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  • 1
    Electronic Resource
    Electronic Resource
    Identification of a Type 1 Diabetes-Associated CD4 Promoter Haplotype with High Constitutive Activity (2004)
    Oxford, UK; Malden, USA : Blackwell Science Ltd
    Scandinavian journal of immunology 59 (2004), S. 0 
    Details
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4+ T cells. We previously found linkage between a CD4-1188(TTTTC)5−14 promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)5−14 alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4-1188T-1050G-521C-181) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1365-3083.2004.01444.x
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  • 2
    Electronic Resource
    Electronic Resource
    A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. 344-350 
    Details
    ISSN: 1432-0428
    Keywords: Glutamic acid decarboxylase ; receiver-operating characteristic plot ; diagnostic accuracy ; islet cell antibodies ; autoimmunity ; diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin-dependent diabetes mellitus (IDDM) is associated with autoreactivity against GAD but the diagnostic sensitivity (positivity in disease) and specificity (negativity in health) of isoform-specific GAD antibodies have yet to be defined in assay systems suitable for screening large number of samples. One set of IDDM patient (n=10) and control (n=50) standard sera were used to develop quantitative antibody assays with in vitro synthesized recombinant 35S-methionine-labelled GAD65 and GAD67, respectively, and protein A-Sepharose to separate free from antibody-bound ligand. Binding levels were not normally distributed (p〈0.0001) and therefore, the diagnostic accuracy of GAD antibodies was analysed by the ROC plots in population-based, consecutively-diagnosed, recent onset, 0–14 year-old patients (n=105), and matched, healthy control subjects (n=157). The ROC plots showed that the diagnostic sensitivity of GAD65 antibodies was 77% and the specificity 92% compared with 8% and 98%, respectively for GAD67 antibodies. In the IDDM sera, GAD65 and GAD67 antibodies were concordant in 7% (6 of 81) and GAD65 antibodies and ICA in 89% (72 of 81) without a correlation between the autoantibody levels. Autoantibodies to recombinant human islet GAD65 are specific and sensitive markers for childhood IDDM in this immunoassay with in vitro synthesized 35S-methioninelabelled recombinant GAD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408469
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  • 3
    Electronic Resource
    Electronic Resource
    On the pathogenesis of IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. S82 
    Details
    ISSN: 1432-0428
    Keywords: Insulin-dependent diabetes mellitus ; free radicals ; cytokines ; beta-cell destruction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2 − and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400830
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  • 4
    Electronic Resource
    Electronic Resource
    A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM (1994)
    Springer
    Diabetologia 37 (1994), S. 344-350 
    Details
    ISSN: 1432-0428
    Keywords: Key words Glutamic acid decarboxylase, receiver-operating characteristic plot, diagnostic accuracy, islet cell antibodies, autoimmunity, diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin-dependent diabetes mellitus (IDDM) is associated with autoreactivity against GAD but the diagnostic sensitivity (positivity in disease) and specificity (negativity in health) of isoform-specific GAD antibodies have yet to be defined in assay systems suitable for screening large number of samples. One set of IDDM patient (n =10) and control (n =50) standard sera were used to develop quantitative antibody assays with in vitro synthesized recombinant 35S-methionine-labelled GAD65 and GAD67, respectively, and protein A-Sepharose to separate free from antibody-bound ligand. Binding levels were not normally distributed (p 〈0.0001) and therefore, the diagnostic accuracy of GAD antibodies was analysed by the ROC plots in population-based, consecutively-diagnosed, recent onset, 0–14 year-old patients (n =105), and matched, healthy control subjects (n =157). The ROC plots showed that the diagnostic sensitivity of GAD65 antibodies was 77 % and the specificity 92 % compared with 8 % and 98 %, respectively for GAD67 antibodies. In the IDDM sera, GAD65 and GAD67 antibodies were concordant in 7 % (6 of 81) and GAD65 antibodies and ICA in 89 % (72 of 81) without a correlation between the autoantibody levels. Autoantibodies to recombinant human islet GAD65 are specific and sensitive markers for childhood IDDM in this immunoassay with in vitro synthesized 35S-methionine-labelled recombinant GAD. [Diabetologia (1994) 37: 344–350]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408469
