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 (T1D) is an autoimmune disease leading to insulin deficiency. Its occurrence is influenced by genetic and environmental factors. The human leukocyte antigen (HLA) region on chromosome 6 accounts for 45% of the genetic susceptibility for the disease, mainly the HLA-DQB1*0201 and HLA-DQB1*0302 alleles. Among the environmental factors involved, early exposure to cow's milk seems to be a trigger. In this study, we investigated the occurrence of T1D in 253 Lebanese Caucasian patients, in relation to HLA-DQB1*0201, HLA-DQB1*0302, HLA-DQB1*0602, gender, and early exposure to cow's milk, as well as to family history of T1D and type-2 diabetes (T2D). Our genetic analysis results show that in the patients studied, 77% and 40% were positive for BQ1*0201 and BQ1*0302, respectively. As for BQ1*0602, only 0.8% of patients were positive for this T1D protective allele, compared with 24% among the controls. Furthermore, our results did not show any gender preference of the disease or any effects of early intake of cow's milk on the age at onset of T1D. When family history of T2D or T1D was studied, our results show a novel finding whereby an immediate family history of T2D, but not T1D, delays the age at onset of T1D.
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PMID:Type-2 diabetes family history delays the onset of type-1 diabetes. 1210 23

Type and type II diabetes are the most common types of diabetes. The ratio of type I to type II diabetes is about 1:9. Type I diabetes is caused by absolute insulin deficiency and is therefore referred to as insulin-dependent diabetes. The disease becomes manifest clinically in childhood or adolescence ("juvenile diabetes"), though onset in adulthood is increasingly being observed. Morphologically a subtotal (>80%) to total loss of B-cells in the pancreatic islets occurs. Lymphocytic insulitis, which disappears after the B-cells have been totally destroyed, is pathogneumonic of type I diabetes. This insulitis is an expression of an autoimmune event that is triggered by a multitude of factors. An important factor appears to be a genetic predisposition (human leukocyte antigen [HLA] DR3/DR4/DQ8) in connection with as-yet-unknown environmental factors (e.g., viruses). Autoantibodies, such as islet cell cytoplasmic antibodies (ICA). insulin autoantibodies (IAA) and/or autoantibodies to the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid carboxylase (GAD), are already detectable in a prediabetic phase, though it is not possible to predict the time of clinical onset. The course of the disease is dependent on age. Young children require insulin therapy sooner than juveniles or adults.
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PMID:Insulin-Dependent Diabetes Mellitus: Islet Changes in Relation to Etiology and Pathogenesis. 1211 88

We herein report on two Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1). The brother, who expressed a characteristic phenotype of APS-1, had developed severe mucocutaneous candidiasis in early infancy and thereafter developed hypoparathyroidism and Addison's disease, along with a severe deterioration of his immunologic function. In contrast, the 44-year-old sister, who showed a noncharacteristic phenotype of APS-1, developed insulin-dependent diabetes with high anti-glutamic acid decarboxylase antibody, mild nail candidiasis, and autoimmune hepatitis with intact immunoreactivity. She had three susceptible human leukocyte antigen (HLA) loci for type 1 autoimmune diabetes. The expression of T cell receptor (TCR)V beta 5.1 increased in both patients, while the brother showed a widely suppressed expression of many TCRV beta families. Both individuals possessed compound heterozygous novel autoimmune regulator (AIRE) gene mutations (L29P and IVS9-1G > C). The same AIRE gene mutations can thus be associated with characteristic and noncharacteristic phenotypes of APS-1, and HLA may possibly influence the phenotype of APS-1.
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PMID:Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. 1217 2

