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201. Endothelial Progenitor Cells in Long-Standing Asymptomatic Type 1 Diabetic Patients with or without Diabetic Nephropathy

Author

Reinhard, Henrik, primary, Jacobsen, Peter Karl, additional, Lajer, Maria, additional, Tarnow, Lise, additional, Astrup, Anne Sofie, additional, Kim, Won Yong, additional, Pedersen, Nadja, additional, Billestrup, Nils, additional, Mandrup-Poulsen, Thomas, additional, Parving, Hans-Henrik, additional, and Rossing, Peter, additional

Published
2011
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212. Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans

Author

Palmer, Jerry P., Helqvist, Steffen, Spinas, Giatgen A., Molvig, Jens, Mandrup-Poulsen, Thomas, Andersen, Henrik U., and Nerup, Jorn

Subjects
Islands of Langerhans -- Health aspects -- Research, Diabetes -- Research, Secretion -- Control -- Health aspects -- Research, Interleukin-1 -- Health aspects -- Research, Health, Control, Research, Health aspects
Abstract

Interaction of Β-Cell Activity and IL-1 Concentration and Exposure Time in Isolated Rat Islets of Langerhans This study was designed to test the hypothesis that target-cell activity influences the degree [...]

Published
1989

220. Suppressor of cytokine signaling 3 (SOCS-3) protects [beta]-cells against interleukin-1[beta]-and interferon-[lambda]-mediated toxicity

Author

Karlsen, Allan E., Ronn, Sif G., Lindberg, Karen, Johannesen, Jesper, Galsgaard, Elisabeth D., Pociot, Flemming, Nielsen, Jens H., Mandrup-Poulsen, Thomas, Nerup, Jorn, and Billestrup, Nils

Subjects
Cytokines -- Research, Interleukin-1 -- Analysis, Interferon -- Analysis, Toxicity testing -- Analysis, Cell research -- Analysis, Science and technology
Abstract

Suppressor of cytokine signaling 3 (SOCS-3) is a negative feedback regulator of IFN-[gamma] signaling, shown up-regulated in mouse bone marrow cells by the proinflammatory cytokines interleukin-1[beta] (IL-1[beta]), tumor necrosis factor-[alpha] (TNF-[alpha]), and IFN-[gamma] IL-1[beta] and IFN-[gamma] alone, or potentiated by TNF-[alpha], are cytotoxic to the insulin producing pancreatic [beta]-cells and [beta]-cell lines in vitro and suggested to contribute to the specific [beta]-cell destruction in Type-1 diabetes mellitus (T1DM). Using a doxycycline-inducible SOCS-3 expression system in the rat [beta]-cell line INS-1, we demonstrate that the toxic effect of both IL-1[beta] or IFN-[gamma] at concentrations that reduced the viability by 50% over 3 days, was fully preventable when SOCS-3 expression was turned on in the cells. At cytokine concentrations or combinations more toxic to the cells, SOCS-3 overexpression yielded a partial protection. Whereas SOCS-3-mediated inhibition of IFN-[gamma] signaling is described in other cell systems, SOCS-3 mediated inhibition of IL-1[beta] signaling has not previously been described. In addition we show that SOCS-3 prevention of IL-1[beta]induced toxicity is accompanied by inhibited transcription of the inducible nitric oxide synthase (iNOS) by 80%, resulting in 60% decreased formation of the toxic nitric oxide (NO). Analysis of isolated native rat islets exposed to IL-1[beta] revealed a naturally occurring but delayed up-regulated SOCS-3 transcription. Influencing SOCS-3 expression thus represents an approach for affecting cytokine-induced signal transduction at a proximal step in the signal cascade, potentially useful in future therapies aimed at reducing the destructive potential of [beta]-cell cytotoxic cytokines in T1DM, as well as other cytokine-dependent diseases.

Published
2001

223. An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

Author

Wagner, Florence F., Lundh, Morten, Kaya, Taner, McCarren, Patrick, Zhang, Yan-Ling, Chattopadhyay, Shrikanta, Gale, Jennifer P., Galbo, Thomas, Fisher, Stewart L., Meier, Bennett C., Vetere, Amedeo, Richardson, Sarah, Morgan, Noel G., Christensen, Dan Ploug, Gilbert, Tamara J., Hooker, Jacob M., Leroy, Mélanie, Walpita, Deepika, Mandrup-Poulsen, Thomas, Wagner, Bridget K., and Holson, Edward B.

Abstract

Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.

