Author: "Thomas Mandrup-Poulsen" / Language: english - Searchworks@Jio Institute Digital Library Search Results

59 results on '"Thomas Mandrup-Poulsen"'

1. Tipping-point transition from transient to persistent inflammation in pancreatic islets

Author: Thomas Holst-Hansen, Pernille Yde Nielsen, Mogens H. Jensen, Thomas Mandrup-Poulsen, and Ala Trusina
Subjects: Biology (General), QH301-705.5
Abstract: Abstract Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway—IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.
Published: 2024
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2. Proinflammatory cytokines suppress nonsense-mediated RNA decay to impair regulated transcript isoform processing in pancreatic β cells

Author: Seyed M. Ghiasi, Piero Marchetti, Lorenzo Piemonti, Jens H. Nielsen, Bo T. Porse, Thomas Mandrup-Poulsen, and Guy A. Rutter
Subjects: β-cells, insulin secretion, transcript, nonsense-mediated decay, RNA decay, RNA processing, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: IntroductionProinflammatory cytokines are implicated in pancreatic ß cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of nonsense-mediated RNA decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß cells.MethodsA luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3, or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. The gain- or loss-of-function of two key NMD components, UPF3B and UPF2, is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques.ResultsCyt attenuate NMD activity in insulin-producing cell lines and primary human ß cells. These effects are found to involve ER stress and are associated with the downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing raise or lower Cyt-induced cell death, respectively, in EndoC-ßH3 cells and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increases alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in the extracellular matrix (ECM), including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitizes ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signaling, potentially serving as a protective response against Cyt-induced NMD component expression.ConclusionOur findings highlight the central importance of RNA turnover in ß cell responses to inflammatory stress.
Published: 2024
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3. S280: INDIVIDUALS WITH HFE C282Y HOMOZYGOSITY AND DIABETES HAVE ALMOST TWO-FOLD RISK OF DEATH COMPARED TO NON-CARRIERS WITH DIABETES: A PROSPECTIVE STUDY OF A 132,542-INDIVIDUAL GENERAL POPULATION COHORT

Author: Mathis Mottelson, Jens Helby, Børge Grønne Nordestgaard, Christina Ellervik, Thomas Mandrup-Poulsen, Jesper Petersen, Stig Egil Bojesen, and Andreas Glenthøj
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2023
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4. Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V

Author: Anniek F. Lubberding, Jinyi Zhang, Morten Lundh, Thomas Svava Nielsen, Mathilde S. Søndergaard, Maria Villadsen, Emil Z. Skovhøj, Geke A. Boer, Jakob B. Hansen, Morten B. Thomsen, Jonas T. Treebak, Jens J. Holst, Jørgen K. Kanters, Thomas Mandrup-Poulsen, Thomas Jespersen, Brice Emanuelli, and Signe S. Torekov
Subjects: Medicine, Science
Abstract: Abstract Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.
Published: 2021
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5. Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

Author: Mark C. Genovese, Gerd R. Burmester, Owen Hagino, Karthinathan Thangavelu, Melitza Iglesias-Rodriguez, Gregory St John, Miguel A. González-Gay, Thomas Mandrup-Poulsen, and Roy Fleischmann
Subjects: Rheumatoid arthritis, Sarilumab, Adalimumab, Glycosylated haemoglobin, IL-6, Inflammation, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p
Published: 2020
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6. FK506-Binding Protein 2 Participates in Proinsulin Folding

Author: Carolin Hoefner, Tenna Holgersen Bryde, Celina Pihl, Sylvia Naiga Tiedemann, Sophie Emilie Bresson, Hajira Ahmed Hotiana, Muhammad Saad Khilji, Theodore Dos Santos, Michele Puglia, Paola Pisano, Mariola Majewska, Julia Durzynska, Kristian Klindt, Justyna Klusek, Marcelo J. Perone, Robert Bucki, Per Mårten Hägglund, Pontus Emanuel Gourdon, Kamil Gotfryd, Edyta Urbaniak, Malgorzata Borowiak, Michael Wierer, Patrick Edward MacDonald, Thomas Mandrup-Poulsen, and Michal Tomasz Marzec
Subjects: FKBP2, proinsulin, proline isomerization, endoplasmic reticulum, Microbiology, QR1-502
Abstract: Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin folding. We found that FKBP2 co-immunoprecipitated with proinsulin and its chaperone GRP94 and that inhibition of FKBP2 expression increased proinsulin turnover with reduced intracellular proinsulin and insulin levels. This phenotype was accompanied by an increased proinsulin secretion and the formation of proinsulin high-molecular-weight complexes, a sign of proinsulin misfolding. FKBP2 knockout in pancreatic β-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in β-cells from pancreatic islets of T2D patients. Based on molecular modeling and an in vitro enzymatic assay, we suggest that proline at position 28 of the proinsulin B-chain (P28) is the substrate of FKBP2’s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding.
Published: 2023
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7. Mitophagy protects β cells from inflammatory damage in diabetes

Author: Vaibhav Sidarala, Gemma L. Pearson, Vishal S. Parekh, Benjamin Thompson, Lisa Christen, Morgan A. Gingerich, Jie Zhu, Tracy Stromer, Jianhua Ren, Emma C. Reck, Biaoxin Chai, John A. Corbett, Thomas Mandrup-Poulsen, Leslie S. Satin, and Scott A. Soleimanpour
Subjects: Endocrinology, Medicine
Abstract: Inflammatory damage contributes to β cell failure in type 1 and 2 diabetes (T1D and T2D, respectively). Mitochondria are damaged by inflammatory signaling in β cells, resulting in impaired bioenergetics and initiation of proapoptotic machinery. Hence, the identification of protective responses to inflammation could lead to new therapeutic targets. Here, we report that mitophagy serves as a protective response to inflammatory stress in both human and rodent β cells. Utilizing in vivo mitophagy reporters, we observed that diabetogenic proinflammatory cytokines induced mitophagy in response to nitrosative/oxidative mitochondrial damage. Mitophagy-deficient β cells were sensitized to inflammatory stress, leading to the accumulation of fragmented dysfunctional mitochondria, increased β cell death, and hyperglycemia. Overexpression of CLEC16A, a T1D gene and mitophagy regulator whose expression in islets is protective against T1D, ameliorated cytokine-induced human β cell apoptosis. Thus, mitophagy promotes β cell survival and prevents diabetes by countering inflammatory injury. Targeting this pathway has the potential to prevent β cell failure in diabetes and may be beneficial in other inflammatory conditions.
Published: 2020
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8. GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity

Author: Stacey Bartlett, Adrian Tandhyka Gemiarto, Minh Dao Ngo, Haressh Sajiir, Semira Hailu, Roma Sinha, Cheng Xiang Foo, Léanie Kleynhans, Happy Tshivhula, Tariq Webber, Helle Bielefeldt-Ohmann, Nicholas P. West, Andriette M. Hiemstra, Candice E. MacDonald, Liv von Voss Christensen, Larry S. Schlesinger, Gerhard Walzl, Mette Marie Rosenkilde, Thomas Mandrup-Poulsen, and Katharina Ronacher
Subjects: Mycobacterium tuberculosis, diabetes, oxysterols, 7α,25-dihydroxycholesterol, GPR183, EBI2, Immunologic diseases. Allergy, RC581-607
Abstract: Oxidized cholesterols have emerged as important signaling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We found that expression of the oxysterol-receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D and was associated with TB disease severity on chest x-ray. GPR183 activation by 7α,25-dihydroxycholesterol (7α,25-OHC) reduced growth of Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis BCG in primary human monocytes, an effect abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-β and IL-10 expression and enhanced autophagy. Mice lacking GPR183 had significantly increased lung Mtb burden and dysregulated IFNs during early infection. Together, our data demonstrate that GPR183 is an important regulator of intracellular mycobacterial growth and interferons during mycobacterial infection.
Published: 2020
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9. Combination of ferric ammonium citrate with cytokines involved in apoptosis and insulin secretion of human pancreatic beta cells related to diabetes in thalassemia

Author: Patchara Rattanaporn, Sissades Tongsima, Thomas Mandrup-Poulsen, Saovaros Svasti, and Dalina Tanyong
Subjects: Ferric ammonium citrate, Cytokines, Pancreatic beta cell, Thalassemia, Diabetes, Insulin, Medicine, Biology (General), QH301-705.5
Abstract: Background Diabetes mellitus (DM) is a common complication found in β-thalassemia patients. The mechanism of DM in β-thalassemia patients is still unclear, but it could be from an iron overload and increase of some cytokines, such as interleukin1-β (IL-1β) and tumor necrosis factor-α (TNF-α). The objective of this study was to study the effect of interaction between ferric ammonium citrate (FAC) and cytokines, IL-1β and TNF-α, on 1.1B4 human pancreatic β-cell line. Methods The effect of the combination of FAC and cytokines on cell viability was studied by MTT assay. Insulin secretion was assessed by the enzyme-linked immunosorbent assay (ELISA). The reactive oxygen species (ROS) and cell apoptosis in normal and high glucose condition were determined by flow cytometer. In addition, gene expression of apoptosis, antioxidant; glutathione peroxidase 1 (GPX1) and superoxide dismutase 2 (SOD2), and insulin secretory function were studied by real-time polymerase chain reaction (Real-time PCR). Results The findings revealed that FAC exposure resulted in the decrease of cell viability and insulin-release, and the induction of ROS and apoptosis in pancreatic cells. Interestingly, a combination of FAC and cytokines had an additive effect on SOD2 antioxidants’ genes expression and endoplasmic reticulum (ER) stress. In addition, it reduced the insulin secretion genes expression; insulin (INS), glucose kinase (GCK), protein convertase 1 (PSCK1), and protein convertase 2 (PSCK2). Moreover, the highest ROS and the lowest insulin secretion were found in FAC combined with IL-1β and TNF-α in the high-glucose condition of human pancreatic beta cell, which could be involved in the mechanism of DM development in β-thalassemia patients.
Published: 2020
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10. Defective Proinsulin Handling Modulates the MHC I Bound Peptidome and Activates the Inflammasome in β-Cells

Author: Muhammad Saad Khilji, Pouya Faridi, Erika Pinheiro-Machado, Carolin Hoefner, Tina Dahlby, Ritchlynn Aranha, Søren Buus, Morten Nielsen, Justyna Klusek, Thomas Mandrup-Poulsen, Kirti Pandey, Anthony W. Purcell, and Michal T. Marzec
Subjects: ER stress, GRP94, proteasome, insulin, inflammation, MHC class-I, Biology (General), QH301-705.5
Abstract: How immune tolerance is lost to pancreatic β-cell peptides triggering autoimmune type 1 diabetes is enigmatic. We have shown that loss of the proinsulin chaperone glucose-regulated protein (GRP) 94 from the endoplasmic reticulum (ER) leads to mishandling of proinsulin, ER stress, and activation of the immunoproteasome. We hypothesize that inadequate ER proinsulin folding capacity relative to biosynthetic need may lead to an altered β-cell major histocompatibility complex (MHC) class-I bound peptidome and inflammasome activation, sensitizing β-cells to immune attack. We used INS-1E cells with or without GRP94 knockout (KO), or in the presence or absence of GRP94 inhibitor PU-WS13 (GRP94i, 20 µM), or exposed to proinflammatory cytokines interleukin (IL)-1β or interferon gamma (IFNγ) (15 pg/mL and 10 ng/mL, respectively) for 24 h. RT1.A (rat MHC I) expression was evaluated using flow cytometry. The total RT1.A-bound peptidome analysis was performed on cell lysates fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC), followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and (pro) IL-1β expression and secretion were investigated by Western blotting. GRP94 KO increased RT1.A expression in β-cells, as did cytokine exposure compared to relevant controls. Immunopeptidome analysis showed increased RT1.A-bound peptide repertoire in GRP94 KO/i cells as well as in the cells exposed to cytokines. The GRP94 KO/cytokine exposure groups showed partial overlap in their peptide repertoire. Notably, proinsulin-derived peptide diversity increased among the total RT1.A peptidome in GRP94 KO/i along with cytokines exposure. NLRP1 expression was upregulated in GRP94 deficient cells along with decreased IκBα content while proIL-1β cellular levels declined, coupled with increased secretion of mature IL-1β. Our results suggest that limiting β-cell proinsulin chaperoning enhances RT1.A expression alters the MHC-I peptidome including proinsulin peptides and activates inflammatory pathways, suggesting that stress associated with impeding proinsulin handling may sensitize β-cells to immune-attack.
Published: 2022
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11. The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 β.

Author: Muhammad Saad Khilji, Danielle Verstappen, Tina Dahlby, Michala Cecilie Burstein Prause, Celina Pihl, Sophie Emilie Bresson, Tenna Holgersen Bryde, Phillip Alexander Keller Andersen, Kristian Klindt, Dusan Zivkovic, Marie-Pierre Bousquet-Dubouch, Björn Tyrberg, Thomas Mandrup-Poulsen, and Michal Tomasz Marzec
Subjects: Medicine, Science
Abstract: A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes. We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by low concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.
Published: 2020
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12. The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Author: Marie Balslev Backe, Chunyu Jin, Luz Andreone, Aditya Sankar, Karl Agger, Kristian Helin, Andreas Nygaard Madsen, Steen Seier Poulsen, Madhusudhan Bysani, Karl Bacos, Charlotte Ling, Marcelo Javier Perone, Birgitte Holst, and Thomas Mandrup-Poulsen
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
Published: 2019
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13. MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage.