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  • 5
    Electronic Resource
    Electronic Resource
    The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells (1996)
    Springer
    Diabetologia 39 (1996), S. 875-890 
    Details
    ISSN: 1432-0428
    Keywords: Nitric oxide ; nitric oxide synthase ; promoter ; transcription factor ; nuclear factor κB ; pancreatic islets ; beta cells ; insulin-producing cells ; insulin-dependent diabetes mellitus ; superoxide dismutase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The radical nitric oxide (NO) is a possible mediator of pancreatic beta-cell damage in insulin-dependent diabetes mellitus (IDDM). NO is produced by the enzyme nitric oxide synthase (NOS), in a reaction where arginine is the main substrate. There are different isoforms of NOS, but in the context of immune mediated beta-cell damage the inducible form of NOS (iNOS) is the most relevant. The beta-cell iNOS is similar and encoded by the same gene on chromosome 17 as the iNOS expressed in macrophages and other nucleated cells. iNOS activation depends on gene transcription and de novo enzyme synthesis, and NO seems to induce a negative feedback on iNOS expression. While iNOS mRNA is induced by interleukin-1Β (IL-1Β) alone in rodent insulin-producing cells, a combination of two (IL-1Β + interferon γ) (IFN-γ) or three (IL-1Β + IFNγ + tumour necrosis factor α) cytokines is required for iNOS activation in human pancreatic islets. The promoter region of the murine iNOS gene has at least 25 binding sites for different transcription factors, and the nuclear transcription factor κB is necessary for cytokine-induced iNOS transcription in both rodent and human pancreatic islets. The nature of other transcription factors relevant for iNOS regulation in these cells remains to be determined. Induction of iNOS is paralleled by induction of several other cytokine-dependent genes in beta cells, including argininosuccinate synthetase, cyclooxygenase and manganese superoxide dismutase. Some of these genes may contribute to beta-cell damage, while others are probably involved in beta-cell defence and/or repair. Regulation of iNOS and other related genes in beta cells is complex, and differs in several aspects from that observed in macrophages. There are also important differences in iNOS regulation between rodent and human pancreatic islets. A detailed knowledge of the molecular regulation of these genes in beta cells may be instrumental in the development of new approaches to prevent beta-cell destruction in early IDDM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00403906
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  • 6
    Electronic Resource
    Electronic Resource
    Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with Type I diabetes mellitus (2000)
    Springer
    Diabetologia 43 (2000), S. 800-808 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Genetics, candidate gene, apoptosis, tolerance, microsatellite, ALPS, c-Myb, SP-1, NF-kB.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate susceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptosis mediated by Fas is important in maintaining peripheral self-tolerance and in down-regulating the immune response and could have a role in immune-mediated beta-cell destruction.¶Methods. We did a molecular scan of the entire human FAS (promoter, exons 1–9 including exon-intron boundaries and the 3 ′UTR) using single strand conformational polymorphism-heteroduplex analysis.¶Results. We identified 15 mutations, of which 11 are new. Of these a g-1194A→T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kB, respectively. A total of 1068 people from a Danish family collection comprising 138 Type I diabetic sib-pair families (289 affected and 121 unaffected offspring) and 103 Type I diabetic parent-offspring multiplex families (103 affected and 112 unaffected offspring) were typed for the three most frequent polymorphisms with high heterozygosity indices and for a FAS microsatellite. Haplotypes were established and data analysed using the extended transmission disequilibrium test, ETDT.¶Conclusion/interpretation. We found no overall evidence for linkage of the FAS polymorphisms to Type I diabetes. We conclude that it is unlikely that the Fas gene does contribute to genetic susceptibility for Type I diabetes. [Diabetologia (2000) 43: 800–808]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051378
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  • 7
    Electronic Resource
    Electronic Resource
    The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells (1996)
    Springer
