Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantibodies to 65 kD glutamic acid decarboxylase (GADAA) and ICA512 (ICA512AA) were measured by radioimmunoassays using as antigens in vitro transcribed and translated [35S]-methionine-labeled human GAD65 and ICA512 (IA-2). The prevalence of GADAA and ICA512AA in sera from 87 patients with IDDM was 39 and 23%, respectively. The frequency and titer of ICA512AA declined sharply within 5 years after the onset of IDDM. Among patients tested within 4 years after diagnosis, the prevalence of ICA512AA was significantly higher in acute onset IDDM than in slowly progressive IDDM (37 versus 6%, P < 0.025) irrespective of age, while there was no difference in GADAA frequency between acute onset and slowly progressive subtypes (51 versus 63%). A total of two patients out of 121 patients with NIDDM were positive for GADAA, and two other NIDDM patients, who were suffering from sarcoidosis, were positive for ICA512AA. Neither of the antibodies were positive in sera from four atypical NIDDM patients, aged < 20 years, who showed ketosis at onset and required insulin followed by excellent metabolic control with diet restriction alone. These observations suggest that ICA512AA are associated with rapid progression of beta cell damage in IDDM. ICA512 radioassay, in combination with GAD assay may provide a useful diagnostic marker for IDDM especially in youth.
 ...
PMID:Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM. 917 63

Presymptomatic autoantibody markers of insulin-dependent (Type 1) diabetes mellitus (IDDM) are less well characterized in adults than in children. We quantitated anti-GAD, anti-ICA512 and ICA by titration to endpoint and compared frequencies and levels in 139 Finnish women from whom 390 serum samples had been archived during antecedent pregnancies for 10 years before and up to 1 year after diagnosis of diabetes. Also, we compared the autoantibody status in adults with IDDM with that of children with newly diagnosed IDDM. Of the 35 women seropositive for 1 or more autoantibodies, 77% developed IDDM, 11% non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), 9% gestational diabetes mellitus requiring insulin (GDM-ins) and 3% GDM controlled by diet. The frequency of antibodies during the 10-year presymptomatic period was 83% for anti-glutamic acid decarboxylase (GAD), 52% for anti-ICA512 and 41% for islet cell antibodies (ICA) for those who developed IDDM, 25%, 17%, and 0% for NIDDM, 12%, 4%, and 8% for GDM-ins and 1%, 0%, and 1% for GDM-diet. Anti-GAD was found most consistently in early samples; 13 of 15 with a single autoantibody at their first test had anti-GAD. Among those who developed IDDM, the frequency of anti-GAD was constant, anti-ICA512 increased threefold, and ICA increased slightly before diagnosis. Levels of the autoantibodies varied between subjects, but were relatively stable in individual subjects. Comparison of tests on the women, and children after diagnosis of IDDM, showed the frequencies and levels to be the same for anti-GAD but lower for anti-ICA512 and ICA in adults. Our observations show in women the long latency of seropositivity before overt IDDM, the predominance of anti-GAD among these three serological markers, and the presence of these markers in NIDDM presumably representing a NIDDM phase of autoimmune insulitis.
 ...
PMID:Autoantibodies associated with presymptomatic insulin-dependent diabetes mellitus in women. 927 95

Glutamic acid decarboxylase (GAD) catalyzes the formation of gamma-aminobutyric acid (GABA), which is a major transmitter in the central nervous system. Two forms of GAD (GAD65 and GAD67) are known to be expressed in human tissues and GAD65 is predominantly expressed in pancreatic beta-cells. Recent findings revealed that GAD functions as an autoantigen in human autoimmunity, especially in insulin-dependent diabetes mellitus (IDDM). GAD is a key antigen for the development of autoimmunity against beta-cells and the production of GADAb precedes other autoantibodies such as IAA and ICA512/IA-2Ab prior to the clinical onset of IDDM. At onset, GADAb is detected in 50-80% of patients using RIA or RBA method. Factors that influence the positivities and titers of GADAb at onset, such as onset age, sex, presence of autoimmunity against thyroid, HLA type, have been reported. After onset, GADAb titer decreased more slowly than that of ICA512/IA-2Ab. These findings suggest that autoantibodies against beta-cells, such as GADAb, may develop independently. The presence of GADAb in relatives of IDDM patients and NIDDM patients predicts the development of beta-cell destruction in combination with other anti-islet autoantibodies.
 ...
PMID:[GAD antibody in IDDM]. 959 23