Author: Anna Lindeløv Vestergaard, Claus Heiner Bang-Berthelsen, Tina Fløyel, Jonathan Lucien Stahl, Lisa Christen, Farzaneh Taheri Sotudeh, Peter de Hemmer Horskjær, Klaus Stensgaard Frederiksen, Frida Greek Kofod, Christine Bruun, Lukas Adrian Berchtold, Joachim Størling, Romano Regazzi, Simranjeet Kaur, Flemming Pociot, and Thomas Mandrup-Poulsen
Subjects: Medicine, Science
Abstract: Inflammatory β-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Pro-inflammatory cytokines cause β-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent β-cell failure in vitro and in vivo, in part by reducing NF-κB transcriptional activity. We investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat, prior to exposure to the pro-inflammatory cytokines IL-1β and IFN-γ for 6 h or 24 h, and miR expression was profiled with miR array. Thirteen miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, miR-455-5p, miR-466b-2-3p, miR-652-5p, and miR-3584-5p) were regulated by both cytokines and Givinostat, and nine were examined by qRT-PCR. miR-146a-5p was strongly regulated by cytokines and KDACi and was analyzed further. miR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced cytokine signaling, including the activity of NF-κB and iNOS promoters, as well as NO production and protein levels of iNOS and its own direct targets TNF receptor associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). miR-146a-5p was elevated in the pancreas of diabetes-prone BB-DP rats at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced β-cell apoptosis, demonstrating the strength of this approach.
Published: 2018
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14. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

Author: Kirsten M Hoelmkjaer, Nicolai J Wewer Albrechtsen, Jens J Holst, Anna M Cronin, Dorte H Nielsen, Thomas Mandrup-Poulsen, and Charlotte R Bjornvad
Subjects: Medicine, Science
Abstract: Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats.
Published: 2016
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15. JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1β-Induced Apoptosis Associated with Abrogated Myc Expression

Author: Michala Prause, Christopher Michael Mayer, Caroline Brorsson, Klaus Stensgaard Frederiksen, Nils Billestrup, Joachim Størling, and Thomas Mandrup-Poulsen
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: The relative contributions of the JNK subtypes in inflammatory β-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1α1, JNK1α2, JNK1β1, JNK1β2, JNK2α1, JNK2α2, JNK3α1, and JNK3α2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1β-induced β-cell apoptosis. JNK1 knockdown prevented IL-1β-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1β-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1β-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1β-induced β-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatory β-cell failure and destruction.
Published: 2016
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16. Tissue Inhibitor Of Matrix Metalloproteinase-1 Is Required for High-Fat Diet-Induced Glucose Intolerance and Hepatic Steatosis in Mice.

Author: Even Fjære, Charlotte Andersen, Lene Secher Myrmel, Rasmus Koefoed Petersen, Jakob Bondo Hansen, Hanne Sørup Tastesen, Thomas Mandrup-Poulsen, Nils Brünner, Karsten Kristiansen, Lise Madsen, and Maria Unni Rømer
Subjects: Medicine, Science
Abstract: Plasma levels of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are elevated in obesity and obesity-related disorders, such as steatosis, but the metabolic role of TIMP-1 is unclear. Here we investigated how the presence or absence of TIMP-1 affected the development of diet-induced glucose intolerance and hepatic steatosis using the Timp1 null mice.Timp1 knockout (TKO) and wild type (TWT) mice were fed chow, high-fat diet (HFD) or intermediate fat and sucrose diet (IFSD). We determined body weight, body composition, lipid content of the liver, energy intake, energy expenditure, oral glucose tolerance, as well as insulin tolerance. In addition, the histology of liver and adipose tissues was examined and expression of selected genes involved in lipid metabolism and inflammation in liver and adipose tissues was determined by RT-qPCR.TKO mice gained less weight and had lower energy efficiency than TWT mice when fed HFD, but not when fed chow or IFSD. Importantly, TKO mice were protected from development of HFD- as well as IFSD-induced glucose intolerance, hepatic steatosis, and altered expression of genes involved in hepatic lipid metabolism and inflammation.Collectively, our results indicate that TIMP-1 contributes to the development of diet-induced hepatic steatosis and glucose intolerance and may be a potential therapeutic target.
Published: 2015
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17. JNK1 protects against glucolipotoxicity-mediated beta-cell apoptosis.

Author: Michala Prause, Dan Ploug Christensen, Nils Billestrup, and Thomas Mandrup-Poulsen
Subjects: Medicine, Science
Abstract: Pancreatic β-cell dysfunction is central to type 2 diabetes pathogenesis. Prolonged elevated levels of circulating free-fatty acids and hyperglycemia, also termed glucolipotoxicity, mediate β-cell dysfunction and apoptosis associated with increased c-Jun N-terminal Kinase (JNK) activity. Endoplasmic reticulum (ER) and oxidative stress are elicited by palmitate and high glucose concentrations further potentiating JNK activity. Our aim was to determine the role of the JNK subtypes JNK1, JNK2 and JNK3 in palmitate and high glucose-induced β-cell apoptosis. We established insulin-producing INS1 cell lines stably expressing JNK subtype specific shRNAs to understand the differential roles of the individual JNK isoforms. JNK activity was increased after 3 h of palmitate and high glucose exposure associated with increased expression of ER and mitochondrial stress markers. JNK1 shRNA expressing INS1 cells showed increased apoptosis and cleaved caspase 9 and 3 compared to non-sense shRNA expressing control INS1 cells when exposed to palmitate and high glucose associated with increased CHOP expression, ROS formation and Puma mRNA expression. JNK2 shRNA expressing INS1 cells did not affect palmitate and high glucose induced apoptosis or ER stress markers, but increased Puma mRNA expression compared to non-sense shRNA expressing INS1 cells. Finally, JNK3 shRNA expressing INS1 cells did not induce apoptosis compared to non-sense shRNA expressing INS1 cells when exposed to palmitate and high glucose but showed increased caspase 9 and 3 cleavage associated with increased DP5 and Puma mRNA expression. These data suggest that JNK1 protects against palmitate and high glucose-induced β-cell apoptosis associated with reduced ER and mitochondrial stress.
Published: 2014
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18. High glucose suppresses human islet insulin biosynthesis by inducing miR-133a leading to decreased polypyrimidine tract binding protein-expression.

Author: Rikard G Fred, Claus H Bang-Berthelsen, Thomas Mandrup-Poulsen, Lars G Grunnet, and Nils Welsh
Subjects: Medicine, Science
Abstract: BACKGROUND: Prolonged periods of high glucose exposure results in human islet dysfunction in vitro. The underlying mechanisms behind this effect of high glucose are, however, unknown. The polypyrimidine tract binding protein (PTB) is required for stabilization of insulin mRNA and the PTB mRNA 3'-UTR contains binding sites for the microRNA molecules miR-133a, miR-124a and miR-146. The aim of this study was therefore to investigate whether high glucose increased the levels of these three miRNAs in association with lower PTB levels and lower insulin biosynthesis rates. METHODOLOGY/PRINCIPAL FINDINGS: Human islets were cultured for 24 hours in the presence of low (5.6 mM) or high glucose (20 mM). Islets were also exposed to sodium palmitate or the proinflammatory cytokines IL-1beta and IFN-gamma, since saturated free fatty acids and cytokines also cause islet dysfunction. RNA was then isolated for real-time RT-PCR analysis of miR-133a, miR-124a, miR-146, insulin mRNA and PTB mRNA contents. Insulin biosynthesis rates were determined by radioactive labeling and immunoprecipitation. Synthetic miR-133a precursor and inhibitor were delivered to dispersed islet cells by lipofection, and PTB was analyzed by immunoblotting following culture at low or high glucose. Culture in high glucose resulted in increased islet contents of miR-133a and reduced contents of miR-146. Cytokines increased the contents of miR-146. The insulin and PTB mRNA contents were unaffected by high glucose. However, both PTB protein levels and insulin biosynthesis rates were decreased in response to high glucose. The miR-133a inhibitor prevented the high glucose-induced decrease in PTB and insulin biosynthesis, and the miR-133a precursor decreased PTB levels and insulin biosynthesis similarly to high glucose. CONCLUSION: Prolonged high-glucose exposure down-regulates PTB levels and insulin biosynthesis rates in human islets by increasing miR-133a levels. We propose that this mechanism contributes to hyperglycemia-induced beta-cell dysfunction.
Published: 2010
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19. In Vitro Inhibition of Insulin Release by Blood Mononuclear Cells from Insulin-Dependent Diabetic and Healthy Subjects: Synergistic Action of IL-1 and TNF

Author: Vitlaly Ablamunits, Flora Baranova, Thomas Mandrup-Poulsen, and Jørn Nerup
Subjects: Medicine
Abstract: Previous studies have demonstrated that peripheral blood mononuclear cells (BMC) from type 1 (insulin-dependent) diabetic patients inhibit insulin release (IR) from rat or mouse islet cells in vitro. This phenomenon is of great interest as a model for islet graft rejection. We found that lipopolysaccharide (LPS)-stimulated BMC of healthy donors and type 1 diabetic patients suppress both basal and stimulated insulin secretion. To study whether this inhibition was due to soluble mediators we added supernatants of LPS-stimulated BMC or recombinant human interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) at concentrations comparable to those found in the supernatants to rat islet cells. The inhibitory effect of BMC on islet cells could be transferred by supernatants of LPS-stimulated BMC. We found that neither IL-1 nor TNF alone inhibit IR from dispersed adult rat islet cells. However, the combination of IL-1 and TNF was highly effective. Ultrafiltration of supernatants of LPS-stimulated BMC through a PM-10 membrane (10 kDa cutoff) deprived the supernatants of the inhibitory activity indicating that only intact IL-1 and TNF (m.w. about 17 kDa), but not smaller IL-1 and TNF fragments, were responsible for the effects on islet cells. These data suggest that activation of BMC and cytokine release at islet graft site may result in an early loss of graft function. Islet transplantation using microcapsules not permeable for molecules with m.w. > 10 kDa would be preferable.
Published: 1994
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20. A randomised, double-blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women

Author: Christian R. Juhl, Josephine Burgdorf, Cecilie Knudsen, Anniek F. Lubberding, Simon Veedfald, Jonas L. Isaksen, Bolette Hartmann, Ruth Frikke‐Schmidt, Thomas Mandrup‐Poulsen, Jens J. Holst, Jørgen K. Kanters, and Signe S. Torekov
Subjects: Adult, Blood Glucose, Cross-Over Studies, Adolescent, Endocrinology, Diabetes and Metabolism, Blood Glucose Self-Monitoring, Moxifloxacin, Young Adult, Endocrinology, Internal Medicine, Humans, Female, Insulin Resistance, Fluoroquinolones
Abstract: AIMS: The voltage-gated potassium channel K v 11.1 is important for repolarising the membrane potential in excitable cells such as myocytes, pancreatic α- and β-cells. Moxifloxacin blocks the K v 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin a drug known to block the K v 11.1 channel. MATERIAL AND METHODS: The effect of moxifloxacin (800 mg/day for four days) or placebo on glucose regulation was assessed in a randomised, double-blind, crossover study of young men and women (age 20-40 years and BMI 18.5-27.5 kg/m 2 ) without chronic disease, using 6-hour oral glucose tolerance tests (OGTT) and continuous glucose monitoring (CGM). RESULTS: Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF-interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the eight days of CGM and during the OGTT. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced early plasma-glucose response (AUC 0-30min ) by 7% (95%CI: -9% to -4%, pCONCLUSIONS: In young men and women, moxifloxacin a drug known to block the K v 11.1 channel increased QT interval, decreased glucose levels, and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia. This article is protected by copyright. All rights reserved.
Published: 2023
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21. A Blunted GPR183/Oxysterol Axis during Dysglycemia Results in Delayed Recruitment of Macrophages to the Lung during Mycobacterium tuberculosis Infection

Author: Minh Dao Ngo, Stacey Bartlett, Helle Bielefeldt-Ohmann, Cheng Xiang Foo, Roma Sinha, Buddhika Jayakody Arachchige, Sarah Reed, Thomas Mandrup-Poulsen, Mette Marie Rosenkilde, and Katharina Ronacher
Subjects: GPR183, diabetes, Macrophages, 25-hydroxycholesterol, Mycobacterium tuberculosis, Oxysterols, Receptors, G-Protein-Coupled, Mice, Infectious Diseases, tuberculosis, Animals, Humans, Tuberculosis, Immunology and Allergy, oxysterols, Lung
Abstract: Background We previously reported that reduced GPR183 expression in blood from tuberculosis (TB) patients with diabetes is associated with more severe TB. Methods To further elucidate the role of GPR183 and its oxysterol ligands in the lung, we studied dysglycemic mice infected with Mycobacterium tuberculosis (Mtb). Results We found upregulation of the oxysterol-producing enzymes CH25H and CYP7B1 and increased concentrations of 25-hydroxycholesterol upon Mtb infection in the lungs of mice. This was associated with increased expression of GPR183 indicative of oxysterol-mediated recruitment of GPR183-expressing immune cells to the lung. CYP7B1 was predominantly expressed by macrophages in TB granulomas. CYP7B1 expression was significantly blunted in lungs from dysglycemic animals, which coincided with delayed macrophage infiltration. GPR183-deficient mice similarly had reduced macrophage recruitment during early infection. Conclusions Taken together, we demonstrate a requirement of the GPR183/oxysterol axis for positioning of macrophages to the site of infection and add an explanation to more severe TB in diabetes patients.
Published: 2022
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22. Divalent metal transporter 1 knock-down modulates il-1β mediated pancreatic beta-cell pro-apoptotic signaling pathways through the autophagic machinery

Author: Honggang Huang, Taewook Kang, Thomas Mandrup-Poulsen, and Martin R. Larsen
Subjects: 0301 basic medicine, Interleukin-1beta, Apoptosis, Mice, 0302 clinical medicine, Insulin-Secreting Cells, iron metabolism, Biology (General), Cation Transport Proteins, Spectroscopy, biology, diabetes, Chemistry, digestive, oral, and skin physiology, Diabetes, Phosphoproteomics, ROS, General Medicine, Iron metabolism, Computer Science Applications, Cell biology, cell cycle arrest, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Signal transduction, Beta cell, autophagy, anti-apoptosis, Signal Transduction, Programmed cell death, QH301-705.5, Catalysis, Article, Inorganic Chemistry, Cell cycle arrest, 03 medical and health sciences, Autophagy, Gene silencing, Animals, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Interleukin-6, Organic Chemistry, DMT1, Anti-apoptosis, 030104 developmental biology, biology.protein
Abstract: Pro-inflammatory cytokines promote cellular iron-import through enhanced divalent metal transporter-1 (DMT1) expression in pancreatic β-cells, consequently cell death. Inhibition of β-cell iron-import by DMT1 silencing protects against apoptosis in animal models of diabetes. However, how alterations of signaling networks contribute to the protective action of DMT1 knock-down is unknown. Here, we performed phosphoproteomics using our sequential enrichment strategy of mRNA, protein, and phosphopeptides, which enabled us to explore the concurrent molecular events in the same set of wildtype and DMT1-silenced β-cells during IL-1β exposure. Our findings reveal new phosphosites in the IL-1β-induced proteins that are clearly reverted by DMT1 silencing towards their steady-state levels. We validated the levels of five novel phosphosites of the potential protective proteins using parallel reaction monitoring. We also confirmed the inactivation of autophagic flux that may be relevant for cell survival induced by DMT1 silencing during IL-1β exposure. Additionally, the potential protective proteins induced by DMT1 silencing were related to insulin secretion that may lead to improving β-cell functions upon exposure to IL-1β. This global profiling has shed light on the signal transduction pathways driving the protection against inflammation-induced cell death in β-cells after DMT1 silencing.
Published: 2021
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23. Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity

