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)

Although the HLA class II genes are clearly associated with insulin-dependent diabetes mellitus (IDDM) in all ethnic groups, considerable variation in the associated haplotypes is observed among the ethnic groups. In Japanese, DRB1*0405-DQA1*0301-DQB1*0401, DRB1*0901-DQA1*0301-DQB1*0303 and DRB1*0802-DQA1*0301-DQB1*0302 are the major susceptibility haplotypes to IDDM, while DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1502-DQA1*0103-DQB1*0601 are the major resistance haplotypes. The hypothesis that alleles encoding amino acids other than aspartic acid at the DQB1 position 57 contribute to IDDM susceptibility is not applicable to the Japanese, mainly because the first and second susceptibility haplotypes listed above have aspartic acid at DQB1 position 57. In the 5' insulin gene polymorphism, the shorter insertion (class 1 allele) is predominant, and is not associated with diabetes in Japanese. Subdivision of the class 1 alleles also failed to show an association with IDDM in Japanese. The insulin gene region appeared to be of less value as a genetic marker for IDDM in Japanese. Little is known about other genetic markers.
Diabetes Res Clin Pract 1994 Oct
PMID:Genetic markers for insulin-dependent diabetes mellitus in Japanese. 785 39

Mexican American patients (n = 35) with insulin-dependent diabetes mellitus (IDDM) and control subjects (n = 39) were HLA-DQA and DQB typed by the polymerase chain reaction technique combined with allele-specific oligonucleotide probes. Either DQB1*0302 or DQB1*0201 was present among 91% (32/35) of the patients compared to 67% (26/39) of controls. Either DQA1*0501 or DQA1*0301 was present in all patients (100% or 35/35) compared to 29/39 (74%) (OR 12.06 Pc < 0.05) of controls. All four of these genes, in cis or trans, were present in 15/35 (43%) of the patients compared to 3/39 (8%) of controls (OR 9.0; Pc < 0.01). The presence of one or more non-susceptibility alleles showed a dose-related decrease in relative risk. Presence of aspartic acid (Asp) at position 57 of the DQ beta chain did not confer protection and non-Asp homozygosity did not confer susceptibility to IDDM in this ethnic group. In conclusion, susceptibility to IDDM in Mexican Americans is associated with particular DQA and DQB combinations, illustrates dose-dependent parameters and contradicts the critical residue hypothesis.
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PMID:Analysis of HLA-DQA1 and -DQB1 genes in Mexican Americans with insulin-dependent diabetes mellitus. 790 90

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both genetic and environmental factors. The major genetic susceptibility to IDDM is conferred by genes in the HLA class II region on chromosome 6. In Caucasians, this susceptibility is thought to be determined by DQA1 and DQB1 genes including the presence of arginine at position 52 of the DQ alpha chain and the absence of aspartic acid at position 57 of the DQ beta chain. In Japanese subjects, IDDM has been found to be associated DR, DQA1, and DQB1 genes. Positive associations with arginine at position 52 of the DQ alpha chain have been demonstrated in Japanese IDDM patients. However, the majority of Japanese IDDM patients do not show positive association to the absence of aspartic acid at position 57 of the DQ beta chain. Susceptibility to IDDM in Japanese subjects appears to be due to combination of DR genes and DQA1-DQB1 haplotypes.
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PMID:[Analysis of HLA-DR, -DQA1, -DQB1 genes in Japanese IDDM patients]. 798 9

We examined the prevalence of HLA-DRB1, DQB1, DQA1 and TAP2 genes in children with insulin-dependent diabetes mellitus (type 1 diabetes). These HLA and TAP2 alleles were identified by dot-blot analysis of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotide probes. The results show that those DQB1 alleles, which carry non-aspartic acid at position 57, in conjunction with DQA1 alleles carrying arginine at position 52, are strongly associated with susceptibility to type 1 diabetes. The prevalence of the TAP2* 0201 allele in diabetic patients was significantly lower than that in normal controls. Analysis of the data suggests that DQ alleles have the primary association with type 1 diabetes and that the association of TAP2 alleles with the disease is secondary.
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PMID:HLA-DQ and TAP2 genes in patients with insulin-dependent diabetes mellitus. 800 38