The aim of this study was to evaluate the frequency and predictive value of diabetes-associated autoantibodies, such as islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD65 (GADA), and the IA-2 molecule (IA-2A) in genetically susceptible children from the general population during the first 2 yr of life. Of 12,170 newborn infants, 1,005 with increased genetic risk of type 1 diabetes (high risk, human leukocyte antigen DQB1*02/*0302; moderate risk, DQB1*0302/x, where x = other than *02, *0301, or *0602) were monitored for ICA, IAA, GADA, and IA-2A at 3- to 6-month intervals from birth up to a minimum age of 2 yr. In addition, all 15 genetically susceptible children from the general population who had participated in regular immunological follow-up and developed clinical type 1 diabetes by the end of April 2000 were analyzed for the development of autoantibodies. Among 1,005 children, 63 (6.3%) tested positive for at least one autoantibody, 31 for ICA (3.1%), 48 for IAA (4.8%), 23 for GADA (2.3%), and 13 for IA-2A (1.3%) at least once by the age of 2 yr. Both ICA and IAA identified 95% [95% confidence interval (CI), 77.2-99.9%] of those who tested persistently positive for multiple (> or = 2) antibodies at the age of 2 yr, GADA identified 86% (CI, 65.1-97.1%), and IA-2A identified 55% (CI, 32.2-75.6%). Close to half of the antibody-positive children (29 of 63) reverted back to antibody negativity. Autoantibodies disappeared more often among those who tested positive for IAA than among those who tested positive for other autoantibodies (P < or = 0.021). Among the 15 children who developed type 1 diabetes, the disease sensitivity of ICA was 80% (CI, 51.9-95.7%), that of IAA was 93% (CI, 68.0-99.8%), that of GADA was 60% (CI, 32.3-83.7%), and that of IA-2A was 40% (CI, 16.3-67.7%). These results suggest that IAA are characterized by high sensitivity, early appearance, and high frequency of transient antibody positivity, whereas ICA detected with a thoroughly standardized assay appear to be more specific for the screening of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes in the Finnish population, which has the highest incidence of type 1 diabetes in the world.
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PMID:Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. 1236 37

To evaluate the contributions of DR3 and DQ8 to the etiopathogenesis of type 1 diabetes in a diabetes-predisposing milieu, we developed human leukocyte antigen (HLA) transgenic mice on the nonobese diabetic (NOD) background in the absence of the endogenous class II molecule, I-A(g7) and studied the incidence of both spontaneous and experimental (induced) autoimmune diabetes. Transgenic expression of HLA-DR3 and -DQ8 (either alone or in combination) did not confer susceptibility to spontaneous or cyclophosphamide-induced type 1 diabetes. Expression of I-A(g7) was mandatory for development of spontaneous or cyclophosphamide-induced diabetes. However, multiple low doses of streptozotocin could induce diabetes in all groups of mice independent of the class II molecules expressed. In unmanipulated mice, only islets from I-A(g7+/+) mice revealed significant intra-islet infiltration. Although a characteristic peri-insulitis/peri-ductulitis was present in Abeta(0)/NOD mice, islets from DR3, DQ8 and DR3 x DQ8 double transgenic mice demonstrated significantly less infiltration. In conclusion, transgenic expression of HLA-DR3 and -DQ8 associated with predisposition to type 1 diabetes alone is not sufficient to induce spontaneous diabetes in NOD mice lacking endogenous class II molecules.
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PMID:Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. 1239 51

In 1993-1996, islet autoantibodies, C-peptide, and HLA-DQ genotypes were evaluated in 345 insulin-treated diabetic patients of all ages from the Skaraborg Diabetes Registry 5-6 years after their diagnosis and in 216 control subjects from the Skaraborg County, Sweden, population. The aims of this study were to clarify the importance of age at diagnosis of diabetes for HLA-DQ associations in patients with classic type 1 diabetes and whether patients considered to have latent autoimmune diabetes of the adult differed in their human leukocyte antigen (HLA) associations. An abnormally low fasting C-peptide value was used as the definition of type 1 diabetes, found in 182 of 345 (53%) patients. No major associations between age at diagnosis and HLA susceptibility or protective genotypes were detected in type 1 diabetic patients. Among the 163 patients with preserved beta-cell function, the frequency of HLA protective genotypes was clearly decreased (5% vs. 42%) in the 46 of 163 with islet antibodies compared with the 117 of 163 antibody-negative patients. The authors conclude that there were no major effects of age at diagnosis on HLA-DQ associations in classic type 1 diabetic patients, whereas lack of HLA-DQ protective genotypes was a feature of patients with slow-progressing type 1 diabetes (latent autoimmune diabetes of the adult).
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PMID:HLA-DQ genotypes in classic type 1 diabetes and in latent autoimmune diabetes of the adult. 1239 95