Author: Nico Fischer, Tina Dahlby, Melissa Koomen, Thomas Mandrup-Poulsen, Charna Dibner, Volodymyr Petrenko, Phillip Alexander Keller Andersen, Seyed Mojtaba Ghiasi, and Peter Horskjær Rose
Subjects: 0301 basic medicine, Male, Interferon-gamma/metabolism/pharmacology, lcsh:Chemistry, Mice, 0302 clinical medicine, ARNTL Transcription Factors/genetics/metabolism, Insulin-Secreting Cells, Insulin, immuno-metabolism, lcsh:QH301-705.5, Spectroscopy, Cells, Cultured, ddc:616, Tumor, Cultured, diabetes, Chemistry, nitric oxide synthase, Diabetes, ARNTL Transcription Factors, General Medicine, Computer Science Applications, 3. Good health, Cell biology, Circadian Rhythm, CLOCK, PER2, medicine.anatomical_structure, Knockout mouse, Epigenetics, Female, Proteasome Endopeptidase Complex, Insulin/metabolism, Cells, Period (gene), Insulin-Secreting Cells/drug effects/metabolism, 030209 endocrinology & metabolism, Nitric Oxide, Catalysis, Article, Histone Deacetylases, Cell Line, Proinflammatory cytokine, Inorganic Chemistry, 03 medical and health sciences, Interferon-gamma, Reactive Oxygen Species/metabolism, Cell Line, Tumor, medicine, biochemistry, Animals, Humans, Viability assay, Physical and Theoretical Chemistry, ddc:612, Molecular Biology, epigenetics, Pancreatic islets, Nitric oxide synthase, Organic Chemistry, HDAC3, Proteasome Endopeptidase Complex/metabolism, 030104 developmental biology, HEK293 Cells, lcsh:Biology (General), lcsh:QD1-999, Nitric Oxide/metabolism, Histone Deacetylases/metabolism, chronobiology, Reactive Oxygen Species, Chronobiology, Immuno-metabolism
Abstract: Pancreatic &beta, cell-specific clock knockout mice develop &beta, cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1&beta, (IL-1&beta, ) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1&beta, and interferon-&gamma, (IFN-&gamma, ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of reverse-erythroblastosis virus &alpha, (Rev-erb&alpha, ), in a dose- and time-dependent manner. The REV-ERB&alpha, /&beta, agonist SR9009, used to mimic cytokine-mediated Rev-erb&alpha, induction, reduced constitutive and cytokine-induced brain and muscle arnt-like 1 (Bmal1) mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 (Ins-1/2) mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast, low (&lt, 5,0 &mu, M) concentrations of SR9009 increased Ins-1 mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1&beta, mediated &beta, cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3, and immunoproteasome activity.
Published: 2020
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24. Pancreatic β-cells respond to fuel pressure with an early metabolic switch

Author: Seyed Mojtaba Ghiasi, Jan Henrik Ardenkjær-Larsen, Pernille Rose Jensen, Ronja Maja Malinowski, Thomas Mandrup-Poulsen, Mathilde H. Lerche, and Sebastian Meier
Subjects: 0301 basic medicine, Excess-fuel handling, Glucose uptake, lcsh:Medicine, Biochemistry, GLUCOSE, PATHWAY, chemistry.chemical_compound, Pyruvic Acid/metabolism, 0302 clinical medicine, Polyol pathway, Insulin-Secreting Cells, Insulin Secretion, Pyruvic Acid, Insulin, Glucose/metabolism, lcsh:Science, Multidisciplinary, Fatty Acids, Diabetes, ISOTOPE-RESOLVED METABOLOMICS, Fatty Acids/metabolism, EXCESS, 030220 oncology & carcinogenesis, Metabolic Networks and Pathways, Signal Transduction, Insulin/metabolism, LINE, Carbohydrate metabolism, Article, Cell Line, 03 medical and health sciences, Metabolomics, Insulin-Secreting Cells/metabolism, STIMULATED INSULIN-SECRETION, DHAP, Pressure, Animals, Metabolomics/methods, 13C NMR, Fatty acid metabolism, Signal Transduction/physiology, lcsh:R, Beta cells, Metabolism, Lipid Metabolism, Lipid Metabolism/physiology, Rats, Metabolic pathway, Glucose, 030104 developmental biology, chemistry, lcsh:Q, DNP, Insulin Secretion/physiology, Metabolic Networks and Pathways/physiology, Biomarkers
Abstract: Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2–8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.
Published: 2020
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25. The Connexin 43 Regulator Rotigaptide Reduces Cytokine-Induced Cell Death in Human Islets

Author: Dan Ploug Christensen, Jakob Bondo Hansen, Thomas Mandrup-Poulsen, Seyed Mojtaba Ghiasi, and Björn Tyrberg
Subjects: 0301 basic medicine, medicine.medical_treatment, Connexin, Apoptosis, NF-κB, lcsh:Chemistry, chemistry.chemical_compound, 0302 clinical medicine, Cell Death/drug effects, Insulin-Secreting Cells, Insulin Secretion, Rotigaptide, lcsh:QH301-705.5, Spectroscopy, Peptide analog, Cytokines/genetics, Cell Death, Chemistry, Connexin 43/genetics, NF-kappa B, Gap Junctions, General Medicine, Mitochondria/drug effects, Computer Science Applications, Cell biology, Mitochondria, Islets of Langerhans/cytology, Cytokine, Insulin-Secreting Cells/drug effects, cardiovascular system, Cytokines, medicine.symptom, Beta cell, Gap Junctions/metabolism, Oligopeptides, Programmed cell death, insulin, Insulin/metabolism, Oligopeptides/pharmacology, 0699 Other Biological Sciences, 030209 endocrinology & metabolism, Inflammation, Catalysis, Article, Cell Line, Inorganic Chemistry, 03 medical and health sciences, Islets of Langerhans, Reactive Oxygen Species/metabolism, Stress, Physiological, 0399 Other Chemical Sciences, medicine, Humans, Physical and Theoretical Chemistry, Molecular Biology, gap junctions, 0604 Genetics, Chemical Physics, Organic Chemistry, Apoptosis/drug effects, Insulin Secretion/drug effects, beta cell, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Gene Expression Regulation, inflammation, Connexin 43, NF-kappa B/metabolism, Reactive Oxygen Species, Biomarkers
Abstract: Background: Intercellular communication mediated by cationic fluxes through the Connexin family of gap junctions regulates glucose-stimulated insulin secretion and beta cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle cells by the prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects islet cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of diabetes. Methods: Apoptosis was measured in human islets shown to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1&beta, + IFNɣ. INS-1 cells shown to lack Cx43 were used to examine if RG protected human islet cells via Cx43 coupling. To study the mechanisms of action of Cx43-independent effects of RG, NO, IkB&alpha, degradation, mitochondrial activity, ROS, and insulin mRNA levels were determined. Results: RG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells, this protective effect was markedly blunted as expected, but unexpectedly, RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels, and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS expression, suggesting that RG blunts cytokine-induced NF-&kappa, B signaling in insulin-producing cells in a Cx43-independent manner. Conclusion: RG reduces cytokine-induced cell death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-&kappa, B signaling.
Published: 2020
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26. Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 Is Essential for Proinsulin Handling

Author: Seyed Mojtaba Ghiasi, Sólrun Petersen, Kristian Klindt, Oana Cheta, Thomas Mandrup-Poulsen, Marcelo J. Perone, Michal Marzec, Peter Arvan, Anders Tengholm, Sophie Emilie Bresson, Caroline Hede Andersen, Clara Prats, Sebastian Barg, Mingyu Yang, Muhammad Saad Khilji, Leena Haataja, Muhmmad Omar-Hmeadi, Björn Tyrberg, Celina Pihl, and Tina Dahlby
Subjects: 0301 basic medicine, endocrine system, Protein Folding, endocrine system diseases, Glucose-regulated protein, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Apoptosis, GRP94, Endoplasmic Reticulum, Exocytosis, 03 medical and health sciences, eIF-2 Kinase, 0302 clinical medicine, Cell Line, Tumor, Insulin-Secreting Cells, Insulin Secretion, Internal Medicine, medicine, Animals, Humans, Insulin, HSP70 Heat-Shock Proteins, Protein kinase A, Proinsulin, biology, Chemistry, Kinase, Endoplasmic reticulum, Membrane Proteins, purl.org/becyt/ford/3.1 [https], Endoplasmic Reticulum Stress, Cell biology, Rats, 030104 developmental biology, Islet Studies, Diabetes Mellitus, Type 2, Chaperone (protein), biology.protein, Chaperone binding, purl.org/becyt/ford/3 [https], GP96, hormones, hormone substitutes, and hormone antagonists
Abstract: Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is underinvestigated. Here, we have explored the importance of glucose-regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within b-cells. We found that GRP94 coimmunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life, and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was accelerated twofold, but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in b-cells selectively activated protein kinase R–like endoplasmic reticulum kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from patients with type 2 diabetes. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion. Fil: Ghiasi, Seyed Mojtaba. Universidad de Copenhagen; Dinamarca Fil: Dahlby, Tina. Universidad de Copenhagen; Dinamarca Fil: Andersen, Caroline Hede. Universidad de Copenhagen; Dinamarca Fil: Haataja, Leena. University of Michigan; Estados Unidos Fil: Petersen, Sólrun. Universidad de Copenhagen; Dinamarca Fil: Omar-Hmeadi, Muhmmad. Uppsala Universitet; Suecia Fil: Yang, Mingyu. Uppsala Universitet; Suecia Fil: Pihl, Celina. Universidad de Copenhagen; Dinamarca Fil: Bresson, Sophie Emilie. Universidad de Copenhagen; Dinamarca Fil: Khilji, Muhammad Saad. Universidad de Copenhagen; Dinamarca Fil: Klindt, Kristian. Universidad de Copenhagen; Dinamarca Fil: Cheta, Oana. Universidad de Copenhagen; Dinamarca Fil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Universidad de Copenhagen; Dinamarca Fil: Tyrberg, Björn. Astrazeneca. IMED Biotech Unit; Suecia Fil: Prats, Clara. Universidad de Copenhagen; Dinamarca Fil: Barg, Sebastian. Uppsala Universitet; Suecia Fil: Tengholm, Anders. Uppsala Universitet; Suecia Fil: Arvan, Peter. University of Michigan; Estados Unidos Fil: Mandrup-Poulsen, Thomas. Universidad de Copenhagen; Dinamarca Fil: Marzec, Michal Tomasz. Universidad de Copenhagen; Dinamarca
Published: 2019

27. Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue

Author: Suzhao Li, Rinke Stienstra, Jonathan Lucien Stahl, Tania Azam, Cees J. Tack, Douglas R. Seals, Isak W. Tengesdal, Benjamin J Swartzwelter, Giulio Cavalli, Janna A. van Diepen, Charles A. Dinarello, Thomas Mandrup-Poulsen, Viola Klück, Dov B. Ballak, Ballak, D. B., Li, S., Cavalli, G., Stahl, J. L., Tengesdal, I. W., Van Diepen, J. A., Kluck, V., Swartzwelter, B., Azam, T., Tack, C. J., Stienstra, R., Mandrup-Poulsen, T., Seals, D. R., and Dinarello, C. A.
Subjects: 0301 basic medicine, medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Adipose tissue, Biochemistry, Voeding, Metabolisme en Genomica, Mice, 0302 clinical medicine, Metabolic Syndrome, Glucose tolerance test, medicine.diagnostic_test, biology, Interleukin, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Recombinant Proteins, Metabolism and Genomics, Adipose Tissue, Metabolisme en Genomica, Cytokines, Nutrition, Metabolism and Genomics, Inflammation Mediators, medicine.medical_specialty, Mice, Transgenic, Carbohydrate metabolism, Diet, High-Fat, 03 medical and health sciences, Insulin resistance, All institutes and research themes of the Radboud University Medical Center, Voeding, Internal medicine, medicine, Animals, Humans, Life Science, Obesity, Molecular Biology, VLAG, Nutrition, Receptors, Interleukin-1 Type I, business.industry, Insulin, Cell Biology, Glucose Tolerance Test, medicine.disease, Insulin receptor, 030104 developmental biology, Endocrinology, Metabolism, biology.protein, Metabolic syndrome, Insulin Resistance, business, 030217 neurology & neurosurgery, Biomarkers, Interleukin-1
Abstract: Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control. Transgenic mice expressing human interleukin 37 (IL-37), an anti-inflammatory cytokine of the IL-1 family, are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 μg/mouse) during the last 2 weeks. Compared with vehicle only–treated mice, IL-37–treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets. The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1α in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37–treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pm IL-37 reduced spontaneous release of TNFα and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.
Published: 2018
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28. The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, low concentrations of interleukin 1 β

Author: Sophie Emilie Bresson, Kristian Klindt, Thomas Mandrup-Poulsen, Phillip Alexander Keller Andersen, Marie-Pierre Bousquet-Dubouch, Celina Pihl, Tenna Holgersen Bryde, Tina Dahlby, Dusan Zivkovic, Muhammad Saad Khilji, Michala Prause, Michal Marzec, Danielle Verstappen, Björn Tyrberg, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0301 basic medicine, Physiology, Molecular biology, [SDV]Life Sciences [q-bio], Interleukin-1beta, Pathology and Laboratory Medicine, Jurkat cells, Biochemistry, Autoantigens, Epitope, Major Histocompatibility Complex, Jurkat Cells, Mice, 0302 clinical medicine, Sequencing techniques, Endocrinology, Animal Cells, Immune Physiology, Insulin-Secreting Cells, Medicine and Health Sciences, Insulin, RNA-Seq, Immune Response, Proinsulin, Innate Immune System, Multidisciplinary, biology, Chemistry, RNA sequencing, Cell biology, Up-Regulation, Cytokines, Medicine, Cellular Types, Research Article, Proteasome Endopeptidase Complex, Endocrine Disorders, Protein subunit, Immune Cells, Science, Immunology, Primary Cell Culture, Major histocompatibility complex, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, MHC class I, Diabetes Mellitus, Animals, Humans, Inflammation, Diabetic Endocrinology, Histocompatibility Antigens Class I, Biology and Life Sciences, Proteins, Protein Complexes, Proteasomes, Cell Biology, Molecular Development, Hormones, Research and analysis methods, 030104 developmental biology, Molecular biology techniques, Diabetes Mellitus, Type 1, Proteasome, Cell culture, Immune System, Metabolic Disorders, Proteolysis, biology.protein, Clinical Immunology, Clinical Medicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes. We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by low concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.
Published: 2020
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29. Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in beta-Cells