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.
Diabetes Res Clin Pract 1994 Mar
PMID:Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay. 807 Mar 5

Recent studies have shown that mutations in human beta-cell glucokinase that impair the activity of this key regulatory enzyme of glycolysis can cause early-onset non-insulin-dependent diabetes mellitus (NIDDM). The amino acid sequence of human glucokinase has 31% identity with yeast hexokinase, a related enzyme for which the crystal structure has been determined. This homology has allowed us to model the three-dimensional structure of human glucokinase by analogy to the crystal structure of yeast hexokinase B. This model of human glucokinase provides a basis for understanding the effects of mutations on its enzymatic activity. Residues in the active site and on the surface of the binding cleft for glucose are highly conserved in both enzymes. Regions far from the active site are predicted to differ in conformation, and 10 insertions or deletions that range in size from 1 to 7 residues are located on the protein surface between elements of secondary structure. The model structure suggests that human glucokinase binds glucose in a similar manner to yeast hexokinase. The glucose-binding site contains a conserved aspartic acid, two conserved glutamic acids, and two conserved asparagines that form hydrogen bond interactions with the hydroxyls of the glucose similar to those observed in other sugar-binding proteins. Mutation of residues in the predicted glucose-binding site has been found to greatly reduce enzymatic activity. This model will be useful for future structure/function studies of glucokinase.
Diabetes 1994 Jun
PMID:Molecular model of human beta-cell glucokinase built by analogy to the crystal structure of yeast hexokinase B. 819 64

The repertoire of V beta 5 and V beta 8 T-cell receptors in pancreatic lesions of autoimmune diabetic NOD mice was analysed by sequencing the CDR3 and adjacent regions. T-cell receptor mRNA isolated from four different cell populations (i.e. spleen, lymph node, infiltrated islets from male and female NOD mice) was amplified by PCR and cloned; out of these, 339 clones were sequenced. Of 170 beta chains sequenced from intra-islet T cells, nearly 90% were unique and six other sequences were found 2 to 4 times. These data argue against any oligoclonality of the islet infiltrate. Despite the lack of clonal restriction, we observed a bias in TcR usage which indicates the existence of some selective pressure with regard to TcR structure. Of the V beta 5 positive cells, 30% to 40% showed a rearrangement of V beta 5 to J beta 2.6 and a complete lack of V beta 5-J beta 1.6 combination. The selective J beta usage was not restricted to islets but was found in all tissues analysed. V beta 8 positive cells did not show such an overrepresentation of V beta-J beta combinations with the exception of clones of infiltrated islets of partially diabetes-resistant male NOD mice. There the rearrangement of V beta 8-J beta 1.1 was markedly over-expressed. Analysis of the CDR3 region did not show selection of specific TcR with regard to region length. However, we found a restricted use of amino acids in the second position of the CDR3 region. V beta 8 chains had conserved an aspartic acid from the germline configuration in about half of the cases in all tissues analysed. V beta 5 chains also showed diversity of position 2 but not islet specificity of rearrangements. Mutated chains had a clear bias towards proline indicating selective pressure in favour of this amino acid. In conclusion, sequence analysis of V beta 5 and V beta 8 TcRs excludes oligoclonality of T-cell receptors in pancreatic lesions. The bias found for J beta usage and CDR3 structure was seen also in extra-pancreatic tissues and thus probably is due to selective pressure during T-cell maturation in thymus or periphery.
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PMID:Molecular analysis of the T-cell receptor V beta 5 and V beta 8 repertoire in pancreatic lesions of autoimmune diabetic NOD mice. 821 86

