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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using time-dependent methods, the temporal relationships between the detection of insulin and islet cell autoantibodies and the onset of insulin dependent diabetes (IDDM) were analyzed in a prospective study of 4694 nondiabetic relatives of 1929 patients with IDDM who had been followed for a median of 4 yr. Insulin autoantibodies were detected in 1.5% of relatives at their initial test whereas an additional 1.0% subsequently became positive for these antibodies during follow-up. Islet cell autoantibodies were detected in 2.6% of the relatives at the time of their first test and an additional 0.9% were observed to develop them during the follow-up period. The risk of developing IDDM was significantly higher (P = 0.0001) among those who were found to have one of these antibodies, but was highest among those under the age of 20 yr at inception of this study who tested positive for both. Among older relatives, the detection of insulin autoantibodies among those who were islet cell antibody positive did not convey an additional risk of IDDM. In a subset of relatives, the presence of either antibody was associated with a higher frequency (P < 0.001) of diabetes associated human leukocyte antigen-DR 3/4 heterozygotes. Islet cell autoantibodies were highly associated with elevated fasting and 60-min glucose concentrations (P = 0.0001) as well as decreased early phase (1 and 3 min) insulin response to an iv glucose tolerance test (P = 0.0001). Insulin antibodies were significantly associated with decreased early phase insulin response to iv glucose (P = 0.0003). These data confirm independent risks associated with each antibody and suggest that their temporal relationship may be an important reflection of the pathogenic process underlying IDDM observations which facilitate its predictability.
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PMID:Insulin and islet cell autoantibodies as time-dependent covariates in the development of insulin-dependent diabetes: a prospective study in relatives. 837 Jun 96

Class I major histocompatibility complex molecules have been shown to be physically associated with insulin receptor molecules on the surfaces of a number of different cell types. The class I human leukocyte antigen (human MHC) phenotype of B lymphoblasts correlates with the affinity of IR for insulin. This correlation could be the result of association of some but not other HLA molecules with IR, or could reflect differences in the way in which association with an HLA molecule affects the function of IR. To distinguish between these possibilities, this study isolated complexes of four different class I HLA molecules with IR. Expression of some of these molecules correlates with high-affinity IR, whereas expression of others correlates with 5- to 10-fold lower affinity IR. This study found that chemical cross-linking was necessary to stabilize HLA-IR complexes, and all four of the class I HLA molecules studied, HLA-A1, HLA-A2, HLA-B5, and HLA-B8, can form complexes with IR.
Diabetes 1993 Apr
PMID:Chemical cross-linking detects association of insulin receptors with four different class I human leukocyte antigen molecules on cell surfaces. 845 13

Target antigens defined by autoantibodies in IDDM include insulin, a putative glycolipid that reacts with islet cell antibodies, and a 64,000-M(r) protein recently identified as glutamic acid decarboxylase. In addition, some IDDM sera that contain antibodies to glutamic acid decarboxylase also coprecipitate a 38,000-M(r) protein from islets. This study used a high titer anti-38,000-M(r) serum to screen bacteriophage lambda cDNA expression libraries and identified human islet and placental clones encoding jun-B, the nuclear transcription protein, of predicted 38,000 M(r). Peripheral blood T-cells exhibited significant proliferation in response to a recombinant fragment of jun-B (amino acids 1-180) in 12 of 17 (71%) recent-onset IDDM subjects, 8 of 16 (50%) ICA-positive first-degree relatives of IDDM subjects who were at risk, 3 of 12 (25%) other autoimmune disease subjects, and 0 of 10 healthy control subjects. Proliferation to tetanus toxoid did not differ significantly between the groups. Responses to jun-B were not related to age, sex, or human leukocyte antigen status. Thus, autoreactive T-cells identify a novel antigen, p38 jun-B, in IDDM and appear to indicate subjects at risk for the development of clinical disease.
Diabetes 1993 Apr
PMID:Transcription factor jun-B is target of autoreactive T-cells in IDDM. 845 14

