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)

Type 1 diabetes is associated with extended haplotypes defined by combinations of specific alleles of genes in the MHC. We have used pulsed field gel electrophoresis mapping to examine the gross structure of the Class II region of the MHC and its relationship to susceptibility to Type 1 diabetes. We have studied heterozygous members of a family in which susceptibility to Type 1 diabetes is associated with an A1/B8/DR3 haplotype and resistance with A2/B7/DR2, an unrelated diabetic DR3,4 patient and a healthy DR4,w10 subject and a DR2/Dw2 cell line. Digestion was performed with the enzymes Sst II, Mlu I, and Pvu I and hybridization with 21-hydroxylase, DRA, DQB, DOB and DPA probes. Within the DQ/DR region the DR4- and DR7-bearing haplotypes studied contain insertions of 140-150kb relative to the DR3 haplotypes whilst the DR2 haplotype in the family was smaller than the DR3 haplotypes by 130kb, whilst that in the cell line was smaller by up to 220kb. This cell line, previously thought to be homozygous by consanguinity, was also shown to be heterozygous in the DP region. Although no differences between diabetic and healthy subjects were observed within the family, these differences in long-range structure may be of importance to the etiology of Type 1 diabetes, as well as to the evolution of the MHC.
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PMID:Large haplotype-specific differences in inter-genic distances in human MHC shown by pulsed field electrophoresis mapping of healthy and type 1 diabetic subjects. 224 84

We investigated the HLA status of patients with diabetes associated with limited joint mobility and microvascular complications. An increased frequency of HLA-B8, DR3 and DR4 in patients with insulin dependent diabetes mellitus (IDDM) compared to controls and patients with noninsulin dependent diabetes mellitus (NIDDM) was confirmed. HLA antigen DQw1 was detected less frequently in patients with IDDM and was negatively associated with limited joint mobility and retinopathy. Limited joint mobility was significantly correlated with disease duration in IDDM, and was associated with neuropathy in both IDDM and NIDDM and with retinopathy in IDDM. No correlation was found between DR3, DR4 and limited joint mobility or diabetic complications. We also investigated the usefulness of nailfold capillary microscopy in a large group of patients with IDDM and NIDDM. Although capillary enlargement and avascular areas were noted in a few patients, nailfold capillary microscopy was not felt to be a useful tool in the evaluation of diabetes.
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PMID:HLA antigens and nailfold capillary microscopy studies in patients with insulin dependent and noninsulin dependent diabetes mellitus and limited joint mobility. 225 97

The aim of this study was to determine which candidates were suitable for immunotherapy among adult insulin dependent diabetic patients of recent onset. A statistical analysis was performed using the results of a multicentre randomized trial of cyclosporine versus placebo after nine months of treatment. When the baseline characteristics of the patients in remission were compared with those not in remission, there was no difference observed either in initial residual beta-cell function (glucagon stimulated C-peptide level), or in immunological markers (T4 and T8 lymphocytes counts, Interleukin 2). The parameters showing the most difference were, in addition to treatment group, the duration of diabetes symptoms and body mass index at inclusion, and the HLA-DR phenotype. This was confirmed using a logistic regression analysis, in which these variables were found to be significantly related to remission. The probability of remission in each individual patient was then calculated using these variables in the mathematical function provided by the logistic model. Ninety eight out of 110 patients were correctly classified using this method. In addition, it must be noted that only subjects adequately treated by cyclosporine were still in complete remission after a one year follow-up. Conversely, it appeared that immunosuppression in subjects having a predicted probability of remission lower than 0.35 using the mathematical function, and being non-DR3, non-DR4 has to be avoided. These results will be useful in optimizing the recruitment of patients in on-going or future trials of immunotherapy in early diabetes.
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PMID:Probability of remission in individual in early adult insulin dependent diabetic patients. Results from the Cyclosporine Diabetes French Study Group. 226 35