In the last few years the improvement of our knowledge of the pathogenesis of type I diabetes mellitus has been possible mainly because of the development of studies of the role played by genetic factors and the better definition of lesion mechanisms. The availability of experimental models such as "non obese diabetic (NOD)" mice and "Bio-Breeding (BB)" rats, which develop a form of type I diabetes similar to that of humans, has provided many data regarding the relevance of T lymphocytes in the pathogenesis of the disease, and made it possible to anticipate the immunopathological steps leading to pre-insulitis, insulitis and, finally, to pancreatic beta-cell destruction. The analysis of sera of patients with type I diabetes has demonstrated the presence, also in the preclinical states, of several autoantibodies directed against specific autoantigenic structures of beta cells, which have come to be useful for early diagnosis and in the monitoring of the disease. However, hard evidence for a relevant role of these autoantibodies in the pathogenesis of the disease does not exist. At present, we can affirm that the expansion of autoreactive T lymphocytes specific for membrane antigens of beta cells is the most relevant immunological event for the induction and sustenance of insular lesions. Autoreactive T lymphocytes may be able to activate several effector systems of lesions through the production of multiple combinations of cytokines. The aetiology of the disease is certainly multifactorial and involves both genetic and environmental factors. With respect to the former, the most accurate studies have been performed on the HLA system. It has been clearly shown that type I diabetic patients more frequently display HLA DR3 and DR4 specificities. The results obtained by the application of molecular techniques have suggested considering as risk factors the occurrence of DQB1 0302 DQB1 0201 alleles, the presence of a neutral amino acid residue in position 57 of the DQ beta chain instead of aspartic acid, as well as an arginine residue in position 52 of the DQ alpha chain. With regard to acquired aetiological factors, the hypothesis that primary lesions of pancreatic islets could be due to some viral infections capable of triggering, through several undefined mechanisms, persistent and self-sustaining autoimmune reactions, has gained some credit.
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PMID:[Current views on the etiopathogenesis of type-I diabetes mellitus]. 821 79

We identified a heterozygous missense mutation that substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient who displayed typical symptoms of Type A syndrome of insulin resistance. The proband's mother and younger brother were also found to be heterozygous for the mutation. We constructed the identified mutant insulin receptor cDNA by site-directed mutagenesis, transfected the mutant cDNA into COS 7 cells, and found that kinase activity of the mutant insulin receptors was markedly impaired. Ala1048 is located in the kinase domain of the insulin receptor beta-subunit and is conserved in most of protein-tyrosine kinases. Besides, neighboring Glu1047 is invariant in all protein kinases and is thought to be involved in interaction with ATP. Photoaffinity labeling of the mutant insulin receptor with ATP analogue, 8-azido (alpha-32P)ATP was not influenced by the mutation, suggesting that the mutation did not inhibit ATP binding but possibly interfered with subsequent phosphoryl transfer. Insulin-stimulated phosphorylation of exogenous substrate by partially purified insulin receptors prepared from COS 7 cells that were cotransfected with wild-type and mutant insulin receptor cDNAs was markedly impaired, whereas autophosphorylation was decreased by approximately 50% of wild-type receptors. These results indicated that the identified heterozygous substitution of Asp for Ala1048 in insulin receptor was responsible for insulin resistance of this patient.
Diabetes 1993 Dec
PMID:Ala1048-->Asp mutation in the kinase domain of insulin receptor causes defective kinase activity and insulin resistance. 824 30

We report on HLA-DQB1 typing in IDDM patients of north east Italian region using an enzymatic method based on the detection of hybridization reaction between PCR amplified DNA from whole blood and allele specific oligonucleotides by an antibody directed against double stranded DNA (DNA-enzyme immunoassay or DEIA). The method is reliable, simple and sensitive as the classical radioactive method with the advantage of using a universal non radioactive detection reagent. Nineteen families, each including one subject with juvenile insulin-dependent diabetes mellitus (IDDM) were analyzed. A strong association between absence of an aspartic acid (Asp) in position 57 of DQB1 beta chain in homozygous conditions and susceptibility to IDDM was found. In contrast with some previous observations, however, no significant association was found between Asp/non-Asp heterozygous genotype and IDDM. No patients were found with an homozygous Asp/Asp genotype, known to be protective in caucasoid population. Of particular interest was the DQB1 allelic distribution in our population sample. The non-Asp allele most frequently found in IDDM subjects was the DQB1 0201 allele and this finding was statistically significant (Pc value < 0.05, relative risk = 5.01). No significant association was found for any other allele including the DQB1 0302 (Pc value = not significant although with relative risk = 3.28) previously reported as the most frequent allele in IDDM caucasoid patients.
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PMID:HLA-DQB1 typing of north east Italian IDDM patients using amplified DNA, oligonucleotide probes and a rapid DNA-enzyme immunoassay (DEIA). 841 76


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