Joachim Størling

Glostrup Hospital, København, Capital Region, Denmark

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Publications (33)178.55 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Background. Lipid accumulation in skeletal muscle is associated with impaired insulin sensitivity in type 2 diabetes. In cardiac myocytes, lipoprotein secretion controlled by apolipoproteinB (apoB) and microsomal triglyceride transfer protein (MTP) affects lipid homeostasis. Design. In this study, we investigated whether expression of a human apoB transgene affects triglyceride accumulation and insulin sensitivity in skeletal muscle in fat fed obese mice. Results. Expression of apoB and MTP mRNA and the human apoB transgene was seen in skeletal muscle of the transgene mice. Human apoB transgenic mice accumulated 28% less triglycerides in skeletal myocytes after one year of fat-feeding as compared with WT mice (32 ± 5, n = 10 vs. 44 ± 4 nmol/mg ww, n = 13, p = 0.04). Moreover, expression of human apoB in fat-fed mice was associated with 32% (p = 0.02) and 37% (p = 0.01) lower plasma insulin levels after 9 and 12 months, respectively, improved intra peritoneal glucose tolerance after 6 months, and a trend towards increased insulin-stimulated glucose uptake in isolated skeletal muscle. Conclusions. The data suggests that overexpression of apoB decreases skeletal muscle lipid accumulation and attenuates peripheral insulin resistance in obese mice.
    Scandinavian journal of clinical and laboratory investigation 03/2014; · 1.38 Impact Factor
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    ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease where local release of cytokines such as IL-1β and IFN-γ contribute to β-cell apoptosis. To identify relevant genes regulating this process we performed a meta-analysis of 8 datasets of β-cell gene expression after exposure to IL-1β and IFN-γ. Two of these datasets are novel and contain time-series expressions in human islet cells and rat INS-1E cells. Genes were ranked according to their differential expression within and after 24 hours from exposure, and characterized by function and prior knowledge in the literature. A regulatory network was then inferred from the human time expression datasets, using a time-series extension of a network inference method. The two most differentially expressed genes previously unknown in T1D literature (RIPK2 and ELF3) were found to modulate cytokine-induced apoptosis. The inferred regulatory network is thus supported by the experimental validation, providing a proof-of-concept for the proposed statistical inference approach.
    Genomics 01/2014; · 3.01 Impact Factor
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    ABSTRACT: Type 1 diabetes is considered an autoimmune disease characterised by specific T cell-mediated destruction of the insulin-producing beta cells. Yet, except for insulin, no beta cell-specific antigens have been discovered. This may imply that the autoantigens in type 1 diabetes exist in modified forms capable of specifically triggering beta cell destruction. In other immune-mediated diseases, autoantigens targeted by the immune system have undergone post-translational modification (PTM), thereby creating tissue-specific neo-epitopes. In a similar manner, PTM of beta cell proteins might create beta cell-specific neo-epitopes. We suggest that the current paradigm of type 1 diabetes as a classical autoimmune disease should be reconsidered since the immune response may not be directed against native beta cell proteins. A modified model for the pathogenetic events taking place in islets leading to the T cell attack against beta cells is presented. In this model, PTM plays a prominent role in triggering beta cell destruction. We discuss literature of relevance and perform genetic and human islet gene expression analyses. Both direct and circumstantial support for the involvement of PTM in type 1 diabetes exists in the published literature. Furthermore, we report that cytokines change the expression levels of several genes encoding proteins involved in PTM processes in human islets, and that there are type 1 diabetes-associated polymorphisms in a number of these. In conclusion, data from the literature and presented experimental data support the notion that PTM of beta cell proteins may be involved in triggering beta cell destruction in type 1 diabetes. If the beta cell antigens recognised by the immune system foremost come from modified proteins rather than native ones, the concept of type 1 diabetes as a classical autoimmune disease is open for debate.
