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  • 1
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; HLA-DR ; HLA-DQ ; polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary HLA DQβ chain, in particular amino acid at position 57, has been reported to contribute to susceptibility and resistance to Type 1 (insulin-dependent) diabetes mellitus in Caucasians. Resistance has been proposed to be conferred by aspartic acid at this position. To ascertain the association of HLA DQβ and DRβ genes with Type 1 diabetes in Japanese subjects, ten Japanese Type 1 diabetic patients were investigated at DNA level. Genomic DNA was amplified by polymerase chain reaction, and dot blot analysis was carried out using the amplified DNA with allele specific oligonucleotide probes. All patients had aspartic acid at position 57 of at least one of their two DQβ chains, and there was no significant difference of amino acids at the same position of DRβ chain in patients compared to control subjects. These data indicate that the protective role of aspartic acid at position 57 of DQβ chain is less significant in Japanese compared with Caucasian subjects.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; HLA-DQA1 gene ; HLA-DQB1 gene ; tumour necrosis factor ; polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In this study HLA-DQA1 and TNF genes in addition to HLA-DQB1 gene were investigated at DNA level for elucidation of the genetic backgrounds of Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. DNA, amplified by polymerase chain reaction, was subjected to allele specific oligonucleotide dot blot analysis, restriction fragment length polymorphism analysis or DNA sequencing. Polymorphism of the TNF gene to NcoI did not correlate with Type 1 diabetes in Japanese patients. DQw1.2 had a protective effect against the disease, the DQA1*1 allele was significantly decreased and DQA1*3 allele was significantly increased. Seventeen out of twenty-two Type 1 diabetic patients (77%) were homozygous for DQA1*3 and five out of twenty-two (23%) heterozygous. The DQA1*3 gene of Type 1 diabetic patients had a normal nucleotide sequence. Furthermore, DQA1*3 was found unexpectedly in two patients without DR4 or DR9. These data indicate that DQA1 gene confers susceptibility and resistance to Type 1 diabetes in Japanese subjects.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Cytomegalovirus ; Epstein-Barr virus ; polymerase chain reaction ; pancreas biopsy ; autoimmunity ; insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Viral infection is assumed to trigger or exacerbate autoimmune responses against pancreatic beta cells leading to the development of insulin-dependent diabetes mellitus (IDDM). We therefore examined by polymerase chain reaction the presence of two candidate viruses, cytomegalovirus and Epstein-Barr virus, in IDDM pancreases. Pancreas tissues were obtained by biopsy under laparoscopy from 16 recent-onset IDDM patients: age 17–53 years; disease duration 0–7 months; six had flu-like symptoms before onset. Frozen sections were made and subjected to DNA amplification. DNA samples were prepared from the frozen sections and polymerase chain reaction was performed using primers specific to cytomegalovirus, Epstein-Barr virus and control gene for HLA-DP. Cytomegalovirus- and Epstein-Barr virus-infected cells were used for positive control. Southern blot analysis could detect cytomegalovirus DNA from as few as 2×10−1 cytomegalovirus-infected cells and Epstein-Barr virus DNA from two Epstein-Barr virus-infected cells. This highly sensitive analysis, however, could not detect cytomegalovirus or Epstein-Barr virus genomes in pancreases of recent-onset IDDM. A single copy human gene (HLA-DP) was amplified from all IDDM pancreases indicating that DNA amplification was performed without inhibition. We conclude that cytomegalovirus or Epstein-Barr virus genomes are unlikely to exist in pancreas biopsy specimens of recent-onset IDDM patients.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords Pancreatic beta cell ; Bcl-2 ; apoptosis ; cytokine ; interleukin-1 ; tumour necrosis factor ; interferon-γ.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cytokines are thought to contribute to the induction of pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. The molecular mechanisms that underlie beta-cell death were investigated by studying cytokine-induced cell death in beta-cell lines. A combination of three cytokines (interleukin-1β, tumour necrosis factor-α, and interferon-γ) induced apoptotic cell death in the mouse pancreatic beta-cell line βTC1, as judged from the appearance of cells with hypodiploid nuclei and oligonucleosomal DNA fragmentation. The same treatment also induced apoptosis in the mouse pancreatic alpha-cell line αTC1 and the NOD/Lt mouse beta-cell line NIT-1, although to a lesser extent than in βTC1 cells. The abundance of endogenous Bcl-2 in βTC1 cells was lower than that in the other two cell lines. Overexpression of human Bcl-2 in βTC1 cells partially protected them from cytokine-induced cell death. These results suggest that apoptosis may be responsible, at least in part, for cytokine-induced beta-cell destruction and that Bcl-2 prevents apoptosis in pancreatic islet cells. [Diabetologia (1996) 39: 530–536]
