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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Belgian Diabetes Registry (BDR) has studied the epidemiology of Type 1 diabetes with clinical onset before age 40 years in the Antwerp district. Both in the age categories 0-14 years and 15-39 years, the incidence approximates 10 new cases per 100,000 inhabitants per years. Most patients are adults. Juvenile-onset diabetic patients who were so far more intensively studied must therefore not be considered as "prototypes" for the disease, but rather represent "atypical" cases with rapid evolution. Participation in international programs (EURODIAB ACE, DIAMOND) has characterized the incidence of Type 1 diabetes in Belgium as being intermediate between values in low-incidence regions (5 to 10 cases/100,000 inhabitants/yr such as in parts of Southern or Eastern Europe) and values in high-incidence regions 30 to 40 cases/100,000 inhabitants/yr such as in Finland and Sardinia). Type 1 diabetes is a heterogenous disease in terms of clinical presentation, etiological factors and biological markers. Clinical and fundamental research on Type 1 diabetes needs to study patient groups which faithfully reflect this heterogeneity. This is best achieved by recruiting patients through diabetes registries. In Belgium, the BDR presently registers about 40% of all new cases of Type 1 diabetes with onset before age 40 years. Until now, more than 1700 patients and about 1100 first degree relatives are registered. This group is representative of the Belgian population of Type 1 diabetic patients with onset before age 40 years. High quality-assays for immune and genetic markers of Type 1 diabetes were designed and validated through repeated participation in international quality control programs. By systematically performing these assays on the representative non-selected samples of BDR-patients, it became possible to further clarify the clinical biology of Type 1 diabetes and to demonstrate hitherto unrecognized associations among disease markers. Certain of these markers (insulin auto-antibodies, IAA; islet cell antibodies, ICA; HLA DQA1*0301-DQB1*0302 risk haplotype) are more frequent for clinical onset before age 10 years and appear associated in that age category. Other markers (glutamate decarboxylase antibodies; GAD-Ab) occur more frequently at onset between age 10 and 40 years, where they are preferentially associated with increased genetic risk. Yet another genetic marker (1/1 susceptibility genotype in the 5' polymorphic region of the insulin gene) occurs regardless of age and presence of auto-antibodies, preferentially in patients without the highest HLA-linked genetic risk. Age-dependent differences in marker frequency and -associations possibly reflect age-dependent differences in etiological factors, in order of appearance of biological markers, or in progression rate of the disease. Presently, more than 90% of the patients under age 40 years carry at least one diabetes-associated immune or genetic marker, which opens perspectives for a better classification of the disease, especially in adults. Preliminary follow-up studies in first-degree relatives of registered patients confirm the diabetes-predictive value of the markers studied. A group of subjects at high risk for the disease could thus be identified. These subjects qualify for participation in preventive intervention trials. In this respect BDR officially represents Belgium in several international programs: EURODI-AB ACE for marker-studies, ICARUS for diabetes prediction, ENDIT for diabetes-prevention and GETREM for optimal diabetes treatment. This collaboration will focus in the near future on neonatal screening and follow-up, objective classification criteria for diabetes in adults, refined diabetes-prediction and preventive intervention studies. BDR may also serve as a tool for systematic research on the complications, innovative treatments and socio-economical aspects of diabetes.
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PMID:The importance of diabetes registries and clinical biology for the study and treatment of type 1 (insulin-dependent) diabetes mellitus. 900 3

The availability of cloned lines of T cells reactive with islet antigens has provided investigators with new tools to study how T cells contribute to autoimmune disease. T-cell clones isolated from the diabetes-prone nonobese diabetic (NOD) mouse are proving to be particularly valuable for analyzing pathogenesis and hold great promise for determining which T-cell subsets are involved in beta-cell destruction versus immunoregulation of the inflammatory process. Diabetogenic T-cell clones have been mostly of the CD4+, Th1 phenotype, but CD8+ T cell clones are also capable of transferring disease. In some cases, T-cell lines and clones (CD4+ and CD8+) have been found to have protective properties. In general T-cell antigen specificities have not been defined, as islet cells or lysates were used as the selecting antigen. However, there is an increasing number of reports of T cells specific for defined islet proteins, such as insulin and GAD, and some of these lines can induce disease. The variety of T-cell clones that have been produced indicate that there may a variety of conditions that lead to or protect against beta-cell destruction and provide further evidence that autoantigens are generated during development of disease.
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PMID:Autoreactive T-cell clones from the nonobese diabetic mouse. 901 59