A hypertonic environment, as it prevails in renal medulla or in hyperosmolar states such as hyperglycemia of diabetes mellitus, has been shown to impair the immune response, thus facilitating the development of infection. The present experiments were performed to test whether hypertonicity influences activation of T lymphocytes. To this end, peripheral blood lymphocytes (PBL) of cytomegalovirus (CMV)-positive donors were stimulated by human leukocyte antigen (HLA)-A2-restricted CMV epitope NLVPMVATV to produce interferon (IFN)-gamma at varying extracellular osmolarity. As a result, increasing extracellular osmolarity during exposure to the CMV antigen indeed decreased IFN-gamma formation. Addition of NaCl was more effective than urea. A 50% inhibition was observed at 350 mosM by addition of NaCl. The combined application of the Ca(2+) ionophore ionomycin (1 microg/ml) and the phorbol ester phorbol 12-myristate 13-acetate (PMA; 5 microg/ml) stimulated IFN-gamma production, an effect again reversed by hyperosmolarity. Moreover, hyperosmolarity abrogated the stimulating effect of ionomycin (1 microg/ml) and PMA (5 microg/ml) on the transcription factors activator protein (AP)-1, nuclear factor of activated T cells (NFAT), and NF-kappaB but not Sp1. In conclusion, osmotic cell shrinkage blunts the stimulatory action of antigen exposure on IFN-gamma production, an effect explained at least partially by suppression of transcription factor activation.
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PMID:Inhibition of interferon-gamma expression by osmotic shrinkage of peripheral blood lymphocytes. 1247 62

Type 1 diabetes (T1D) arises from autoimmune destruction of the beta cells of the pancreas leading to a complete dependence on exogenous insulin for survival. Like many autoimmune disorders, the etiology of T1D is complex, resulting from the action of multiple genes and environmental factors. Identification of genes that contribute to T1D susceptibility should improve disease prediction and contribute to the understanding of the underlying pathology of the disorder. Two regions of the human genome, the human leukocyte antigen (HLA) region and the insulin gene region are generally thought to contain susceptibility loci for T1D. Although additional putative T1D loci have been reported, the supporting evidence has often been of modest significance and findings have displayed poor reproducibility across multiple studies. This review summarizes the current state of genetic linkage and association studies in T1D and suggests future directions. We argue that much of the difficulty in mapping T1D susceptibility loci has resulted from inadequate sample sizes and we illustrate the substantial gains in power that can be achieved by pooling data across studies. These findings suggest that substantial progress toward the identification of susceptibility genes in T1D and other genetically complex disorders may be achieved through increased collaboration and consortium mapping efforts.
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PMID:Mapping genes for autoimmunity in humans: type 1 diabetes as a model. 1249 15

The aim of the study was to investigate the participation of human leukocyte antigen (HLA) class II alleles in the expression of type 2 diabetic and in nondiabetic subjects with and without family history of diabetes. The purpose was to evaluate any HLA association and to look for different patterns of insulin resistance and insulin secretion, comparing subjects with a low probability of developing diabetes, as a result of their family history. We recruited 87 healthy subjects without family history of diabetes, 48 healthy subjects with family history, and 47 type 2 diabetic patients. All of them were Mexican Mestizos of central Mexico. Using a standard 75-g oral glucose tolerance test, insulin resistance was determined and insulin secretion was assessed with the HOMA model. DRB1, DQA1 and DQB1 alleles were typed using polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) and sequence specific primers (PCR-SSP). Nondiabetic subjects had similar HOMA-IR and DeltaI 30/DeltaG 30 index (HOMA). A significant decreased frequency of DRB1*0403 (p = 0.01; odds ratio [OR] = 0.20) was demonstrated in type 2 diabetic patients, and DRB1*0701 (p = 0.02; OR = 0.17) in nondiabetics with family history of diabetes. These alleles associated with protection against type 2 diabetes, share glutamic acid at position-74 and were previously demonstrated to contribute to protection against type I diabetes.
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PMID:Protective effect of DRB1 locus against type 2 diabetes mellitus in Mexican Mestizos. 1250 21

The human transporter associated with antigen processing (TAP1 and TAP2) genes are located in the human leukocyte antigen (HLA) class II region of the genome and encode proteins that form a heterodimer essential for the transport of endogenous peptides into the endoplasmic reticulum for assembly with HLA class I molecules. Type 1 diabetes is an autoimmune disease that is associated with the HLA region of the genome, with HLA class II genes conferring the greatest statistical risk. The presentation of self-peptides by HLA class I molecules is defective in individuals with this disease, and both TAP1 and TAP2 are potential contributors to this defect. Denaturing gradient gel electrophoresis (DGGE) was applied to screen all 11 exons and the 3' flanking region of TAP2 for polymorphisms in individuals with type 1 diabetes patients and controls. Seventy polymorphisms, including 51 in introns, 4 in the 3' flanking region, and 15 in exons, were identified. Sequencing of polymorphic DNA fragments revealed several new polymorphisms, including a Gln --> Arg substitution at codon 611 and a GT --> GC polymorphism affecting the donor splice site of intron 4, that might be of functional significance. None of the polymorphisms examined differed in frequency between individuals with type 1 diabetes and controls.
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PMID:Polymorphisms of human TAP2 detected by denaturing gradient gel electrophoresis. 1250 27


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