Published
2016
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224. Skeletal Muscle to Pancreatic β-Cell Cross-talk: The Effect of Humoral Mediators Liberated by Muscle Contraction and Acute Exercise on β-Cell Apoptosis

Author

Christensen, Camilla S., Christensen, Dan P., Lundh, Morten, Dahllöf, Mattias S., Haase, Tobias N., Velasquez, Jessica M., Laye, Matthew J., Mandrup-Poulsen, Thomas, and Solomon, Thomas P. J.

Abstract

Context:Mechanisms explaining exercise-induced β-cell health are unknown.Objective:This study aimed to define the role of muscle contraction and acute exercise–derived soluble humoral mediators on β-cell health.Design:In vitro models were used.Setting:University.Participants:Healthy subjects.Intervention(s):Conditioned media (CM) were collected from human skeletal muscle (HSkM) cells treated with or without electrical pulse stimulation (EPS). Antecubital and femoral venous blood serum were collected before and after an exercise bout. CM and sera with or without IL-6 neutralization were used to incubate insulin-producing INS-1 cells and rat islets for 24 h in the presence or absence of proinflammatory cytokines (IL-1β+IFN-γ).Main Outcome Measure(s):INS-1 and islet apoptosis and accumulated insulin secretion.Results:IL-1β+IFN-γ increased INS-1 and islet apoptosis and decreased insulin secretion. EPS-treated HSkM cell CM did not affect these variables. Exercise-conditioned antecubital but not femoral sera prevented IL-1β+IFN-γ-induced INS-1 and islet apoptosis. Femoral sera reduced insulin secretion under normal and proinflammatory conditions in INS-1 but not islet cells. EPS increased HSkM cell IL-6 secretion and exercise increased circulating IL-6 levels in antecubital and femoral serum. IL-6 neutralization demonstrated that muscle-derived IL-6 prevents INS-1 and islet apoptosis in the absence of IL-1β+IFN-γ, but augments apoptosis under proinflammatory conditions, and that muscle-derived IL-6 supports islet insulin secretion in the absence of IL-1β+IFN-γ.Conclusions:Unidentified circulating humoral mediators released during exercise prevent proinflammatory cytokine-induced β-cell apoptosis. Muscle-derived mediators released during exercise suppress β-cell insulin secretion. Furthermore, muscle-derived IL-6 seems to prevent β-cell apoptosis under normal conditions but contributes to β-cell apoptosis under proinflammatory conditions.

Published
2015
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227. IDDM7 links to insulin-dependent diabetes mellitus in Danish multiplex families but linkage is not explained by novel polymorphisms in the candidate gene GALNT3 Communicated by: R.G.H. Cotton Online Citation: Human Mutation, Mutation in Brief #299 (1999) Online http://journals.wiley.com/1059-7794/pdf/mutation/299.pdf

Author

Kristiansen, Ole P., primary, Pociot, Flemming, additional, Bennett, Eric P., additional, Clausen, Henrik, additional, Johannesen, Jesper, additional, Nerup, Jørn, additional, and Mandrup-Poulsen, Thomas, additional

Published
2000
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228. Use of vitamin D supplements during infancy in an international feeding trial.

Author

Lehtonen, Eveliina, Ormisson, Anne, Nucci, Anita, Cuthbertson, David, Sorkio, Susa, Hyytinen, Mila, Alahuhta, Kirsi, Berseth, Carol, Salonen, Marja, Taback, Shayne, Franciscus, Margaret, González-Frutos, Teba, E Korhonen, Tuuli, L Lawson, Margaret, J Becker, Dorothy, P Krischer, Jeffrey, Knip, Mikael, M Virtanen, Suvi, Mandrup-Poulsen, Thomas, and Arjas, Elias

Subjects
VITAMIN D in human nutrition, DIETARY supplements, INFANT nutrition, TYPE 1 diabetes, INFANT diseases, MATERNAL age
Abstract

ObjectiveTo examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.DesignLongitudinal study.SettingInformation about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.SubjectsInfants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.ResultsDaily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.ConclusionsMost of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation. [ABSTRACT FROM AUTHOR]

Published
2014
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229. Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies.

Author

Ellervik, Christina, Mandrup Poulsen, Thomas, Tybjærg-Hansen, Anne, and Nordestgaard, Børge G.