In the Asian populations, it is not uncommon for adult patients with NIDDM to eventually lose beta-cell function and develop IDDM. Accepting that IDDM is an autoimmune disease, which occurs on a genetic background, it could by hypothesized that by measuring autoantibody prevalence and HLA DQ gene polymorphism, known important prediagnostic markers of IDDM, the prevalence of adult-onset IDDM in patients with previously undiagnosed NIDDM patients could be estimated. To do this, anti-GAD prevalence and HLA DQ A1 and DQ B1 polymorphisms after PCR amplification of genomic DNA were analyzed in 121 newly diagnosed diabetic patients of Yonchon cohort and compared to the results with those of 100 matched health control subjects. We also compared the results with those of other populations to assess the difference of genotype distribution. The overall prevalence of anti-GAD antibodies was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 controls had positive antibodies. Among those who were positive, their titer of antibodies to GAD were not high. No statistically significant differences in the distribution of either mean levels of anti-GAD or DQA1 and DQB1 alleles were found comparing NIDDM patients to controls. Interestingly, the frequency of DQB1*non-Asp-57 and DQA1*Arg-52 alleles in the Korean adult control population was similar to that of US Caucasians (DQB1*non-Asp-57: 0.431 vs. 0.475; DQA1*Arg-52: 0.492 vs. 0.463). The low prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 susceptibility alleles among recent-onset NIDDM patients, not different compared to controls suggests that diabetes in Korean adults is unlikely to have an autoimmune component to its pathogenesis.
Diabetes Res Clin Pract 1996 Oct
PMID:Low prevalence of immunogenetic markers of IDDM in adult Koreans with diabetes detected on OGTT. 901 68

Antibodies to glutamic acid decarboxylase (anti-GAD) predict the progression of adults masquerading as NIDDM to insulin dependency and predict the eventual occurrence of IDDM in healthy pregnant women in Finland. Almost 80% of prediabetic and newly diagnosed IDDM cases are positive for anti-GAD. However, approximately 20% of these groups do not have a humoral response to GAD so it cannot be claimed that anti-GAD is the exclusive autoimmune phenomenon. Nevertheless, 94% of children with newly diagnosed IDDM that we studied had an autoimmune response to either GAD, ICA or IAA, singly or in combination. The anti-GAD assay also has a substantial role in the diagnosis and classification of diabetes presenting in adult life since a proportion of adults who present with apparent NIDDM actually have a slowly evolving autoimmune insulitis, a condition we have called latent autoimmune diabetes in adults (LADA). It appears likely that anti-GAD will be predictive for IDDM in both first degree relatives and the general population. As a result of the cost and relative ease of performance, it will provide a practical alternative to ICA, particularly in population screening. Comparisons of testing for anti-GAD and ICA as predictors of IDDM using large population groups are now in progress in our laboratory.
Diabetes Res Clin Pract 1996 Oct
PMID:Antibodies to glutamic acid decarboxylase in the prediction of insulin dependency. 901 81

