHOR]

Published
2017
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121. The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

Author

't Hart, Leen M, Fritsche, Andreas, Nijpels, Giel, van Leeuwen, Nienke, Donnelly, Louise A, Dekker, Jacqueline M, Alssema, Marjan, Fadista, Joao, Carlotti, Françoise, Gjesing, Anette P, Palmer, Colin N A, van Haeften, Timon W, Herzberg-Schäfer, Silke A, Simonis-Bik, Annemarie M C, Houwing-Duistermaat, Jeanine J, Helmer, Quinta, Deelen, Joris, Guigas, Bruno, Hansen, Torben, Machicao, Fausto, Willemsen, Gonneke, Heine, Robert J, Kramer, Mark, Holst, Jens Juul, de Koning, Eelco J P, Häring, Hans-Ulrich, Pedersen, Oluf, Groop, Leif, de Geus, Eco J C, Slagboom, P Eline, Boomsma, Dorret I, Eekhoff, Elisabeth M W, Pearson, Ewan R, Diamant, Michaela, 't Hart, Leen M, Fritsche, Andreas, Nijpels, Giel, van Leeuwen, Nienke, Donnelly, Louise A, Dekker, Jacqueline M, Alssema, Marjan, Fadista, Joao, Carlotti, Françoise, Gjesing, Anette P, Palmer, Colin N A, van Haeften, Timon W, Herzberg-Schäfer, Silke A, Simonis-Bik, Annemarie M C, Houwing-Duistermaat, Jeanine J, Helmer, Quinta, Deelen, Joris, Guigas, Bruno, Hansen, Torben, Machicao, Fausto, Willemsen, Gonneke, Heine, Robert J, Kramer, Mark, Holst, Jens Juul, de Koning, Eelco J P, Häring, Hans-Ulrich, Pedersen, Oluf, Groop, Leif, de Geus, Eco J C, Slagboom, P Eline, Boomsma, Dorret I, Eekhoff, Elisabeth M W, Pearson, Ewan R, and Diamant, Michaela

Abstract

The incretin hormone glucagon-like-peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip we identified three novel genetic loci with large effects (30-40%) on GLP-1 stimulated insulin secretion during hyperglycemic clamps in non-diabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n=232, all p≤8.8*10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51±0.16% (5.6±1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G allele carriers but there was no effect on GLP-1 RA treatment in type 2 diabetes patients (n=527). Furthermore, in pancreatic tissue we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments.Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes and response to DPP-4 inhibitor treatment.

Published
2013

122. Cytokine and chemokine production by human pancreatic islets upon enterovirus infection

Author

LS Virologie, Schulte, Barbara M, Lanke, Kjerstin H W, Piganelli, Jon D, Kers-Rebel, Esther D, Bottino, Rita, Trucco, Massimo, Huijbens, Richard J F, Radstake, Timothy R D J, Engelse, Marten A, de Koning, Eelco J P, Galama, Jochem M, Adema, Gosse J, van Kuppeveld, Frank J M, LS Virologie, Schulte, Barbara M, Lanke, Kjerstin H W, Piganelli, Jon D, Kers-Rebel, Esther D, Bottino, Rita, Trucco, Massimo, Huijbens, Richard J F, Radstake, Timothy R D J, Engelse, Marten A, de Koning, Eelco J P, Galama, Jochem M, Adema, Gosse J, and van Kuppeveld, Frank J M

Published
2012

123. Exercise and Type 2 Diabetes Mellitus: Changes in Tissue-specific Fat Distribution and Cardiac Function

Author

Jonker, Jacqueline T., primary, de Mol, Pieter, additional, de Vries, Suzanna T., additional, Widya, Ralph L., additional, Hammer, Sebastiaan, additional, van Schinkel, Linda D., additional, van der Meer, Rutger W., additional, Gans, Rijk O. B., additional, Webb, Andrew G., additional, Kan, Hermien E., additional, de Koning, Eelco J. P., additional, Bilo, Henk J. G., additional, and Lamb, Hildo J., additional

Published
2013
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124. Genetically Engineered Human Islets Protected From CD8-mediated Autoimmune Destruction In Vivo

Author

Zaldumbide, Arnaud, primary, Alkemade, Gonnie, additional, Carlotti, Françoise, additional, Nikolic, Tatjana, additional, Abreu, Joana RF, additional, Engelse, Marten A, additional, Skowera, Anja, additional, de Koning, Eelco J, additional, Peakman, Mark, additional, Roep, Bart O, additional, Hoeben, Rob C, additional, and Wiertz, Emmanuel JHJ, additional

Published
2013
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126. The Adipocytokine Nampt and Its Product NMN Have No Effect on Beta-Cell Survival but Potentiate Glucose Stimulated Insulin Secretion

Author

Spinnler, Robert, primary, Gorski, Theresa, additional, Stolz, Katharina, additional, Schuster, Susanne, additional, Garten, Antje, additional, Beck-Sickinger, Annette G., additional, Engelse, Marten A., additional, de Koning, Eelco J. P., additional, Körner, Antje, additional, Kiess, Wieland, additional, and Maedler, Kathrin, additional