We assessed HLA-DR types and investigated serum samples for islet-cell cytoplasmic antibodies (ICA) in 31 Danish patients with chronic pancreatitis. The antigen frequencies were compared with those in 1177 unrelated healthy Danish controls. Twenty patients had insulin-dependent diabetes and 11 had normal intravenous glucose tolerance. No significant differences in the frequencies of DR3, DR4, or DR2 were found between patients with insulin-dependent diabetes and patients with normal glucose tolerance or between any of these groups and controls. ICA were negative in all patients with chronic pancreatitis. It is concluded that the beta-cell dysfunction in insulin-dependent diabetes in chronic pancreatitis differs from that of classical insulin-dependent diabetes.
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PMID:Insulin-dependent diabetes mellitus secondary to chronic pancreatitis is not associated with HLA or the occurrence of islet-cell antibodies. 226 74

Type I diabetes is strongly associated with the major histocompatibility complex (MHC) class II region (DR and DQ loci), and to a lesser extent the class III region (complement C4 loci). Restriction fragment length polymorphism analysis was employed to investigate the C4 and heat shock protein 70 (HSP70) loci of 176 patients with type I diabetes and 92 healthy controls. In the patient population there was an excess of deletions of the C4A locus (48.5% vs 22.1%, P less than 0.0005). The HSP70 probe in conjunction with the restriction endonuclease Pst I detects two alleles of 9 or 8.5 kilobases (kb). The 8.5 kb allele was significantly increased in the patient group compared to healthy controls (0.569 vs 0.353, respectively, P less than 0.0005). Furthermore, a C4A deletion nearly always occurred with the 8.5 kb HSP70 allele, suggesting that it may be a marker of the HLA-A1,B8,C4A deletion, DR3 extended haplotype.
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PMID:Complement C4 and heat shock protein 70 (HSP70) genotypes and type I diabetes mellitus. 227 64

Properdin factor B(Bf) allotypes were determined in patients with insulin dependent (type 1) diabetes mellitus (n = 15); in patients with non-insulin dependent diabetes mellitus n = 15); and in healthy Nigerians (n = 252) from various tribal groups. In all three groups only commonly reported Bf allotypes namely BfF, F1, S and S1 were observed. More important, BfF1 allele was significantly increased in patients with insulin dependent (type 1) diabetes mellitus (expected 1/15, observed 5/15), X2 = P less than 0.005). It is suggested that this allele is probably the same as that reported in caucasoids and is part of a supratype or ancestral haplotype defined by HLA-B18, C4A3, C4A3, BQo, BfF1, DR3 marking type 1 (insulin dependent) diabetes mellitus.
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PMID:Properdin factor B allotypes in diabetic Nigerians. A preliminary report on chromosome 6 markers. 228 96

Restriction fragment length polymorphism using an HLA-DQ beta-chain genomic probe showed that 63 children with insulin-dependent (type 1) diabetes mellitus (IDDM) were all (100%) positive for the BamH1 fragments 12 kb and/or 4 kb compared to 98% (62/63) for HLA-DR3 and/or 4 and 75% (47/63) for HLA-B8 and/or 15. The 36 (56%) DR3-positive children were all 4-kb-positive; however, a total of 44 (70%) children were 4-kb-positive (P less than 0.02). The 55 (87%) DR4-positive children were all 12-kb-positive, but a total of 56 (89%) were 12-kb-positive (NS). The heterozygosity at the HLA region increased from 11/63 (18%) for HLA-B8/15 to 29/63 (46%) for HLA-DR3/4 (P less than 0.0004) and to 37/63 (59%) for the HLA-DQ 4 kb/12 kb fragments (P less than 0.02). The test of an equal probability of a positive result under the adjacent pair of tests indicates that the increased risk of developing IDDM in association with HLA-DQ is to a great extent due to heterozygosity at this locus. There were no differences between the 4 kb/12 kb and the DR3/4-positive IDDM children with respect to fasting or meal-stimulated C peptide, insulin requirement, or levels of insulin antibodies formed during the first 12 months of insulin therapy. Our results support the hypothesis that HLA-DQ is closely associated with an increased risk of childhood IDDM, and when typed for at this locus parameters of the clinical course were homogeneous, suggesting that factors other than HLA-DQ may determine previously observed differences between IDDM children in clinical or functional parameters.
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PMID:HLA heterozygosity in insulin-dependent diabetes is most frequent at the DQ locus. 233 66