    Diabetologia 09/2013; · 6.49 Impact Factor
  • Joachim Storling, Caroline Anna Brorsson
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    ABSTRACT: In type 1 diabetes (T1D), the insulin-producing β cells are destroyed by an immune-mediated process leading to complete insulin deficiency. There is a strong genetic component in T1D. Genes located in the human leukocyte antigen (HLA) region are the most important genetic determinants of disease, but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function. Recent studies, however, indicate that most T1D candidate genes are expressed in human islets suggesting that the functions of the genes are not restricted to immune cells, but also play roles in the islets and possibly the β cells. Several candidates change expression levels within the islets following exposure to proinflammatory cytokines highlighting that these genes may be involved in the response of β cells to immune attack. In this review, the compiling evidence that many of the candidate genes are expressed in islets and β cells will be presented. Further, we perform the first systematic human islet expression analysis of all genes located in 50 T1D-associated GWAS loci using a published RNA sequencing dataset. We find that 336 out of 857 genes are expressed in human islets and that many of these interact in protein networks. Finally, the potential pathogenetic roles of some candidate genes will be discussed.
    Current Diabetes Reports 08/2013; · 3.17 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) contribute to target-cell damage in inflammatory and iron-overload diseases. Little is known about iron transport regulation during inflammatory attack. Through a combination of in vitro and in vivo studies, we show that the proinflammatory cytokine IL-1β induces divalent metal transporter 1 (DMT1) expression correlating with increased β cell iron content and ROS production. Iron chelation and siRNA and genetic knockdown of DMT1 expression reduce cytokine-induced ROS formation and cell death. Glucose-stimulated insulin secretion in the absence of cytokines in Dmt1 knockout islets is defective, highlighting a physiological role of iron and ROS in the regulation of insulin secretion. Dmt1 knockout mice are protected against multiple low-dose streptozotocin and high-fat diet-induced glucose intolerance, models of type 1 and type 2 diabetes, respectively. Thus, β cells become prone to ROS-mediated inflammatory damage via aberrant cellular iron metabolism, a finding with potential general cellular implications.
    Cell Metabolism 10/2012; 16(4):449-461. · 14.62 Impact Factor
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    ABSTRACT: Large scale quantitative phosphoproteomics depends upon multidimensional strategies for peptide fractionation, phosphopeptide enrichment, and mass spectrometric analysis. Previously, most robust comprehensive large-scale phosphoproteomics strategies have relied on milligram amounts of protein. We have set up a multi-dimensional phosphoproteomics strategy combining a number of well-established enrichment and fraction methods: An initial TiO(2) phosphopeptide pre-enrichment step is followed by post-fractionation using sequential elution from IMAC (SIMAC) to separate multi- and mono-phosphorylated peptides, and hydrophilic interaction liquid chromatography (HILIC) of the mono-phosphorylated peptides (collectively abbreviated "TiSH"). The advantages of the strategy include a high specificity and sample preparation workload reduction due to the TiO(2) pre-enrichment step, as well as low adsorptive losses. We demonstrate the capability of this strategy by quantitative investigation of early interferon-γ signaling in low quantities of insulinoma cells. We identified ~6600 unique phosphopeptides from 300μg of peptides/condition (22 unique phosphopeptides/μg) in a duplex dimethyl labeling experiment, with an enrichment specificity>94%. When doing network analysis of putative phosphorylation changes it could be noted that the identified protein interaction network centered upon proteins known to be affected by the interferon-γ pathway, thereby supporting the utility of this global phosphoproteomics strategy. This strategy thus shows great potential for interrogating signaling networks from low amounts of sample with high sensitivity and specificity.
    Journal of proteomics 08/2012; 75(18):5749-61. · 5.07 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases. For type 1 diabetes, >40 susceptibility loci have been discovered. However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated with disease, and they do not typically inform the broader context in which the disease genes operate. Here, we integrated type 1 diabetes GWAS data with protein-protein interactions to construct biological networks of relevance for disease. A total of 17 networks were identified. To prioritize and substantiate these networks, we performed expressional profiling in human pancreatic islets exposed to proinflammatory cytokines. Three networks were significantly enriched for cytokine-regulated genes and, thus, likely to play an important role for type 1 diabetes in pancreatic islets. Eight of the regulated genes (CD83, IFNGR1, IL17RD, TRAF3IP2, IL27RA, PLCG2, MYO1B, and CXCR7) in these networks also harbored single nucleotide polymorphisms nominally associated with type 1 diabetes. Finally, the expression and cytokine regulation of these new candidate genes were confirmed in insulin-secreting INS-1 β-cells. Our results provide novel insight to the mechanisms behind type 1 diabetes pathogenesis and, thus, may provide the basis for the design of novel treatment strategies.