Published
2013
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127. Intravital Microscopy Through an Abdominal Imaging Window Reveals a Pre-Micrometastasis Stage During Liver Metastasis

Author

Ritsma, Laila, primary, Steller, Ernst J. A., additional, Beerling, Evelyne, additional, Loomans, Cindy J. M., additional, Zomer, Anoek, additional, Gerlach, Carmen, additional, Vrisekoop, Nienke, additional, Seinstra, Daniëlle, additional, van Gurp, Leon, additional, Schäfer, Ronny, additional, Raats, Daniëlle A., additional, de Graaff, Anko, additional, Schumacher, Ton N., additional, de Koning, Eelco J. P., additional, Rinkes, Inne H. Borel, additional, Kranenburg, Onno, additional, and Rheenen, Jacco van, additional

Published
2012
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129. Non-invasive assessment of microcirculation by sidestream dark field imaging as a marker of coronary artery disease in diabetes

Author

Djaberi, Roxana, primary, Schuijf, Joanne D, additional, de Koning, Eelco J, additional, Wijewickrama, D Champa, additional, Pereira, Alberto M, additional, Smit, Johannes W, additional, Kroft, Lucia J, additional, Roos, Albert de, additional, Bax, Jeroen J, additional, Rabelink, Ton J, additional, and Jukema, J Wouter, additional

Published
2012
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130. ASSOCIATIONS BETWEEN LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND VASCULAR STIFFNESS AS ASSESSED WITH APPLANATION TONOMETRY IN ASYMPTOMATIC PATIENTS WITH DIABETES

Author

Roos, Cornelis, primary, Auger, Dominique, additional, Djaberi, Roxana, additional, de Koning, Eelco J., additional, Rabelink, Ton J., additional, Smit, Jan W., additional, Pereira, Alberto M., additional, Bax, Jeroen, additional, Delgado, Victoria, additional, Jukema, Johan, additional, and Scholte, Arthur, additional

Published
2012
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131. Type 2 Diabetes Susceptibility Gene Expression in Normal or Diabetic Sorted Human Alpha and Beta Cells: Correlations with Age or BMI of Islet Donors

Author

Kirkpatrick, Clare L., primary, Marchetti, Piero, additional, Purrello, Francesco, additional, Piro, Salvatore, additional, Bugliani, Marco, additional, Bosco, Domenico, additional, de Koning, Eelco J. P., additional, Engelse, Marten A., additional, Kerr-Conte, Julie, additional, Pattou, François, additional, and Wollheim, Claes B., additional

Published
2010
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133. VASCULAR STIFFNESS AS A PREDICTOR OF ABNORMAL MYOCARDIAL PERFUSION IN ASYMPTOMATIC PATIENTS WITH DIABETES MELLITUS

Author

Roos, Cornelis J., primary, Djaberi, Roxana, additional, Schuijf, Joanne, additional, de Koning, Eelco J., additional, Rabelink, Ton J., additional, Smit, Jan W., additional, Pereira, Alberto M., additional, Stokkel, Marcel P., additional, Scholte, Arthur J., additional, van der Wall, Ernst E., additional, Jukema, J. Wouter, additional, and Bax, Jeroen J., additional

Published
2010
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135. Endothelial Dysfunction in Diabetic Patients with Abnormal Myocardial Perfusion in the Absence of Epicardial Obstructive Coronary Artery Disease

Author

Djaberi, Roxana, primary, Roodt, Jos op 't, additional, Schuijf, Joanne D., additional, Rabelink, Ton J., additional, de Koning, Eelco J., additional, Pereira, Alberto M., additional, Stokkel, Marcel P., additional, Smit, Jan W., additional, Bax, Jeroen J., additional, and Jukema, J. Wouter, additional

Published
2009
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137. Differentiation of Bone Marrow-Derived Endothelial Progenitor Cells Is Shifted into a Proinflammatory Phenotype by Hyperglycemia

Author

Loomans, Cindy J. M., primary, van Haperen, Rien, additional, Duijs, Jacques M., additional, Verseyden, Caroline, additional, de Crom, Rini, additional, Leenen, Pieter J. M., additional, Drexhage, Hemmo A., additional, de Boer, Hetty C., additional, de Koning, Eelco J. P., additional, Rabelink, Ton J., additional, Staal, Frank J. T., additional, and van Zonneveld, Anton Jan, additional

Published
2009
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142. Genetic regulation of RNA splicing in human pancreatic islets

Author

Atla, Goutham, Bonàs-Guarch, Silvia, Cuenca-Ardura, Mirabai, Beucher, Anthony, Crouch, Daniel J. M., Garcia-Hurtado, Javier, Moran, Ignasi, Irimia, Manuel, Prasad, Rashmi B., Gloyn, Anna L., Marselli, Lorella, Suleiman, Mara, Berney, Thierry, de Koning, Eelco J. P., Kerr-Conte, Julie, Pattou, Francois, Todd, John A., Piemonti, Lorenzo, and Ferrer, Jorge

Abstract

Background: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.

Published
2022
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143. Physical Activity at Altitude: Challenges for People With Diabetes.

