Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml), and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA greater than or equal to 39 nU/ml) versus 4% (6 of 141) among DR4- relatives (P less than 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4-, P = 0.003, Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs, and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that, in first-degree relatives of patients with type I diabetes, there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity, and we hypothesize that DR4-associated diabetes susceptibility, distinct from DR3-associated susceptibility, may be secondary to this influence.
Diabetes 1991 Jun
PMID:Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes. 204 Mar 87

The mechanism of pancreatic beta-cell destruction in type I (insulin-dependent) diabetes mellitus (IDDM) involves autoimmune events directed against these cells. Anti-beta-cell autoimmunity occurs in genetically predisposed individuals and may precede clinical manifestations of IDDM by several years. Markers for beta-cell autoimmunity, especially islet-cell antibodies, are being used with increasing reliability both for detection of IDDM and for evaluating the risk of development of the disease. HLA alleles associated with IDDM include DR3 and DR4, with the risk of IDDM being especially high in individuals with the heterozygous combination DR3/DR4. Recent advances in molecular biology have resulted in more accurate identification of genetic variants and even of amino acid sequences associated with IDDM. These markers can be used to identify patients with genetic susceptibility to the disease. The mechanism of action of genes associated with IDDM is as yet unknown but probably involves the receptor function of HLA molecules for antigens during immune responses.
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PMID:[New data concerning the etiology of insulin-dependent diabetes]. 206 53

The HLA haplotype and its relationships with clinical, biological and immunological parameters were analyzed in a group of 87 Spanish type 1 diabetic patients at the clinical onset of the disease. The frequency of HLA-B18, DR3 and DR4 antigens was significantly increased whereas DR2, DR5 and DR7 were decreased in comparison with 189 healthy unrelated controls without family history of diabetes. DR3 showed a maximum relative risk for diabetes (5.5) whereas DR4 had a lower one (4.0). HLA-DR4 patients were younger at the time of diagnosis than DR4 negative (16.7 vs 21.4 years). We found no statistically significant relationship between HLA antigens and the other variables studied including the presence of islet cell antibodies, complement fixing islet cell antibodies, insulin autoantibodies, organ-specific antibodies, fasting and maximal glucagon stimulated C-peptide levels, initial glycemia and glycosylated hemoglobin.
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PMID:HLA antigens in Spanish type 1 diabetic population. Correlations with clinical, biological and autoimmune markers. 207 84

Fifteen women with positive islet cell antibodies were identified in a group of 115 consecutive patients found to have impaired glucose tolerance in pregnancy. These subjects were postulated to be at increased risk of later developing type 1 diabetes mellitus. They were examined post--partum for HLA types known to be associated with this disease and for any increase in Interleukin 2 receptor expression or alteration of T cell subsets of possible relevance to its pathogenesis. Fifteen women negative for islet antibodies and with normal glucose tolerance during previous pregnancy and 15 women with a normal fasting plasma glucose who had never been pregnant were studied as controls. Using flow cytometric techniques a significant increase in both the number and proportion of activated (Interleukin 2 receptor, CD25) lymphocytes in the peripheral blood of women who had islet cell antibodies and previous impaired glucose tolerance in pregnancy was found (0.14 +/- SE 0.03 x 10(9)/l; 7.1 +/- 1.1%) when compared with normal parous controls (0.09 +/- 0.01 x 10(9)/l; 4.2 +/- 0.6%), p less than 0.01 x 10(9)/l; showed significant increases when compared with nulliparous controls (0.04 +/- 0.01 x 10(9)/l; 2.1 +/- 0.2%), p less than 0.01. No differences were detected between the three groups with respect to total T-lymphocytes (CD3), helper T-lymphocytes (CD4), suppressor cytotoxic T-lymphocytes (CD8), or the inducer of suppressor (Leu 3+/Leu 8+) subset of T-lymphocytes. Three women persistently islet cell antibody positive, two of whom were HLA DR4, showed impaired glucose tolerance at the time of lymphocyte subset analysis, while two further patients, one DR3 and the other DR4, had developed type 1 (insulin-dependent) diabetes. No correlation between increased Interleukin 2 receptor expression and glucose intolerance was demonstrated. We conclude that islet cell antibody positive women with impaired glucose tolerance during pregnancy are at increased risk of later developing type 1 diabetes but that heightened immune activation present in these women is in part a post-pregnancy phenomenon.
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PMID:Increased interleukin 2 receptor expression in post-gestational women: relationship to impaired glucose tolerance and islet cell antibodies in pregnancy. 210 86