Author: Michal Marzec, Marianne Böni-Schnetzler, Edward B. Holson, Morten Lundh, Christian Simon, Mattias S. Dahllöf, Thomas Mandrup-Poulsen, Marie Balslev Backe, Tina Dahlby, and Bridget K. Wagner
Subjects: 0301 basic medicine, insulin secretion, Histone methyltransferase activity, GLT, Apoptosis, 0302 clinical medicine, ENDOPLASMIC-RETICULUM STRESS, Insulin-Secreting Cells, HISTONE DEACETYLASES, Spectroscopy, Cells, Cultured, diabetes, Chemistry, histone methyltransferase, EZH2, General Medicine, Lipids, LONG-TERM EXPOSURE, Computer Science Applications, Cell biology, 030220 oncology & carcinogenesis, Histone methyltransferase, FATTY-ACIDS, ER stress, Signal Transduction, EXPRESSION, INHIBITION, NF&#954, macromolecular substances, INSULIN-SECRETION, Catalysis, Article, PROTEIN EZH2, Inorganic Chemistry, 03 medical and health sciences, Downregulation and upregulation, INS-1 CELLS, Humans, Enhancer of Zeste Homolog 2 Protein, Physical and Theoretical Chemistry, Enhancer, Molecular Biology, Transcription factor, Organic Chemistry, PANCREATIC-ISLETS, HDAC3, 030104 developmental biology, Glucose, Sweetening Agents, Unfolded protein response, histone deacetylases, NFκB
Abstract: Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced &beta, cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the &beta, cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. &beta, Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF&kappa, B) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NF&kappa, B pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.
Published: 2020
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30. The intermediate proteasome is constitutively expressed in pancreatic beta cells and upregulated by stimulatory, non-toxic concentrations of interleukin 1 β

Author: Danielle Verstappen, Dusan Zivkovic, Muhammad Saad Khilji, Celina Pihl, Michala Prause, Kristian Klindt, Thomas Mandrup-Poulsen, Sophie Emilie Bresson, Tina Dahlby, Marie-Pierre Bousquet-Dubouch, Michal Marzec, Björn Tyrberg, Nils Billestrup, and Tenna Holgersen Bryde
Subjects: biology, Chemistry, Protein subunit, Cell, Epitope, Cell biology, medicine.anatomical_structure, Proteasome, Downregulation and upregulation, MHC class I, biology.protein, medicine, Beta (finance), Proinsulin
Abstract: A central and still open question regarding the pathogenesis of autoimmune diseases, such as type 1 diabetes, concerns the processes that underlie the generation of MHC-presented autoantigenic epitopes that become targets of autoimmune attack. Proteasomal degradation is a key step in processing of proteins for MHC class I presentation. Different types of proteasomes can be expressed in cells dictating the repertoire of peptides presented by the MHC class I complex. Of particular interest for type 1 diabetes is the proteasomal configuration of pancreatic β cells, as this might facilitate autoantigen presentation by β cells and thereby their T-cell mediated destruction. Here we investigated whether so-called inducible subunits of the proteasome are constitutively expressed in β cells, regulated by inflammatory signals and participate in the formation of active intermediate or immuno-proteasomes.We show that inducible proteasomal subunits are constitutively expressed in human and rodent islets and an insulin-secreting cell-line. Moreover, the β5i subunit is incorporated into active intermediate proteasomes that are bound to 19S or 11S regulatory particles. Finally, inducible subunit expression along with increase in total proteasome activities are further upregulated by non-toxic concentrations of IL-1β stimulating proinsulin biosynthesis. These findings suggest that the β cell proteasomal repertoire is more diverse than assumed previously and may be highly responsive to a local inflammatory islet environment.
Published: 2019
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31. Urinary nucleic acid oxidation product levels show differential associations with pharmacological treatment in patients with type 2 diabetes

Author: Christian Torp-Pedersen, Laura Kofoed Kjær, Trine Henriksen, Torben Hansen, Oluf Pedersen, Cramer Christensen, Ivan Brandslund, Thomas A. Gerds, Henrik E. Poulsen, Thomas Mandrup-Poulsen, and Vanja Cejvanovic
Subjects: Adult, Male, 0301 basic medicine, endocrine system diseases, Urinary system, Administration, Oral, Type 2 diabetes, Pharmacology, medicine.disease_cause, Biochemistry, law.invention, 8-oxo-7,8-dihydroguanosine, 03 medical and health sciences, law, medicine, Humans, Hypoglycemic Agents, oxidative stress, In patient, Aged, Clinical pharmacology, 030102 biochemistry & molecular biology, business.industry, nutritional and metabolic diseases, RNA, DNA, General Medicine, DNA oxidation, Middle Aged, medicine.disease, 8-Oxo-7,8-dihydro-2-deoxyguanosine, 030104 developmental biology, Diabetes Mellitus, Type 2, Nucleic acid, Female, clinical pharmacology, type 2 diabetes, business, Oxidation-Reduction, Oxidative stress
Abstract: The relationship between RNA and DNA oxidation and pharmacological treatment has not been systematically investigated in patients with type 2 diabetes (T2D). We aimed to investigate the association between pharmacological treatments and levels of urinary markers of nucleic acid oxidation in T2D patients. Vejle Diabetes Biobank cohort data was nested into nationwide registry data. Multiple logistic regression was used to associate drug usage with risk of high (above median) RNA and DNA oxidation. Data from 2664 T2D patients (64% male, age range: 25-75) were included. Questionnaire-validated lipid lowering drug use was associated with low RNA oxidation (Odds ratio, OR 0.71, 95% CI: [0.59-0.87]). Insulin and non-specific antidiabetic drugs were associated with low DNA oxidation (insulin: OR 0.60, 95% CI [0.49-0.73]). Oral antidiabetics were associated with high DNA oxidation and RNA oxidation (OR 1.30, 95% CI [1.10-1.53] and OR 1.26, 95% CI [1.07-1.29]). Our findings indicate that diabetes-related drugs are associated with RNA and DNA oxidation and further studies are required to determine causality in T2D patients.
Published: 2019
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32. No direct effect of SGLT2 activity on glucagon secretion

Author: Nicolai J. Wewer Albrechtsen, Fiona M. Gribble, Nils Wierup, Seyed Mojtaba Ghiasi, Lihua Chen, Jens J. Holst, Alexander Aivazidis, Alice E. Adriaenssens, Frank Reimann, Cathrine Ørskov, Thomas Mandrup-Poulsen, Daniel B. Andersen, Björn Tyrberg, and Rune E. Kuhre
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, endocrine system, Insulin/metabolism, Somatostatin secretion, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Blotting, Western, Alpha (ethology), 030209 endocrinology & metabolism, Glucagon, Alpha cell, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Animals, Sodium-Glucose Transporter 1/genetics, Glucagon/metabolism, Rats, Wistar, Pancreas/metabolism, Delta cell, Somatostatin/metabolism, Chemistry, Insulin, Glucagon secretion, Immunohistochemistry, Rats, Sodium-Glucose Transporter 2/genetics, 030104 developmental biology, Endocrinology, Sodium/Glucose Cotransporter 2, Female, Islets of Langerhans/metabolism, Chickens
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 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
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33. Limited benefit of haemoglobin glycation index as risk factor for cardiovascular disease in type 2 diabetes patients

Author: Frank L.J. Visseren, G F N Berkelmans, Y. van der Graaf, Jan Westerink, Thomas Mandrup-Poulsen, and H.B. Østergaard
Subjects: Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus type 2, Endocrinology, Haemoglobin glycation index, Risk Factors, Internal medicine, Diabetes mellitus, Glycaemic control, medicine, Internal Medicine, Humans, HbA(1c), Myocardial infarction, HbA, Risk factor, Stroke, Aged, Glycated Hemoglobin, business.industry, HGI, Hazard ratio, Type 2 Diabetes Mellitus, General Medicine, Middle Aged, medicine.disease, Cardiovascular disease, Diabetes and Metabolism, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Cohort, Cardiology, Female, business, Diabetic Angiopathies
Abstract: Background The haemoglobin glycation index (HGI) has been proposed as a marker of interindividual differences in haemoglobin glycosylation. Previous studies have shown a relationship between high HGI and risk of cardiovascular disease (CVD) in patients with diabetes. However, no studies have investigated the role of previous CVD in this association. Methods The study cohort comprised patients with type 2 diabetes mellitus (T2DM; n =1910) included in the Second Manifestations of Arterial Disease (SMART) study. The relationship between either HGI or HbA 1c and a composite of cardiovascular events as the primary outcome, and mortality, cardiovascular mortality, myocardial infarction and stroke as secondary outcomes, was investigated using Cox proportional-hazards models. Similar analyses were performed after stratification according to previous CVD. Results A 1-unit higher HGI was associated with a 29% greater risk of a composite of cardiovascular events (HR: 1.29, 95% CI: 1.06–1.57) in patients without previous CVD, whereas no such relationship was seen in patients with previous CVD (HR: 0.96, 95% CI: 0.86–1.08). The direction and magnitude of the hazard ratios (HRs) of HGI and HbA 1c in relation to outcomes were similar. Additional adjustment for HbA 1c in the association between HGI and outcomes lowered the HRs. Conclusion Similar to HbA 1c , higher HGI is related to higher risk of cardiovascular events in patients with T2DM without CVD. As HbA 1c has proved to be a comparable risk factor, and obtaining and interpreting the HGI is complicated, any additional benefit of applying the HGI in clinical settings is likely to be limited.
Published: 2019

34. The connexin 43 regulator Rotigaptide reduces cytokine-induced cell death in human islets

Author: Thomas Mandrup-Poulsen, Dan Ploug Christensen, Seyed Mojtaba Ghiasi, and Jakob Bondo Hansen
Subjects: Programmed cell death, Peptide analog, Chemistry, medicine.medical_treatment, Insulin, Connexin, Cell biology, chemistry.chemical_compound, Cytokine, Mechanism of action, Apoptosis, medicine, cardiovascular system, Rotigaptide, medicine.symptom
Abstract: AbstarctBackgroundIntercellular communication mediated by cationic fluxes through the Connexin-family of gap-junctions regulates glucose-stimulated insulin-secretion and beta-cell defense against inflammatory stress. Rotigaptide (RG, ZP123) is a peptide analog that increases intercellular conductance in cardiac muscle-cells by prevention of dephosphorylation and thereby uncoupling of Connexin-43 (Cx43), possibly via action on unidentified protein phosphatases. For this reason, it is being studied in human arrhythmias. It is unknown if RG protects beta-cell function and viability against inflammatory or metabolic stress, a question of considerable translational interest for the treatment of beta-cell failure in diabetes.MethodsApoptosis was measured in human islets known to express Cx43, treated with RG or the control peptide ZP119 and exposed to glucolipotoxicity or IL-1b + IFNg. INS-1 cells shown to lack Cx43 were used to verify if RG protected human islet-cells via Cx43-coupling. To study mechanisms of action of Cx43-independent effects of RG, NO, IkBa degradation, mitochondrial activity, ROS and insulin mRNA levels were determined.ResultsRG reduced cytokine-induced apoptosis ~40% in human islets. In Cx43-deficient INS-1 cells this protective effect was markedly blunted as expected, but unexpectedly RG still modestly reduced apoptosis, and improved mitochondrial function, insulin-2 gene levels and accumulated insulin release. RG reduced NO production in Cx43-deficient INS-1 cells associated with reduced iNOS-expression, suggesting that RG blunts cytokine-induced NF-kB signaling in insulin-producing cells in a Cx43-independent manner.ConclusionRG reduces cytokine-induced cell-death in human islets. The protective action in Cx43-deficient INS-1 cells suggests a novel inhibitory mechanism of action of RG on NF-kB signaling.
Published: 2018
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35. Iron Status and Gestational Diabetes—A Meta-Analysis

Author: Thomas Mandrup-Poulsen, Yanxin Wu, Yachana Kataria, Peter de Hemmer Horskjær, and Christina Ellervik
Subjects: Iron Overload, endocrine system diseases, Iron, Physiology, Nutritional Status, 030209 endocrinology & metabolism, Transferrin receptor, Review, Sensitivity and Specificity, 03 medical and health sciences, Hemoglobins, iron, 0302 clinical medicine, Pregnancy, Receptors, Transferrin, Medicine, Humans, transferrin, 030212 general & internal medicine, chemistry.chemical_classification, Nutrition and Dietetics, biology, business.industry, Transferrin saturation, ferritin, Transferrin, Odds ratio, medicine.disease, Ferritin, Gestational diabetes, Diabetes, Gestational, Observational Studies as Topic, chemistry, Dietary Supplements, Ferritins, biology.protein, Female, pregnancy, Hemoglobin, gestational diabetes, business, Biomarkers, Iron, Dietary, Food Science
Abstract: A meta-analysis of the association of iron overload with gestational diabetes mellitus (GDM) may inform the health debate. We performed a meta-analysis investigating the association of iron biomarkers and dietary iron exposure with GDM. We identified 33 eligible studies (N = 44,110) published in 2001-2017. The standardized mean differences (SMD) in women who had GDM compared to pregnant women without were 0.25 mu g/dL (95% CI: 0.001-0.50) for iron, 1.54 ng/mL (0.56-2.53) for ferritin, 1.05% (0.02 to 2.08) for transferrin saturation, and 0.81 g/dL (0.40-1.22) for hemoglobin. Adjusted odds ratio for GDM were 1.58 (95% CI: 1.20-2.08) for ferritin, 1.30 (1.01-1.67) for hemoglobin, and 1.48 (1.29-1.69) for dietary heme intake. We did not find any differences in TIBC or transferrin concentration in women with and without GDM. We also did not find any association of increased transferrin receptor or increased intake of total dietary iron, non-heme iron or supplemental iron, with increased odds ratios for GDM. Considerable heterogeneity was present among the studies (0-99%), but no evidence of publication bias. Accumulating evidence suggests that circulating and dietary iron biomarkers among pregnant women are associated with GDM, but the results should be interpreted with caution due to the high heterogeneity of analyses. Randomized trials investigating the benefits of iron reduction in women at high risk for GDM are warranted.
Published: 2018
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36. Acute administration of interleukin-6 does not increase secretion of glucagon-like peptide-1 in mice