    Diabetes 02/2012; 61(4):954-62. · 7.90 Impact Factor
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    ABSTRACT: Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting β-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico "phenome-interactome analysis" on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for β-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1β and IFN-γ) that mediate β-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1β-induced NF-κB activity and protection against IL-1β-mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches.
    Proceedings of the National Academy of Sciences 06/2011; 108(37):E681-8. · 9.74 Impact Factor
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    ABSTRACT: Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic β-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse β-cells, exposure of rat islets to ApoCIII alone (50 μg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1β + interferon-γ, ApoCIII reduced cytokine-mediated islet cell death and impairment of β-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL-1β-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor κB-inhibitor inhibitor of κB and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt.
    Endocrinology 06/2011; 152(8):3040-8. · 4.72 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2011; 12(1):4-4.
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    ABSTRACT: Interleukin-1β Interleukin-1β (IL-1β) is a key regulator of the body's inflammatory response and is produced after infection, injury, and an antigenic challenge. Cloned in 1984, the single polypeptide IL-1β has been shown to exert numerous biological effects. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, and Type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure, and Type 2 diabetes. The macrophage is the primary source of IL-1β, but epidermal, epithelial, lymphoid, and vascular tissues also synthesize IL-1. Recently, IL-1β production and secretion have also been reported from pancreatic islets. Insulin-producing β-cells β-cells within the pancreatic islets are specifically prone to IL-β-induced destruction and loss of function. Macrophage-derived IL-1β production in insulin-sensitive organs leads to the progression of inflammation inflammation and induction of insulin resistance in obesity. This chapter explains the mechanisms involved in the inflammatory response during diabetes progression with specific attention to the IL-1β signal effects influencing insulin action and insulin secretion insulin secretion . We highlight recent clinical studies, rodent and in vitro experiments with isolated islets using IL-1β as a potential target for the therapy of Type 2 diabetes.
    Handbook of experimental pharmacology 01/2011;
  • Joachim Størling, Regine Bergholdt
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    ABSTRACT: A prerequisite for designing good drugs that perform through clinical development with the final goal to treat human diseases is a detailed understanding of the mechanisms underlying disease. This is particularly true for complex diseases such as diabetes. It has become increasingly clear that complex traits or phenotypes are the result of an interplay between environmental factors and numerous genes and proteins that jointly affect the functionality of biological systems. Since interactions between proteins in networks and pathways make up biological systems, it is essential that we learn more about how networks and pathways are influenced by environmental factors and genetic variation and how such influences cause disease. In this chapter, we will discuss recent data, advancement and ideas on how more valid druggable targets to treat diabetes may be predicted by the application of bioinformatics and systems biology. Keywordsβ-cells-Diabetes aetiology-Drug targets-GWAS-Phenotype description-Protein networks-Systems biology
    12/2010: pages 407-418;
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    ABSTRACT: In type 1 diabetes, inflammatory and immunocompetent cells enter the islet and produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); each contribute to β-cell destruction, mediated in part by nitric oxide. Inhibitors of histone deacetylases (HDAC) are used commonly in humans but also possess antiinflammatory and cytokine-suppressing properties. Here we show that oral administration of the HDAC inhibitor ITF2357 to mice normalized streptozotocin (STZ)-induced hyperglycemia at the clinically relevant doses of 1.25-2.5 mg/kg. Serum nitrite levels returned to nondiabetic values, islet function improved and glucose clearance increased from 14% (STZ) to 50% (STZ + ITF2357). In vitro, at 25 and 250 nmol/L, ITF2357 increased islet cell viability, enhanced insulin secretion, inhibited MIP-1α and MIP-2 release, reduced nitric oxide production and decreased apoptosis rates from 14.3% (vehicle) to 2.6% (ITF2357). Inducible nitric oxide synthase (iNOS) levels decreased in association with reduced islet-derived nitrite levels. In peritoneal macrophages and splenocytes, ITF2357 inhibited the production of nitrite, as well as that of TNFα and IFNγ at an IC(50) of 25-50 nmol/L. In the insulin-producing INS cells challenged with the combination of IL-1β plus IFNγ, apoptosis was reduced by 50% (P < 0.01). Thus at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors β-cell survival during inflammatory conditions.