To examine whether the presence of thyrogastric autoantibodies is associated with an increased susceptibility towards developing type 1 diabetes we have tested for thyroid (microsomal and thyroglobulin) and gastric-parietal cell antibodies in 86 pairs of identical twins, 47 discordant and 39 concordant for type 1 diabetes. Autoantibodies were detected in both twins of a pair in 35 and in neither twin in 45 pairs. In only 6 pairs (3 discordant) was there a discrepancy in the antibody results between co-twins. The frequency of antibodies was similar in twin pairs discordant, (21/44, 48%), and concordant, (14/36, 39%), for diabetes. Thyrogastric antibodies were not more frequent in pairs that were female, diagnosed above the age of 20, or had HLA DR3 as opposed to DR4. We conclude that thyrogastric autoantibodies are common in both type 1 diabetic patients and their non-diabetic identical twins. Their presence appears to be genetically determined but does not increase the susceptibility of developing diabetes. The presence of autoantibodies does not appear to indicate a separate aetiological type of diabetes.
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PMID:Are thyrogastric autoantibodies associated with an increased susceptibility to developing type 1 (insulin-dependent) diabetes? A study in identical twins. 212 77

Juvenile insulin-dependent diabetes mellitus develops in susceptible children exposed to unknown environmental factors. If the genes responsible for susceptibility could be identified, it should be possible to understand the method of injury to beta cells as well as identify the infectious or other agents involved. For a decade it has been known that one or more of the susceptibility genes must be within the major histocompatibility complex (MHC). Unfortunately, there are at least 20 different genes in the complex and it has not been possible to determine which are actually responsible. Therefore, we undertook to apply a new concept and new technology to the problem. Over several years we have shown that the diabetogenic gene(s) are contained within conserved ancestral haplotypes which can then be used as markers of the DNA which must contain the gene(s), whether present in a patient or an asymptomatic carrier such as a parent. This approach avoids the confusion which has resulted from using DR3 or DR4 which are only sometimes associated with the relevant genes. The new technology involves pulsed field gel electrophoresis which allows examination of large fragments of DNA containing all of the MHC, and makes it possible to identify deletions and duplications which were otherwise undetectable. In the first instance we compared two ancestral haplotypes [1,8,3 (8.1) and 18,F1,3 (18.2)] known to contain the relevant genes, and contrasted the DNA with that of another ancestral haplotype [3,7,2(7.1)] which is known to lack these genes. We have shown that there are three major deletions common to the two carrier haplotypes but absent in the protective haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Supratypes and ancestral haplotypes in IDDM: potential importance of central non-HLA MHC genes. 218 61

Urinary albumin excretion (UAE) was determined by radioimmunoassay in two 24 h urine collections from 125 diabetic children and adolescents and from 71 normal children matched for age and sex. Thirteen patients (10.4%) aged greater than 12 years had microalbuminuria, i.e. log transformed UAE levels above the upper normal range (24.5 mg/24 h). UAE values were positively correlated with age, GH secretion, but not with duration of disease, glycosylated hemoglobin, renal size or N-acetyl-beta-glucosaminidase excretion. Diabetic normoalbuminuric children aged 10 years and older had significantly higher UAE than controls and than younger diabetic patients matched for duration of disease. HLA DR3/DR4 heterozygosity frequency was significantly higher (p less than 0.01) in the microalbuminuric group than in the normoalbuminuric. All microalbuminuric subjects (n = 8) with short duration of disease (3.92 +/- 3.43 yr) developed diabetes at puberty. In conclusion, our cross-sectional study suggests: if a number of factors are combined, i.e. HLA DR3/DR4 heterozygosity, onset of disease at puberty and higher GH values, the probability of developing abnormal levels of UAE will increase.
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PMID:Microalbuminuria in diabetic children and adolescents. Relationship with puberty and growth hormone. 219 Apr 42

