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Development of diabetes mellitus caused by pancreatic beta-cell destruction of autoimmune origin is the result of a long lasting process. The most easily examinable feature of this stage is the occurrence of the islet cell antibodies. The sera which are positive for islet cell cytoplasmic antibodies (ICA), examined by indirect immunofluorescence, contain a mixture of antibodies. The glutamic acid decarbocylase (GAD), the tyrosin phosphatase (IA2), the insulin, and the GM2-1 glycolipid can be the targets of these antibodies. One can routinely examine the ICA, the GADA, the IA2 antibodies. The detection of antibodies against insulin (IAA) and GM-2-1 glycolipid is not invented in the routine laboratory work. The aim of the authors was the evaluation of clinical significance of occurrence of islet cell antibodies: one hundred and eighteen nondiabetic children an adult human being without known diabetic first degree relatives and 366 type 1 diabetic children and adult patients served as controls. The authors evaluated the predictive value of the different islet cell antibodies to the development of type 1 diabetes mellitus in 596 nondiabetic children with type 1 diabetic first degree relatives. The authors looked for markers of beta-cell destruction among sera of 320 diabetics manifested after 30 years of age with at least half a year of non-insulin-dependency and in the sera of 68 females suffered from gestational diabetes after 0-14 years of the index pregnancy. Finally the authors report 7 cases in which the examination of islet cell antibodies helped the diagnosis and classification of diabetes mellitus. Indirect immunofluorescence method was used for the detection of ICA, radioimmunoassay for that of GADA and IA2 antibodies. There was no positive reaction for ICA and GADA in the nondiabetic population without diabetic first degree relatives. Among the freshly diagnosed type 1 diabetic children 39% were positive for only ICA, 44% for only GADA and 80% for any antibodies. Among the freshly manifested type 1 diabetic adults ICA positivity only was observed in 21%, GADA positivity only in 7.1% and 93% for any antibodies. From the 595 nondiabetic children with type 1 diabetic first degree relatives 23 were positive for ICA, from whom 5 became diabetic during a two years observation period. These diabetic children had multiplex autoantibodies besides ICA. One child from this group, who was negative for ICA became diabetic, too. Among type 2 diabetic patients 13% were positive for ICA alone, 17% were positive for GADA alone and 27% were positive for any antibodies. The insulin dependency manifested in a short time was associated with antibody positivity. Among the gestational diabetics 10 were found positive for ICA. From them, 7 were type 1 diabetics, and 3 were type 2 diabetics at the time of the detection of antibodies. The authors suggest the need of determination of islet cell antibodies in the group of nondiabetic first degree relatives of type 1 diabetic patients (ICA, GADA, IA2 and IAA), in the group of non-insulin-dependent diabetics (ICA and GADA) as a screening for later insulin dependency, and in gestational diabetes after delivery (ICA) as screening for type 1 diabetes mellitus.
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PMID:[Detection of antibodies against pancreatic islet cells in clinical practice]. 1064 15

The alterations of TGF-beta1 production are believed to contribute to the development of insulin-dependent diabetes mellitus (IDDM) in animal models as well as in humans. There is also increasing evidence about the role of this cytokine in the pathogenesis of diabetic vascular complications. The aim of our study was to evaluate in vitro TGF-beta1 production by peripheral blood of newly diagnosed type 1 diabetes patients and subjects in the pre-clinical stage of the disease in comparison to healthy controls and relatives of IDDM patients with low genetic risk for diabetes development. The study was carried out in three groups of subjects: 22 patients with a recently diagnosed type 1 diabetes, their 24 first degree relatives with a different genetic risk of IDDM development and 18 healthy volunteers (control group). In all studied groups whole blood was taken for morphology parameters. HbA1C and for 72 h cultures with PHA stimulation for the estimation of TGF-beta1 in vitro production. TGF-beta1 concentration in supernatants were quantified by ELISA. In the first degree relatives HLA typing (for DR3, DR4 and DQB1*0602 alleles), measurements of anti-pancreatic antibodies (ICA, GADA, IA-2A, IAA) and intravenous glucose tolerance tests were performed. The levels of TGF-beta1 in the supernatants were significantly higher in diabetic patients (P < 0.0002) and in their first degree relatives (P < 0.05) in comparison to the control group. In the group of first degree relatives TGF-beta1 levels were highest in subjects with the presence of two or more pancreatic autoantibodies and/or with impaired insulin release in IVGTT, but lowest in relatives with protective DQB1*0602 alleles (P < 0.01). There was also a significant positive correlation between the TGF-beta1 levels and HbA1C in the IDDM subjects and first degree relatives (P < 0.03). Our study suggests that the alterations of TGF-beta1 levels could be associated with the activity of autoimmune process leading to pancreatic B cells destruction and may have a role in the pathogenesis of diabetic complications, but further studies in humans are needed.
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PMID:The analysis of in vitro transforming growth factor-beta1 (TGF-beta1) production by peripheral blood in overt and pre-clinical type 1 diabetes mellitus. 1071 34

