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 hypothesis that early exposure of the infant to cow's milk (or lack of breast-feeding) predisposes the child to type 1 diabetes dates from the 1980s. It has important implications, but remains controversial because the evidence on which it is based has been indirect and is open to criticism. Two meta-analyses of multiple studies in which diabetes prevalence was associated retrospectively with infant feeding revealed only a marginal increase in relative risk. Two recent prospective studies found no apparent association between development of antibodies to islet antigens and feeding patterns in high-risk infants with a first-degree type 1 diabetic relative. Studies reporting increased humoral and cellular immunity to cow's milk proteins in children with type 1 diabetes often lack appropriate controls and standardization and do not, in themselves, establish a causal connection to disease pathogenesis. A review of published data leads to the conclusion that increased immunity to cow's milk proteins is not disease-specific, but reflects genetic predisposition to increased immunity to dietary proteins in general, associated with the HLA haplotype A1-B8-DR3-DQ2 (A1*0501, B1*0201), which also predisposes to celiac disease and selective IgA deficiency. We suggest that the cow's milk hypothesis could be productively reframed around mucosal immune function in type 1 diabetes. Breast milk contains growth factors, cytokines, and other immunomodulatory agents that promote functional maturation of intestinal mucosal tissues. In the NOD mouse model, environmental cleanliness may influence diabetes incidence through mucosal mechanisms, and exposure of the mucosa to insulin (present in breast milk) induces regulatory T-cells and decreases diabetes incidence. The mucosa is a major immunoregulatory barrier, and cow's milk happens to be the first dietary protein it encounters. The basic question is whether impaired mucosal immune function predisposes to type 1 diabetes.
Diabetes 1999 Aug
PMID:Cow's milk and type 1 diabetes: the real debate is about mucosal immune function. 1042 65

Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are associated with disease risk. We have developed a radioassay for autoantibodies to tissue transglutaminase (tTG) following the report that this enzyme is 'the' endomysial autoantigen (EMA) of celiac disease. The radioassay for transglutaminase autoantibodies is similar to that utilized for detecting anti-islet autoantibodies. The 'cut-off' for the IgA autoantibody assay was established as 3 x 100th percentile of 184 healthy control subjects at an index of 0.05. Ninety-eight of 847 patients with type 1 diabetes (11.6%) had tissue transglutaminase autoantibodies (tTG). All EMA-positive patients were positive (49/49) for transglutaminase autoantibodies, as were 49/540 EMA-negative patients. Twenty transglutaminase-positive patients consented to intestinal biopsy and 15 biopsies were positive for celiac disease. All patients with a transglutaminase level greater than 0.70 (13/13) had a positive biopsy, while none (0/3) with a level <0.3 had a positive biopsy. The prevalence of transglutaminase autoantibodies was higher in diabetic patients with HLA DQ2 or DQ8. One third of DQ2 homozygous patients (22/68) expressed transglutaminase autoantibodies vs. less than 2% of patients lacking DQ2 or DQ8. A simple radioassay for IgA transglutaminase autoantibodies detects all endomysial antibody positive patients and detects transglutaminase autoantibodies in 5% of endomysial autoantibody negative patients. The prevalence of transglutaminase autoantibodies is associated with DQ2 and DQ8 and in particular DQ2 homozygosity. Autoimmunity to transglutaminase is remarkably prevalent amongst patients with type 1 diabetes expressing certain class II HLA alleles.
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PMID:One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies. 1044 Nov 79

Genetic studies of Malnutrition related diabetes are few. We have analyzed HLA class II gene polymorphism in different types of diabetes mellitus patients from Cuttack in Eastern India. Patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and malnutrition-related diabetes mellitus (MRDM), which is subdivided into protein-deficient diabetes mellitus (PDDM) and fibrocalculous pancreatic diabetes (FCPD), were studied and their associations with autoantibody markers. IDDM and PDDM were associated with DR3 and DQ2 but not DR4 and DQ8. FCPD was positively associated with DQ9 (A*0201-B*0303). The association of DQ9 with FCPD suggests differences in the genetic background for susceptibility between IDDM and MRDM in the Cuttack population. There is no association seen between HLA-DR-DQ and NIDDM patients from Eastern India. Clinical classification of diabetes into IDDM, NIDDM and MRDM does not identify the underlying pathological mechanisms. Presence of autoantibodies to IDDM autoantigens in clinical MRDM and NIDDM identifies the slow-onset form of IDDM. Due to the absence of autoantibody assays for diagnosis of IDDM in India, slow onset IDDM is not diagnosed and the patients are classified as NIDDM or MRDM. Our study demonstrates that the presence of GAD65 antibody and DR3-DQ2 positivity in MRDM and NIDDM patients in Eastern India would suggest the presence of slow-onset IDDM. Our data would indicate alternatively that MRDM can coexist with IDDM in these patients and malnutrition could be one of the reasons for the slower onset in IDDM-prone individuals.
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PMID:Association of HLA class II alleles with different subgroups of diabetes mellitus in Eastern India identify different associations with IDDM and malnutrition-related diabetes. 1045 26

