Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes is an autoimmune disease that may be becoming more prevalent. It has a polygenic mode of inheritance with a major gene being present in the HLA DQ locus on chromosome 6. Inferential data suggest that environmental factors may be important to genetic penetrance albeit we still lack proof for involvement of often maligned viruses. Patients with IDD and their families are predisposed to organ-specific autoimmunities which should be routinely screened for. Autoantibodies to insulin, to a beta cell cytoplasmic lipid containing moiety and to a beta cell protein of 64KDa, which is believed to be the GABA forming enzyme GAD, can be used to predict IDD among relatives and probably the general population as well. Immunosuppressive therapy can modify the course of IDD after diagnosis and should be able to delay the clinical onset if given before diagnosis. Rigorous insulin therapy should also be given as needed to control hyperglycemia and avoid glucose toxicity to the islets. Such trials are now underway.
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PMID:Immunology of diabetes mellitus. 832 19

Insulin-dependent diabetes mellitus is common in Tunisia. Eighty-six pediatric cases managed at the diabetes clinic of a department of pediatrics in Tunis from 1979 through 1989 were studied. Relevant clinical and biological findings were abstracted from case-records. Admissions of patients with diabetes mellitus accounted for approximately 0.44% of admissions to the pediatric ward during the study period. Mean age of patients was 7 years. Sex ratio was 0.89. Polyuria with polydipsia and ketoacidosis were the two most common presenting manifestations. Mean blood glucose level at diagnosis was 22.44 mmol/l. Rate of consanguinity was 48%. HLA typing studies demonstrated a high prevalence of DR3 and DR4 alleles and especially of simultaneous expression of both these alleles. Several factors are incriminated in the development of childhood insulin-dependent diabetes mellitus.
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PMID:[An analytic study of cases of childhood diabetes in a pediatric department in Tunis]. 175 Jul 45

1. In no ethnic group is the overall association between systemic sclerosis and the MHC strong enough for direct clinical use. MHC associations do support the classification of the disease into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. 2. Indications are that associations between specific subsets of patients with systemic sclerosis and genetic markers will assume greater importance both diagnostically and prognostically. The group with lung fibrosis look prime candidates, for example. 3. Genetic markers are useful means of relating chemically induced systemic sclerosis like disorders with the classical disease. Vinyl chloride disease provides an example. 4. Evidence is emerging of strong associations between certain genetic markers and autoantibody production; a similar story has emerged in systemic lupus erythematosus. We believe that, eventually, genetic tests will be used to influence treatment in at least a subset of patients with systemic sclerosis but that a dramatic breakthrough will not be made until we know how the genetics of the disease relate to the primary biochemical disease characteristic--that is, the overproduction of collagen. In this respect it has been suggested that the 5' flanking DNA of dermal collagen genes is particularly susceptible to the action of Scl-70 (topoisomerase I). A problem is how to tie this and the other observations discussed above together. The association of autoantibodies with topoisomerase I provides a tentative link between the MHC and collagen gene expression. Although the role and reason for anti-Scl-70 in systemic sclerosis is unknown, humoral autoimmunity, at least in systemic lupus erythematosus, seems to be strongly dependent on specific HLA genes. With an understanding of the function of MHC products at the molecular level, HLA and disease associations can now be analysed on a mechanistic level. For insulin dependent diabetes mellitus it has been shown that the MHC determined susceptibility to the disease is conferred by neutral residues (Val, Ser, Ala), at position 57 of the DQ beta chain, while Asp at this position correlates with resistance. A similar phenomenon has been described in rheumatoid arthritis. Although DR4 in general is associated with rheumatoid arthritis, it is heterogeneous, but a subtype of DR4 which is characterised by positively charged residues at positions 70 and 71 of the beta chains is not found in patients with rheumatoid arthritis (Wordsworth B P et al, unpublished data). A similar approach applied to the study of systemic sclerosis is likely to be similarly rewarding. The precise subtyping of the class II genes and the characterisation of their associated haplotypes is therefore required for a complete understanding of the contribution of the MHC to the disease. Additional genes linked to the MHC must not be overlooked, and are relevant to associations of haplotypes with the disease. Of particular interest are the recent reports of a new class of proteins, which are determined by genes in the MHC and which are considered to play a part in the assembly of the antigen peptide/MHC molecule complex.
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PMID:Major histocompatibility complex class II genes and systemic sclerosis. 175 Jul 98

Out of a random population of 4208 non-diabetic pupils without a family history of Type I diabetes 44 (1.05%) individuals had islet cell antibody (ICA) levels greater or equal to 5 Juvenile Diabetes Foundation (JDF) units. 39 of these ICA-positives could be repeatedly tested for circulating insulin autoantibodies (CIAA) using a competitive radiobinding assay. The results were compared with the insulin responses in the intravenous glucose tolerance tests (IVGTT) and with HLA types. Six pupils were positive for CIAA. All of them had complement-fixing ICA, and 5 of them were HLA-DR4 positive. Three of the 6 showed a first-phase insulin response below the first percentile of normal controls. Our data indicate that in population-based studies CIAA can be considered as a high risk marker for impaired beta-cell function in non-diabetic ICA-positive individuals.
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PMID:Insulin autoantibodies as determined by competitive radiobinding assay are positively correlated with impaired beta-cell function--the Ulm-Frankfurt Population Study. 176 78