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Diabetes mellitus ; insulin resistance ; IGF-1 ; IRS-1 ; cell growth.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Although both increased cell growth and impaired insulin signalling have been associated with diabetes, this association has not been investigated. Insulin-like growth factor-1 (IGF-1), a structural and functional analog of insulin, may play a part in the aberrant insulin receptor-mediated signalling observed in diabetes. Methods. To investigate the consequence of this impaired signalling on cell proliferation and transformation, we transfected Chinese hamster ovary cells with cDNA encoding a kinase-defective insulin receptor. Results. In these mutant cells, the mitogenic and metabolic effects of insulin were reduced compared with control cells (p 〈 0.05) and this was due to a dominant negative effect. In contrast, these mutant cells showed a higher mitogenic response to IGF-1 than control cells, although IGF-1 receptor expression was similar in both cell lines. There was no statistically significant difference in mitogenic response, however, to platelet-derived growth factor, basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor. Variables of the IGF-1 signalling pathway, including tyrosine phosphorylation of insulin receptor substrate-1 and activation of mitogen-activated protein kinase and phosphatidyl inositol 3 kinase, were also augmented in mutant cells. Insulin receptor substrate-1 message and protein abundance were higher in mutant than in control cells. Moreover, mutant cells had a higher mitogenic potential in low-serum-containing medium, suggesting that these cells have a transformed phenotype. Conclusion/interpretation. These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes. [Diabetologia (1999) 42: 763–772]
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Keywords HNF-cascade, gene expression, insulin secretion, mutation, genetics.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Molecular defects of the genes for transcription factors, hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-1β and insulin promoter factor-1 cause maturity-onset diabetes of the young (MODY1, 3, 5, and 4, respectively). This suggests the HNF-related transcription cascade is important in insulin secretion which is induced by glucose. These genes and the gene encoding glycolytic enzyme glucokinase (MODY2) are, however, responsible for only 15–20 % of cases of MODY in the Japanese. Searching for a novel form of MODY in this population, we cloned a new candidate gene encoding human HNF-3β, a winged helix transcription factor, which also belongs to the same HNF-transcription cascade.¶Methods. The cDNA clone for human HNF-3β was isolated from a liver cDNA library. The gene was also cloned from a genomic library and its organization and chromosomal localization were determined. We screened 68 Japanese subjects with MODY/early-onset diabetes for mutations in this gene.¶Results. Human HNF-3β is composed of 457 amino acids. The human gene, which was mapped to the segment 30 cR from SHGC-37 039 on chromosome 20 p by radiation hybrid mapping, spans approximately 4.5 kb and consists of three exons. Direct sequencing of the exons and flanking regions identified one missense mutation A328 V and seven polymorphisms, although the functional significance of the mutation in the pathogenesis of diabetes is not known.¶Conclusion/interpretation. The characterization of the structure of the HNF-3β gene and its mapping in the framework of markers will be helpful in genetic studies of the various forms of diabetes mellitus. [Diabetologia (2000) 43: 121–124]
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  • 7
    ISSN: 1432-0428
    Keywords: Non-obese diabetic (NOD) mice ; retrovirus ; gag protein p30 ; autoimmunity ; cyclophosphamide ; pathogenesis ; Western blot analysis ; ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We investigated the presence of retroviral protein in the pancreatic islets of non-obese diabetic mice to prove that the virus-like particle observed specifically in the pancreatic Beta cell of these mice was retrovirus. Western blot analysis probed with anti-retrovirus antibody demonstrated the existence of retroviral gag (group specific antigen) protein p30 in the islets of female non-obese diabetic mice. Islets of non-obese diabetic mice which were treated with cyclophosphamide, known to accelerate the development of insulitis and diabetes mellitus, have shown both a significantly increased number of retrovirus-like particles (type C) and enhanced expression of gag protein p30, compared to those of mice not treated with cyclophosphamide. These results confirmed the presence of type C retrovirus in non-obese diabetic mouse Beta cells and suggest a role for retrovirus in the development of insulitis and diabetes in these mice.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0428