Author: Carolyn F. Deacon, Sara J. Lind, Bolette Hartmann, Rune E. Kuhre, Nicolai J. Wewer Albrechtsen, Berit Svendsen, Tina Dahlby, Emilie Balk-Møller, Thomas Mandrup-Poulsen, C. Christiansen, and Jens J. Holst
Subjects: 0301 basic medicine, medicine.medical_specialty, insulin, endocrine system, Physiology, medicine.medical_treatment, 030209 endocrinology & metabolism, Carbohydrate metabolism, Glucagon, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Glucagon-Like Peptide 1, Physiology (medical), Internal medicine, Insulin Secretion, Intestine, Small, medicine, Metabolism and Regulation, Animals, Secretion, glucose, Pancreas, Cellular and Molecular Endocrinology, Original Research, Chemistry, Interleukin-6, Pancreatic islets, Insulin, digestive, oral, and skin physiology, Glucagon secretion, Bombesin, IL‐6, Glucagon-like peptide-1, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Female, GLP‐1, hormones, hormone substitutes, and hormone antagonists
Abstract: Interleukin 6 (IL‐6) is a cytokine secreted from skeletal muscle in response to exercise which, based on animal and cell studies, has been suggested to contribute to glucose metabolism by increasing secretion of the incretin hormone glucagon‐like peptide‐1 (GLP‐1) and affecting secretion of insulin and glucagon from the pancreatic islets. We investigated the effect of IL‐6 on GLP‐1 secretion in GLP‐1 producing cells (GLUTag) and using the perfused mouse small intestine (harboring GLP‐1 producing cells). Furthermore, the direct effect of IL‐6 on insulin and glucagon secretion was studied using isolated perfused mouse pancreas. Incubating GLUTag cells with 1000 ng/mL of IL‐6 for 2 h did not significantly increase secretion of GLP‐1 whereas 10 mmol/L glucose (positive control) did. Similarly, IL‐6 (100 ng/mL) had no effect on GLP‐1 secretion from perfused mouse small intestine whereas bombesin (positive control) increased secretion. Finally, administering IL‐6 (100 ng/mL) to perfused mouse pancreases did not significantly increase insulin or glucagon secretion regardless of perfusate glucose levels (3.5 vs. 12 mmol/L glucose). Acute effects of IL‐6 therefore do not seem to include a stimulatory effect on GLP‐1 secretion in mice.
Published: 2018
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37. Probing of biochemical pathways in clonal pancreatic β–cells by quantitative dDNP of metabolite extracts

Author: Ronja Maja Malinowski, Ghiasi, Seyed M., Thomas Mandrup-Poulsen, Pernille Rose Jensen, and Jan Henrik Ardenkjær-Larsen
Published: 2017

38. A guiding map for inflammation

Author: Luke A. J. O'Neill, Peter Pickkers, Tom van der Poll, Paul M. Ridker, David A. Schwartz, Michel Chonchol, Mihai G. Netea, Frank L. van de Veerdonk, Charles A. Dinarello, Jos W. M. van der Meer, Frances R. Balkwill, Thomas Mandrup-Poulsen, Mark S. Gresnigt, Britta Siegmund, Leo A. B. Joosten, Joost Schalkwijk, Kristen L. Nowak, Clifford J. Steer, Fabio Cominelli, Kingston H. G. Mills, Daniel L. Kastner, Peter Libby, Marc Y. Donath, Evangelos J. Giamarellos-Bourboulis, Martin Korte, Douglas T. Golenbock, Michael T. Heneka, Eicke Latz, Hal M. Hoffman, Alberto Mantovani, Herbert Tilg, Richard S. Hotchkiss, AII - Inflammatory diseases, Infectious diseases, Center of Experimental and Molecular Medicine, and Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Subjects: 0301 basic medicine, Immunology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Inflammation, Cellular Immunology, Bioinformatics, Communicable Diseases, Article, Biological pathway, immunology [Immunity, Cellular], 03 medical and health sciences, immunology [Inflammation], Immunity, medicine, Immunology and Allergy, Humans, ddc:610, Immunity, Cellular, business.industry, immunology [Communicable Diseases], 3. Good health, Immunity, Humoral, 030104 developmental biology, Chronic disease, immunology [Immunity, Humoral], Acute Disease, Chronic Disease, medicine.symptom, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract: Contains fulltext : 177132.pdf (Publisher’s version ) (Closed access) Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.
Published: 2017
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39. Proinflammatory Cytokines Activate the Intrinsic Apoptotic Pathway in β-Cells

Author: Reid Aikin, Thomas Mandrup-Poulsen, Lykke Blaabjerg, Steven Paraskevas, Lawrence Rosenberg, Lars G. Grunnet, Dusica Maysinger, Joachim Størling, Nils Billestrup, and Morten Tonnesen
Subjects: Programmed cell death, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Interleukin-1beta, Apoptosis, Receptors, Tumor Necrosis Factor, Proinflammatory cytokine, Dephosphorylation, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Internal medicine, Commentaries, Insulin-Secreting Cells, Internal Medicine, medicine, Cadaver, Animals, Humans, Rats, Wistar, 030304 developmental biology, Inflammation, 0303 health sciences, biology, Cell Death, Tumor Necrosis Factor-alpha, Cytochrome c, Caspase 9, Tissue Donors, Cell biology, Rats, Cytokine, Endocrinology, Diabetes Mellitus, Type 1, Islet Studies, Proto-Oncogene Proteins c-bcl-2, biology.protein, Commentary, DNA fragmentation, Cytokines, Tumor necrosis factor alpha, Original Article, 030217 neurology & neurosurgery
Abstract: OBJECTIVE Proinflammatory cytokines are cytotoxic to β-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced β-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in β-cells. RESEARCH DESIGN AND METHODS Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1β, interferon-γ, and/or tumor necrosis factor-α). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively. RESULTS We found that proinflammatory cytokines induced calcineurin-dependent dephosphorylation of Bad Ser136, mitochondrial stress, cytochrome c release, activation of caspase-9 and -3, and DNA fragmentation. Inhibition of Bad Ser136 dephosphorylation or Bax was found to inhibit cytokine-induced intrinsic proapoptotic signaling. CONCLUSIONS Our findings demonstrate that the intrinsic mitochondrial apoptotic pathway contributes significantly to cytokine-induced β-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis.
Published: 2009

40. Mixed-Meal Tolerance Test Versus Glucagon Stimulation Test for the Assessment of β-Cell Function in Therapeutic Trials in Type 1 Diabetes

Author: Hubert Kolb, Johnny Ludvigsson, Tadej Battelino, Thomas Mandrup-Poulsen, Paula McGee, John M. Lachin, Paolo Pozzilli, Carla J. Greenbaum, and Burkhard Haastert
Subjects: Research design, Adult, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Gastroenterology, Glucagon, Sensitivity and Specificity, chemistry.chemical_compound, Random Allocation, Internal medicine, Diabetes mellitus, Insulin-Secreting Cells, Diet, Diabetic, Internal Medicine, medicine, Humans, Age of Onset, Adverse effect, Child, Advanced and Specialized Nursing, Type 1 diabetes, Clinical Trials as Topic, C-Peptide, C-peptide, business.industry, Racial Groups, Clinical Care/Education/Nutrition/Psychosocial Research, Fasting, medicine.disease, Clinical trial, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Tolerability, business, Biomarkers
Abstract: OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS—In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS—Among individuals with up to 4 years’ duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R2 = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. CONCLUSIONS—The MMTT is preferred for the assessment of β-cell function in therapeutic trials in type 1 diabetes.
Published: 2008

41. A Systematic Comparison of Purification and Normalization Protocols for Quantitative MicroRNA Expressional Profiling in Insulin-Producing Cells

Author: Morten Lundh, Claus Heiner Bang-Berthelsen, Jonathan Lucien Stahl, Flemming Pociot, Anna L. Vestergaard, Guy Wayne Novotny, Thomas Mandrup-Poulsen, Emil M.H. Pallesen, and Maaike Blankestijn
Subjects: 0301 basic medicine, Normalization (statistics), RNA Stability, purification, Microarray, Computational biology, Biology, Real-Time Polymerase Chain Reaction, Catalysis, lcsh:Chemistry, Inorganic Chemistry, Transcriptome, 03 medical and health sciences, Insulin-Secreting Cells, microRNA, Animals, pancreas, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Regulation of gene expression, Genetics, Gene Expression Profiling, Communication, Organic Chemistry, Reproducibility of Results, General Medicine, quantification, Rats, Computer Science Applications, Gene expression profiling, MicroRNAs, qPCR, normalization, 030104 developmental biology, Real-time polymerase chain reaction, Gene Expression Regulation, lcsh:Biology (General), lcsh:QD1-999, method
Abstract: As microRNAs (miRs) are gaining increasing attention as key regulators of cellular processes, expressional quantification is widely applied. However, in the processing of relatively quantified data, the importance of testing the stability of several reference mRNAs and/or miRs and choosing among these for normalization is often overlooked, potentially leading to biased results. Here, we have optimized the purification of miR-enriched total RNA from pancreatic insulin-producing INS-1 cells. Additionally, we optimized and analyzed miR expression by a qPCR-based microarray and by specific qPCR and tested the stability of candidate reference mRNAs and miRs. Hence, this study gives a widely applicable example on how to easily and systematically test and decide how to normalize miR quantification. We suggest that caution in the interpretation of miR quantification studies that do not comprise stability analysis should be exerted.
Published: 2016
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42. BMI is an important driver of β-cell loss in type 1 diabetes upon diagnosis in 10 to 18-year-old children

Author: Chantal Mathieu, Werner A. Scherbaum, Johnny Ludvigsson, N. Hosszufalusi, Maria Nordwall, Nicholas J. Wareham, D. Mauricio, A. Barker, Thomas Mandrup-Poulsen, Angelo Lauria, B. Van der Schueren, F. K. Gorus, Ilse Weets, Richard David Leslie, Paolo Pozzilli, Nanette C. Schloot, Metajuridica, Fundamental rights centre, Pathology/molecular and cellular medicine, and Diabetes Pathology & Therapy
Subjects: Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, MEDLINE, Endocrinology, Insulin resistance, Diabetes mellitus, Internal medicine, Insulin-Secreting Cells, medicine, Humans, Longitudinal Studies, Child, Body mass index, cell count, Type 1 diabetes, business.industry, biomarkers, General Medicine, medicine.disease, Cell loss, Diabetes Mellitus, Type 1, Multicenter study, Cohort studies, Female, C-peptide, business, Cohort study
Abstract: ObjectiveBody weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis.DesignMulticentre longitudinal study carried out at diagnosis and up to 1-year follow-up.MethodsData on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (n=126; >5 years n=295; >10 years n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c.ResultsIn individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10–18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m2 higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002).ConclusionsThese observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10–18 years. This should be considered in studies of β-cell function in type 1 diabetes.
Published: 2015

43. Helsinki alert of biodiversity and health

Author: Ilkka Hanski, Tari Haahtela, Charlotte Ling, Patrice D. Cani, Martti Färkkilä, Martin J. Blaser, Erika von Mutius, Maria Saarela, Markku Koskenvuo, Juha Kere, Göran Pershagen, Bruce Beutler, Mikael Knip, Marc Veldhoen, Harald Renz, Outi Vaarala, Johan G. Eriksson, Maria C. Jenmalm, Graham A. W. Rook, Thomas Mandrup-Poulsen, Mika J. Mäkelä, John Bienenstock, Leena von Hertzen, Willem M. de Vos, Tiina Paunio, and Kimmo Kontula
Subjects: Gerontology, medicine.medical_specialty, Medicinska och farmaceutiska grundvetenskaper, Biodiversity, Sedentary lifestyle, Context (language use), Gut flora, Behavioural disorders, Adaptive Immunity, Environment, Microbiology, chronic inflammatory disease, microbiota, sedentary lifestyle, Western diet, 03 medical and health sciences, 0302 clinical medicine, Microbiologie, 11. Sustainability, Medicine, Humans, Urban living, 030304 developmental biology, VLAG, Inflammation, 0303 health sciences, biology, business.industry, Public health, Microbiota, Urbanization, Human microbiome, Chronic inflammatory disease, General Medicine, Basic Medicine, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, 3. Good health, 030228 respiratory system, 13. Climate action, Diet, Western, Chronic Disease, bacteria, Sedentary Behavior, business
Abstract: Urban living in built environments, combined with the use of processed water and food, may not provide the microbial stimulation necessary for a balanced development of immune function. Many chronic inflammatory disorders, including allergic, autoimmune, metabolic, and even some behavioural disorders, are linked to alteration in the human commensal microbiota. Sedentary lifestyle is associated with reduced exposure to a broad spectrum of environmental micro-organisms and surplus energy balance, both risk factors of chronic inflammatory disorders. According to the Biodiversity Hypothesis, an environment with diverse macrobiota and microbiota modifies and enriches the human microbiota, which in turn is crucial in the development and maintenance of appropriate immune function. These issues were discussed in the symposium Chronic Inflammation, Lifestyle and Environment , held in Helsinki, 20 - 22 August 2014, under the sponsorship of the Yrjo Jahnsson Foundation. This paper briefly outlines the recent findings in the context of the environment, lifestyle, and health; discusses the forces that undermine immune tolerance in urban environments; and highlights the possibilities to restore broken immune tolerance among urban dwellers, summarizing the main messages in four statements and calling for actions to combat major public health threats.
Published: 2015

44. Altering β-cell number through stable alteration of miR-21 and miR-34a expression

Author: Guy Wayne Novotny, Dan Ploug Christensen, Lars Groth Grunnet, Thomas Mandrup-Poulsen, and Marie Balslev Backe
Subjects: Programmed cell death, Endocrinology, Diabetes and Metabolism, Cell number, Inflammation, Apoptosis, Cell Count, Biology, Nitric Oxide, Transfection, Proinflammatory cytokine, Endocrinology, Diabetes mellitus, Insulin-Secreting Cells, microRNA, medicine, Animals, Cells, Cultured, Cell Proliferation, medicine.disease, Cell biology, Rats, MicroRNAs, Gene Expression Regulation, Cell culture, Gene Knockdown Techniques, Cytokines, medicine.symptom, Research Paper
Abstract: An insufficient functional β-cell mass is a prerequisite to develop diabetes. Thus, means to protect or restore β-cell mass are important goals in diabetes research. Inflammation and proinflammatory cytokines play important roles in β-cell dysfunction and death, and recent data show that 2 miRNAs, miR-21 and miR-34a, may be involved in mediating cytokine-induced β-cell dysfunction. Therefore, manipulation of miR-21 and miR-34a levels may potentially be beneficial to β cells. To study the effect of long-term alterations of miR-21 or miR-34a levels upon net β-cell number, we stably overexpressed miR-21 and knocked down miR-34a, and investigated essential cellular processes. miRNA expression was manipulated using Lentiviral transduction of the β-cell line INS-1. Stable cell lines were generated, and cell death, NO synthesis, proliferation, and total cell number were monitored in the absence or presence of cytokines.Overexpression of miR-21 decreased net β-cell number in the absence of cytokines, and increased apoptosis and NO synthesis in the absence and presence of cytokines. Proliferation was increased upon miR-21 overexpression. Knockdown of miR-34a increased net β-cell number in the absence of cytokines, and reduced apoptosis and NO synthesis in the absence and presence of cytokines. Proliferation was decreased upon miR-34a knockdown.As overexpression of miR-21 increased proliferation, but also apoptosis and NO synthesis, the potential of miR-21 as a therapeutic agent to increase β-cell survival is doubtful. Knockdown of miR-34a slightly decreased proliferation, but as apoptosis and NO synthesis were highly reduced, miR-34a may be further investigated as a therapeutic target to reduce β-cell death and dysfunction.
Published: 2014

45. Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection

Author: Nicolai Juul Birkbak, Morten Lundh, Christopher T. Workman, Steven Paraskevas, Susanne Mandrup, Søren Fisker Schmidt, Reid Aikin, Lykke Blaabjerg, Lars Groth Grunnet, Daniel Noesgaard, Dan Ploug Christensen, Paolo Mascagni, Gianluca Fossati, Conny Gysemans, Chantal Mathieu, Thomas Mandrup-Poulsen, Nils Billestrup, Mattias S. Dahllöf, Valmen Monzani, Lorenzo Piemonti, Charles A. Dinarello, Pathology/molecular and cellular medicine, Christensen, Dan Ploug, Gysemans, Conny, Lundh, Morten, Dahllöf, Mattias Salling, Noesgaard, Daniel, Schmidt, Søren Fisker, Mandrup, Susanne, Birkbak, Nikolai, Workman, Christopher T, Piemonti, Lorenzo, Blaabjerg, Lykke, Monzani, Valmen, Fossati, Gianluca, Mascagni, Paolo, Paraskevas, Steven, Aikin, Reid A, Billestrup, Nil, Grunnet, Lars Groth, Dinarello, Charles A, Mathieu, Chantal, and Mandrup Poulsen, Thomas
Subjects: Time Factors, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Nod, Hydroxamic Acids, Hydroxamic Acid, Epigenesis, Genetic, chemistry.chemical_compound, Mice, Mice, Inbred NOD, Insulin-Secreting Cells, Histone Deacetylase Inhibitor, Phosphorylation, HYDROXAMIC ACIDS, Promoter Regions, Genetic, NOD mice, Vorinostat, Multidisciplinary, phosphorylation, Research Support, Non-U.S. Gov't, autoimmunity, FOXP3, Biological Sciences, Chromatin, Cytokines, Female, epigenetic, medicine.drug, Human, Protein Binding, mice, GATA3 Transcription Factor, Biology, histone deacetylase inhibitors, Histone Deacetylases, Proinflammatory cytokine, Cell Line, RATS, Downregulation and upregulation, Research Support, N.I.H., Extramural, Histone Deacetylase, medicine, Journal Article, Animals, Humans, Givinostat, Cytokine, Inflammation, posttranslational modification, Animal, Rats, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, Disease Models, Animal, Diabetes Mellitus, Type 1, chemistry, inflammation, Insulin-Secreting Cell, Immunology, Cancer research, Rat, chromatin, Histone deacetylase, Protein Processing, Post-Translational, histone deacetylases
Abstract: Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes. ispartof: Proceedings of the National Academy of Sciences of the United States of America vol:111 issue:3 pages:1055-9 ispartof: location:United States status: published
Published: 2014
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46. The lysine deacetylase inhibitor givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing

Author: Lars Groth Grunnet, Mattias S. Dahllöf, Thomas Mandrup-Poulsen, Paolo Mascagni, Charles A. Dinarello, Morten Lundh, and Dan Ploug Christensen
Subjects: Chemokine, Transcription, Genetic, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Interleukin-1beta, Inflammation, Real-Time Polymerase Chain Reaction, Proinflammatory cytokine, chemistry.chemical_compound, Interferon-gamma, Endocrinology, Insulin-Secreting Cells, medicine, Diabetes Mellitus, CXCL10, Animals, Humans, Interferon gamma, RNA, Messenger, Rats, Wistar, Givinostat, biology, Molecular biology, Cell biology, Rats, Chemokine CXCL10, Histone Deacetylase Inhibitors, Cytokine, chemistry, Apoptosis, biology.protein, Carbamates, medicine.symptom, medicine.drug, Research Paper
Abstract: Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1β, IFNγ, and CXCL10, contribute to β-cell failure and loss in DM via IL-1R, IFNγR, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1β secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and β-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts β-cell toxicity induced by the combination of IL-1 and IFNγ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing β-cell expression of the β-cell toxic inflammatory molecules IL-1β and CXCL10 induced by single cytokines. Results: CXCL10 did not induce transcription of IL-1β mRNA. IL-1β induced β-cell IL-1β mRNA and both IL-1β and IFNγ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1β-induced IL-1β mRNA expression in INS-1 and rat islets and IL-1β processing in INS-1 cells. Givinostat also reduced IFNγ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1β induced Cxcl10 transcription was unaffected in both. Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1β, IFNγ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1β processing by western blotting of cell lysates. Conclusion/Interpretation: Inhibition of β-cell IL-1β expression and processing and Cxcl10 transcription contributes to the β-cell protective actions of KDACi. In vitro β-cell destructive effects of CXCL10 are not mediated via IL-1β transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.
Published: 2012

47. Proliferation of sorted human and rat beta cells

Author: Philippe A. Halban, Nils Billestrup, Thierry Berney, Domenico Bosco, Thomas Mandrup-Poulsen, Julie Kerr-Conte, Géraldine Parnaud, François Pattou, Marc Y. Donath, and C. Bruun
Subjects: Adult, medicine.medical_specialty, Insulin-Secreting Cells/cytology/physiology, Adolescent, Endocrinology, Diabetes and Metabolism, Cellular differentiation, medicine.medical_treatment, Population, Cell Culture Techniques, Islets of Langerhans Transplantation, Cell Culture Techniques/methods, Cell Separation, Biology, Extracellular matrix, Diabetes Mellitus/therapy, Islets of Langerhans Transplantation/methods, Species Specificity, Internal medicine, Insulin-Secreting Cells, Internal Medicine, medicine, Diabetes Mellitus, Animals, Humans, ddc:576.5, education, Beta (finance), education.field_of_study, ddc:617, Growth factor, Pancreatic islets, Cell Differentiation, Middle Aged, Flow Cytometry, Flow Cytometry/methods, In vitro, Cell biology, Extracellular Matrix, Rats, Endocrinology, medicine.anatomical_structure, Beta cell
Abstract: AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.
Published: 2008