Patients with insulin-dependent diabetes mellitus, autoimmune thyroid disease, Addison's disease, and alopecia areata are at increased risk of celiac disease. We investigated whether patients with more than one autoimmune endocrinologic disorder are even more susceptible to celiac disease or have celiac-type mucosal inflammation. All 62 patients found to have such multiple diseases in 1994-1996 were investigated. Small bowel biopsy was performed on all voluntary nonceliac subjects. The villous structure and density of intraepithelial lymphocytes were examined, and HLA-DQ alleles were determined. Seven (11%) patients had celiac disease: six cases were detected earlier and there was one new case; in addition, two had minor villous deterioration and five an increased density of mucosal intraepithelial gammadelta+ T-cells. HLA-DQ2 or DQ8 alleles were found in all subjects with mucosal changes. Patients with multiple autoimmune disorders clearly run an increased risk of developing celiac disease, and some of them have minor mucosal changes compatible with the early signs of the disease.
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PMID:Celiac disease and autoimmune endocrinologic disorders. 1096 32

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.
Exp Clin Endocrinol Diabetes 1999
PMID:Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population. 1052 14

Type 1 diabetes is a complex disease where numerous genes are involved in the pathogenesis. Genes that account for approximately 50% of the familial clustering of the disease are located within or in the vicinity of the HLA complex on chromosome 6. Some DRB1, DQA1 and DQB1 genes are known to be involved, in addition to as yet unidentified HLA-linked genes. The DR4-DQ8 and DR3-DQ2 haplotypes are known to confer high risk for developing the disease, particularly when occurring together. Approximately 10% of patients, however, do not carry any of these high-risk HLA class II haplotypes. We have performed genotyping of DRB1, DQA1 and DQB1 alleles in non-DR3-DQ2/non-DR4-DQ8 patients and controls from Sweden and Norway to test if any HLA associations were observed in these patients. Our results clearly demonstrate several statistically significant differences in the frequency of HLA haplotypes between patients and controls. Case-control analysis including the relative predispositional effect test, and transmission disequilibrium test (TDT) analysis in Norwegian type 1 diabetes families revealed that the DQA1*03-DQB1*0301, DQA1*0401-DQB1*0402, DQA1*0101-DQB1*0501, DQA1*03-DQB1*0303 and DQA1*0102-DQB1*0604 haplotypes may also confer risk. Our analyses also supported independent risks of certain DRB1 alleles. The study clearly demonstrates that HLA associations in type 1 diabetes extends far beyond the well-known associations with the DR4-DQ8 and DR3-DQ2 haplotypes. Our data suggest that there is a hierarchy of HLA class II haplotypes conferring risk to develop type 1 diabetes.
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PMID:HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes. 1067 67

Specific HLA DQ and DR alleles have been associated with susceptibility to type 1 diabetes. HLA DQ8 and DQ2 have been shown to strongly predispose to disease and to be in linkage disequilibrium with at-risk DR4 and DR3 alleles, respectively. Inheritance of a mixed DR3/DR4 haplotype confers the greatest risk. A double transgenic mouse expressing both DR3 and DQ8 was generated to investigate potential major histocompatibility complex class II interactions. The DR3/DQ8 transgenic mice developed a spontaneous loss of tolerance to GAD65, in which the T-cell response to GAD65 was restricted by HLA DR. Although the mice also showed spontaneous insulitis, they did not progress to overt diabetes. Mice expressing either transgene (DQ8 or DR3) alone showed mild infiltration of their islets, which disappeared when DQ8 or DR3 was co-expressed with a resistant DR2 allele or the neutral DQ6 allele. Therefore, in a fashion analogous to human diabetes, the murine model demonstrated a requirement for a combination of at-risk DR and DQ allotypes for the initiation of spontaneous autoimmunity.
Diabetes 2000 Apr
PMID:Co-expression of HLA DR3 and DQ8 results in the development of spontaneous insulitis and loss of tolerance to GAD65 in transgenic mice. 1087 Nov 91