An immunoprecipitation assay for autoantibodies (Abs) to the human islet cell antigen IA-2 has been developed using 125I-labelled recombinant IA-2 expressed in E. coli. With this assay IA-2 Abs were detected in 103/217 (47%) of IDDM patients of different ages and with different disease duration. IA-2 Ab prevalence was higher in younger patients (at the age of 15 years or below) with the recent onset IDDM (64/113; 57%) compared to patients above the age of 15 years (11/25; 44%). One of 40 (2.5%) Graves' disease patients and five of 204 (2.5%) of NIDDM patients were also positive. IA-2 Abs were not detected in sera from patients with Hashimoto's thyroiditis (n=32), myasthenia gravis (n=20) or systemic lupus erythematosus (n=10). IA-2 Ab measurements based on 125I-labelled IA-2 showed a good correlation with the results of an immunoprecipitation assay based on 35S-labelled IA-2 produced in the in vitro transcription/translation system (r=0.78; n=113; p<0.001). Out of 217 IDDM sera which were tested for IA-2 Abs, 140 (65%) were positive for Abs to glutamic acid decarboxylase (GAD) and 166 (76%) were positive for Abs to IA-2 and/or Abs to GAD. In addition, Abs to IA-2, to GAD and to insulin were analysed in sera from recent onset IDDM patients who had not been treated with insulin (n=117). In all, 76/117 (65%) of these sera were positive for GAD Abs, 66/117 (56%) for IA-2 Abs, 45/117 (38%) for insulin Abs. However, 98/117 (84%) were positive for at least one of the three Abs confirming earlier observations on the complementarity of Ab testing in IDDM. Overall, the IA-2 Ab assay based on 125I-labelled recombinant IA-2 showed good sensitivity, precision and specificity which, combined with an easy and convenient protocol, makes it attractive for routine use.
 ...
PMID:Autoantibodies to IA-2 in insulin-dependent diabetes mellitus. Measurements with a new immunoprecipitation assay. 1061 17

In light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.
 ...
PMID:Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. 1061 47

LADA or type 1.5 diabetes is a slowly progressive form of autoimmune diabetes of adults and represents a considerable proportion (about 5-10%) of all diabetic patients. Associations with high risk HLA genotypes and autoimmune phenomena (GAD, IA2, ICA) show similarities with type 1 diabetes, but phenotypical characteristics of these patients do not allow the correct identification without screening of GAD antibodies. The relatively low antibody titers against islet-cell antigens in LADA patients may be sign of a less aggressive form of autoimmune diabetes and could be responsible for the long non-insulin requirement phase of this diabetes type. Similar as in prediabetic relatives of type 1 diabetic patients the risk for beta cell failure in adult "type 2 diabetic" patients increases with the number of antibodies positive. Consequently, low titers of GAD--in particular in elderly patients--do not predict a progressive and rapid loss of beta-cell failure, when associations with high risk genotypes or other islet-cell antibodies are lacking. Patients with LADA share insulin resistance with type 2 diabetic patients, but display a more severe defect in stimulated beta-cell capacity than patients with classical type 2 diabetes. With respect to features of the metabolic syndrome, patients with LADA have lower BMI, blood pressure and triglyceride levels compared with classical type 2 diabetes patients. Early identification of LADA patients will be mandatory, when effective immune interventions are available for prevention of the beta-cell destructive process and insulin requirement of these patients.
 ...
PMID:Progress in the characterization of slowly progressive autoimmune diabetes in adult patients (LADA or type 1.5 diabetes). 1146 May 97