    Keywords: Islet cell antibody ; Type 1 (insulin-dependent) diabetes ; standards ; quality control ; Juvenile Diabetes Foundation units
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Forty-one assays were analysed at the 3rd International Workshop on the standardisation of islet cell antibodies. Analysis of precision demonstrated assays consistently detecting blind duplicates within one doubling dilution and capable of discriminating one doubling dilution differences in islet cell antibody concentration. Some assays, however, reported duplicates discrepantly by more than seven doubling dilutions, and consequently could not distinguish even large quantities of islet cell antibodies. Precision was best in assays from laboratories which had participated in all three Standardisation Workshops and was not dependent upon methodology. The use of the Juvenile, Diabetes Foundation reference islet cell antibody standard and standard curves reduced the scatter of results, and was best amongst assays with better precision. Twenty-seven assays reported all ten blood donor sera as negative. However, 14 assays did not, and specificity (negativity in health) was 〈50% in three assays. Low specificity was strongly associated with poor precision. The detection limit of assays ranged from 〈5 to 50 JDF units and was partially dependent upon methodology. Assays incorporating extended incubation had the lowest detection limits without a decrease in the specificity of the ten blood donor sera. Precise quantification is fundamental for the standardisation and comparability of islet cell antibodies. Precise quantitative assays have been identified and reference standards and common units established.
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  • 9
    ISSN: 1432-0428
    Keywords: Keywords MODY ; HNF-1α ; insulin ; arginine ; mutation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Mutations in the hepatocyte nuclear factor-1α gene are a common cause of the type 3 form of maturity-onset diabetes of the young. We examined the clinical features and molecular basis of hepatocyte nuclear factor-1α (HNF-1α) diabetes. Methods. Thirty-seven Japanese subjects with early onset Type II (non-insulin-dependent) diabetes mellitus and 45 with Type I (insulin-dependent) diabetes mellitus were screened for mutations in this gene. Functional properties of mutant HNF-1α were also investigated. Results. Three new mutations [G415R, R272C and A site of the promoter ( + 102G-to-C)] were found. Insulin secretion was impaired in the three subjects. Insulin and glucagon secretory responses to arginine in the subject with the R272C mutation were also diminished. Molecular biological studies indicated that the G415R mutation generated a protein with about 50 % of the activity of wild-type HNF-1α. The R272C mutation had no transactivating or DNA binding activity and acted in a dominant negative manner. The + 102 G-to-C mutation in the A site of the promoter activity was associated with an increase in promoter activity and it had 42–75 % more activity than the wild-type sequence. Conclusion/interpretation. Mutations in the HNF-1α gene may affect the normal islet function by different molecular mechanisms. [Diabetologia (1999) 42: 621–626]
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  • 10
    ISSN: 1432-0428
    Keywords: Type 1 (insulin-dependent) diabetes mellitus ; pathology ; pathogenesis ; diagnosis ; pancreas biopsy ; laparoscopy ; immunohistochemistry ; MHC class I antigen ; MHC class II antigen ; immunotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We attempted to examine the immunopathological change of the pancreatic islets of newly diagnosed Type 1 (insulin-dependent) diabetic patients and thereby to obtain useful information for the therapy of the patients. For this purpose, pancreas biopsy under laparoscopy was performed 2–4 months after the onset of Type 1 diabetes in seven newly diagnosed patients. All biopsies were performed safely without any complications. Immunohistochemical examination of the biopsy specimens revealed a marked decrease of insulin-containing cells, preservation of glucagon-containing cells, and various degrees of expression of MHC class I and class II antigens in islet cells and in endothelial cells within and around the islets. Signs of active autoimmune phenomena, e. g. lymphocytic infiltration or immunoglobulin deposition in islets, were not detected in any of these patients by light microscopical evaluation. We conclude that pancreas biopsy under laparoscopy has shown various immunological changes in the islets of newly diagnosed Type 1 diabetic patients. Pancreas biopsy, however, may not be suitable under the present protocol for the selection of patients for immunotherapy because of problems including sampling errors.
    Type of Medium: Electronic Resource
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