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)

We examined the apolipoprotein E polymorphism of an obese patient presenting non-insulin-dependent diabetes, hypertension and moderate lipid disturbances. The apolipoprotein E genotyping carried out from leukocyte DNA using PCR amplification and restriction enzyme digestion demonstrated homozygosity for the rare apoE1[Gly127-->Asp; Arg158--> Cys] (Weisgraber allele). The nucleotide change results in a glycine to aspartic acid substitution at amino acid 127 in the apolipoprotein E2.
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PMID:Genotyping of a patient homozygous for a rare apolipoprotein E1 [Gly127-->Asp; Arg158-->Cys] (Weisgraber allele). 875 Jun 11

MHC associations with IDDM in the Korean population were studied to investigate genetic susceptibility to this disorder. The frequencies of HLA-DR3, -DR4 and -DR9 were significantly higher in diabetic patients. However, the frequency of DR2 was significantly decreased in diabetic patients. DQA1*0301 and DQA1*0501 were positively and DQA1*0102 and DQA1*0201 negatively associated with IDDM. DQB1*0301 and DQB1*0601 were negatively associated with IDDM. Heterodimers DQA1*0301-DQB1*0201, DQA1*0501-DQB1*0201 and DQA1*0501-DQB1*0302 were positively associated with DQA1*0102-DQB1*0601 negatively associated with IDDM. The frequencies of DR3-DQA1*0301-DQB1*0201 and -DQA1*0501-DQB1*0201 were significantly higher in diabetic patients. The frequencies of DR4-DQA1*0301-DQB1*0201 and DR9-DQA1*0301-DQB1*0303 were significantly higher in diabetic patients. The presence of non-aspartic acid at position 57 of the DQ beta-chain was not associated with susceptibility to IDDM. However, the frequency of Arg 52 homozygotes was significantly higher in diabetic patients. These results suggest a role of the MHC molecule and also suggest racial differences in susceptibility to IDDM even within the Asian populations.
Diabetes Res Clin Pract 1996 Mar
PMID:Role of HLA class II alleles in Korean patients with IDDM. 879 97

Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C-peptide (IFur) and between the C-peptide and A-chain (IIFur) and/or containing a histidine B10 to aspartic acid point mutation were subcloned into a mammalian expression vector (pCMV) containing the cytomegalovirus (CMV) promoter. The altered cleavage sites enable the insulin to be processed by the ubiquitous endoprotease furin. The histidine B10 to aspartic acid mutation creates a more stable form of insulin leading to an increase in insulin accumulation. Myoblasts transfected with a proinsulin cDNA construct mutated at all three sites (pCMV.IFur.IIFur.B10), a construct with only the furin sites (pCMV.IFur.IIFur), and a construct containing only the mutation at the B10 position (pCMV.B10) accumulated 852 +/- 16, 150 +/- 13, and 883 +/- 39 microU (pro)insulin/ml, respectively, in the culture medium during a 48-hr incubation. (Pro)insulin was detected in the culture medium within 2 hr post-transfection. Significant (pro)insulin release continued for 1 week and gradually diminished over a month. Approximately 50% of the proinsulin released from rat myoblasts transfected with pCMV.IFur.IIFur.B10 was completely processed into mature insulin based on densitometric analysis of autoradiographs of gels containing immunoprecipitated 35S-Cys-labeled (pro)insulin. However, only a trace of the proinsulin encoded by pCMV.B10 was processed. In an isolated rat adipocyte [14C]glucose oxidation assay, insulin released from myoblasts transfected with pCMV.IFur.IIFur.B10 was active biologically, displaying more biological activity than normal human insulin. Plasmid expression was studied by transfecting myoblasts with the beta-galactosidase (beta-Gal) gene in pCMV, allowing them to divide and fuse into multinucleated myotubes, followed by staining for beta-Gal. Approximately 80% of myotubes expressed beta-Gal. The results indicate that proinsulin encoded by genetically modified proinsulin cDNA is processed into mature insulin, which is secreted at high levels, making myoblasts a viable target cell for gene therapy of IDDM.
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PMID:Synthesis and processing of genetically modified human proinsulin by rat myoblast primary cultures. 882 70

We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.
Exp Clin Endocrinol Diabetes 1996
PMID:Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor. 898 Oct 16

The WHO DiaMond Molecular Epidemiology Sub-Project is testing the hypothesis that the geographic differences in IDDM incidence reflect population variation in the frequency of IDDM susceptibility genes (i.e., DQA1 and DQB1 alleles with sequences coding for arginine (R) in position 52 of the DQ alpha-chain, and an amino acid other than aspartic acid (ND) in position 57 of the DQ beta-chain, respectively) using a standardized case-control design. Data from twelve populations which have completed (or have nearly completed) recruitment and HLA molecular analyses are presented. There was an approximate 2-fold increase in the frequencies of DGA1*0301, DQB1*0201 and DQB11*0302 among IDDM cases compared to non-diabetic controls in most populations. Interestingly, DQA*0301 was more common in low versus moderate-high incidence countries. DQB1*0201 and DQB1*0302 were more prevalent in the moderate-high incidence areas. DQA1*R and DQB1*ND were both consistent markers of IDDM risk, with stronger associations in moderate-high versus low incidence areas. In general, individuals homozygous for both DQA1*R and DQB1*ND had the highest genotype-specific IDDM incidence rates, which approximated risk estimates for first degree relatives in several countries. These data revealed considerable variation in the frequencies of DQB1 and DQA1 alleles across countries, which likely contribute to the global patterns of IDDM incidence.
Diabetes Res Clin Pract 1996 Oct
PMID:Molecular IDDM epidemiology: international studies. WHO DiaMond Molecular Epidemiology Sub-Project Group. 901 79

