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 combination of the HLA complement allotypes BFS, C2C, C4AQ0 (deleted gene) and C4B1, termed SC01 complotype, usually present in the HLA-B8,DR3,DQw2 diabetogenic haplotype, has also been found in a novel "low frequency" HLA-B49,DR4,DQw8 haplotype associated with Spanish insulin-dependent diabetes mellitus (IDDM). Family studies of C4 antigenic determinants Rodgers/Chido and their specific C4d nucleotide sequences confirm that this novel haplotype bearing Chido -3, -6 is not due to a recent recombination from the common HLA-B8,DR3 haplotype bearing Chido 3,6; moreover, Chido analysis at the serological or DNA level is presently the only way to distinguish both SC01 complotypes, since BF, C2, steroid 21-hydroxylase and C4 genes do not reveal other differences by restriction fragment analysis. On the other hand, HLA-B49,SC01,DR4 is the first DR4-bearing IDDM-susceptible haplotype with a deleted C4 gene described so far and the only DR4-bearing haplotype found in the Spanish population. This report further supports the fact that extended haplotypes with deleted (or "not duplicated") genes in the class III region contain IDDM-susceptibility more often than non-deleted (or "duplicated") haplotypes in the Spanish and other Mediterranean populations.
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PMID:C4 Chido 3 and 6 distinguish two diabetogenic haplotypes: HLA-B49, SC01,DR4,DQw8 and B8,SC01,DR3,DQw2. 168 41

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

Studies were carried out to determine if diabetes mellitus influenced the activities of adrenal steroidogenic enzymes. Adult male rabbits were made diabetic by an i.v. infusion of alloxan (100 mg/kg) and were killed 1 or 2 months later. Mitochondrial cytochrome P-450 concentrations were not affected by diabetes but steroid 11 beta-hydroxylase activity was greater in the diabetics than in controls after both 1 and 2 months. The type I spectral change produced by 11-deoxycorticosterone, the substrate for 11 beta-hydroxylation, was also greater in mitochondria from diabetics. By contrast, mitochondrial cholesterol side-chain cleavage activity was similar in controls and diabetics. Microsomal cytochrome P-450 concentrations were unaffected by diabetes but 21-hydroxylase activity was significantly lower in adrenal microsomes from diabetics than from controls. The results indicate that alloxan-induced diabetes alters adrenocortical steroid metabolism which may contribute to changes in the pattern of steroid secretion noted by other investigators.
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PMID:Changes in adrenocortical monooxygenase activities in alloxan-diabetic rabbits. 338 37

The authors report a case of severe hyperkalemia (7 mmol/l) in an insulin-dependent diabetic in the absence of renal failure. This hyperkalemia was due to hypoaldosteronism caused by inadequate hormone biosynthesis in the absence of 21-hydroxylase. Replacement therapy allowed normalization of clinical and laboratory parameters. The various causes of hyperkalemia in the absence of renal failure in insulin-dependent diabetes are discussed, notably the renin deficiency hypoaldosteronism syndrome. This case study is remarkable for a number of reasons, including the very limited degree of virilization, the occurrence of a pregnancy, and the degree of salt excretion. This is a new observation in the diabetic, and is apparently a coincidental association since deficits in 21-hydroxylase are not usually associated with insulin-dependent diabetes.
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PMID:[21-hydroxylase deficit revealed by hyperkalemia in the absence of renal failure in an insulin-dependent diabetic (author's transl)]. 697 92