A case of a 59-year-old male patient with advanced microangiopathic complications at the diagnosis of diabetes mellitus is reported. The patient was referred to ophthalmological investigation due to progressive loss of visual acuity. Although diabetes mellitus was not known, proliferative diabetic retinopathy with significant visual loss was found at fundus examination. Not only newly diagnosed diabetes mellitus (initial fasting blood glucose 19.0 mmol/, HbA1c: 11.6%) but the presence of advanced sensory, motor and autonomic diabetic neuropathy (nervus peroneus motor conduction velocity: 32.1 m/s, nervus suralis sensory conduction velocity could not be detected, postural decrease in systolic blood pressure: 20 mmHg, beat-to-beat variation 6 beats/min, 30:15 ratio 1.03) as well as signs of advanced diabetic nephropathy (daily urinary protein excretion: 1.2-5.7 g, serum creatinine value: 101 mumol/l, sitting blood pressure: 150/100-180/100 mmHg) could be documented by further investigations at Medical Department. Avoiding short-term strict metabolic control insulin therapy was initiated and adequate long-term diabetic control was achieved later (HbA1c: 6.5-6.2%). In order to classify the diabetes, repeated measurements of serum C-peptide, ICA, GADA and IA2-antibodies were performed and type 2 diabetes was diagnosed. After a transient deterioration the proliferative retinopathy remained unchanged. Although laser photocoagulation was performed, no improvement in the visual acuity could be achieved. Only a minor improvement of neurological alterations was documented by repeated electrophysiological investigation at follow-up. Although the antihypertensive treatment (ACE-inhibitor drug in combination with calcium channel blocker) resulted in a significant decrease of elevated blood pressure, only a transient improvement of proteinuria could be achieved. Despite regular control, the advanced microangiopathic complications of diabetes mellitus carry poor prognosis.
 ...
PMID:[Advanced microangiopathic complications at the diagnosis of diabetes mellitus]. 1155 63

The clinical manifestation of type 1 diabetes is the endpoint of a long-lasting immune-mediated destruction process of the B-cells. Autoantibodies originating from this process can be applied in the diagnosis and clinical discrimination of autoimmune diabetes as well as in the prediction of this disease. At clinical diagnosis between 80-90% of patients with type 1 diabetes are positive for antibodies to B-cell antigens, such as ICA and antibodies to glutamic acid decarboxylase or IA2. These antibodies can also be detected in the presymptomatic period before onset of the disease, and can thus be used to predict type 1 diabetes. Using a combination of antibodies, diabetes can be predicted in 70-80% of future cases of diabetes, with a positive predictive value between 30-80%, depending on the type of antibody tested for and the population studied. Between 5 and 30% of patients initially diagnosed with type 2 diabetes will show progression to insulin dependency and turn out to have type 1 within three years of diagnosis. It is clinically relevant to identify these patients early in the course of disease, as deterioration of metabolic control results in an increased risk for macro- and micro-vascular complications. Autoantibodies to glutamic acid decarboxylase or ICA are of high diagnostic sensitivity in these cases and are better predictors for future insulin dependency than biochemical or clinical parameters. Increasing knowledge on the applicability of antibodies for diabetes prediction and diagnosis and the development of commercial assays for antibodies to glutamic acid decarboxylase and IA2 antibodies has enabled the implementation of B-cell autoantibodies in routine diagnostic settings.
 ...
PMID:Prediction and diagnosis of type 1 diabetes using beta-cell autoantibodies. 1159 13