48. 40(th) EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author: S. Artigas, A V Dreval, Mark I. McCarthy, C Watson, Peter H. Bennett, M Quint, Y Ikeda, E Alpert, F Schiele, H Sekihara, Erik Gylfe, P Lowe, J Kuhlmann, Alain Golay, V Longo, Shahidul Alam Khan Akm., L G Mantovani, M Zawodniak-Szalapska, G Winkler, T Harrity, L Virág, U Johne, Kuo S-W., Linda C Tapsell, J Rodriguez, Michel Komajda, K Kankova, Carole A. Cull, M Sporna, E Estilles, U Ribel, M C Spruce, E Buzzigoli, T Prazak, J K McLaughlin, M K Lingohr, M Lim, F Calara, A Siebenhofer, G Meregalli, Roberto Anichini, A D Baron, R Kurashvili, P C Butler, G I Fantus, T. E. De Gooyer, Park Y-M., R. Walther, S Heinrich, Agnieszka Zawiejska, S Mukherjee, Nikolaos Papanas, G Wong, Ian D. Caterson, David M. Maahs, Shuichi Kaneko, Alexandra E. Butler, Francisco Javier Ampudia-Blasco, O N Kong, Attali J-R., C A Hedman, K Oshinyemi, Nicolle Müller, I C Cranston, N Okumus, M V Vlaiculescu, Balasubramanian Ravikumar, W W Cheatham, K Mukasa, K B Biswas, Annunziata Lapolla, Phil McEwan, G Mader, Gilles Chassot, Dragi Anevski, Werner A. Scherbaum, M Donath, C Hesselmann, R A Gandhi, David E. Moller, Ezio Bonifacio, C Garcia, V Ifandi, P Hornnes, Nieuwenhoven Fav., C Puech, S Pérez-Del-Pulgar, Kim S-R., G Hines, C Rubio Terrés, Michael Gaster, N. Hosszufalusi, A Scholze, Andrew A. Young, Stavros Liatis, F Hariri, S Tan, Paul Valensi, Allan E. Karlsen, J Kim, E. Moberg, J Kaiser, L Berman, G Nelson, A Altkrüger, P Kothare, D B Cook, S Doran, G. van Dijk, Shahnaz Shahinfar, Kim C-S., P Stahl, M Manousaki, S Sigrist, S K Lim, M. P. Stern, A Guberti, C Rezzani, J McKenney, Karl Thomaseth, Sofia Carlsson, M Julia, R Brillante, I Rubesova, T Darkow, E Matsumoto, Wendy M. Macfarlane, M Di Martino, G Bardini, Rossella Menghini, D Duhot, E Farcasiu, Annalisa Natalicchio, I Lindner, J Buvat, Christian L. Brand, Harry Dorchy, Iwona Pietrzak, Z T Luo, P Home, M Ekelund, Jesper Gromada, Kristine Færch, F Piarulli, H Kim, R Mentel, Zsuzsanna K. Zsengellér, Dullaart Rpf., Anton Luger, Thomas A. Pearson, V Manicardi, P Rösen, Feng Y-M., R Morganti, Lars Hansen, Demuth H-U., Haruo Kasai, A Shostak, Rudi Steffensen, G Taylor, Markolf Hanefeld, C Santini, E Hamaguchi, Roberto Miccoli, F Storms, M Cooper, Y Lee, Allison E. Aiello, P Smith, T Suehiro, K Treece, M Waluś, Timothy A Welborn, Simone Baltrusch, E Kontela, S Chai, J Crean, H Yokoyama, Johan G. Eriksson, Rafael Hernández Hernández, J Rodríguez-Saldaña, M P Tornero, G Formoso, D. Lovell, E Bingham, A Mylonakis, M Manteghetti, D Fedele, Antonio Martín-Duce, Ralph A. DeFronzo, D Salcedo, Kurt Højlund, Antonio Petrone, Sheu Whh., C Gutierrez, Flavia Pricci, S Kurita, Z G Abbas, M M Benedetti, Philippe A. Halban, Daniel J. Cox, O Ljungkvist, Justine Davies, J Palsgaard, Lars Sjöström, E Bosi, L Janin-Manificat, W. F. Kelly, M. Fernandez, E Colak, O V Mulyarchik, B Kronshage, F Lang, M Erfurth, Takashi Kadowaki, N Jendrike, U Walter, J Wishart, Y. Neye, D Kim, N Furuhashi, M Barsotti, D Florow, L Ke, L Borgquist, N C Jackson, Ffolliott M. Fisher, V Baskar, K Yoshioka, Bryan A. Wolf, G Chabrier, R Skoumal, Livio Luzi, H Kose, I Pharisien, B. Klein, H Winiarska, M C Johnson, L Griffiths, Nonna Kravchun, C Combe, Baptist Gallwitz, J Zdychova, L Skorda, Jorma Ilonen, W Gao, I N Steen, A Terrinoni, P D Ambery, W Kern, C M Kusminski, Cho M-H., Paolo Pozzilli, Louise G. Grunnet, E Schönle, David R Matthews, Robert W. Taylor, Y Cohen, Kim H-S., M P Eccles, N B Tutuncu, D McDowell, Richard M. Bergenstal, K Takamatsu, T Steiner, Jaan Palgi, Valdemar Grill, N Niculescu, G Federici, S Lehto, P. M. McKeigue, M Barone, Michael E. Trautmann, S Smirnov, J Mannion, M Eto, C Rousseau, M Conti, C S Ernest, Antonio Ceriello, D H Schweitzer, Jung E-D., Andreas Festa, Avijit Lahiri, A Shepelkevich, A Murro, A Kollmann, Jonathan R.S. Arch, R Landgraf, Son H-Y., I Engelsberger, E Agardh, S Rodríguez-Mulero, P J Kraml, K Lee, D. F. Du Toit, E Kim, G Fadini, Williams Ajk., Philip Home, M B Antcieferov, C Perlemoine, D Perrea, Song X-L., D Ruggieri, Krister Bokvist, Heidi Sørensen, Bilbao, G Yoshino, J P Taylor, Shen H-M., S M Furier, R Urquhart, J Wohlgelernter, Jianping Weng, T. Baba, Q Hong, C Silva, Castaigne J-P., M Felaco, X X Zhang, M Jaroň, Milla Rosengård-Bärlund, J G Papp, Toshio Miyata, Lervang H-H., Park M-K., I Kinalska, A Long, Oomen Phn., N Kogawa, Ippolita Patrizia Patera, S. Karadeniz, Dinesh Selvarajah, D S Chung, A Wensaas, Richard Imrich, M Recasens, J Ruxer, O Buchea, E Wilpart, S P Stepanenko, Le Ttd., H Ohgawara, Mariaconsuelo Valentini, A Mondok, M Peltonen, Marianne O. Larsen, K Chatzianagnostou, Agneta Ståhle, A L Ferrari, L Bordier, F Maingrette, A Matsuda, G Vukomanovic, Jakob D. Wikstrom, T Yamakita, E Gorostiaga, J Jin, B Gopalan, Heinz Drexel, S Hewitt, Rury R. Holman, C Dieterle, T L Ruchti, N Asatiani, M Sidira, A Iezzi, A J Sommerfield, D Châtenet, M L Olsen, R Bergemann, C Koehler, T L Kuraeva, B Balas, Christian Berne, E Santos-Mazo, G Smith, A Siejka, R Kožnarová, A Mattina, S Sheikh, A Adomeit, M Rasmussen, J. Fagerudd, N Busciantella Ricci, Nuria Vilarrasa, E Hammar, T L Thoms, L Aydın, Ron G. Rosenfeld, A Nikolajuk, R Gos, C L Morgan, H L Yu, D Dheelchand, S Ramrath, N Boudriga, Jerome I. Rotter, C Jahannault, W M Weston, Folke Lindgärde, M Hertlova, D Knight, A Monroy-Mayorga, E Pardini, A Chamson-Reig, B Franke, Janie McCluskey, Joseph Bryan, C Nikolopoulou, Christie M. Ballantyne, Fausto Santeusanio, L Pegoraro, M Lee, A Klimenko, S Jaiveer, K. Pettersson-Fernholm, Michael A. Nauck, A Ekbom-Schnell, G Deferrari, Riccardo Schiaffini, S. Pampanelli, Khan Aka., David Hopkins, Maija Wessman, M Kamarinos, Noh J-H., O Ebisui, K McCarroll, Jeppe Sturis, Peter Nowotny, N Gorbenko, Åke Sjöholm, David G. Maggs, A E Halseth, B Cresci, A A Ortiz-Gress, A Korakovouni, O Matejkova, C E Mogensen, C J Lin, Ramon Gomis, H Seaman, C Granier, Yang C-H., F Assah, O Sanchez, Fausto Machicao, Peter G. Morris, Alberto Ortiz, A Giardinelli, D Bracaglia, A Gonzalo, S Pavlatos, Andreas Lechner, F Canovic, L Sjolind, Allan Vaag, Birgitte Bruun Nielsen, David A. Ziegler, Vito Lampasona, R Gershoni-Baruch, A. Dei Cas, H Renz, E Mena, Matthew Waltham, Kim D-M., H Levanen, D D Mick, Valentina Alexandrovna Peterkova, E Meskhishvili, Sarah Nutland, R Bustani, John R. Lindsay, M Christoforidou, A Abicht, E Harno, K Cyganek, A Fitchet, S Neelotpol, P Nikishin, P Serradas, J Hinrichsen, M Halvorson, M Chovatia, B Voet, Jinny Willis, E Parretti, M Haslbeck, M Wellard, L Teng, Julio Wainstein, J S Fischer, K. Lalic, D Roggenland, I Gich, R Anwar, Maurizio Cassader, D Serota, X J Li, R J Schotzinger, Vilmundur Gudnason, Björn Zethelius, S A Wootton, W Andrzejewski, R Rezsohazy, R Gao, T Klimentova, T Mazurek, I Bruckner, C Dohrmann, R E James, G daSilva Xavier, Kim S-Y., A Dorca, Stuart J. Pocock, Terri J. Allen, I Giovos, P B Parab, N H Andersen, P Fotinakis, Miriam Cnop, H Lee, Norbert Tennagels, Omorodola I. Abatan, F Ailett, I. Lager, D Manzella, H Hut, Larry A. Distiller, G Lip, Lim S-K., Rong Zhang, T Tsuno, Steen Knudsen, M. Bajardi, Manuel Benito, Dai Sugimoto, Melvin J. Prince, D W Dunstan, D Rankins, K A Majali, G Ozansoy, Isabella Russo, S Uçak, G Annuzzi, R Talar-Wojnarowska, K Lange, S Neugebauer-Baba, Campbell H. Thompson, Eric Renard, P. D. Mountjoy, Z Morrison, Elizabeth A. Davis, Franco Cavallo, C Corvaja, R Antuña, Craig John Currie, H Linnebjerg, He Y-L., A J Palmer, Mariola R. Chacón, H Malinska, M. Jones, R Lichnovská, K Mandes, Paolo Tessari, T Mokhort, A Laina, H. L. Y. Chan, I Schmidt, R Banks, Richard G. IJzerman, L Ksinantova, G Setti, H Vaudry, A Gallo, V Spallone, Chen J-W., Thomas Danne, A Chong, M Hallschmid, S Aczel, S Hulme, N Islam, M Hosoi, P M Ternan, P Di Bartolo, N Bishara, T Shibasaki, Martin A. Osterhoff, Im S-S., M Jecht, T Hamaguchi, S Mattera, K Ways, Elizabeth Northam, U Rajala, Reinhard W. Holl, L Yang, S Panaiotopoulos, K Horvath, R Kluge, Thora B. Bodvarsdottir, Y Dong, Irene Alemanno, C McDougall, Reimar W. Thomsen, M Campbell, W Rabl, John Öhrvik, Yuichiro Yamada, Paola Ungaro, W Benzer, Mike Sampson, Roberto Trevisan, R G Radu, Aas A-M., P E Lobo, Ricardo Scott, S M Son, Josephine M. Forbes, T A Hillier, K L Wyne, Louis L. Nguyen, J Farmer, M H Tan, Kwon H-S., J Yang, L Sandvik, Franco Folli, A K Jenum, M Nguyen, W Pratipanawatr, A L Frederiksen, Rebecca Smith, Lee H-J., A Schäfer, C Manuelli, G S Denver, T Vukovich, B Maceira, K Matsumoto, K. Chokkalingam, Nurcan Üçeyler, P Modi, Timothy M. Morgan, S Mertens, B M Singh, Michaela Riedl, K Iso, C Cucurullo, G. F. Bottazzo, M Calvani, K Hur, J Wetzels, Kazuhiro Takahashi, Y Aso, H Stammer, M G Masding, Fitsum Guebre-Egziabher, J L González-Sánchez, L Armstrong, Alberto Maran, Peter G.F. Swift, S S Popovic, J Starczynski, E Vitacolonna, Luigi Laviola, R W Gelling, Marina Cardellini, D Barilla, Rosa de Diego Martínez, W H Landschulz, Anne Mette Rosenfalck, R K Wong, Kevin E. Schneider, K Peros, Giuseppe Nanni, F Zhang, I Rákóczi, T Iburi, M Nakhjavani, X Q Zhang, S Tournis, Per Lav Madsen, Graham A. Hitman, A. Tura, K Laubner, N D Kostic, Lawrence M. Dolan, R. Sinha Roy, J A Wagner, J. Tuomilehto, J Hauptman, M Abdel-Ghany, D Lacombe, Toralph Ruge, Johannes A Maassen, Triantafyllos Didangelos, K Sasaki, I Argüelles, Klaus Levin, C Popow, Emanuel Christ, R Chetty, L Baillet-Blanco, Jo-Ann Salmon, T Mine, James L. Trevaskis, I Franke, J Gorski, E A Andrianova, A Dayan, A Caballero, Aleksandra Gilis-Januszewska, M Yasujima, Z Kasalová, C.D.A. Stehouwer, F. K. Gorus, G A Nichols, A Glowania, David P. Strachan, P Fredlund, N. F. da Silva, P Reboldi, M Sausbier, K H Groenier, G Stuccio, N Guttman, K R Ahmed, A D Ristic, T Kapellen, J Coutcher, Aldo V. Greco, Oswald Wagner, A Zagayko, Maria Alevizaki, B B Zhang, W F Ferris, Jenny Fredriksson, Lois Jovanovic, J Hänninen, R De Giglio, Kazuo Yagui, O Potterat, P Hamliton, R E Scranton, B Mankovsky, A Stylianou, B Fellström, Abdel-Wahab Yha., M Kitagawa, Katherine L. Baldock, F R Johnson, F Baigts, S D'Addato, F J Sanz, A Mistry, S D Wise, T Pratipanawatr, U R Fölsch, James R.C. Parkinson, Claudia Sommer, C Park, F E Griffiths, M L Martí, R Demirtunc, S Taniguchi, J Lundkvist, T Siegmund, Juan Sztajzel, C Dienesch, F Baumgartner, L Scalone, T M Mckolanis, K Otake, Ullrik Pedersen-Bjergaard, T M Vriesendorp, Michael B. Wheeler, Henry Schmitt, Peter Hovind, S Lange, Stephane Roze, L. Van Gaal, B Klaproth, Anthony E. Civitarese, D Eckland, A Dagar, D F Hopkins, Kari Stefansson, C Gonzalez-Yanes, B Meyboom-de Jong, D. J. Betteridge, K Buhling, M Crepaldi, Ana M. Wägner, L Renna, L Volpe, R McBride, V Corbo, E O Brennesvik, R P Hayes, R Abdollahnia, G Viviani, C F Liew, Francisco Pérez-Bravo, Jeffrey Baron, Brian M. Frier, H H Samira, D Szentendrei, K. J. Schjoedt, W K Waldhäusl, D Gniuli, D Zou, G Tschank, V Urbančič, A L Nolan, Albertini J-P., J Malcomson, M Larbig, C Cheyssac, K Aurich, C M Kesson, S Heller, Maija E. Miettinen, R F Luco, Adrian J. Cameron, Luigi Mattiello, Z. Metelko, X E Zhang, M Parramón, I. G. 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Jensen, A D'Avanzo, J Monaghan, K P Yeo, Guivarch P-H., B Bauduceau, D Weghuber, P Tatti, J Ybarra, S Gwozdziewiczová, E Gasparini, B Saltin, Charlotte Granhall, Howard Leventhal, R Marin, M Tumiati, Cicero Afg., L Csémy, B Berger, S Mikros, D Dall'Asta, M Shahmanesh, Y G Vasiljev, F Potthoff, H S Randeva, G De Berardis, J O Logan, K Warncke, P Uitterlinden, E Rehring, K Gilmore, K Shankhdhar, V V Bojko, M Vahatalo, E A Korolyova, D Wiemann, P G Lankisch, D Hendrie, F Galtier, M Rybarczyk, Gisela Dahlquist, N N Rudovich, G Stein, A Liebl, F Tan, A Westerlund, S Gronemann, I Franklin, Jonathan A. Prince, Peter Arner, E Skliros, T. Sparre, M Vigas, Maddalena Trombetta, L. Bjerre Knudsen, A C Sima, I Dubroca, Alastair Gray, I Weets, R Ferraresi, Schauer Ujw., E. Leinonen, S Corazza, Jonathan Levy, P K Prakash, R Guzder, S. Barnhill, John Blangero, J Herreros, G. de Vries, Cheng Ptw., A Macías-Batista, K. 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Hansen, T Watanabe, Gang Hu, Malik Rja., T Kennedy-Martin, Ulla M Smidt, J.M. Dekker, A A Fisher, H Liu, R E Pratley, B Sun, C Fledelius, J F Raposo, R Langham, Ahn S-Y., B R Waterhouse, Shaoping Deng, W Ricart, S V Melnichenko, Henrike Sell, M. Tomalino, N Takeda, Paola Massucco, A Harlan, W Henrich, C D Byrne, R Junik, Khalid Hussain, D Pop Gorceva, Torben Hansen, C Ritterath, K Ogawa, D V Phan, Bradley S Metcalf, Robb E. Moses, Juan P. Frias, Hitoshi Ishii, C Brisard, P Wolkow, H H Maurer, Ingo Rustenbeck, Juris J. Meier, Octavian Savu, S D Lin, V B Bregovski, A Fox, S Cicala, M. Koenen, L Vignati, O de Divitiis, Constantin Ionescu-Tirgoviste, Kilian Rittig, J Song, Riccardo Candido, F Cohen-Boulakia, U Shankhdhar, P Jahan, Antonio Tiengo, E Liepinsh, C Álvarez, Sigurd Lenzen, James E. 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Rodriguez rosas, H, Peiró martinez, I, Macías batista, A, Harte, A, Rodriguez cuenca, S, Valsamakis, G, Chetty, R, Anderson, L, Roca, P, Matyka, K, Lasalle, J, Hershon, K, Berman, L, Gibson, E, Gillen, D, Maroni, J, Simmons, D, Hiukka, A, Forder, P, Leinonen, E, Hilden, H, Fruchart, J, Keech, A, Farnier, M, Freeman, M, Macdonell, G, Perevozskaya, I, Mitchel, Y, Gumbiner, B, Didangelos, T, Athyros, V, Mikhailidis, D, Papageorgiou, A, Bouloukos, V, Pehlivanidis, A, Symeonidis, A, Elisaf, M, Mckenney, J, Insull, W, Lewin, A, Maccubbin, D, Kush, D, Schuster, H, Barter, P, Stender, S, Bonnet, J, Morrell, J, Watkins, C, Kallend, D, Stalenhoef, A, Ballantyne, C, Murin, J, Tonstad, S, Rose, H, Wilpshaar, W, Jenkins, A, Karschimkus, C, Dragicevic, G, Rowley, K, Wolthers, T, Best, J, Voet, B, Murdoch, S, Marcovina, S, Brunzell, J, Caparevic, Z, Kostic, N, Ilic, S, Sartore, G, Piarulli, F, Cantaro, S, Reitano, R, Fiore, C, Marin, R, Bassan, S, Manzato, E, Fedele, D, Solini, A, Santini, E, Thornalley, P, Babaei jadidi, R, Karachalias, N, Kupich, C, Ahmed, N, Fowler, A, Baker, A, Starczynski, J, O'Hare, P, Szepietowska, B, Szelachowska, M, Puch, U, Glebocka, A, Quinn, D, Mcternan, C, Bonser, R, Idzior walus, B, Woźniakiewicz, E, Dimitriou, K, Apostolou, O, Kontela, E, Devangelio, E, Gould, E, Serri, O, Roussin, A, Buithieu, J, Mamputu, J, Renier, G, Giordanetti, S, De Amici, E, Poggi, G, Turpini, C, Fratino, P, Garzaniti, A, Banu, I, Paries, J, Roman, G, Negrean, M, Bala, C, Nita, C, Kistorp, C, Gustafsson, F, Chong, A, Lip, G, Galatius, S, Ari, N, Sahilli, M, Ceylan isık, A, Ozansoy, G, Karasu yilmaz, C, Matteucci, E, Rosada, J, Pallini, M, Evangelista, I, Cassetti, G, Giusti, C, Giampietro, O, Capaldo, B, Galderisi, M, Cicala, S, Turco, A, Imbroinise, A, Nosso, G, D'Errico, A, De Divitiis, O, Klimontov, V, Korolyova, E, Jeltova, L, Bondar, I, Tarkun, I, Arslan, B, Canturk, Z, Tarkun, P, Agacdiken, A, Komsuoglu, B, Méneveau, N, Pierre justin, E, Alsayed, M, Sabbah, R, Paulin, S, Marcu, S, Tauveron, I, Zimmermann, C, Schiele, F, Seronde, M, Vautrin, P, Lusson, J, Thieblot, P, Bernard, Y, Mistry, A, Pye, M, Peovska, I, Maksimovic Pavlovic, J, Vavlukis, M, Pop Gorceva, D, Bosevski, M, Scognamiglio, R, Negut, C, De Kreutzenberg, S, Madonna, R, De Caterina, R, Willerson, J, Geng, Y, Vahsen, S, Ledwig, D, Ramrath, S, Frantz, S, Schmidt, I, Calvillo, L, Dienesch, C, Elbing, I, Bischoff, H, Ertl, G, Bauersachs, J, Davydov, A, Mkrtum'Yan, A, Baranova, L, Ikeda, Y, Suehiro, T, Osaki, F, Ota, K, Arii, K, Kumon, Y, Hashimoto, K, Doney, A, Morris, A, Palmer, C, Byun, S, Doo, H, Pagnin, E, Calo, L, Fadini, G, Kubaszek, A, Chai, S, Chai, Q, Rasmussen, L, Ledet, T, Wogensen, L, Lengyel, C, Varró, A, Virág, L, Magyar, J, Bíró, T, Jost, N, Skoumal, R, Nánási, P, Tóth, M, Horkay, F, Papp, J, Zacharopoulou, O, Athanaselis, S, Tsokos, N, Doupis, J, Psallas, M, Cokkinos, D, Pavlatos, S, Liatis, S, Akhobadze, T, Dzneladze, L, Samarguliani, I, Taskiran, M, Rasmussen, V, Jensen, G, Fisher, A, Petrovsky, N, Srikusalanukul, W, Budge, M, Trifunovic zamaklar, D, Zivkovic, M, Jelic, V, Vukomanovic, G, Ristic, A, Seferovic, P, Costa, J, Duarte, S, Manley, S, Sailesh, S, Venkataraman, A, Haider, Y, Groza, I, Oprean, M, Ardelean, A, Morosanu, A, Darkow, T, Vanderplas, A, Mamas, M, Mcelduff, P, Burns, J, Edwards, R, Fitchet, A, Young, R, Gibson, J, Lichiardopol, R, Niculescu, N, Totora, A, Pencea, C, Tomescu, I, Cinteza, M, Manicardi, V, Coscelli, C, Navazio, A, Catellani, E, Michelini, M, Dall'Asta, D, Guberti, A, Piazza, A, Gasparini, E, Pantaleoni, M, Guiducci, U, Manari, A, Sejil, S, Janand delenne, B, Avierinos, J, Habib, G, Labastie, N, Vague, P, Lassmann vague, V, Luźniak, P, Tatoń, J, Wojciechowska Luźniak, A, Zairis, M, Lyras, A, Patsourakos, N, Tsirimbis, V, Foussas, S, Lupón, J, Urrutia, A, Herreros, J, González, B, Coll, R, Altimir, S, Prats, M, Valle, V, Abreu padí, C, Rábago, G, Ivanova, L, Brasacchio, D, Harno, E, Keenan, A, Li, H, Lu, Z, Ke, L, Liu, H, Jeong, I, Chae, M, Choi, M, Yoo, H, Kim, C, Yun, M, Na, M, Kang, Y, Kong, O, Son, S, Kim, I, Tanaka, N, Hosoi, M, Matsuyama, Y, Fukumoto, M, Yamakita, T, Yoshioka, K, Ishii, T, Sato, T, Fujii, S, Aoki, T, Shibata, T, Mizutani, N, Suzuki, J, Fowelin, J, Samuelsson, P, Brandrup wogsen, G, Okumura, K, Tokmakova, A, Staroverova, D, Antcieferov, M, Shutichina, I, Kuntchevich, G, Vriesendorp, T, Morélis, Q, Legemate, D, Schaper, F, Mainas, E, Gkioulmpasanis, I, Panagiotou, I, Vassilikos, G, Skorda, L, Sidira, M, Christoforidou, M, Alaveras, A, Artikis, V, Evdemon, E, Lechleitner, M, Koch, T, Ebenbichler, C, Sturm, W, Moretti, L, Moruzzo, D, Boldrini, E, Pandolfo, C, Kameyama, M, Iwasa, R, Cho, M, Nam, J, Huh, K, Kaplar, M, Paragh, G, Erdei, A, Csongradi, E, Garai, I, Varga, J, Galuska, L, Udvardy, M, Higa, M, Kaneko, Y, Hiroi, N, Koziarska, D, Nowacki, P, Majkowska, L, Luzniak, P, Wojciechowska luźniak, A, Tushuizen, M, Nieuwland, R, Snoeck, D, Sturk, A, Diamant, M, Aguiar, L, Bahia, L, Villela, N, Laflor, C, Conde, C, Bottino, D, Dorigo, D, Bouskela, E, Pu, S, Luo, Z, Lam, K, Dan, Q, Xu, A, Shen, J, Cheng, K, Xu, J, Thamer, C, Stefan, N, Haap, M, Heller, E, Tschritter, O, De Prado, A, Ortiz, A, Ybarra, J, Gich, I, Pou, J, Ehren, M, Roggenland, D, Reinsen, B, Klein, H, Rittig, K, Stock, J, Kocher, B, Balletshofer, B, Shon, H, Chung, D, Nakatani, Y, Matsuhisa, M, Kaneto, H, Hatazaki, M, Yoshiuchi, K, Katakami, N, Kawamori, D, Ohtoshi, K, Sakamoto, K, Matsuoka, T, Ozawa, K, Ogawa, S, Hori, M, Yamasaki, Y, Zitouni, K, Harry, D, Nourooz zadeh, J, Earle, K, Olesen, P, Franco, L, Corvaja, C, Semplicini, A, Ceylan işık, A, Arı, N, Rösen, P, Lee, I, Park, K, Jung, E, Shin, D, Jo, S, Obuobie, K, Prakash, P, Hanna, F, Lazarus, J, Varadhan, L, Gurushankar, J, James, D, Sheikh, S, Gaede, P, Zou, D, Vilarrasa, N, Perez maraver, M, Mena, E, Perez, D, Setti, G, Buckingham, R, Urbančič, V, Stefanovska, A, Bernjak, A, Ažman juvan, K, Kocijančič, A, Glowania, A, Filters, T, Fosmark, D, Torjesen, P, Kilhovd, B, Berg, T, Sandvik, L, Hanssen, K, Mentink, C, Donchenko, G, Stepanenko, S, Maingrette, F, Deng, H, Lindenmair, A, Freudenthaler, A, Baumgartner parzer, S, Nizheradze, K, Khoruzhenko, A, Tronko, N, Sheu, W, Ou, H, Shen, H, Lin, T, Wu, H, Yang, C, Mogylnytska, L, Schmoelzer, I, Davies, J, Band, M, Struthers, A, Prázný, M, Škrha, J, Kasalová, Z, Neelotpol, S, Jahan, P, Kauschke, S, Harrop, C, Schäfer, A, Widder, J, Eigenthaler, M, Walter, U, Uchimura, I, Ikebukuro, M, Kaibara, M, Hirata, M, Helal, R, Pervin, F, Yang, X, Jansson, P, Nagaev, I, Jack, M, Carvalho, E, Sunnerhagen, K, Cam, M, Cushman, S, Smith, U, Creely, S, Farmer, J, Gustafson, B, Kusminski, C, Krusinova, E, Wohl, P, Klementova, M, Lanska, V, Mcdougall, C, Kelly, I, Abbas, Z, Lutale, J, Archibald, L, Karunajeewa, H, Stingemore, N, Stuccio, G, Mcgechie, D, Muller, L, Hak, E, Goudzwaard, W, Montorsi, F, Homering, M, Sprenger, K, Goldstein, I, Asnaghi, V, Ferrari, G, Rastaldi, M, Gabellini, D, Dell'Antonio, G, Maestroni, A, Ruggieri, D, Luzi, L, Piemonti, L, Zerbini, G, Anafaroglu, I, Tutuncu, N, Sultana, M, Siddiqua, N, Iwasaki, T, Nakajima, A, Yoneda, M, Mukasa, K, Tanaka, S, and Sekihara, H
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, EASD, Endocrinology, Diabetes and Metabolism, Human physiology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Family medicine, Internal Medicine, Medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published: 2004

