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)

The localization of TNF genes on the short arm of chromosome 6 between HLA B and the complement genes focused attention to that genetic region which harbors many immunologically relevant genes and is also thought to hold susceptibility genes for a variety of autoimmune diseases that are linked to specific alleles of particular loci in the HLA D region. Since the recently established HLA-DR-DQ variation accounts only for part of the genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) we searched for genomic variation of the tumour necrosis factor (TNF) alpha. We have identified a TNF-alpha restriction fragment length polymorphism (RFLP) with NcoI and analysed diabetic patients including their families, controls and homozygous typing cell lines (HTC) defined by the 10th International Histocompatibility Workshop. Segregation analysis in families and HTC results show a strong linkage of the TNF-alpha 5.5 kb allele with DR types in particular with A1B8DR3. This tight linkage of TNF-alpha alleles with extended haplotypes and the significant increase of heterozygotes in patients could lead to some explanation of the DR3 association with a variety of autoimmune diseases particularly IDDM.
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PMID:TNF-alpha gene polymorphisms: association with type I (insulin-dependent) diabetes mellitus. 257 13

Human genomic DNA samples from 19 Korean patients and 31 controls of known serological DR antigen specificity were studied for insulin-dependent diabetes mellitus (IDDM)-associated variation in HLA-DR beta and -DQ beta restriction fragment length polymorphisms (RFLPs). Genotyping allowed for accurate assignment of HLA-DR types. For HLA-DRw6, a 12kb/DR beta/Taq I fragment was decreased in Korean IDDM (p less than 0.05). However, we could not find an increased frequency of a 12kb/DQ beta/Bam HI fragment or decreased frequency of a 3.7kb/DQ beta/Bam HI fragment in Korean IDDM. These results suggest a possible protective role of the HLA-DRw6 specificity in IDDM, irrespective of ethnic background, the absence of a specific DQ beta RFLP pattern associated with IDDM in Koreans, and the difference of the Korean population in the genetic of IDDM, compared to the Caucasoid population.
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PMID:RFLP analysis of HLA-DR beta and -DQ beta genes in the Korean patients with insulin-dependent diabetes mellitus. 257 78

The particular susceptibility to insulin-dependent diabetes mellitus (IDDM) conferred by HLA-DR3,4 heterozygosity has been suggested to be an effect of transcomplementation of HLA class II molecules. To test this hypothesis of special IDDM-specific hybrid determinants and to evaluate the T-cell repertoire towards a specific antigen in IDDM patients we generated a total of 352 PPD-specific T-cell lines by the soft-agar cloning technique and studied their restriction by HLA class II molecules. Of these lines, 227 were from nine IDDM patients, of whom six were DR3,4 heterozygotes, and 125 from 10 healthy controls. Forty-six T-cell lines elicited specific responses in at least two experiments and in addition to T-cell lines demonstrating class-II-restricted PPD specificity, lines with an alloreactivity occurred. HLA-DQ-restricted PPD-specific T-cell lines were not identified and a possible DP restriction (DPw2) was only observed with one line. These data indicate that PPD is preferentially presented to T cells in the context of HLA-DR/Dw. Presentation of PPD by hybrid molecules in IDDM patients or by IDDM-specific class II epitopes recognized by the T-cell lines was not demonstrated. By restriction fragment length polymorphism analysis using a probe for the joining region of the T-cell receptor gamma gene, T-cell lines generated by the soft-agar cloning technique were found to be oligoclonal. It is concluded that soft-agar cloning should be followed by subsequent limiting dilution in order to assure monoclonality. Different preparations of antigen-presenting cells (APC) were tested. In several cases the T-cell lines were not able to respond to PPD presented by Epstein-Barr-virus-transformed lymphoblastoid cell lines (LCL). It was demonstrated that lipopolysaccharides (LPS) of E. coli potently reduce the proliferative response of antigen-specific and alloreactive T cells when T-cell-depleted peripheral blood mononuclear cells (E- cells) were used as APC, whereas only limited inhibition was observed when LCL were used as APC in the presence of LPS. This effect of LPS is suggested to be mediated by increased prostaglandin secretion by monocytes among the E- cells since indomethacin abolished the effect of LPS. This observation may have implications for T-cell cloning procedures since we have found that most commercially available culture media are heavily contaminated with endotoxin.
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PMID:Characterization of PPD-specific T-cell lines generated in type I (insulin-dependent) diabetic and healthy individuals. 258 37

