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A Kasuga

Publications and source records attributed to A Kasuga.

At least 37 records · Page 2Linked to original sources
PubMed1997

Autoantibody against IA-2 improves the test sensitivity for insulin-dependent diabetes mellitus in Japanese patients of child onset.

We previously reported that IA-2 autoantibodies (Ab) facilitated the diagnosis of Japanese insulin-dependent diabetes mellitus (IDDM), but the number tested was not large enough to investigate whether IA-2Ab can improve the diagnostic accuracy. In this report, sera from 78 patients with less than 2 year-disease duration (the mean (range) ages were 19.2 (6-52) years old) were tested in order to clarify that the combination of IA-2Ab and glutamic acid decarboxylase 65 (GAD65)Ab would improve the test sensitivity for IDDM. Both of the autoantibodies were frequently detected in Japanese abrupt-onset IDDM but the frequency of GAD65Ab was higher than that of IA-2Ab (69% and 47%, respectively, P = 0.024). The two autoantibodies were discordant in respect to both positivity and titer. The positivity for IA-2Ab decreased with the increasing onset-age of the patients (76, 47, 37, 21% for each quartile of age tested), but the frequency of GAD65Ab was unaffected. Among the youngest quartile (< or = 12 years old), IA-2Ab, in combination with GAD65Ab, significantly improved sensitivity (68% to 92%, P < 0.05), but when we tested patients over 12 years old, IA-2Ab caused little, if any, improvement in sensitivity. We confirmed that IA-2 antibody was detected in IDDM among Japanese, as seen in Caucasians, but the test sensitivity was improved only in young IDDM patients among Japanese.

Adolescent↗
PubMed1996

Antibody to the M(r) 65,000 isoform of glutamic acid decarboxylase are detected in non-insulin-dependent diabetes in Japanese.

It was recently reported that antibodies against glutamic acid decarboxylase (GADAb) have a high positive predictive value for insulin-dependency in non-insulin-dependent diabetic (NIDDM) patients. We studied 289 patients classified at onset as having NIDDM. Patients positive for GAD65Ab had a disease onset at a younger age, lower body mass index (BMI) and lower serum C-peptide concentration, and were more often treated with insulin. Among 73 insulin-treated patients, patients with lower C-peptide level (n = 30, C-peptide < or = 0.9 ng/ml) showed a higher frequency of GAD65Ab (46.7%) than patients with normal C-peptide (n = 53, C-peptide > 0.9; 7.5%, P < 0.0001). The 206 remaining non-insulin-treated patients were divided into 48 short-duration (less than 5 years from diagnosis) and 158 long-duration patients. Frequency of GAD65Ab in short-duration patients (10.4%) was significantly higher than that in long-duration patients (3.2%, P < 0.05). Among short-duration patients, there was no significant difference in C-peptide levels between GAD65-positive and negative patients (2.175 and 2.226 ng/ml). In conclusion, GAD65Ab, a marker of insulin deficiency, may predict the development of insulin dependency in non-insulin-dependent Japanese diabetic patients before serum C-peptide concentration decreases.

Adolescent↗
PubMed1996

Detection of autoantibodies to the pancreatic islet heat shock protein 60 in insulin-dependent diabetes mellitus.

Autoantibodies against heat shock protein (hsp) 60 have been reported to be detected in sera of non-obese diabetic mice, in an experimental model of IDDM. However, there are only a few studies which have examined IDDM patients for antibodies against mammalian hsp60. We produced murine hsp60 derived from pancreatic beta cells which has high homology to human hsp60 and examined antibodies against the hsp60 in IDDM patients using an enzyme-linked immunosorbent assay. We extended the analysis to patients with other immune-mediated diseases and non-insulin-dependent diabetes mellitus (NIDDM). Positive sera for hsp60 antibody were more frequently detected in 13 out of 84 IDDM (15.5%) and 5 out of 25 rheumatoid arthritis patients (20%), when compared to healthy subjects (1/85; 1.2%, P < 0.001 and P < 0.01, respectively). The levels of hsp60 antibodies of IDDM (0.218 +/- 0.227) and rheumatoid arthritis patients (0.259 +/- 0.191) were significantly higher than those of healthy subjects (0.076 +/- 0.131, P < 0.001, P < 0.01, respectively). Patients with slowly progressive IDDM (n = 26), autoimmune thyroid disease (n = 42), or NIDDM (n = 40) had levels of hsp60 antibodies similar to those in healthy subjects. We found no relationship between the levels of hsp60 antibodies and islet cell antibodies (ICA) or antibodies to glutamic acid decarboxylase (GAD65) in IDDM patients. In conclusion, hsp60 antibodies were detected in Japanese IDDM as well as in rheumatoid arthritis patients. Although the positivity was low, the detection of hsp60 antibodies may be helpful for diagnosis of IDDM especially in GAD65 Ab- or JCA-negative Japanese patients.

Autoantibodies↗
PubMed1996

HLA class II is associated with the frequency of glutamic acid decarboxylase M(r) 65,000 autoantibodies in Japanese patients with insulin-dependent diabetes mellitus.