    Molecular Medicine 12/2010; 17(5-6):369-77. · 4.47 Impact Factor
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    ABSTRACT: Since having been cloned in 1984, IL-1beta has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1beta is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases and type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure and type 2 diabetes. Macrophage are the primary source of IL-1, but epidermal, epithelial, lymphoid and vascular tissues also synthesize IL-1. IL-1beta production and secretion have also been reported from pancreatic islets. Insulin-producing beta-cells within pancreatic islets are specifically prone to IL-beta-induced destruction and loss of function. Macrophage-derived IL-1beta production in insulin-sensitive organs, leads to progression of inflammation and induction of insulin resistance in obesity. We summarize the mechanisms involved in inflammation and specifically the IL-1beta signals that lead to the progression of insulin resistance and diabetes. We highlight recent clinical studies and experiments in animals and isolated islets using IL-1beta as a potential target for the therapy of type 2 diabetes.
    Expert opinion on biological therapy 10/2009; 9(9):1177-88. · 3.22 Impact Factor
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    ABSTRACT: Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca(2+) depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) contributes to beta-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca(2+) depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor kappaB (NFkappaB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFkappaB activation, as assessed by IkappaB degradation and NFkappaB DNA binding. Inhibition of NFkappaB or the Bcl-2 family member Bax pathways protected beta-cells against TG- but not SNAP-induced beta-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFkappaB and Bax.
    Endocrinology 07/2009; 150(9):4094-103. · 4.72 Impact Factor
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    ABSTRACT: Proinflammatory cytokines are cytotoxic to beta-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytokine-induced beta-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in beta-cells. Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and/or tumor necrosis factor-alpha). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively. 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. Our findings demonstrate that the intrinsic mitochondrial apoptotic pathway contributes significantly to cytokine-induced beta-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis.
    Diabetes 06/2009; 58(8):1807-15. · 7.90 Impact Factor
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    ABSTRACT: G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn(++) sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes.
    Endocrinology 03/2009; 150(6):2577-85. · 4.72 Impact Factor
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    ABSTRACT: The tale of cytokines and the beta-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo studies in spontaneously diabetic and transgenic animal models. Only very recently have steps been taken to translate the accumulating compelling preclinical data into clinical trials. The aim of this chapter is to present an overview of early and recent key observations from our own groups as well as other laboratories that serve to illuminate the road from concept to clinical translation.
    Endocrine Reviews 06/2008; 29(3):334-50. · 14.87 Impact Factor
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    ABSTRACT: An insufficient number of insulin-producing beta-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1beta, interferon- gamma and tumor necrosis factor-alpha. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes.
    Cellular and Molecular Life Sciences CMLS 05/2008; 65(7-8):1248-55. · 5.62 Impact Factor
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    ABSTRACT: The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1beta and IFNgamma, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFkappaB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of pro-apoptotic genes. NFkappaB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1beta and IFNgamma. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFkappaB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1beta induced a bi-phasic phosphorylation of inhibitor protein kappa Balpha (IkappaBalpha) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IkappaBalpha degradation and NFkappaB DNA binding. HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFkappaB transactivating activity.
    Diabetologia 05/2007; 50(4):779-89. · 6.49 Impact Factor

Publication Stats

768 Citations
178.55 Total Impact Points


  • 2011–2014
    • Glostrup Hospital
      København, Capital Region, Denmark
  • 2013
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2009–2011
    • Universität Bremen
      • Zentrum für biomolekulare Interaktionen CBIB
      Bremen, Bremen, Germany
  • 2010
    • University of Colorado
      • Department of Medicine
      Denver, CO, United States
  • 2003–2009
    • Steno Diabetes Center
      Gjentofte, Capital Region, Denmark
  • 2003–2008
    • University of Zurich
      Zürich, Zurich, Switzerland