Diabetes mellitus is a frequent metabolic disease characterised by a complex and inconstant phenotypic expression that complicates the classification of patients and sometimes delays their optimal management. In that slowly progressive disease leading to severe and irreversible complications, the use of early and specific genetic, immunological and/or metabolic markers may help in the classification of diabetic patients and in the orientation of therapeutic strategies; furthermore, it is also an essential aid in the early screening of subjects at risk of developing the disease. The assessment of classical immunological markers, such as islet cell antibodies (ICA) or anti-insulin antibodies (IAA) has been recently completed by the screening of new promising markers such as GAD- and IA2-antibodies. The presence of these markers confirms the autoimmune component of the disease and thus supports the diagnosis of type 1 diabetes, even if clinical symptoms are absent or inconsistent. In addition, it represents a strong argument in favour of the initiation of specific immunological therapies to preserve B-cell number and function.
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PMID:[The dosage of anti-GAD and anti-IA2 autoantibodies: an aid to the early diagnosis of type 1 diabetes]. 1082 7

Antibodies recognising different pancreatic autoantigens (Abs) are detected many years before the clinical onset of insulin-dependent diabetes mellitus (IDDM). The humoral immune alterations, observed in the susceptible subjects, for example in first degree relatives of IDDM patients, could serve as predictive markers of IDDM development. It has recently been suggested that the predictive value of these humoral markers is associated with the number of the studied antibodies directed against different pancreatic antigens (ICA, GADA, IA-2,A IAA). The aim of the study was the estimation of the prevalence and titre of the antibodies directed against protein tyrosine phosphatase-2 (IA-2) and glutamic acid decarboxylase (GAD) in patients with newly diagnosed diabetes type 1 and their first degree relatives. The investigations were carried out in 52 diabetics (aged 5-25 years) and 136 first degree relatives. IA-2A and GADA were performed by radiobinding assay (RIA) using 2 microliters of serum and recombinant S35-labelled GAD65 and IA-2 antigens. The threshold of Abs detection was > or = 97.5 centile (of healthy schoolchildren). At least one of the antibody marker was detected in 92.7% of newly diagnosed IDDM patients, slightly more frequently observed were GADA (78.8%) than IA-2A (71.2%). The presence of 2 types of antibodies was found in 8.7% of parents and 9.4% of the siblings. The results of our study confirm high sensitivity and specificity of the combined measurement of IA-2A and GADA in recognising of autoimmune alterations in diabetes type 1 development. Taking into consideration small volume of the serum suitable for Abs measurement and possibility of the combined estimation of these Abs it seems that IA-2A and GADA combined measurement could actually serve as a screening marker for the detection of high risk of IDDM subjects also in the Polish population, but studies concerning their predictive value in the general population are suggested.
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PMID:[IA-2 and anti-GAD antibodies in patients with newly diagnosed type 1 diabetes and their first degree relatives]. 1090 82

Islet cell antibodies (ICA) continue to serve as the basis of the principal serological test for definition of active autoimmunity of beta-cells. Its disadvantages are the need for human pancreatic tissue and difficulty in obtaining quantitative results. In the past decade biochemically-defined beta-cell antigens were described, leading to the development of sensitive and specific autoantibody assays, to predict insulin-dependent diabetes mellitus (IDDM). We examined the value of combined biochemically-based serological assays, such as autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and ICA512 (ICA512A) to replace the traditional ICA assay. Blood samples of 114 newly diagnosed IDDM patients, aged 12 +/- 5 yrs (range 2 months-29 years) were tested for ICA (indirect immunofluorescence), IAA, GADA and ICA512A (radiobinding assay). The latter 2 assays were performed using recombinant human [35S]-labeled antigen produced by in vitro transcription/translation. We found that fewer sera scored positive for ICA and/or IAA (80.7%, 92/114) than for 1 or more of IAA, GAD, or ICA512 (88.6%, 101/114). We conclude that combined testing for IAA, GAD and ICA512 can replace the traditional ICA/IAA test to predict IDDM and is helpful in the differential diagnosis of insulin-dependent and noninsulin-dependent diabetes.
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PMID:[Islet autoantibody assays in type I diabetes: superiority of passage from use of ICA to traditional tests]. 1090 10