Subjects
*HEMOCHROMATOSIS, *TRANSFERRIN, *DIABETES, *PEOPLE with diabetes, *EARLY death, *PATIENTS
Abstract

OBJECTIVE Mortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown. RESEARCH DESIGN AND METHODS In two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346). RESULTS The cumulative survival rate was reduced in individuals with diabetes with TS ≥50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ≥50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P= 0.0001), with an HR for TS ≥70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ≥50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype. CONCLUSIONS Individuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death. [ABSTRACT FROM AUTHOR]

Published
2014
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232. Metabolism and the inflammasome in health and ageing

Author

Mandrup-Poulsen, Thomas

Abstract

Extracellular danger-associated molecular patterns signal to NOD-like receptors, but the exact signalling pathways remain unclear. The inflammasomes, a subgroup of these receptors, translate danger signals into inflammatory responses by maturing IL-1 and IL-18. In 2017, researchers reported novel functions of the mutual interaction between metabolism and the inflammasomes in health and disease.

Published
2018
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233. Interleukin-1β-induced Rat Pancreatic Islet Nitric Oxide Synthesis Requires Both the p38 and Extracellular Signal-regulated Kinase 1/2 Mitogen-activated Protein Kinases

Author

Larsen, Claus M., primary, Wadt, Karin A.W., additional, Juhl, Lone F., additional, Andersen, Henrik U., additional, Karlsen, Allan E., additional, Su, Michael S.-S., additional, Seedorf, Klaus, additional, Shapiro, Leland, additional, Dinarello, Charles A., additional, and Mandrup-Poulsen, Thomas, additional

Published
1998
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243. Suppressor of Cytokine Signaling (SOCS)-3 inhibits cytokine-mediated mitogen-activated protein kinase/nuclear factor-[kappa]B activation, nitrogen oxide production, and apoptosis in rat pancreatic [beta]-cells

Author

Heding, Peter E., Groth Ronn, Sif, Kruhoffer, Mogens, Falck Orntoft, Torben, Frobose, Helle, Karlsen, Allan Ertman, Nerup, Jorn, Mandrup-Poulsen, Thomas, and Billestrup, Nils

Subjects
Protein kinases -- Health aspects, Protein kinases -- Research, Diabetes -- Diagnosis, Diabetes -- Care and treatment, Health
Abstract

The cytokines interleukin (IL)-I and interferon (IFN)-[gamma] are believed to be mediators of immune-mediated [beta]-cell destruction in type 1 diabetes. Inhibition of the nuclear factor (NF)-[kappa]B and mitogen-activated protein kinase (MAPK) pathways protects [beta]-cells against cytokine-induced apoptosis, partly because of inhibition of inducible nitric oxide synthase expression and nitric oxide (NO) generation. We have previously shown that suppressor of cytokine signaling (SOCS)-3 prevents cytokine-induced NO production and apoptosis in a [beta]-cell line. The aim of this study was to investigate by microarray the gene pattern induced by IL-1 and its suppression by SOCS-3 in a [beta]-cell line. Furthermore, we also investigated whether SOCS-3 inhibits the NF-[kappa]B and MAPK pathways, NO production, and apoptosis induction in primary rat [beta]-cells. By microarray analysis (Affymetrix U34A Array), we found that IL-1 stimulation (150 pg/ml, 6 h) upregulated 23 annotated genes, 15 of which were inhibited by SOCS-3. Interestingly, of these 15 genes, 9 have previously been reported to be NF-[kappa]B dependent. Using an adenovirus expression approach, we found by Western blotting that SOCS-3 inhibited I[kappa]B degradation and MAPK activation in dispersed rat islets cultures exposed to IL-1 (250 pg/ml, 15 min). In addition, both NO production and apoptosis induction by IL-1 + IFN-[gamma] (250 and 10 ng/ml, 24 h) were suppressed 50% by SOCS-3. In conclusion, we show that expression of SOCS-3 inhibits NF-[kappa]B-dependent gene transcription in a [beta]-cell line and inhibits I[kappa]B degradation and MAPK activation in primary rat [beta]-cells. These findings elucidate the signaling pathways involved in the mechanism by which SOCS-3 reduces cytokine-induced toxicity in [beta]-cells., Peter E. Heding, (1) Sif Groth Ronn, (1) Mogens Kruhoffer, (2) Torben Falck Orntoft, (2) Helle Frobose, (1) Allan Ertman Karlsen, (1) Jorn Nerup, (1) Thomas Mandrup-Poulsen, (1) Nils Billestrup [...]