The gene frequencies, haplotype relative risks, and zygotic assortments of HLA-DR in three ethnically defined samples of insulin-dependent diabetes mellitus (IDDM) patients were determined in a prospective family study. Although DR3 and DR4 were positively associated with IDDM in the probands of 123 northern European, 94 Ashkenazi Jewish, and 49 New York Hispanic families, significant excess of DR*3/4 heterozygotes was observed only among the probands from families of northern European ancestry. There was also a significant decrease in the frequency of Bw62,DR4 haplotypes derived by northern European patients from their mothers compared with their fathers. This difference, together with data reported in the literature, suggests that the expressivity of the susceptible genotype(s) in IDDM patients may be modified by protective maternal effects associated with Bw62,DR4 and probably other DR4 haplotypes. Samples of IDDM patients from populations with high frequencies of these modifiers should have different DR-gene frequencies contributed by fathers and mothers, capable of accounting for the observed Hardy-Weinberg disequilibrium. We postulate that, because the mechanism of action of these modifiers is distinct from that of the susceptibility gene, the difference must be considered in devising strategies for elucidation of the mode of inheritance of the disease and for understanding the molecular nature of the susceptibility.
Diabetes 1990 Sep
PMID:No excess of DR*3/4 in Ashkenazi Jewish or Hispanic IDDM patients. 238 93

The susceptibility determinants of Type 1 (insulin-dependent) diabetes mellitus are known to be associated with both HLA-DR3 and DR4. In our study we wished to determine if the parental origin of these antigens could influence susceptibility to the disease. We analysed the inheritance of DR3 and DR4 haplotypes from the father or mother (DR3p, DR4p, DR3m and DR4m, respectively), in the index cases and in the affected and non-affected siblings of 246 diabetic simplex and 41 multiplex families without affected parents. An independent series of 80 multiplex families (GAW 5) was also studied. Among the DR3,4 positive index cases and affected siblings, the paternal and maternal DR3 and DR4 antigens were not distributed randomly: 62% and 72%, respectively, had received DR4 from their father and DR3 from their mother (DR4p/DR3m), while only 38% and 28%, respectively, had received a paternal DR3 together with a maternal DR4 (DR3p/DR4m). This differed significantly from the 50% expected ratio (p less than 0.01) and was not observed in unaffected siblings. No excess of maternal DR3 in the absence of DR4 and no excess of paternal DR4 in the absence of DR3 were observed. The finding suggests that some maternal DR3 related event (presumably during pregnancy) might play an enhancing role in the pathogenesis of Type 1 diabetes. It also implies that siblings with both DR4p and DR3m have a significantly higher risk for disease than those with DR3p and DR4m.
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PMID:Excess of maternal HLA-DR3 antigens in HLA DR3,4 positive type 1 (insulin-dependent) diabetic patients. 240 98

Noninsulin dependent diabetes mellitus (NIDDM) is associated with an entirely different set of genetic alterations from insulin-dependent diabetes mellitus (IDDM). Over 90% of IDDM carry HLA type DR3, DR4 or both. Several theories have been proposed to explain how the genetic alterations are translated into a beta cell destructive process. All involve the elaboration of a beta cell autoantigen. A major current research focus is on the development of pharmacologic approaches to the control of the beta cell destructive process (cyclosporine A). This has led to a shift in interest to the early identification of individuals at risk for IDDM. Many questions remain to be answered. In our paper emphasis is placed on epidemiological research. In Allegheny County, Pennsylvania, we have found an incidence of 1.73 cases/1000 (incidence rate of 15/100,000/year). There were marked geographical variations (incidence rate of 1/100,000/year in Asian countries, of 40/100,000/year in Finland). This suggests that there are major environmental determinants leading to expression of disease in genetically susceptible individuals. There are no geographical differences in the main age of onset, the sex ratio and the clinical patterns in the initial course of newly detected IDDM. In all parts of the world islet cell antibodies are positive in 60-80% of newly diagnosed IDDM. Migration of children from their native homeland with a low incidence rate to a country with high incidence rate was accompanied by an increase of incidence. The following potential environmental factors have been considered: viral infections, environmental toxins, nutrients, and stress. In our view IDDM occurs in genetically susceptible individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:What do epidemiologic observations tell us about the etiology of insulin dependent diabetes mellitus? 240 77


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