The relationship between glycemic control and complications of insulin-dependent diabetes mellitus (IDDM) remains controversial. With the use of glycosylated hemoglobin (HbA1) to assess glycemic control from diagnosis onward, the Pittsburgh Prospective Insulin-Dependent Diabetes Mellitus Cohort Study prospectively evaluated 80 new cases of IDDM diagnosed at Children's Hospital of Pittsburgh. This study presents findings in 62 patients at 5 yr postdiagnosis. Only 7 patients, all girls, had any retinopathy (microaneurysms). These subjects had an elevated 5-yr mean HbA1 compared to those with no retinopathy (13.0 vs. 11.7%; P less than .05). Six female subjects who had an elevated albumin excretion rate (AER; greater than or equal to 20 micrograms/min) had a higher 5-yr mean HbA1 (13.3%) than the 26 subjects with AER less than 20 micrograms/min (11.8%; P less than .05). Current HbA1 was correlated with AER (r = +.36, P less than .05) and systolic blood pressure (r = +.49, P less than .01) in females. However, these associations were not observed in males. Positive correlations were found between HbA1 (5-yr mean and current) and serum triglyceride and cholesterol, but only in females was HbA1 inversely related to high-density lipoprotein cholesterol. However, HbA1 was independent of sex, HLA-DR type, and urine C-peptide status. Age adjustment did not change the above results. These analyses suggest that glycemic control is related to AER, systolic blood pressure, presence of microaneurysms, and serum triglyceride and cholesterol concentrations during the first 5 yr of IDDM. However, these associations appear to be predominant in girls.
Diabetes Care
PMID:Diabetes complications and glycemic control. The Pittsburgh Prospective Insulin-Dependent Diabetes Cohort Study Status Report after 5 yr of IDDM. 261 4

HLA phenotypes and haplotypes in relation to organ-specific autoantibody responses were studied in 82 Japanese patients with Type 1 (insulin-dependent) diabetes. HLA-DRw9 antigen and HLA phenotype of DRw9/X (X:not DR4) were increased in patients with organ-specific autoantibodies other than islet cell antibody (CP less than 0.02, RR = 4.02 and p less than 0.05 RR = 2.30, respectively); whereas HLA-DR4 antigen and HLA phenotype of DR4/X (X: not DRw9) were increased in those without the autoantibodies (CP less than 0.001, RR = 3.95 and p less than 0.01, RR = 2.46, respectively). HLA haplotype of Bw61-DRw9 was increased in patients with the autoantibodies (p less than 0.005, RR = 4.94), and HLA haplotype of Bw54-DR4 was increased in those without the autoantibodies (p less than 0.001, RR = 5.52). The relative risk of HLA-DR4/DRw9 was the highest among all HLA-DR phenotypes or genotypes in patients either with or without the autoantibodies. No association was, however, found between the incidence of islet cell antibody and HLA-DR phenotypes. These findings suggest that Type 1 diabetes among Japanese is immunogenetically heterogeneous as is Type 1 diabetes among Caucasians; and the differences in HLA-association of Type 1 diabetes among ethnic groups might give a clue to understanding of a role of HLA-antigens in the development of Type 1 diabetes.
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PMID:Immunogenetic heterogeneity in type 1 (insulin-dependent) diabetes among Japanese HLA antigens and organ-specific autoantibodies. 265 Nov 87

According to month of diagnosis, 165 children who developed Type 1 (insulin-dependent) diabetes mellitus at the age of 0-16.2 years (mean +/- SD, 7.6 +/- 4.1 years) could be divided into 69 patients diagnosed during peak seasons (epidemic cases) and 96 patients diagnosed during months of low incidence (non-epidemic cases). Seasonality of onset of symptoms and of diagnosis was observed in both sexes in all age groups. The patients diagnosed during peak seasons had shorter duration of symptoms (13.2 +/- 8.1 days) as compared to 22.9 +/- 10.3 days; p less than 0.001 in the patients diagnosed during months of low incidence. At diagnosis, 88.4% (61/69) of the epidemic group had ketonuria as compared to 71.9% (69/96); p less than 0.06 in the non-epidemic patients. The values of C-peptide, insulin antibodies, haemoglobin A1c and HLA-DR phenotype frequencies in the 69 epidemic patients were compared with those of the 96 non-epidemic patients. In the epidemic patients, the C-peptide values of 0.11 +/- 0.05 mmol/l at diagnosis had increased to 0.12 +/- 0.05 mmol/l at one month and 0.13 +/- 0.06 mmol/l at 3 months. These values were significantly lower (p less than 0.001) than in the non-epidemic patients at the same time points: 0.17 +/- 0.08 nmol/l; p less than 0.001, 0.23 +/- 0.11 nmol/l; p less than 0.001, and 0.22 +/- 0.10 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Seasonality of type 1 (insulin-dependent) diabetes mellitus: values of C-peptide, insulin antibodies and haemoglobin A1c show evidence of a more rapid loss of insulin secretion in epidemic patients. 265 53