The polymorphic variable number of tandem repeats in the 5' upstream region of the human insulin gene is a well-known non-human leukocyte antigen locus contributing to genetic susceptibility to IDDM. Controversy exists about the question as to whether INS susceptibility haplotypes are or are not preferentially inherited together with HLA-DR4 haplotypes. We investigated whether genetic interaction between INS and the HLA complex can be better defined using DQ genotypic and phenotypic markers in addition to DR serology. The 5' INS 1/1 genotype was positively associated with IDDM both in non-DR4 subjects (relative risk = 4.3; 95% confidence interval, 1.6-11.5) and DR4 subjects (relative risk = 4.2; 95% confidence interval, 1.9-9.0). Further subdivision of IDDM patients and matched control subjects according to HLA-DQA1 and HLA-DQB1 genotype or phenotype also failed to show any association between 5' INS and HLA class II genes in diabetic patients. The 5' INS and HLA class II polymorphisms therefore provide independent risk markers, which may both contribute to the genetic screening of a high-risk population among nondiabetic individuals.
Diabetes 1993 Jun
PMID:5' insulin gene polymorphism confers risk to IDDM independently of HLA class II susceptibility. 849 8

To evaluate the association of autoimmunity to glutamic acid decarboxylase (GAD) with insulin-dependent diabetes mellitus (IDDM) and IDDM-associated human leukocyte antigen (HLA) types, we studied a unique group of 47 patients with autoimmune polyendocrine syndrome type 1, a recessive disease not associated with HLA. GAD65 antibodies (GAD65-Ab), GAD67-Ab, islet cell antibodies, and HLA-DQA1, -DQB1, and -DRB1 were analyzed in relation to IDDM or a decreased insulin secretory capacity. GAD65-Ab were found in six of the eight diabetic patients 0.9-8.0 yr before the onset of IDDM and in 16 (41%) nondiabetic patients during a follow-up of 2.4-19.5 yr. Eleven (28%) nondiabetic patients had GAD67-Ab and islet cell antibodies. Fasting C peptide (mean +/- SD, 0.5 +/- 0.24 vs. 1.03 +/- 0.49 nmol/L; P = 0.003) and first phase insulin response (75.6 +/- 37.9 vs. 166.4 +/- 112.7 mU/L; P = 0.019) were lower in patients with than in those without GAD65-Ab. No HLA genotype predominated in the IDDM patients or GAD65-Ab-positive nondiabetic patients, but the IDDM high risk genotypes were decreased in frequency among the patients with GAD65-Ab. In conclusion, nondiabetic autoimmune polyendocrine syndrome type 1 patients frequently have GAD65-Ab together with a decreased insulin secretory capacity, suggesting subclinical islet cell inflammation not invariably progressing to diabetes. This is not associated with HLA haplotypes conferring susceptibility to or protection from IDDM.
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PMID:Antibodies to glutamic acid decarboxylase and insulin-dependent diabetes in patients with autoimmune polyendocrine syndrome type I. 863 56

To study the frequency of antibodies to glutamic acid decarboxylase (GAD65A) at the diagnosis of insulin-dependent diabetes mellitus (IDDM) and to evaluate the relation of these antibodies to other IDDM-associated autoantibodies and genetic risk markers of the disease, we analyzed 747 newly diagnosed diabetic children younger than 15 yr of age (mean, 8.4 yr) for GAD65A, islet cell antibodies, insulin autoantibodies, and human leukocyte antigen DR alleles. GAD65A were detected in 73.2% of the children, with a higher frequency in females than in males (77.1% vs. 70.1%; P = 0.04) and in index cases aged 10 yr or older than in younger children (79.0% vs. 68.7%; P = 0.004). The index cases positive for GAD65A had higher levels of islet cell antibodies (median, 40 vs. 34 Juvenile Diabetes Foundation units; P = 0.003) and insulin autoantibodies (median, 55 vs. 43 nU/mL; P = 0.03) than those testing negative for GAD65A. Human leukocyte antigen DR3/non-DR4 children had the highest GAD65A levels, whereas DR2-positive cases had levels of GAD65A similar to those found in other subjects. One third of the index cases (33.9%) tested positive for all three autoantibodies, 43.1% for two antibodies, and 18.2% for one antibody, whereas 4.8% were triple negative. The females had multiple antibodies (at least two antibodies) more often than the males (81.3% vs. 73.5%; P = 0.01). There was a significant trend for a higher frequency of multiple antibodies in young children (83.0% in those under 5 yr and 73.2% in those 10 yr or older; P = 0.02) and a higher frequency in DR3/4 heterozygous children than in those with DR3/non-DR4 (83.3% vs. 63.2%; P = 0.02). The results show that GAD65A antibodies are more frequent in girls and adolescents with newly diagnosed IDDM and suggest that DR3/non-DR4 subjects have increased GAD65A levels. Multiple antibodies in diabetic children are associated with young age, female sex, and DR3/4 heterozygosity.
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PMID:Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes. Childhood Diabetes in Finland Study Group. 867 60

