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)

Major determinants of susceptibility to Type 1 (insulin-dependent) diabetes (IDDM) have been mapped to the HLA complex, near to or identical with genes encoding class II molecules. The association of IDDM with HLA-DR3 and/or DR4 antigens and the highest risk for DR3/4 heterozygotes suggest a synergistic effect of the two haplotypes. The characterization at the molecular level of the class II region has provided evidence that DQ rather than DR determinants may primarily influence the disease. In caucasians the susceptibility strongly correlates with the absence of aspartic acid at position 57 on the DQ beta chain and/or the presence of arginine at position 52 on the DQ alpha chain. The formation of a putative DQ susceptibility molecule (DQ alpha Arg52+, DQ beta Asp57-) accounts best for the disease associations when trans-complementation between alpha and beta chains encoded by different haplotypes is postulated to explain the excess of heterozygotes. Observations in other populations and in animal models indicate, however, that other residues on DQ alpha and beta chains, other class II (DR beta) molecules and non-HLA linked genes also contribute to the susceptibility. The mechanism(s) by which susceptibility determinants influence IDDM is not known. It is probably in relation with the role of class II molecules in the antigen presentation to T lymphocytes.
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PMID:[The role of the HLA system in the genetics of Type I diabetes mellitus]. 145 12

The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.
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PMID:Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. 146 84

In some cases patients with Type 2 (non-insulin-dependent) diabetes mellitus fail to respond to treatment with oral hypoglycaemic agents. These patients may respond in the same way as Type 1 (insulin-dependent) diabetic patients. Cellular immune aggression (defined as the capacity of peripheral mononuclear cells to inhibit stimulated insulin secretion by dispersed rat islet cells), insulin autoantibodies, C-peptide response and HLA antigens were determined in 31 Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents and in 22 control subjects. Nine (29.03%) of the 31 Type 2 diabetic patients showed positive cellular immune aggression (2 SD below control group) and 22 (70.97%) presented no cellular immune aggression. There was a relationship between positive cellular immune aggression and each of the following parameters: age, body mass index and microangiopathy. No correlation was found between positive cellular immune aggression and glycaemia, HbA1, blood lipids or atherosclerosis. Patients with positive cellular immune aggression showed a significantly lower glucagon-stimulated C-peptide response vs those with no cellular immune aggression. Within a sub-group of patients who had never been treated with insulin, insulin autoantibodies were present in four of six patients with positive cellular immune aggression. DR2 antigen was found with decreased frequency in patients whereas no DR3/DR4 heterozygotes were observed. Our data support the hypothesis that a group of Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents presented autoimmunity towards pancreatic Beta cells.
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PMID:Cellular and humoural autoimmunity markers in type 2 (non-insulin-dependent) diabetic patients with secondary drug failure. 147 68

Susceptibility to insulin-dependent diabetes mellitus (IDDM) correlates with the absence of aspartic acid in position 57 of the DQB1 and/or the presence of arginine in position 52 of the DQA1. It has been postulated that transcomplementation between the DQ alpha and beta chains of the two haplotypes could create new molecules conferring susceptibility to IDDM. Finland has the highest incidence of IDDM in the world (35/100,000). In a nationwide study of IDDM in childhood (DiMe study) HLA genotyping using conventional serology was carried out according to genetic-epidemiological principles. We simulated DQA1 and DQB1 alleles in 707 consecutively diagnosed IDDM probands and 98 non-diabetic children based on serology, restriction fragment length polymorphism results and sequence data assuming no recombination between DQ and DR. In 34% of Finnish children with IDDM all four combinations (two in cis and two in trans) could lead to SS heterodimers. Two-thirds of these combinations were explained by DR3,DR4 heterozygotes. In 50% of IDDM children half and in 11% a quarter of the combinations could lead to heterodimers. In 38 IDDM patients (5%) the formation of hybrid molecules was not possible. In 59% of the controls SS heterodimers were possible and should therefore have an underlying genetic susceptible for IDDM assuming the theory of transcomplementation is correct. These findings, together with the fact that the lowest frequency of DR3,DR4 heterozygosity (21%) was seen in Finland, show that heterozygosity for DQ and DR cannot explain the differences seen in IDDM incidence.
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PMID:DQA1 and DQB1 heterodimers in insulin-dependent diabetes mellitus: a genetic-epidemiological study in Finland. DiMe Study Group. 148 50

It is well known that certain genes in the HLA-D region confer increased susceptibility to insulin-dependent diabetes mellitus (IDDM). Previous studies have documented an increased risk associated with the HLA-DR beta chain alleles, DR3 and DR4, and the DQ beta chain allele DQB1*0302 (formerly DQw8). Since DQ alpha is also polymorphic and has been strongly implicated as the primary IDDM susceptibility locus in other races, we wanted to assess the contribution of DQ alpha to IDDM in Caucasians. This information would enable us to define more precisely the class II association with IDDM as well as gain insight into issues of cis versus trans association of DQ heterodimers in this disease. To this end, the DQ alpha genotype was determined for a large group of diabetic and normal Caucasian individuals who had been HLA-DQ beta and HLA-DR typed previously. Using the polymerase chain reaction and a set of twelve oligonucleotide probes, we determined the DQ alpha genotype of 323 patients with IDDM and 182 normal subjects. We found that certain DQ alpha alleles are decreased in the diabetic population compared with normal subjects (i.e. DQA1*0102 and *0103), while others are significantly increased in patients with IDDM (i.e. DQA1*0301 and *0501). In addition, certain combinations of DQ alpha alleles are associated with increased susceptibility to disease (i.e. DQA1*0301, *0501). These results parallel our findings at the DQ beta locus; however, because of the various associations between DQ alpha and DQ beta chains, the risks conferred by DQ alpha are generally lower than those at DQ beta. Moreover, our data indicate that, in Caucasians, no single DQ alpha allele accounts for the highest degree of susceptibility to IDDM as in other races, although DQ alpha analysis may be informative in a few cases. When done in combination, however, oligonucleotide analyses at both DQ alpha and DQ beta complement each other and provide a more complete assessment of the HLA-associated component of disease susceptibility in IDDM.
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PMID:Analysis of HLA genotypes and susceptibility to insulin-dependent diabetes mellitus: HLA-DQ alpha complements HLA-DQ beta. 150 99