Published
2005

244. The growth arrest and DNA damage-inducible gene (gadd45[beta]) inhibits proapoptotic Jun N[H.sub.2]-terminal kinase signaling in pancreatic [beta]-cells exposed to interleukin-1[beta]

Author

Larsen, Claus M., Franzoso, Guido, Billestrup, Nils, and Mandrup-Poulsen, Thomas

Subjects
Diabetes -- Genetic aspects, DNA damage -- Research, Pancreatic beta cells -- Research, Health
Abstract

By the induction of apoptosis in pancreatic [beta]-cells, interleukin (IL)-1[beta] is believed to be an important mediator of the [beta]-cell destruction leading to type 1 diabetes. The apoptotic effect of IL-1[beta] is primarily mediated by Jun N[H.sub.2]-terminal kinase (JNK), because inhibition of JNK activity completely blocks IL-1[beta]-induced [beta]-cell apoptosis. The growth arrest and DNA damage-inducible gene (gadd45[beta]) has been reported to inhibit JNK activation via inhibition of the upstream kinase MKK7. The aim was to investigate gadd45[beta] regulation by IL-1[beta] in [beta]-cells and non-[beta]-cells and to evaluate the involvement of gaddA5[beta] in [beta]-cell JNK signaling. The methods used were quantitative RT-PCR on RNA isolated from cells exposed to cytokines and Western blotting. IL-1[beta] caused a minor induction of gadd45[beta] mRNA in two [beta]-cell lines (INS-1E and [beta]TC3) compared with IL-1[beta]-exposed NIH-3T3 fibroblasts (11- and 4-fold vs. 120-fold, respectively), indicating insufficient gadd45[beta] induction by IL-1[beta] in [beta]-cells. As a preliminary evaluation of gadd45[beta] involvement in [beta]-cell JNK signaling, pools of overexpressing INS-1E and [beta]TC3 cells (transfection efficiency ~50%) were exposed to IL-1[beta]. gadd45[beta] overexpression reduced 1L-1[beta]-induced JNK activation by 42 and 63% in INS-1E and [beta]TC3 cells, respectively. This identifies gadd45[beta] as a [beta]-cell JNK inhibitor, and the impact of this inhibition on cytokine-induced [beta]-cell apoptosis will be further investigated., Claus M. Larsen, (1) Guido Franzoso, (2) Nils Billestrup, (1) Thomas Mandrup-Poulsen (1,3) From the (1) Steno Diabetes Center, Gentofte, Denmark; the (2) University of Chicago, Chicago, Illinois; and the [...]

Published
2005

249. Total Mortality by Elevated Transferrin Saturation in Patients With Diabetes.

Author

ELLERVIK, CHRISTINA, ANDERSEN, HENRIK ULLITS, TYBJÆRG-HANSEN, ANNE, FRANDSEN, MERETE, BIRGENS, HENRIK, NORDESTGAARD, BØRGE G., and MANDRUP-POULSEN, THOMAS

Subjects
DIABETES, MORTALITY, TRANSFERRIN, TUMORS, TYPE 1 diabetes, DIABETES risk factors, EARLY medical intervention, LIFE expectancy
Abstract

OBJECTIVE--It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the geno-HFE type. We investigated total and cause-specific mortality according to increased transferrin saturation (≥50 vs. <50%), whether mortality is driven by the genotype, and whether early HFE measurement of transferrin saturation helps to predict mortality outcome. RESEARCH DESIGN AND METHODS--Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and genotype if transferrin saturation HFE was above 50%. RESULTS--In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation ≥50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation ≥50 vs. <50%. In patients with late-onset type 1 diabetes and transferrin saturation ≥50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1. CONCLUSIONS--Increased transferrin saturation and genotype C282Y/C282Y predict HFE total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy. [ABSTRACT FROM AUTHOR]

Published
2013
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250. Serum adipokines as biomarkers of beta-cell function in patients with type 1 diabetes: positive association with leptin and resistin and negative association with adiponectin.

Author

Pham, Minh Nguyet, Kolb, Hubert, Mandrup‐Poulsen, Thomas, Battelino, Tadej, Ludvigsson, Johnny, Pozzilli, Paolo, Roden, Michael, and Schloot, Nanette C.

Abstract

Background We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes. Methods One hundred and eighteen patients with type 1 diabetes (20.3 ± 7.5 years) diagnosed <5 years underwent standardized mixed meal test (MMTT) for 2 h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis. Results Patients were divided by their adipokine levels in subgroups above or below the median level ('high versus low'). High adiponectin levels (>10.6 µg/mL) were associated with lower C-peptide compared to the low adiponectin subgroup ( p < 0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders ( p < 0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests ( p < 0.05). Serum adipokines fell during MMTT ( p < 0.05). Conclusions Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2013
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