Author

de Mol, Pieter, de Vries, Suzanna T., de Koning, Eelco J. P., Gans, Reinold O. B., Bilo, Henk J. G., and Tack, Cees J.

Subjects
INFLUENCE of altitude, PHYSICAL activity, DIABETES, HYPOXEMIA, HYPERGLYCEMIA, HYPOGLYCEMIA
Abstract

BACKGROUND A growing number of subjects with diabetes take part in physical activities at altitude such as skiing, climbing, and trekking. Exercise under conditions of hypo-baric hypoxia poses some unique challenges on subjects with diabetes, and the presence of diabetes can complicate safe and successful participation in mountain activities. Among others, altitude can alter glucoregulation. Furthermore, cold temperatures and altitude can complicate accurate reading of glucose monitoring equipment and storage of insulin. These factors potentially lead to dangerous hyperglycemia or hypoglycemia. Over the last years, more information has become available on this subject. PURPOSE To provide an up-to-date overview of the pathophysiological changes during physical activity at altitude and the potential problems related to diabetes, including the use of (continuous) blood glucose monitors and insulin pumps. To propose practical recommendations for preparations and travel to altitude for subjects with diabetes. DATA SOURCES AND SYNTHESIS We researched PubMed, medical textbooks, and related Internet sites, and extracted human studies and data based on relevance for diabetes, exercise, and altitude. LIMITATIONS Given the paucity of controlled trials regarding diabetes and altitude, we composed a narrative review and filled in areas lacking diabetes-specific studies with data obtained from nondiabetic subjects. CONCLUSIONS Subjects with diabetes can take part in activities at high, and even extreme, altitude. However, careful assessment of diabetes-related complications, optimal preparation, and adequate knowledge of glycemic regulation at altitude and altitude-related complications is needed. [ABSTRACT FROM AUTHOR]

Published
2014
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145. Do Knee Osteoarthritis and Fat‐Free Mass Interact in Their Impact on Health‐Related Quality of Life in Men? Results From a Population‐Based Cohort

Author

Visser, A. Willemien, de Mutsert, Renée, Bloem, Johannes L., Reijnierse, Monique, Kazato, Hanako, le Cessie, Saskia, den Heijer, Martin, Rosendaal, Frits R., Kloppenburg, Margreet, Rosendaal, Frits R., de Mutsert, Renée, Rabelink, Ton J., Smit, Johannes W. A., Jukema, J. Wouter, de Roos, Albert, le Cessie, Saskia, Hiemstra, Pieter S., Kloppenburg, Margreet, Huizinga, Tom W. J., Pijl, Hanno, de Koning, Eelco J. P., Assendelft, Willem J. J., Reitsma, Pieter H., van Dijk, Ko Willems, de Vries, Aiko P. J., Lamb, Hildo J., Jazet, Ingrid M., Dekkers, Olaf M., Biermasz, Nienke R., Blom, Jeanet W., Rensen, Patrick C. N., Cobbaert, Christa M., den Heijer, Martin, Dekker, Jacqueline M., and Penninx, Brenda W.

Abstract

To investigate whether obesity and other risk factors interact with knee osteoarthritis (OA) in its adverse impact on health‐related quality of life (HRQOL). In 1,262 participants of the Netherlands Epidemiology of Obesity Study, a population‐based cohort (age 45–65 years, 53% women, and median body mass index [BMI] 27 kg/m2), knee OA was defined following modified American College of Rheumatology criteria. BMI and fat‐free mass (as proxy for muscle mass) were assessed by bioelectrical impedance analysis, and comorbidities by self‐report. HRQOL was assessed using the Short Form 36 physical component summary (PCS) score. Linear regression analyses were performed to examine associations between knee OA and PCS score, adjusting for age and sex and stratified for BMI, fat‐free mass, and comorbidities. Knee OA (prevalence 16%) was associated with a 7.2‐points lower PCS score (95% confidence interval −9.5, −4.8). PCS score was also negatively associated with obesity and comorbidities; however, no interaction with knee OA was seen. Low fat‐free mass was associated with a lower PCS score and interacted with knee OA in men. Interaction between concurring OA and low fat‐free mass attributed to 64% of the decrease in PCS score, as compared with men without OA and with high fat‐free mass. Knee OA was associated with a lower HRQOL, as were its risk factors, obesity, comorbidities, and low fat‐free mass. In men, fat‐free mass interacted with knee OA, leading to an additional decrease of HRQOL in the case of concurrence. Especially in the former, improvement of fat‐free mass may improve HRQOL in knee OA patients.

Published
2015
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148. Conversion of mature human β-cells into glucagon-producing α-cells.

Author

Spijker, H Siebe, Ravelli, Raimond B G, Mommaas-Kienhuis, A Mieke, van Apeldoorn, Aart A, Engelse, Marten A, Zaldumbide, Arnaud, Bonner-Weir, Susan, Rabelink, Ton J, Hoeben, Rob C, Clevers, Hans, Mummery, Christine L, Carlotti, Françoise, and de Koning, Eelco J P

Abstract

Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration. [ABSTRACT FROM AUTHOR]

Published
2013
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