The discovery of the key role played by the immune system in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) opens up new possibilities for its early diagnosis, at the stages preceding its clinical manifestation. Analysed are the markers of genetic susceptibility to IDDM associated with some major histocompatibility complex antigens (specifically with HLA-DR 3, HLA-DR4, and HLA-DQ), of the cellular and humoral anti-islet autoimmunity, as well as the origin of the islet-cell autoantigens. The markers' significance for the diagnosis and prognosis is discussed.
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PMID:[Molecular biological aspects of the pathogenesis of diabetes mellitus]. 266 69

The HLA-DQ beta-chain gene shows a close association with susceptibility or resistance to autoimmune insulin-dependent diabetes mellitus (IDDM) and it has been suggested that the amino acid in position 57 may be of pathogenetic importance. To study the expression of the IDDM associated HLA-DQ beta-chain alleles, we immunized rabbits with 12 to 13 amino acid long peptides representing HLA-DQw7 and -DQw8 allelic sequences, differing only by one amino acid in position 57 being aspartic acid (Asp) and alanine (Ala), respectively. Immunoblot analysis of lymphoblastoid cells showed that several antisera recognized a 29-kDa protein, equivalent to the expected molecular size of the HLA-DQ beta-chain to yield two antisera specific for HLA-DQw7 (pos. 57Asp) and three antisera for HLA-DQw8 (pos. 57Ala) positive cells. Analysis of HLA-DR 3/4 positive IDDM patients (n = 24) and controls (n = 19) showed that all (100%) patients were positive for pos. 57Ala antiserum compared to 13 of 19 (68%) of the controls. The remaining six controls reacted with the pos. 57Asp antisera, whereas none of the patients did. We have therefore successfully been able to generate site-specific antibodies that distinguish single amino acid substitutions in predetermined positions of allelic HLA-DQ beta-chain gene products. Such sera should become useful to detect and investigate HLA associated susceptibility to autoimmune diseases in man.
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PMID:Site-specific antibodies distinguish single amino acid substitutions in position 57 in HLA-DQ beta-chain alleles associated with insulin-dependent diabetes. 273 2

The study of HLA histocompatibility antigens and insulin-dependent diabetes mellitus (IDDM) in non-White populations may provide a unique opportunity to more accurately define the diabetes susceptibility gene(s) located within the HLA region. To determine whether HLA haplotypes differ between ethnic groups, we compared 105 HLA haplotypes from 55 Mexican-American IDDM patients with 272 haplotypes from 136 IDDM patients of non-Hispanic White descent. The accurate determination of genotypes and haplotypes requires the study of family units. Therefore, all diabetic patients in this study were from studies of families having one or more siblings with IDDM. In the Mexican-American group, HLA-DR3 and -DR4 were the most common HLA-DR alleles and were present in comparable frequencies in the non-Hispanic White group (HLA-DR3, 27% of Mexican-American and 29% of non-Hispanic White haplotypes; DR4, 46% of Mexican-American and 43% of non-Hispanic White haplotypes). However, the HLA-B/DR-containing haplotypes and haplotype frequencies differed between the two groups. Several common haplotypes (B8/DR3, B15/DR4) in the non-Hispanic White group occurred less frequently in the Mexican-American group. In contrast, uncommon haplotypes in the non-Hispanic White group comprised nearly 50% of the DR4-containing haplotypes (B35/DR4, B40/DR4, B44/DR4) in the Mexican-American group. Although both DR3- and DR4-haplotype frequencies differed significantly between the two groups, the relative frequency of DR3- but not DR4-containing haplotypes was similar in both ethnic groups. This adds to the evidence suggesting that different susceptibilities are provided by the haplotypes carrying the DR3 and DR4 alleles.
Diabetes Care
PMID:Different HLA haplotypes in Mexican Americans with IDDM. 275 54

DNA from Caucasian normal healthy control subjects, non-gravid patients with insulin-dependent diabetes mellitus (IDDM) and gravida with gestational diabetes mellitus (GDM) were analyzed with DNA probes for HLA markers associated with HLA-DR and HLA-DQ to compare the hybridization patterns of their DNA after digestion with restriction endonucleases. We report HLA-DQ beta restriction endonuclease fragments to be presented with increased frequency in Caucasian gravida with GDM as well as in subjects with IDDM. These findings provide further evidence for genetic heterogeneity in GDM and are compatible with the presence of slowly evolving IDDM in some women with "carbohydrate intolerance of variable severity with onset or first recognition during pregnancy".
Diabetes Res 1987 Nov
PMID:Gestational diabetes mellitus is associated with HLA-DQ beta-chain DNA endonuclease fragments. 283 74


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