According to the most recent classification of diabetes mellitus the latent autoimmune diabetes in adults belongs to the group of type 1 autoimmune diabetes mellitus, as a slowly progressive form. It is not clear whether LADA is a distinct clinical entity or it is a part of the clinical spectrum of type 1 diabetes mellitus. The authors compare the antropologic (body mass index, waist to hip ratio), immunologic (occurrence of islet cell cytoplasmic autoantibodies and autoantibodies against glutamic acid decarboxylase and tyrosin phosphatase), genetic (HLA DR and DQ alleles known to be associated to type 1 diabetes mellitus) characteristics and occurrence of the features of the metabolic syndrome in the groups of type 1 and type 2 diabetes and LADA. 81 type 1 and 190 type 2 diabetics and 38 LADA patients were involved into the study. Freshly diagnosed type 1 diabetics served for controls of the autoantibody study: 48 patients manifested < or = 16 years of age and 89 type 1 diabetics manifested above 16 years of age. The three main diabetic groups differed in age: the average age in the type 1, type 2 and LADA groups were 37, 63 and 58 years respectively. There was no difference among the three groups in gender. The duration of the disease differed significantly between the type 2 and LADA groups (4.0 and 8.0 years respectively). In spite of the shorter duration of the disease in the LADA group, compared to the type 2 diabetics the frequency of insulin dependency was significantly higher in the LADA (81.6%) than in the type 2 group (46.7%). The BMI and WHR were comparable between the type 1 and LADA patients (average values were 23 and 0.83 in type 1 patients and 23.25 and 0.89 in LADA). The type 2 group differed significantly from type 1 and LADA (average values were 29.1 and 0.5). The concentration of glycated hemoglobin was comparable in the three groups. But there was a significant difference in HbA1c concentration between the freshly diagnosed subgroups of type 1 and LADA patients: 10.85% and 8% respectively. The fasting C-peptid levels were significantly higher in the sera of type 2 diabetics (0.75 pmol/l) compared to type 1 (0.2 pmol/l) and LADA patients (0.29 pmol/l). There was a significant difference in C-peptid concentrations between the type 1 and LADA groups, too. The insulin deficiency in LADA seemed to be not as severe as in type 1 diabetes. The serum total cholesterol and triglyceride levels were significantly higher and the HDL cholesterol concentration significantly lower in type 2 diabetics comparing to type 1 and LADA patients and there was no significant difference in this respect between the type 1 and LADA groups. The frequency of occurrence of hypertension differed no significantly between type 2 and LADA, but that of in type 1 diabetes was significantly lower than both type 2 and LADA. The occurrence of multiple autoantibodies (ICA + GADA + anti-IA2) was much more frequent in type 1 diabetes compared to LADA. In the sera of LADA patients the occurrence of ICA and GADA alone or ICA + GADA was characteristic (31.5% - 21.1% - 15.8% respectively). There was no difference between type 1 diabetes and LADA in the occurrence of the alleles of the MHC kown to be associated with type 1 diabetes. The occurrence of the haplotypes HLA DQ2/DR3 and/or DQ8/DR4 was observed in two thirds of type 1 diabetic and LADA patients. Chronic diabetic complications were observed in all of the groups and there was only a secondary connection of the complications with the type of the diabetes. Based on the results the authors suggest that LADA is a part of the clinical spectrum of type 1 diabetes of autoimmune origin.
 ...
PMID:[Latent autoimmune diabetes in adults(LADA): part of the clinical spectrum of type-1 diabetes mellitus of autoimmune origin]. 1177 Jan 76

The IA-2 is a major autoantigen of type 1 diabetes belonging to the protein tyrosine phosphatase family. We report on the humoral autoimmunity to an alternatively-spliced variant of IA-2 (IA-2 variant) and autoimmune-mediated diabetes age of onset association with IA-2 autoantibody epitope specificities, in 144 recent-onset patients with type 1 diabetes and 54 GAD autoantibody-positive patients with type 2 diabetes. The cytoplasmic domain of IA-2 (IA-2ic) detected a somewhat greater proportion of patients expressing autoantibodies than IA-2 variant (56%vs. 52% of patients with type 1 diabetes and 17%vs. 9% of GAD autoantibody-positive patients with type 2 diabetes). Conversely, only 1% of IA-2 variant autoantibody-positive patients failed to react to IA-2ic construct. Among 80 patients with type 1 diabetes who were positive for autoantibodies to IA-2ic, 8% recognized the juxtamembrane region (JM, representing amino acids 601-629) only, 64% bound the protein tyrosine phosphatase (PTP)-like domain of IA-2 only, and 29% bound both JM and PTP epitopes. Autoantibodies to the PTP-like domain were prevalent in children and adolescents with type 1 diabetes. The age of disease onset in patients with IA-2JM autoantibodies only, was significantly higher than those in patients reacted with the PTP-like domain of IA-2 (P< 0.02). Among GAD autoantibody-positive patients with type 2 diabetes reacted with IA-2ic, 44% bound the JM region only, and 33% bound epitopes in the PTP-like domain only; 22% had autoantibodies to both regions. The frequency of GAD autoantibody-positive patients with type 2 diabetes positive for autoantibodies to the JM region only, was significantly higher than that in patients with type 1 diabetes (P< 0.01). IA-2PTP autoantibodies were significantly associated with HLA-DR4, while the additional reactivity to IA-2JM was associated with HLA-DR9 allele. These results suggest that autoantibody recognition of IA-2 epitopes in autoimmune diabetes is associated with age of disease onset, which may reflect the intensity of the beta-cell destruction process.
 ...
PMID:Association between IA-2 autoantibody epitope specificities and age of onset in Japanese patients with autoimmune diabetes. 1177 57


1 2 3 4 Next >>