Conventional detection of islet cell antibodies is based on indirect immunofluorescence performed on frozen human pancreas sections. The number and nature of epitopes recognized by antibodies detected by such techniques are unknown. To determine the existence of heterogeneous fluorescence patterns of islet cell antibodies on pancreatic sections, we selected two sera showing a distinctive granular fluorescence. We then tested random sera from patients with Type 1 (insulin-dependent) diabetes mellitus for their ability to block ultimate binding of fluorescein isothiocyanate-labelled immunoglobulins purified from these two sera with a characteristic granular pattern. Among 102 subjects with recent-onset Type 1 diabetes, 79 had detectable anti-islet cell antibodies; 21 showed complete blockade of the binding to islets of granular fluorescein isothiocyanate-labelled immunoglobulins. The majority of these 21 patients were women carrying a DR3 non-DR4 DQB1*0201 allele, with under-representation of DRB1*0402 and 0405. Discrimination between islet cell antigenic specificities may help in identifying islet cell autoantibodies in autoimmune Type 1 diabetes.
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PMID:Islet cell antibody heterogeneity among type 1 (insulin-dependent) diabetic patients. 151 8

Lack of an aspartic acid 57 in the HLA-DQ beta chain was introduced as a genetic marker of insulin-dependent diabetes mellitus (IDDM). Because 25% of the control population carries the same marker, we analyzed the DQ locus for the presence of more specific disease susceptibility markers, taking into account a possible role for the polymorphic DQA gene. We thereby identified the DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) genotype which was detected in 30% of the 268 typed IDDM patients and only in 1% of the 331 typed healthy controls, resulting in a relative risk of 35. This genetic marker was more frequent in patients with clinical onset before age 18 years (36%) than in patients diagnosed between age 18 and 40 years (22%) and was not observed in patients with non-IDDM. The new susceptibility genotype DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) may explain the well-known excess of DR3/DR4 heterozygous IDDM patients and is expected to help identify individuals at risk for developing the disease.
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PMID:Complementation of HLA-DQA and -DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus. 154 46

Glucose tolerance has been assessed in cystic fibrosis (CF) children using HbA1C and plasma glucose and insulin determinations during an oral glucose tolerance test (OGTT), along with the determination of HLA-DR and islet-cell (ICA) and anti-insulin (IAA) antibodies. Of 49 patients (25 males, 24 females), aged 2 to 21 years (mean = 10.9 years), 29 had normal glucose tolerance (WHO criteria) during OGTT, 14 had impaired glucose tolerance (IGT) and 6 had an isolated hyperglycemia at 120 min. Fasting plasma glucose and HbA1C were significantly higher in IGT than in normoglycemic patients. However, these two parameters showed poor individual predictive value of disturbance in glucose tolerance. Of 14 patients with abnormal OGTT, 7 were aged below 10 years, with 2 as young as 5 years; 8 patients were females. HLA antigens characteristic of type I diabetes tended to be found less frequently in CF patients than in the general population: 9% were DR3, 7% were DR4 and none was DR3/DR4. There were no HLA differences according to glucose tolerance. ICA and IAA were respectively detected in only one patient. Stimulated plasma insulin was low but did not correlate with glucose tolerance. In conclusion, impaired glucose tolerance is common in cystic fibrosis and can be found early in life. Although insulin secretion is decreased in this population, it does not seem to be the only factor responsible for impaired glucose intolerance. The absence of the genetical and immunological characteristics of type I diabetes confirms that glucose intolerance in cystic fibrosis is due to other pathogenetic mechanisms.
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PMID:[Research of factors for glucose intolerance in mucoviscidosis]. 155 Apr 46

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers composed of a DQ alpha chain with an arginine at residue 52 (Arg52+) combined to a DQ beta chain lacking an aspartic acid at residue 57 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Mar
PMID:Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility. 155 98

HLA-A, B, C, DR and DQ typing was performed in 381 Italian insulin-dependent diabetic patients and in 905 normal Italian subjects. The diabetic patients had significantly higher frequencies of HLA-Cw7, B8, B18, DR3, DR4, DQw2 and DQw3 and significantly lower frequencies of HLA-B17, Bw51, DR2, DR7 and DRw11. The frequency of heterozygosity for HLA-DR3/DR4 was significantly higher in patients who developed the disease in the first 2 years of life and DR3+/DR4-, DQw2 and DQw3 alleles were higher in those aged less than 14 years at onset. The HLA-DR4 allele was associated with onset of diabetes in autumn and HLA-B18 with onset in Autumn-winter. Diabetic children who were breast fed had a later onset of insulin-dependent diabetes mellitus than those who were bottle fed but these differences were independent of HLA typing (11.8 +/- 0.72 years vs 9.23 +/- 0.42 years; mean +/- SEM). We conclude that: (1) in general, HLA distribution in Italian insulin-dependent diabetic patients reflects previous data reported in other European and North American populations; (2) HLA-DR3 and DR4 are strongly associated with insulin-dependent diabetes in Italy as well, and these alleles seem to predispose to an earlier onset of the disease; and (3) breast feeding may delay the onset of the disease.
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PMID:HLA-antigens in Italian type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding in the onset of the disease. 157 60


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