To examine the role of DNA loci within the human leukocyte antigen (HLA) region and insulin-dependent diabetes mellitus (IDDM), we studied fine mapping of HSP70-2 gene. Polymerase chain reaction (PCR)-based genotyping was then developed and applied to type HSP70-2 in 59 patients with IDDM and 83 unrelated controls recruited from the inhabitants of northern Taiwan. Southern blot analysis revealed a diallelic PstI polymorphism of the HSP 70-2 gene, i.e., 9.6- and 8.5-kb alleles. The polymorphic site was mapped in the intragenic PstI sequences (nucleotides 1051-1056) of the HSP70-2 gene. PCR-based restriction fragment length polymorphism studies revealed that the frequency of the 8.5-kb allele was increased in IDDM (56.8%, vs. 40.4% in controls; p < 0.009), with a relative risk of 1.93 (95% confidence interval = 1.20-3.11). The genotypic frequencies of 9.6/9.6, 9.6/8.5, and 8.5/8.5 were 17.0, 52.5, and 30.5% for IDDM were different from those of controls (36.1, 47.0, and 16.9%, respectively; the homozygous 9.6/ 9.6 genotype was significantly decreased in the IDDM group, p < 0.02). In conclusion, we provide a simple, rapid, and nonradioactive method for HSP70-2 genotyping. Our data confirmed that the 8.5-kb allele of HSP70-2 was associated with IDDM susceptibility in the Taiwanese population.
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PMID:A rapid method to study heat shock protein 70-2 gene polymorphism in insulin-dependent diabetes mellitus. 888 48

The problem of defining combinations of variants unique to a sequence is efficiently addressed as a set covering computation. The unique-combinations method is introduced, which identifies patterns in biological sequence data that distinguish a sequence from a group of other sequences. This method is further developed to describe features consistently present in one group of sequences but not in a second group. The approach is incorporated into a novel analytical tool, designed for use in studies of polymorphic sequence data, such as mitochondrial, human leukocyte antigen (HLA), or viral pathogen sequences. The unique combinations method is well suited to applications in medical genetics and evolutionary genetics. An example implementation of the unique-combinations method yields greatly improved risk assessment for insulin-dependent diabetes mellitus (IDDM) from amino acid patterns isolated in an analysis of HLA class II DQA1-DQB1 patient and control genotypes.
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PMID:On distinguishing unique combinations in biological sequences. 889 58

Insulin, glutamate decarboxylase (GAD) and the protein tyrosine phosphatase-like molecule IA-2 are major targets of humoral autoimmunity in insulin-dependent diabetes mellitus (IDDM). These autoantibodies are heterogeneous with respect to age and patient human leukocyte antigen (HLA) phenotype. We have previously demonstrated that GAD and IA-2 antibodies potentially identify different subsets of IDDM patients. The aim of this study was to determine whether GAD and IA-2 autoantibodies were associated with different HLA DR phenotypes. We studied 160 patients with IDDM onset before age 16 years. At disease onset serum was tested for GAD and IA-2 antibodies by immunoprecipitation by in vitro-translated 35S-methionine labelled recombinant proteins. IA-2 antibodies were significantly associated with HLA DR4: 67 (86%) of 78 patients with HLA DR4 vs 31 (38%) of 82 non-DR4 patients had IA-2 antibodies (Pc < 0.0001) and IA-2 antibody levels were higher in patients with HLA DR4 (Pc < 0.0001). In contrast, GAD antibodies were more prevalent (Pc < 0.05) and antibody levels highest (Pc < 0.01) in patients with HLA DR3 phenotypes. These data provide further evidence that, in IDDM, production and titre of major autoantibody specificities are associated with HLA class II alleles.
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PMID:Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM. 889 11

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.
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PMID:CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus. 898 48


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