The differential antibody response to glutamic acid decarboxylase (anti-GAD) and to islet cell cytoplasm (ICA) according to HLA-DR and DQ genotypes were examined in 28 Spanish patients with Type I diabetes mellitus (11.1 +/- 10.4 year diabetes duration) and their 41 first degree non-diabetic relatives. Anti-GAD was detected by radioimmunoprecipitation and ICA by indirect immunofluorescence and HLA-DR/DQ alleles were assigned by PCR and sequence specific oligonucleotide probes. The frequency in patients of positivity for ICA was 7.1% and of anti-GAD+ 64.3%, and in relatives, the frequency of ICA+ was 4.9%, and anti-GAD+ 9.8%. Concurrent positivity for ICA and anti-GAD existed in only one patient, and in none of the relatives. We confirm for a Spanish population the high frequency of risk genotypes for Type I, involving DR3, DR4 and DQB1*0302 (DQ8) which were present in 26 of 28 (93%) patients and 32 of 41 (78%) relatives. The most frequent genotypes were DR3/DQB1*0201/DQA1*0501-DR4/DQB1*0302/DQA1*0301( 9 patients, 32%; 6 relatives, 15%), DR3/DQB1*0201/ DQA1*0501-DR3/DQB1*0201/DQA1*0501 (5 patients, 18%; 7 relatives, 17%) and DE3/DQB1*0201/DQA1*0501-DR1/ DQB1*0501/DQA1*0101(5 patients, 18%; 1 relative, 2%). Positivity for anti-GAD or for ICA did not correlate with gender, or age at onset or duration of DM. The distribution of high risk HLA genotypes were similar regardless the anti-GAD or anti-ICA status either in patients or in their relatives.
Diabetes Res Clin Pract 1996 Oct
PMID:HLA-DR, DQ and anti-GAD antibodies in first degree relatives of type I diabetes mellitus. 901 82

Correct classification of diabetic patients in adulthood at the time of diagnosis is often difficult. Some may be initially diagnosed as having non-insulin-dependent diabetes mellitus and be treated with diet and/or oral hypoglycaemic agents (OHA) but later require insulin treatment. Islet cell antibodies and antibodies to GAD 65 have been associated with the development of insulin deficiency in this group of patients. In the present study, 150 patients with the initial diagnosis of type 2 diabetes mellitus in adulthood (30-60 years) were seen regularly over a period of 5 years in our diabetes outpatient clinic. Though treatment was started with diet or diet plus OHA, insulin therapy had to be introduced in a subset of patients. In all cases, serum obtained at the time of the initial diagnosis was analysed for islet cell antibodies and GAD 65 antibodies, as well as for thyroid and adrenal autoantibodies as possible markers for polyendocrine involvement. Islet cell antibody status, body mass index and the presence of thyroid and adrenal autoantibodies showed no significant correlation to subsequent insulin requirement (< 2 years after diagnosis). In contrast, GAD 65 antibodies were significantly associated with the occurrence of clinical insulin dependency less than 2 years after the initial diagnosis (P < 0.01), thus identifying a substantial proportion of patients requiring insulin therapy within the first 2 years after the diagnosis of type 2 diabetes. Determination of GAD 65 antibodies in patients with late-onset diabetes may contribute to their correct classification and adequate treatment.
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PMID:GAD 65 antibody but not ICA positivity in adult-onset diabetic patients is associated with early progression to clinical insulin dependency. 903 70

Some patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) are positive for antibodies to glutamic acid decarboxylase (anti-GAD), which have been shown to be a useful marker for the diagnosis and prediction of insulin-dependent (Type 1) diabetes mellitus (IDDM). Anti-GAD positive NIDDM patients tend to develop insulin deficiency. We investigated the prevalence of anti-GAD in 200 NIDDM with secondary failure of oral hypoglycaemic therapy (SF) and 200 NIDDM well controlled by diet and/or sulphonylurea agents (NSF). Twenty-two of 200 (11%, p < 0.05) SF patients and 6 of 200 (3%) NSF patients were anti-GAD positive. The positive. The positive rate for anti-GAD was as high as 23.8% in the non-obese and insulin deficient SF patients. The SF patients with anti-GAD tended to be non-obese and to have an impaired release of endogenous insulin. The internal before development of secondary failure was not associated with the presence of anti-GAD in this study. In conclusion we found that anti-GAD was positive in as many as 11% of the SF patients, suggesting that autoimmune mechanisms may play an important role in the pathogenesis of secondary failure or sulphonylurea therapy.
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PMID:Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy. 904 93

