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It has been reported that there is a heterogeneity in the clinical course of Japanese patients with type 1 diabetes. To elucidate the associations of expression of autoantibodies to multiple islet antigens with age of onset and mode of diagnosis of diabetes in Japanese patients with type 1 diabetes, autoantibodies against the protein tyrosine phosphatase-like molecules ICA512 (IA-2) and phogrin (IA-2β) (ICA512/phogrin-A), GAD (GADA), insulin (IAA), and islet cell cytoplasm (ICA) were determined in sera from 73 Japanese patients with type 1 diabetes obtained within 14 days of diagnosis. Patients were divided into groups based on the age of onset (≤10 years, n=24 and >10 years, n=49) or the mode of onset (abrupt onset, n=59 and urinary screening identified, n=14). Of 73 new-onset patients with type 1 diabetes, 43 (59%) and 32 (44%) had ICA512A and phogrin-A levels exceeding the 99th percentile of 184 normal control subjects, respectively. Forty-five patients (62%) were positive for either ICA512A or phogrin-A. The frequencies for other autoantibodies were 71% for GADA, 48% for IAA, and 62% for ICA. The frequency of ICA512/phogrin-A was significantly higher in patients with an age of onset less than 10 years (83%) than in patients aged >10 years (51%, P<0.01). The positivity of ICA512/phogrin-A was less in patients whose diabetes was diagnosed by the urine glucose screening test (21%, P<0.001) than in abrupt onset patients (71%). Combined analysis (≥1 antibody) of GADA, IAA, and ICA512/phogrin-A detected 88% of abrupt onset and 93% of screening-positive patientsvs. 70% and 29%, respectively, for ICA (P<0.0005). These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis.

We evaluated the frequency of antibodies to glutamic acid decarboxylase (GAD-Ab) in Japanese patients diagnosed initially as having non-insulin-dependent diabetes mellitus (NIDDM) and investigated a possible link between the presence of GAD-Ab and development of the insulin-dependent (ID) state. The population sample consisted of 583 Japanese NIDDM patients (age at onset >30 years) who were initially non-ketotic and did not require insulin treatment during at least 6 months of observation. GAD-Ab were measured using radioimmunoassay. The clinical characteristics of GAD-Ab+patients were carefully examined at four-year intervals from the onset of diabetes. We also examined the ID state by measuring the level of postprandial serum C-peptide and i.v. glucagon-stimulated serum C-peptide. The overall prevalence of GAD-Ab in Japanese NIDDM patients was 3.8%. The frequency of GAD-Ab+did not significantly decrease with a long history of diabetes. GAD-Ab+patients had a lower body mass index, compared with GAD-Ab−(20.8±2.9 vs 23.0±3.7,P<0.005), lower postprandial C-peptide levels (0.7±0.6 vs 1.4±1.2,P<0.01), and an early commencement of insulin therapy (3.6±4.7 vs 8.3±6.6,P<0.01). GAD-Ab+patients who had already developed the ID state had characteristically higher titers of GAD-Ab (421.4±359.1) and a higher frequency of islet cell antibodies (ICAs) (77.8%), compared with GAD-Ab+NID patients (titer: 60.2±86.9,P<0.005, 23.1%,P<0.05, respectively). GAD-Ab+ICAs+patients showed higher frequencies of ID state at any diabetic duration compared with GAD−ICAs−, while GAD-Ab+ICAs−patients did not differ in the frequency of the ID state from GAD−ICAs−. Our results suggest that the presence of both GAD-Ab and ICAs represents a high risk for IDDM in GAD-Ab+NIDDM patients.

Autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64 kDa islet cell protein and islet cell antibodies (ICA) were measured in 79 Japanese patients with insulin-dependent diabetes mellitus (IDDM). The overall prevalences of GAD antibodies, 64K antibodies, and ICA in these patients were 69.6% (55/79), 48.1% (38/79), and 46.8% (37/79), respectively. However, in a subset of these patients with recent onset IDDM (&lt;1 year) the prevalences of GAD antibodies, 64K antibodies, and ICA were 78.8% (26/33), 66.7% (22/33), and 78.8% (26/33), respectively. Furthermore, the prevalences of GAD antibodies, 64K antibodies, and ICA were significantly decreased in patients with long standing diabetes at 60.9% (28/46), 34.8% (16/46), and 23.9% (11/46), respectively. However, when these patients were divided into two groups by the presence or absence of organ-specific autoimmune disease (OSAD), the mean levels of GAD antibodies and ICA in the patients who gave a positive result were significantly higher in patients with OSAD (397 units and 98 JDF units, respectively) than in patients without OSAD (74 units and 39 JDF units, respectively). These results demonstrate that it is important to evaluate the prevalences and levels of islet-specific autoantibodies when considering duration and co-existence of autoimmune disease in patients with IDDM. Copyright 1994, 1999 Academic Press

A recent report identified two islet cell cytoplasmic antibody subclasses using an immunohistochemical method. The islet cytoplasmic antibody subclass which reacts with only Beta-cells was termed 'Beta-cell islet cell cytoplasmic antibodies' and another islet cell cytoplasmic antibody subclass which reacts with Beta and non-Beta cells was called 'whole islet cell cytoplasmic antibodies'. The whole islet cell cytoplasmic antibody reactivity with pancreatic islet has been shown not to be abolished by pre-incubation with rat brain homogenate. In this study, we examined the inhibitory effect of purified glutamic acid decarboxylase to islet cell cytoplasmic antibody reactivity among whole islet cell cytoplasmic antibodies and assessed the heterogeneity of islet cell cytoplasmic antibodies. Autoantibodies to 64,000 Mr islet cell protein (64 K antibodies) were also determined by conventional method. Sera from 17 Type 1 (insulin-dependent) diabetic patients containing whole islet cell cytoplasmic antibodies with more than 20 Juvenile Diabetes Foundation units were used. In 11 (78.6%) of 14 sera positive for 64 K antibodies, the reactivity of islet cell cytoplasmic antibodies was markedly blocked by pre-incubation with purified glutamic acid decarboxylase. In contrast, none of the 64 K antibody-negative sera were blocked. All of the patients showed similar clinical characteristics regardless of the inhibitory effect of glutamic acid decarboxylase on islet cell cytoplasmic antibodies, except for islet cell cytoplasmic antibody titer and glutamic acid decarboxylase antibody titer. The mean log 2 islet cell cytoplasmic antibody titer was 2.4 ± 0.6 (mean ± SD) JDF unit in the 'markedly blocked' group and 1.6 ± 0.3 (mean ± SD) in the 'never blocked' group. The islet cell cytoplasmic antibody titer was significantly higher (P&lt;0.05) in the former, and the mean glutamic acid decarboxylase antibody titer was 624 ± 127.0 (mean ± SE) units in the 'markedly blocked' group and 127 ± 55.5 (mean ± SE) in the 'never blocked' group. The glutamic acid decarboxylase antibody titer was also significantly higher(P&lt;0.05) in the former. We demonstrated here that some whole islet cell cytoplasmic antibodies are absorbed by purified glutamic acid decarboxylase, suggesting heterogeneity of islet cell cytoplasmic antibodies among the 64 K glutamic acid decarboxylase antibody positive group. Copyright 1994, 1999 Academic Press