A total of 15 families were investigated: probands with insulin-dependent diabetes mellitus and their relatives of the 1st degree of progeny (43 persons) in order to study the distribution of HLA antigens and their interrelationship with the gravity of a course of diabetes mellitus and the type of GTT. Antigens DR3 and/or DR4 were revealed in 93% of probands, especially in heterozygous patients (57.1%). A low level of C-peptide (0.21 +/- 0.03 ng/ml) was noted in most of the probands excluding 3 patients with nephropathy. Distinct relationship of antigens DR3 and DR4 with a clinical course of disease and its severity was undetectable. Antigens DR3 or/and DR4 were detected in 96% of the relatives with the prevalence of antigen DR4 (in 54.2%). During GTT normal tolerance was observed in 82.1% (23 persons), disorders were noted in 4, insulin-dependent diabetes mellitus--in one. Most of the relatives (82.6%) with normal glucose tolerance had antigens DR3 and/or DR4. Irrespective of the type of DR antigens the probands' relatives were characterized by moderate hyperinsulinism (by the results of IRI and C-peptide of blood serum).
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PMID:[An analysis of the interrelationship of the HLA genotype and carbohydrate metabolism in the families of probands with insulin-dependent diabetes mellitus]. 220 51

Our understanding of the role of HLA genes associated with insulin-dependent diabetes mellitus (IDDM) is in disarray, despite recent improvements in the definition of specific alleles and haplotypes. Some genes are highly associated with IDDM, other genes are associated with resistance to IDDM, and some highly associated susceptibility genes are markedly influenced by trans-associated synergistic effects (DR3/4 heterozygotes) or protective effects (DR2/4 heterozygotes). This plethora of genetic associations has spawned the notion that there are many contributing susceptibility genes, which, in turn, has led to the search for shared structural features among different genes on IDDM-associated haplotypes. From a more mechanistic point of view, however, the wide range of variable IDDM associations, with both cis- and trans-encoded protective and/or synergistic effects, suggests a different approach. This article proposes a hypothesis in which the different HLA associations with IDDM can be simply explained by a single unifying concept: a hierarchy of affinities determines the interaction between a diabetogenic peptide and different class II molecules, and an individual is susceptible to IDDM if the class II molecule in that individual with the highest affinity for such a peptide is a DQ beta susceptibility gene. The explicit formulation of this proposal and its genetic implications provide an explanation for HLA-encoded dominant "protection" and for some of the more subtle genetic observations related to cis and trans influences in IDDM susceptibility.
Diabetes 1990 Oct
PMID:A unified hypothesis for the complex genetics of HLA associations with IDDM. 221 67

The highest risk for the development of type I diabetes resides with first-degree relatives of the diabetic proband, this risk being in the order of 2.9%, 6.6% and 4.9% for parents, siblings and children of the proband, respectively. The major genetic markers associated with the development of insulin-dependent diabetes mellitus (IDDM) is the possession of the HLA alleles DR3/DR4 and more recently the absence of aspartate in the 57th position on the beta-chain of the HLA DQ gene (HLA DQ beta Asp 57 negative). The most important auto-immune marker for predicting preclinical IDDM is the presence of high titres (greater than 40 Juvenile Diabetes Foundation units) of islet cell antibodies (ICA), while the finding of insulin auto-antibodies (IAA) is a good predictive marker in children less than 5 years of age. The presence in a susceptible individual of ICA plus IAA is a better predictor of impending IDDM than the presence of either of these two markers alone. Antibodies which precipitate an islet membrane protein (MW 64K) are highly sensitive and specific markers of preclinical IDDM. The presence of 64K antibodies may well be the most important predictive marker of impending IDDM in the future. The progressive decline of the first phase of insulin secretion in response to an intravenous glucose challenge is associated with the onset of IDDM within 18 months. Of the immunotherapeutic agents at present used in clinically manifest IDDM, azathioprine has been shown to be ineffective in increasing the remission phase, while the value of nicotinamide is controversial.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Can we predict and/or prevent type I diabetes? 221 82


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