Adrenal autoantibodies characteristic of autoimmune Addison disease are directed towards steroid 21-hydroxylase (21-OH; EC 1.14.99.10). We describe a new assay to measure 21-OH autoantibodies (21-OH Abs), based on immunoprecipitation by the antibodies of 35S-labeled human 21-OH. Using this immunoprecipitation assay (IPA), we detected 21-OH Abs in 42 of 64 (66%) patients with Addison disease and in 14 of 19 (74%) patients with autoimmune polyendocrine syndromes type I and type II. No 21-OH Abs were detected by the IPA in any patients with Addison disease attributable to tuberculosis (n = 9) or adrenoleukodystrophy (n = 9) or in patients with autoimmune thyroid disease (n = 28), systemic lupus erythematosus (n = 10), myasthenia gravis (n = 10), rheumatoid arthritis (n = 10), or insulin-dependent diabetes mellitus (n = 12). None of the 26 sera from healthy normal blood donors was positive for 21-OH Abs by the assay. We found good agreement between 21-OH Abs measured by IPA and by Western blotting (r = 0.83, n = 123, P < 0.001). The inter- and intraassay CVs for IPA were well < 10% at high, medium, and low concentrations of 21-OH Abs. Overall, our studies indicate that the IPA provides a specific, sensitive, and convenient system for measuring 21-OH Abs.
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PMID:Immunoprecipitation assay for autoantibodies to steroid 21-hydroxylase in autoimmune adrenal diseases. 788 6

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.
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PMID:HLA associations with inclusion body myositis. 792 82

We have studied the sera from 304 patients with insulin-dependent diabetes mellitus (IDDM) for steroid 21-hydroxylase (P450c21) autoantibodies by an in vitro translation and immunoprecipitation assay. Autoantibodies to P450c21 were found in 7 patients with IDDM (2.3%). When the IDDM patients with P450c21 antibodies were analyzed for their HLA, 6 of them (86%) belonged to the HLA DQB1*0201-positive group. A strong correlation (r = 0.91, P < 0.001) of immunoprecipitation results was observed with adrenocortical autoantibodies detected by indirect immunofluorescence, indicating that the adrenal autoantibodies in patients with IDDM were anti-P450c21 autoantibodies. The levels of P450c21 autoantibodies were significantly higher (P < 0.05) in patients with IDDM than in 13 (9 P450c21 autoantibody positive) patients with Addison's disease. Although the occurrence of P450c21 antibodies in IDDM was relatively low, antibody-positive patients had high antibody levels and may have an ongoing subclinical process of adrenal autoimmunity.
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PMID:Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. 900 40

The diagnostic specificity of recombinant 21-hydroxylase autoantibodies (21OH-Ab) for Addison's disease was tested in adult patients with either Graves' disease (GD), insulin-dependent diabetes mellitus (IDDM), or polyendocrinopathy, as well as in healthy controls. Using a radiobinding assay with in vitro translated recombinant human 21-hydroxylase, we found 21OH-Ab in 24/28 (86%) idiopathic Addison patients, and using an immunofluorescence assay we found adrenal cortex autoantibodies (ACA) in 12/28 (43%) patients (P = 0.002). All the 12 ACA-positive sera were also positive for 21OH-Ab and ACA were found in 11/15 (73%) patients with less than 15 years and in 1/13 (8%) patients with 15-38 years of disease duration (P = 0.002). 21OH-Ab were present in 3/92 (3%) patients with GD, in 1/180 (0.6%) with IDDM and in 0/106 healthy subjects. The 21OH-Ab-positive GD and IDDM patients were also positive for ACA. None of 17 patients with polyendocrinopathy, but without Addison's disease, had 21OH-Ab. None of the 180 Belgian IDDM patients had Addison' s disease or developed an adrenal insufficiency at follow up. In two out of three Graves patients, the presence of 21OH-Ab was associated with clinical and biochemical signs of adrenal insufficiency. Of the 89 21OH-Ab-negative patients with GD none had Addison's disease at the time of blood sampling, and 79 were followed up for 5.6-7.5 years and none developed clinical signs of adrenal insufficiency. We conclude that the presence of 21OH-Ab in patients with endocrine autoimmune diseases is highly specific for Addison's disease.
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PMID:21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry. 903 Aug 73