49. Islet Protein Expression Changes during Diabetes Development in Islet Syngrafts in BB-DP Rats and During Rejection of BB-DP Islet Allografts

Author: Arkadiusz Nawrocki, Jørn Nerup, Thomas Mandrup-Poulsen, Larsen Pm, Ulla Bjerre Christensen, Fey Sj, Henrik U. Andersen, and T. Sparre
Subjects: Graft Rejection, medicine.medical_specialty, Langerhans cell, Immunology, Islets of Langerhans Transplantation, Biology, Nitric Oxide, Islets of Langerhans, Internal medicine, Heat shock protein, Gene expression, medicine, Immunology and Allergy, Animals, Insulin, Transplantation, Homologous, Electrophoresis, Gel, Two-Dimensional, Rats, Inbred BB, Cells, Cultured, NOD mice, geography, geography.geographical_feature_category, Proteins, Islet, In vitro, Rats, Transplantation, Transplantation, Isogeneic, medicine.anatomical_structure, Endocrinology, Diabetes Mellitus, Type 1, Animals, Newborn, Autoradiography, Pancreas, Interleukin-1
Abstract: Interleukin 1beta (IL-1) is cytotoxic to rat pancreatic beta-cells in vitro, and increased expression of IL-1 mRNA is found in the islets of Langerhans during development of diabetes in BB/Wor/Mol-BB2 (BB-DP) rats and NOD mice. It has been proposed that IL-1 induces a race between protective and deleterious proteins in the beta-cells during development of diabetes, and that heat shock proteins 70 and 90, and manganese superoxide dismutase, all inducible by IL-1 are potentially protective proteins. We have established a database of approximately 2000 neonatal rat-islet proteins by two-dimensional gel (2-D gel) electrophoresis of [35S]-methionine labelled neonatal Wistar Furth rat islets. In these IL-1 was shown to up- or down-regulate the islet-expression level of 99, and to induce de novo synthesis of 6 proteins. The identity of most of the IL-1 induced proteins is unknown and under study. In this study we wished to investigate if changes in protein expression induced in vitro by IL-1 stimulation of islets are also seen in vivo during spontaneous development of diabetes in BB-DP rats, and during islet allograft rejection. Two-hundred neonatal BB-DP rat islets were grafted under the kidney capsule of either 30-day-old BB-DP rats killed at onset of diabetes or of 30-day-old Wistar Kyoto (WK) rats, killed 12 days after grafting. Proteins in excised islet-grafts and in vitro IL-1 exposed isolated neonatal BB-DP rat islets were labelled with [35S]-methionine, and processed for 2-D gel electrophoresis. Fluorographs of the gels were analysed by computer. A total of 1815 proteins were found in 3 of 3 12.5% polyacrylamide gels. Interleukin-1 was found to change expression level of 82 of these proteins (22 up- and 60 down-regulated) in neonatal BB-DP rat islets in vitro. Of these 82 proteins 33 (4 up- and 29 down-regulated) also changed level of expression during disease occurrence in syngeneic islet grafts from diabetic BB-DP rats, and 29 (4 up- and 25 down-regulated) during rejection of BB-DP islets grafted to WK rats. Changes in the expression level of 14 (3 up- and 11 down-regulated) of the 82 proteins altered by IL-1 in vitro were only found in syngeneic islet grafts in diabetic BB-DP rats, and changes in the expression level of 8 (2 up- and 6 down-regulated) of these 82 proteins expression were only found in BB-DP islet allografts in WK recipients. Identification of these proteins may be important in understanding the mechanisms of islet destruction during development of insulin-dependent diabetes mellitus and during islet allograft rejection.
Published: 2000
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50. Interleukin-1beta induced changes in the protein expression of rat islets: a computerized database

Author: Stephen J. Fey, Jørn Nerup, Arkadiusz Nawrocki, Peter Mose Larsen, Thomas Mandrup-Poulsen, Henrik U. Andersen, and Kim Ry Hejnaes
Subjects: Databases, Factual, medicine.medical_treatment, Clinical Biochemistry, Rats, Inbred WF, Biochemistry, Analytical Chemistry, chemistry.chemical_compound, Islets of Langerhans, Antigen, Culture Techniques, medicine, Animals, Humans, Electrophoresis, Gel, Two-Dimensional, Gel electrophoresis, Cryopreservation, geography, geography.geographical_feature_category, Isoelectric focusing, Chemistry, Insulin, Interleukin, Proteins, Reproducibility of Results, Islet, Molecular biology, Recombinant Proteins, Rats, Cytokine, Animals, Newborn, Acrylamide, Regression Analysis, Isoelectric Focusing, Interleukin-1
Abstract: Udgivelsesdato: 1997-Oct Insulin-dependent diabetes mellitus is caused by an autoimmune destruction of the beta-cells in the islets of Langerhans. The cytokine interleukin 1 inhibits insulin release and is selectively cytotoxic to beta-cells in isolated pancreatic rat islets. The antigen(s) triggering the immune response as well as the intracellular mechanisms of action of interleukin 1-mediated beta-cell cytotoxicity are unknown. However, previous studies have found an association of beta-cell destruction with alterations in protein synthesis. Thus, two-dimensional (2-D) gel electrophoresis of pancreatic islet proteins may be an important tool facilitating studies of the molecular pathogenesis of insulin-dependent diabetes mellitus. 2-D gel electrophoresis of islet proteins may lead to (i) the determination of qualitative and quantitative changes in specific islet proteins induced by cytokines, (ii) the determination of the effects of agents modulating cytokine action, and (iii) the identification of primary islet protein antigen(s) initiating the immune destruction of the beta-cells. Therefore, the aim of this study was to create databases (DB) of all reproducibly detectable protein spots on 10% and 15% acrylamide 2-D gels of neonatal rat islets (10% and 15% DB), labeled under standardized culture conditions. 1235 and 557 spots were present in 5 of 5 gels in the 15% isoelectric focusing (IEF) and nonequilibrium pH gradient electrophoresis (NEPHGE) DB, respectively, whereas 995 and 378 spots were present in 5 of 5 gels in the 10% IEF and NEPHGE DB, respectively, yielding a reproducibility of spot detection between 75.2% and 91.7%. In both DBs, the average coefficient of variation of the percentage of integrated optical density (CV% of %IOD) for spots present in all gels was between 42.4% and 45.7%. When the same sample was analyzed in consecutive sets of gels on different days (interassay analysis), the average CV% of %IOD was 35.5%-36.1%. When the same sample was analyzed repeatedly in one set of gels (intra-assay analysis), the average CV% of %IOD was 30.2% in the IEF gels, while the average CV% of %IOD was 45.7% in the NEPHGE gels. Addition of interleukin-1beta (IL-1beta) to the cultures resulted in statistically significant modulation or de novo synthesis of 105 proteins in the 10% gels. In conclusion, we present the first 10% and 15% acrylamide 2-D gel protein databases of neonatal rat islets of Langerhans and demonstrate its usage to identify proteins altered in expression by IL-1beta.
Published: 1997
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