Type 1 diabetes mellitus (IDDM) results from a chronic process of autoimmune destruction of beta cells of the Langerhans islets. The presence of autoantibodies (ICA, GADA, anti-IA2, IAA) in serum precedes the clinical onset of the disease. Genetic predisposition for IDDM is connected with HLA, CTLA-4 and insulin gene region. The aim of the study was the genetic and immunological analysis of a triplet. One of them developed Type 1 diabetes mellitus. We analysed HLA class II, CTLA-4 and insulin gene polymorphisms in the whole family. Besides, we investigated immunological status of three brothers. All patients present identical genotype for VNTR loci: D1S80, D17S5 and Apo B, as well as for HLA-DRB1, -DQA1, -DQB1, CTLA-4 gene and all studied insulin gene polymorphisms. That proves their monozigosity. The triplet presents strong genetic predisposition for IDDM. The two patients without overt diabetes have increased levels of ICA, GADA, IA2 and IAA.
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PMID:Type 1 diabetes and prediabetic state in a monozygotic triplet. 1091 59

Predications indicate a potentially explosive increase in the prevalence of diabetes worldwide, especially in developing countries such as Indonesia. Studies of people living in rural areas of East Java and Bali show a prevalence rate of 1.5% in 1982 to 5.7% in 1995 among the urban population. Ujung Pandnag also experienced an increase, and recent studies in Manado found a dramatically high rate of 6.1% in urban areas. Preliminary results indicate varying prevalence between those living in urban and rural areas. Currently, Indonesia has an estimated 1.2-2.3% prevalence among people over 15 years. Geographically variation appears to be an influential factor, due to differences in ethnics, race, culture and lifestyle. Studies of diabetic families show a significantly high prevalence and, clinically speaking, the mode of treatment indicates the type of diabetes. Those who respond well to OHA among young diabetics (<40) are assumed to have the MODY variation of the disease. The level of obesity among the general population has increased, due partly to increased calorie intake and is a significant factor in the increased rate of diabetes. It is also more common among the elderly, as our results will show. The new types of the disease are clinically more difficult to assess than the classical types 1 and 2, as they require relatively costly genetic and immunological studies. The rate of LADA type diabetes was found to be relatively high (>20% for ICA and IAA and 2.3% for GAOA). A concensus on diabetes management has now been formulated in Indonesia and these guidelines are now used by all Indonesian health care professionals.
Diabetes Res Clin Pract 2000 Oct
PMID:The epidemiology and management of diabetes mellitus in Indonesia. 1102 78

Prediction of Type 1 diabetes for study of preventive therapies requires screening the general population, where 85% of new cases occur. Even with HLA-based prescreening, nearly 20% of all children will need multiple serum autoantibody testings. High-throughput, economical, and accurate methods are therefore essential. We have developed such a radiobinding method, using 96-well microtiter plates and a novel immune complex capture method via membrane-bound Protein A. Each microtiter plate contained a standard negative control serum, and low-, medium-, and high-level positive control sera. All sera were evaluated in triplicate. This readily allowed quality control criteria both for triplicates of individual sera and for each 96-well plate. Inter-assay coefficients of variation (CVs) were all </=16%, while intra-assay CVs were all </=10%. The assay was found to be sensitive (to detect autoantibodies in patients) and specific (low reactivity in thousands of healthy volunteers). The format worked well using diverse antigens such as 35S-met-GAD65, 35S-met-ICA512/IA2, 35S-met-Phogrin, and 125I-insulin, and could be used for simultaneous screening of reactivity to both GAD65 and ICA512/IA2 in the same well. Diagnostic accuracy compared favorably with microcentrifuge tube-based Protein A-agarose GAD65 and IA2 autoantibody radiobinding assays and with acid-charcoal-polyethylene glycol (PEG) based competitive insulin autoantibody assays. In the case of 125I-insulin, comparing signal in the absence versus presence of cold insulin competitor was not necessary. Total serum volumes required were only 6 microl for GAD and ICA512, and only 15 microl for IAA. The method costs less than all other commonly used formats, and should be useful for population screening.
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PMID:A novel high-throughput method for accurate, rapid, and economical measurement of multiple type 1 diabetes autoantibodies. 1103 22

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.
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PMID:ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 1113 89

This study presents a 2-yr follow-up of 281 patients, aged 15-34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0. 27; 0.16-0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28-0.78 nmol/L; P: < 0. 001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10-0.37 nmol/L; P: = 0. 0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2. 6; 95% confidence interval, 1.7-4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1-5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in beta-cell function. It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained beta-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased beta-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in beta-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.
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PMID:Prognostic factors for the course of beta cell function in autoimmune diabetes. 1113 17


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