We evaluated the presence of autoantibodies to glutamic acid decarboxylase (GAD), competitive insulin autoantibodies (IAA) and islet cell antibodies (ICA) in sera from 288 non-diabetic patients with autoimmune thyroid disease (AITD), including 212 patients with Graves' disease and 76 with Hashimoto's thyroiditis, and in 235 age- and sex-matched healthy control subjects. GAD antibodies and IAA were assayed using radioimmunoassay with125I-labelled purified pig brain GAD and human insulin, respectively. Titers of greater than 4.7 units for GAD antibodies and 50nU/ml for IAA, respectively, the mean+3SD of 235 age- and sex-matched healthy individuals, were defined as positive. The mean titers of GAD antibodies in patients with Graves' disease and in patients with Hashimoto's thyroiditis were 3.6±4.6 (mean±SD, range 0.6–52.0) units and 3.2±1.4 (range 0.6–10.0) units, respectively. Titer of GAD antibodies in patients with AITD was significantly higher than in healthy controls (P<0.0005). Thirteen of 212 (6.1%) patients with Graves' disease and 6 of 76 (7.9%) patients with Hashimoto's thyroiditis had positive GAD antibody titers, whereas titers in healthy control sera were <4.7 units in all but two individuals (P<0.005). In competition analysis with purified unlabelled GAD, binding tracer was inhibited in all of 13 GAD antibody-positive Graves' sera and 5 of 6 GAD antibody-positive sera from patients with Hashimoto's thyroiditis. Eight of 212 (3.8%) patients with Graves' disease and 3 of 76 (3.9%) patients with Hashimoto's thyroiditis, but none of healthy controls had IAA levels exceeding the range for normal controls (P<0.005). Positive IAA levels ranged between 50 and 2383nU/ml. Strikingly, all of 19 GAD antibody-positive sera were negative for IAA. ICA were not detected in any of the patients or healthy controls. These data demonstrate that GAD antibodies in sera of AITD patients are of low titer but significantly elevated compared to healthy controls, and are independent of the appearance of IAA. They also indicate that, in patients with AITD, an autoimmune response to GAD may occur with no relationship to production of IAA.

The incidence of malformation is increased in infants of hyperthyroid or hypothyroid woman. Although many papers reported that the fetus is insulted from maternal thyroid hormone, the placenta (maternalfetal barrier) is not yet fully developed before 11.5 days of gestation in rat embryos, suggesting the effect of thyroid hormone on early rat embryogenesis. This study was, therefore, undertaken to investigate whether excess or lack of thyroid hormones would affect early embryogenesis in rat embryo culture. Malformations including open neuropore and microencephaly were observed in 10 of 30 embryos incubated in hyperthyroid serum, and in 12 of 42 cultured in T3-enriched normal serum. Similar malformations were observed in 14 of 42 embryos cultured in hypothyroid serum and in 10 of 30 cultured in hypothyroid serum supplemented with T3. The frequencies of these malformations were significantly higher than in the control embryos (0 in 72 embryos) cultured with normal rat serum. These results suggest that the maternal thyroid status might play an important role for the complication of fetal malformations during early gestational period.

Without Abstract:

Alteration in mesangial cell function induced by high glucose levels is implicated in the development of diabetic nephropathy. The aim of this study was to investigate the mechanism by which high glucose attenuates mesangial cell proliferation. Thymidine incorporation in cultured mesangial cells decreased in the presence of high glucose concentrations in a dose dependent manner, with the maximum decrease of 25% occurring at a glucose concentration of 55.5 mM. Phosphorylation of mitogen-activated protein (MAP) kinase was abolished when the cells were treated with 55.5 mM glucose compared with 11.1 mM glucose. The concentration of intracellular cAMP doubled in the presence of 55.5 mM glucose. The addition of 8Br-cAMP (1.0 mM) to the culture media containing 11.1 mM glucose decreased thymidine incorporation by 34%, similar to the effect of high glucose. In order to clarify the contribution of protein kinase A (PKA) to the MAP kinase cascade, we used PKA inhibitor (H-8). The addition of H-8(10μM) recovered MAP kinase phosphorylation in the presence of 55.5 mM glucose. Our data indicated that the inhibition of this mitogenic pathway mediated by activation of PKA, which is probably induced by high glucose levels, may play an important role in the perturbation of mesangial cells.