HLA-DQA11 and DQB1 alleles coding for arginine (R) in position 52, and an amino acid other than aspartic acid (ND) in position 57, respectively, are strong genetic markers for IDDM in Caucasians. However, their contribution to the occurrence of the disease in Asian populations is less clear. As part of the WHO DiaMond Molecular Epidemiology Sub-Project, HLA-DQ molecular typing was performed for IDDM cases and non-diabetic controls from three populations in the Western Pacific Rim Region where incidence rates have been established (Hokkaido, Japan; Seoul, Korea; Auckland, New Zealand). DQA1*R homozygosity was significantly associated with IDDM in all areas. DQB1*ND homozygosity was also related to IDDM in Korea and New Zealand, but not in Japan. Individuals who were homozygous for DQA1*R and DQB1*ND were at highest IDDM risk in Korea and New Zealand, with the most striking findings in Auckland. In Japan, individuals carrying two DQA1*R, but only one DQB1*ND allele, were most likely to develop IDDM. These data revealed considerable genetic heterogeneity between Japan and Korea and suggest that DQA1*R and DQB1*ND alleles may explain a larger proportion of IDDM incidence in Caucasian compared to Asian populations.
Diabetes Res Clin Pract 1996 Oct
PMID:Molecular epidemiology of IDDM in the Western Pacific Rim Region. WHO DiaMond Molecular Epidemiology Sub-Project Group. 901 80

Amino acid 57 of DQ beta chains is of functional importance as it influences peptide binding, is part of B and T cell epitopes, and is associated with susceptibility and resistance to insulin-dependent diabetes mellitus and humoral immunodeficiencies. Polymorphism of codon 57 is conserved in primates and in HLA class II B genes implying that balancing selection operates on this residue. Previously, three DQB1 allele pairs have been described, that only differ at residue 57. In an African-American Black individual with the HLA phenotype A23.30;B58,63;Cw6;DR18,12;DR52;DQ5,2, we found a fourth example of this dimorphism: the new DQB1*0203 allele, that was identical to DQB1*0202 except for codon 57, which encodes aspartic acid and alanine respectively in the two alleles. The class II haplotype carrying the new allele was deduced to be DRB1*0302,DRB3*0101,DQA1*05011,DQB1*0203.
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PMID:DQB1*0202 and the new DQB1*0203 allele: a fourth pair of DQB1 alleles differing only at codon 57. 909 36

This article focuses on recent developments that have defined the autoimmune nature of this entity and its genetic basis, especially the crucial roles of aspartic acid at position 57 of the DQ beta chain and arginine at position 52 of the DQ alpha chain of the HLA complex on chromosome 6 in conferring susceptibility; other genetic markers on other genes are mentioned. These genetic markers help to explain the worldwide differences in prevalence and incidence of type 1 diabetes. Because the autoimmune process may be gradual, markers of beta pancreatic cell damage, such as islet cell antibodies, glutamic acid decarboxylase antibodies, and insulin autoantibodies, coupled with evidence of progressive failure of insulin secretion may be used to predict the future onset of disease. In turn, accurate prediction may permit preventive intervention. Two intervention trials are mentioned: (1) Diabetes Prevention Trial for Type 1, a multicenter trial in the United States using insulin; and (2) European Nicotinamide Diabetes Intervention Trial in Europe using nicotinamide as the preventive or delaying agent. These first steps reflect the remarkable progress and understanding of this major problem of childhood and the hopes for its future prevention.
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PMID:Aspects of the etiology, prediction, and prevention of insulin-dependent diabetes mellitus in childhood. 913 Sep 20

Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.
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PMID:[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America]. 950 14

The molecular mechanism by which some, but not all, variants of encephalomyocarditis (EMC) virus selectively infect pancreatic beta-cells in mice and induce IDDM has been an enigma for more than a decade. We report here that the binding site of the EMC viral capsid protein VP1 determines viral diabetogenicity. Recombinant chimeric EMC viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 of the major capsid protein VP1 bind poorly to beta-cells. In contrast, recombinant chimeric EMC viruses containing alanine or glycine at position 152 of the VP1 bind efficiently to and infect beta-cells, resulting in the development of diabetes. Three-dimensional molecular modeling reveals that the van der Waals interactions are greater and the residues surrounding position 152 of the VP1 are more closely packed in recombinant chimeric viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 than in recombinant chimeric viruses containing alanine or glycine at the same position. Our studies reveal that the surface areas surrounding alanine or glycine at position 152 of the VP1 are more accessible, thus increasing the availability of the binding sites for attachment to beta-cell receptors and resulting in viral infection and the development of diabetes.
Diabetes 1998 Apr
PMID:Determination of encephalomyocarditis viral diabetogenicity by a putative binding site of the viral capsid protein. 956 90


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