We hypothesized that genetic determinants of expression of persistent antiislet autoantibodies would similarly influence the expression of transient autoantibodies. To test this hypothesis, we prospectively evaluated sera from 478 relatives (SOC: sibling-offspring cohort) of patients with type 1 diabetes as well as 793 newborns from the general population (NEC: newborn nonrelative cohort) selected for expression of specific human leukocyte antigen haplotypes. Eight relatives of 478 (1.7% of SOC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). In contrast, 28 relatives (5.9%) had persistent antiislet autoantibodies, and 14 (50%) were DR3/4(DQ2/8) heterozygotes. Thirteen children of 793 (1.6% of NEC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). Seven of the NEC (0.9%) had persistent antiislet autoantibodies, and 4 (57.1%) were DR3/4(DQ2/8) heterozygous. Expression of persistent autoantibodies was strongly related to human leukocyte antigen status and family history of type 1 diabetes. In contrast, the expression of transient antiislet autoantibodies did not differ by family history of diabetes, and none of the DR3/4(DQ2/8) relatives and DR3/4(DQ2/8) newborns expressed transient autoantibodies. Our results indicate that children can express transient antiislet autoantibodies, but such transient autoantibodies are relatively infrequent and are not correlated with known genetic risk factors for type 1 diabetes.
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PMID:Transient antiislet autoantibodies: infrequent occurrence and lack of association with "genetic" risk factors. 1090 88

The major histocompatibility complex (MHC) is the most important susceptibility locus for type I diabetes in humans and NOD mice. NOD mice express a single MHC class II molecule (I-Ag7) which carries a unique beta chain sequence. In humans, DQ alleles that encode DQ8 and DQ2 confer the highest risk for the disease. Soluble DQ8 and I-Ag7 were used to directly compare the binding specificity of these MHC molecules. Peptides from three islet antigens--insulin, GAD 65 and HSP 60--bound to both CQ8 and I-Ag7. These peptides included epitopes that are immunodominant in NOD mice, namely insulin (9-23), GAD (206-220) and HSP 60 (441-460). All of these peptide sequences are highly conserved between the human and murine antigens. The binding specificity of DQ8 and I-Ag7 was similar, but not identical, since two peptides eluted from splenocytes of NOD mice did not bind to DQ8. DQ8 formed long-lived complexes with the majority of these peptides, indicating that DQ8 is not a poor peptide binder. These results demonstrate functional similarities between human and murine MHC class II molecules that confer susceptibility to type I diabetes.
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PMID:Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes. 1100 82

The frequency of reticulin (ARA), endomysium (EmA), and gut epithelial cell (GECA) autoantibodies, and gliadin antibodies (AGA), was investigated in 86 Spanish diabetic patients by indirect immunofluorescence (IFI) and ELISA, along with their HLA phenotype. Four patients (5%) showed ARA-IgG (R1 pattern), eight (9%) showed AGA-IgG, and eight (9%) showed AGA-IgA. No EmA or GECA-positive patients were found. In diabetic patients, HLA-DR7 is increased in ARA-IgG+ vs. ARA-IgG- (though not significantly), and HLA-DR6 and HLA-DQ1 are significantly increased in the AGA-IgG+ group vs. the AGA-IgG- group. Comparison with a non-diabetic coeliac group showed that HLA-DR4 and HLA-DQ3 are significantly increased in the AGA-IgA+ group, whereas HLA-DQ2 shows a significant decrease in the AGA-IgG+ and AGA-IgA+ patients. Finally, when compared to the healthy group, HLA-DR7 frequency is decreased in the ARA-IgG- group, while HLA-DQ3 is significantly increased and HLA-DR6 and HLA-DQ1 significantly decreased in the AGA-IgG- group.Altogether, these data suggest that the genetic background leading to the appearance of coeliac-specific autoantibodies in Spanish diabetic patients differ depending on the autoantibody produced and is also different to the genetic background leading to diabetes in Spain.
J Diabetes Complications
PMID:Coeliac- and enteropathy-associated autoantibodies in Spanish insulin-dependent diabetes mellitus patients and their relation to HLA antigens. 1125 25


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