Particular HLA-DQ beta chain alleles were reported as immunogenetic markers of type I diabetes mellitus with young onset of the disease. In a homogeneous German population, we studied HLA-DR specificities and HLA-DQ beta chain alleles in young-onset (less than 21 years of age; n = 185) and adult-onset (greater than 40 years of age; n = 48) insulin-dependent diabetics. In both cohorts of type I diabetics, the HLA-DR3 and -DR4 specificities were significantly increased. The presence of an HLA haplotype with an amino acid other than aspartic acid at position 57 of the DQ beta chain was significantly associated with type I diabetes in both cohorts (etiologic fraction: 93% and 73%). We conclude that the presence of DNA sequences coding for an amino acid other than aspartic acid at the 57th position of the DQ beta chain provides a molecular risk marker for type I diabetes of both and adult onset.
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PMID:Prevalence of HLA-DQ beta chain non-Asp alleles in type I (insulin-dependent) diabetics with young and older ages of onset. 179 91

Cytoplasmic islet cell antibodies (ICA) were determined in a group of non-diabetic Caucasian schoolchildren (n = 4208). The prevalence rate for ICA positivity was 1.05 per cent (95 per cent confidence interval: 0.8-1.4 per cent). Analysis of HLA risk factors revealed that HLA-DRB1*03 (p less than 0.01), HLA-DRB1*04 (p less than 0.01) and HLA haplotypes with non-charged amino acids (non-Asp) at codon 57 of the HLA-DQ beta (p less than 0.01) chain were significantly increased when compared to controls. High levels of islet cell antibodies, i.e. Juvenile Diabetes Federation units (JDF units) equal to or greater than 30 JDF units were found to be associated with amino acids other than aspartic acid at codon 57 of the DQ beta chain molecule. Also the persistence of circulating ICA was found to be associated with non-Asp homozygosity of the proband (p less than 0.03).
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PMID:The level and the persistence of islet cell antibodies in healthy schoolchildren are associated with polymorphic residues of the HLA-DQ beta chain. 179 50

An analysis of the HLA-types of 351 children in whom a diagnosis of insulin dependent diabetes mellitus (IDDM) had been made between 1960 and 1990 revealed that although the frequencies of HLA-DR3, -DR4, -DR3/4, -B8 and -Bw62 were increased there was, depending on the year of diagnosis, a marked fluctuation in the frequencies of these HLA-antigens and in the frequency with which -B8 was associated with -DR3 and -Bw62 with -DR4 suggesting heterogeneity/variation in agents initiating/triggering IDDM.
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PMID:Frequencies of HLA-DR3, -DR4, -B8 and -Bw62 in diabetic children diagnosed between 1960 and 1990. 180 81

Juvenile diabetics have severe loss of beta cell function and require replacement therapy with insulin. Insulin antigenicity can produce anti-insulin antibodies resulting in allergic reactions and insulin resistance. The role of insulin-anti-insulin antibody complexes in the development and progress of chronic diabetic complications like microangiopathy is not very clear. In the present study, there was statistically a significant trend of higher insulin antibody binding levels in IDDM patients who developed retinopathy. Though there was a trend of higher insulin antibody in IDDM patients with retinopathy, there was no association between insulin antibody and HLA antigen which some authors have reported.
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PMID:Anti-insulin antibodies and retinopathy in juvenile onset type-1 diabetes. 181 Aug 80

HLA-DR specificities in 72 Addison's (AD) patients and 808 local controls were compared. We confirmed earlier reports that the HLA-DR3 specificity is significantly increased in AD patients. In our study a relative risk of 3.4 chi 2 = 22.5; pc = 0.01) for the disease was calculated. Analysis of HLA-DQB1 alleles in DR4+ Addison's patients with diabetes mellitus (N = 6) and without IDDM (14 of 18 individuals tested) revealed that the HLA-DQw8 allele (DQB1*0302) was significantly increased in AD patients with IDDM (chi 2 = 13.5; p = 0.001); conversely, a clustering of the HLA-DQw7 allele was detected in DR4+ Addison's patients without IDDM. We thus conclude that particular polymorphic alleles corresponding to non-charged amino acids at position 57 of the HLA-DQ beta-chain [non-Asp-57 alleles] are associated with IDDM also in Addison's patients.
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PMID:The HLA-DQ beta non-Asp-57 allele: a predictor of future insulin-dependent diabetes mellitus in patients with autoimmune Addison's disease. 187 64

Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2,304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas other remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoantibodies and genetic factors associated with the development of type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients. 188 91


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