Autoantibodies (Abs) to steroid 21-hydroxylase (21-OH) are a major component of adrenal cortex Abs and are characteristic of autoimmune Addison's disease. We have developed a new method for measuring Abs to 21-OH based on 125I-labeled recombinant human 21-OH produced in yeast. With this assay, 21-OH Abs were detected in 43 of 60 (72%) sera from patients with isolated Addison's disease, 11 of 12 (92%) autoimmune polyglandular syndrome type I sera, 27 of 27 (100%) autoimmune polyglandular syndrome type II sera, and 24 of 30 (80%) sera from patients who were positive for adrenal cortex antibodies by immunofluorescence but had no overt Addison's disease. 21-OH Abs were found by 125I assay in 4 of 150 (2.7%) sera from patients with insulin-dependent diabetes mellitus, 1 of 77 (1.3%) Graves' sera, 1 of 67 (1.5%) Hashimoto's sera, and 6 of 243 (2.5%) sera from healthy blood donors. 21-OH Abs were not detected in 9 sera from patients with Addison's disease due to tuberculosis, 32 sera from patients with noninsulin-dependent diabetes mellitus, 35 sera from patients with myasthenia gravis, or 17 sera from patients with premature ovarian failure. There was good agreement between the 125I-labeled 21-OH assay and an assay based on 35S-labeled 21-OH produced in an in vitro transcription/translation system (r = 0.86; n = 129; P < 0.001). In the case of sera from patients with Addison's disease, insulin-dependent diabetes mellitus, Graves' disease, and Hashimoto's disease and from healthy blood donors that were low positive in the 125I assay, neutralization studies with unlabeled 21-OH confirmed the presence of specific 21-OH Abs. Overall, the 21-OH Ab assay based on 125I-labeled 21-OH showed good sensitivity, precision, and disease group specificity. This, combined with a simple assay protocol and the convenience of 125I handling and counting, make it attractive for routine use. Further investigations with the new assay should allow wider assessment of the prevalence and pattern of inheritance of adrenal autoimmunity. In addition, studies of the effect of treatment or possible preventative measures on 21-OH Ab levels in individuals without overt adrenal failure may suggest ways of delaying the onset of autoimmune Addison's disease.
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PMID:Steroid 21-hydroxylase autoantibodies: measurements with a new immunoprecipitation assay. 914 30

We describe two patients with liver kidney microsomal antibody type 1 (LKM1)-positive autoimmune hepatitis (AIH) with associated endocrinopathies. The first patient had insulin-dependent diabetes (IDDM), and the second patient had Addison's disease and hypoparathyroidism, and is also positive for islet cell antibodies, without overt diabetes. To account for the existence of multiple endocrinopathy in these patients, we investigated whether there is sequence similarity between the target of LKM1 antibodies, cytochrome P4502D6 (CYP2D6), and other human proteins, and if so, whether this structural similarity produces a detectable cross-reactive immune response. Our database search identified two proteins, carboxypeptidase H, an autoantigen in insulin-dependent diabetes, and 21-hydroxylase, the major autoantigen in Addison's disease, that share sequence similarity to the second major LKM1 epitope on CYP2D6. We tested the reactivity of sera from these patients to the homologous regions of the three autoantigens using an enzyme-linked immunosorbent assay (ELISA). The cut-off for positivity was established by testing sera from 22 healthy children. To determine the significance of reactivity to the peptide homologues of the three autoantigens, we investigated 16 additional patients with LKM1 AIH and 20 children with chronic hepatitis B virus infection as pathological controls. We found that reactivity to the second major epitope of CYP2D6 is significantly associated with reactivity to the homologous regions of carboxypeptidase H (CPH) and 21-hydroxylase (21-OHase) in patients with LKM1 AIH, and that this simultaneous recognition is cross-reactive. We suggest that a cross-reactive immune response between homologous autoantigens may contribute to the development of multiple endocrinopathies in LKM1 AIH.
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PMID:Immunological cross-reactivity to multiple autoantigens in patients with liver kidney microsomal type 1 autoimmune hepatitis. 979 98


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