    Diabetologia 39 (1996), S. 875-890 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Nitric oxide ; nitric oxide synthase ; promoter ; transcription factor ; nuclear factor k B ; pancreatic islets ; beta cells ; insulin-producing cells ; insulin-dependent diabetes mellitus ; superoxide dismutase.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The radical nitric oxide (NO) is a possible mediator of pancreatic beta-cell damage in insulin-dependent diabetes mellitus (IDDM). NO is produced by the enzyme nitric oxide synthase (NOS), in a reaction where arginine is the main substrate. There are different isoforms of NOS, but in the context of immune mediated beta-cell damage the inducible form of NOS (iNOS) is the most relevant. The beta-cell iNOS is similar and encoded by the same gene on chromosome 17 as the iNOS expressed in macrophages and other nucleated cells. iNOS activation depends on gene transcription and de novo enzyme synthesis, and NO seems to induce a negative feedback on iNOS expression. While iNOS mRNA is induced by interleukin-1β (IL-1β ) alone in rodent insulin-producing cells, a combination of two (IL-1β + interferon γ) (IFN-γ ) or three (IL-1β + IFNγ + tumour necrosis factor α) cytokines is required for iNOS activation in human pancreatic islets. The promoter region of the murine iNOS gene has at least 25 binding sites for different transcription factors, and the nuclear transcription factor k B is necessary for cytokine-induced iNOS transcription in both rodent and human pancreatic islets. The nature of other transcription factors relevant for iNOS regulation in these cells remains to be determined. Induction of iNOS is paralleled by induction of several other cytokine-dependent genes in beta cells, including argininosuccinate synthetase, cyclooxygenase and manganese superoxide dismutase. Some of these genes may contribute to beta-cell damage, while others are probably involved in beta-cell defence and/or repair. Regulation of iNOS and other related genes in beta cells is complex, and differs in several aspects from that observed in macrophages. There are also important differences in iNOS regulation between rodent and human pancreatic islets. A detailed knowledge of the molecular regulation of these genes in beta cells may be instrumental in the development of new approaches to prevent beta-cell destruction in early IDDM. [Diabetologia (1996) 39: 875–890]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00403906
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  • 8
    Electronic Resource
    Electronic Resource
    Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells (1998)
    Springer
    Diabetologia 41 (1998), S. 1482-1491 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Neuropeptide Y ; Y1 receptor ; insulin secretion ; insulinoma cells.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Neuropeptide Y (NPY) has been shown to inhibit insulin secretion from the islets of Langerhans. We show that insulin secretion in the insulinoma cell line RIN 5AH is inhibited by NPY. 125I-Peptide YY (PYY) saturation and competition-binding studies using NPY fragments and analogues on membranes prepared from this cell line show the presence of a single class of NPY receptor with a Y1 receptor subtype-like profile. Inhibition of insulin secretion in this cell line by NPY fragments and analogues also shows a Y1 receptor-like profile. Both receptor binding and inhibition of insulin secretion showed the same orders of potency with NPY 〉 [Pro34]-NPY 〉 NPY 3–36 〉 〉 NPY 13–36. The Y1 receptor antagonist, BIBP 3226, blocks NPY inhibition of insulin secretion from, and inhibits 125I-PYY binding to, RIN 5AH cells. Northern blot analysis using a Y1-receptor specific probe shows that NPY Y1 receptors are expressed by RIN 5AH cells. Y5 receptors are not expressed in this cell line. Neuropeptide Y inhibition of insulin secretion is blocked by incubation with pertussis toxin, implying that the effect is via a G-protein (Gi or Go) coupled receptor. Neuropeptide Y inhibits the activation of adenylyl cyclase by isoprenaline in RIN 5AH cell lysates, and the stimulation of cAMP by glucagon-like peptide-1 (7–36) amide (GLP-1). It also blocks insulin secretion stimulated by GLP-1, but not by dibutyryl cyclic AMP. Hence, we suggest that NPY inhibits insulin secretion from RIN 5AH cells via a Y1 receptor linked through Gi to the inhibition of adenylyl cyclase. [Diabetologia (1998) 41: 1482–1491]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250051095
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  • 9
    Electronic Resource
    Electronic Resource
    The inducible nitric oxide synthase gene, Nos2, maps to mouse Chromosome 11 (1994)
    Springer
    Mammalian genome 5 (1994), S. 318-320 
    Details
    ISSN: 1432-1777
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00389549
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