Migration of lymphocytes to the pancreas is a prerequisite for insulitis in IDDM. Mucosal vascular addressin (MAdCAM-1), involved in the recirculation of lymphocytes to the gut, has been found in the inflamed islets in NOD mice. In humans, triggers of the gut immune system (e.g., early exposure to cow's milk proteins in infancy, exposure to enteroviral infections) have been associated with IDDM. To study the possible link between the gut immune system and IDDM, we tested the expression of the alpha4beta7-integrin, a homing receptor for MAdCAM-1, on GAD65-reactive lymphocytes. Using immunomagnetic cell sorting, we depleted the lymphocytes with high expression of alpha4beta7-integrin in the peripheral blood mononuclear cell population from IDDM patients and patients with autoimmune polyendocrine disease type 1 (APD-I). The depletion led to a marked decrease (mean 70%) in the cellular response against GAD65 in three of six IDDM patients and in one subject at high risk for IDDM. A decrease of 37% in the GAD response was observed after depletion in the case of one APD-I patient who also had IDDM. Cellular response to tetanus toxoid increased in the majority of patients as well as in three control subjects studied. We demonstrated that a remarkable population of islet cell antigen-reactive lymphocytes express the gut-specific homing receptor, which emphasizes the role of gut immunity in IDDM. The manipulation of the gut immune system is therefore proposed as a tool for modulation of the autoimmunity against pancreatic beta-cells in IDDM.
Diabetes 1997 Apr
PMID:Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gut-specific homing receptor alpha4beta7-integrin. 907 97

The aim of our study was to investigate the relative prevalence of the different forms of diabetes in young adults and their respective clinical characteristics. Included were 51 nonobese patients (BMI < 27 kg/m2) with diabetes diagnosed before age 40, excluding typical IDDM. Each patient was subjected to screening for glucokinase gene (MODY2) and mitochondrial DNA (at nucleotide 3243) mutations, to HLA class II genotyping, and screening for the presence of islet cell antibodies (ICAs) and anti-GAD antibodies. Informative families were analyzed for linkage of diabetes to chromosome 12q (MODY3). Based on clinical criteria, patients were subdivided into MODY (n = 19) and non-MODY (n = 32). In the MODY group, we identified three patients with MODY2, one with the 3243 mitochondrial mutation, and another with autoimmune diabetes. One of the five MODY families available for linkage study was shown to have MODY3. In the non-MODY group, we found five patients with autoimmune diabetes and one with MODY2. No clinical parameter was helpful to classify patients in one of these subclasses of diabetes; however, the glucagon-stimulated C-peptide was useful to discriminate between MODY2 patients and the others. In conclusion, young and lean non-insulin-dependent diabetic patients constitute a very heterogeneous group, although they present similar clinical characteristics. The clinical distinction of MODY and non-MODY patients allows correct classification in, at most, 75% of the patients and thus is not sufficient to predict clinical course. However, immunological and genetic parameters allowed us to classify only 25% of the patients in specific diagnostic classes.
Diabetes 1997 Apr
PMID:Diagnostic heterogeneity of diabetes in lean young adults: classification based on immunological and genetic parameters. 907 2

Insulin autoantibodies (IAAs) are present in approximately 60% of type I diabetes patients at onset and are used as predictors for the disease. Although the prevalence of IAAs in the general population has been reported to be <1%, preliminary data have pointed out a higher proportion of IAA positivity in newborn cord-blood serum, and some authors have suggested that they are immunoglobulin G antibodies, resulting from a hypothetical gestational insulitis. To characterize this insulin-binding activity, we analyzed cord-blood sera from 100 healthy newborns, as well as serum from 21 of their mothers at delivery, 179 new-onset type I diabetic patients, and 200 healthy control subjects. IAAs were present in 0.5% of the control subjects and 54% of new-onset type I diabetic patients. On the other hand, 96% of the newborn cord-blood sera showed anti-insulin activity, while it was detected in only 14% of their mothers. No significant differences were observed between cord sera and the general population for islet-cell or anti-GAD autoantibodies. Anti-insulin activity in cord serum was not bound by protein A or protein G, in contrast with type I diabetes-related IAA activity. We conclude that this insulin-binding activity, present in most newborn cord sera and specific to the child, is not IgG mediated. These data, together with the absence of other pancreatic autoimmunity markers in this population, suggest that it is an isolated phenomenon not related to type I diabetes or other pancreatic autoimmune processes and is due to the presence of a cross-reacting molecule in cord blood that has yet to be identified.
Diabetes 1997 Apr
PMID:Anti-insulin activity in normal newborn cord-blood serum: absence of IgG-mediated insulin binding. 907 16


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