Autoantibodies to glutamic acid decarboxylase (GAD65Ab) are common in both caucasian and Japanese patients with insulin-dependent diabetes mellitus (type 1), while the type 1-associated HLA haplotypes differ. In the present study, we analyzed GAD65Ab in relation to HLA-DQ and -DR alleles in Japanese type 1 patients. GAD65Ab were found in 58% short-duration (less than 5 years) type 1, 23% long-duration type 1, 56% slowly progressive type 1, 3% type 2 patients, and 1.7% healthy individuals. In 75 HLA-typed type 1 patients, the GAD65Ab frequency was higher in short-duration patients with DRB1*08 allele (100%, Pc < 0.05). GAD65Ab frequencies in DQB1*0302, DQB1*0303, and DRB1*09-positive, long-duration type 1 patients were lower than those in short-duration type 1 patients (14%, 19%, and 20%, Pc < 0.02 compared with short-duration type 1, 90%, 75%, and 71%, respectively), while the frequency varied less in DQB1*04 individuals (44% and 30% in short- and long-duration type 1 patients, respectively). These findings were also observed among patients with DRB1*04, i.e., the haplotype DRB1*0405-DQB1*0401 showed less variation in frequency of GAD65Ab (44% and 35% in short- and long-duration type 1 patients, respectively), while DRB1*04xx-DQB1*0302 showed lower frequency in long-duration type 1 than short-duration (13% and 100%, respectively). Thus, HLA class II is associated with frequency GAD65Ab, and this association might be affected by disease duration in Japanese type 1 patients.

Adolescent↗
PubMed1996

Association between HLA and islet cell antibodies in diabetic patients with a mitochondrial DNA mutation at base pair 3243.

Islet cell antibodies (ICA), autoantibodies to glutamic acid decarboxylase (GAD) and HLA genotypes were examined in 31 patients with diabetes and a mitochondrial gene mutation located at base pair 3243 (mtDNA 3243 mutation). ICA was detected in 42% (13/31) of these patients compared to 0 of 90 among healthy control subjects. The ICA showed a "non-restricted" pattern of staining in all 13 ICA-positive patients. In a sensitive radioligand assay only 2 of 31 (6%) diabetic patients with the mutation were positive for both GAD65 autoantibodies and ICA, while the remaining 29 patients were GAD65 antibody negative. The ICA-positive patients had an increased frequency of the HLA-DQA1*0301 allele compared to control subjects (p < 0.05). Of the diabetic patients with the mutation 45% (14/31) had progressive clinical course of beta-cell failure. These results indicate that patients with an mtDNA 3243 mutation may develop islet autoimmunity associated with ICA and GAD autoantibodies. We hypothesize that the presence of HLA-DQA1*0301 in individuals with the mtDNA 3243 mutation increases the risk for diabetes and associated autoantibodies against islet cell antigens.

Adult↗
PubMed1996

Hyperglycemia decreases dehydroepiandrosterone in Japanese male with impaired glucose tolerance and low insulin response.

Recent studies indicate that experimentally induced hyperinsulinemia may reduce serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S). Serum DHEA and DHEA-S decrease in diabetic patients, but the mechanism by which hyperglycemia decreases DHEA and DHEA-S is unknown. In this study, we investigated the effect of hyperglycemia on DHEA and DHEA-S in impaired glucose tolerance (IGT) by means of the 75g-oral glucose tolerance test (OGTT). We selected 30 male IGT patients receiving diet therapy only, whose insulinogenic Index was under 0.3. Oral glucose challenge significantly reduced DHEA (P = 0.0001) and DHEA-S (P < 0.05) at 60 and 120 min after OGTT. Setting the value of DHEA and DHEA-S at time zero as 100%, we calculated the DHEA and DHEA-S values at 60 and 120 min after OGTT as %DHEA(-S) 60 min and %DHEA(-S) 120 min, respectively. DHEA and DHEA-S at time zero showed no correlation with BMI, HbA1c, the sum of insulin values (sigma IRI) or the area under the curve of plasma glucose (AUC). We found decreases in %DHEA 60 min (r = -0.411, P < 0.05), %DHEA-S 60 min (r = -0.508, P < 0.01) and %DHEA-S 120 min (r = -0.393, P < 0.05) as AUC increased, but sigma IRI showed no correlation with %DHEA(-S) 60 min or %DHEA(-S)120 min. We conclude that the depression of DHEA and DHEA-S after OGTT is attributable to hyperglycemia in male Japanese IGT with low insulin response.

Dehydroepiandrosterone↗
PubMed1996

Antibodies to the 37,000-Mr tryptic fragment of islet antigen were detected in Japanese insulin-dependent diabetes mellitus patients.

Sera from 30 Japanese insulin-dependent diabetes mellitus (IDDM) patients of short duration were examined to determine whether they had antibodies to proteolytic fragments of islet antigen, the molecular weights of which were 37,000 and/or 40,000 Mr (37KAb). The median age and disease duration of the patients were 13 (range 6-22) years old and 12 (range; 0-24) months, respectively. Twelve out of the 30 IDDM patients (40%) had 37KAb, while none of the 16 control subjects was positive for 37KAb. The frequency of the 37KAb was not correlated with disease duration tested. We further investigated the antibodies to ICA512, by radioligand binding assay, which has been proposed to be a target antigen for the 37 KAb. Twenty-two (73.3%) patients had antibodies to ICA512 (ICA512AA), but none of the control subjects did. The levels of ICA512AA, which were described as indexes using standard sera, were significantly higher in the patients than in the control subjects (1.436 +/- 2.674 and 0.001 +/- 0.002, respectively, P < 0.05). The frequency of antibodies to glutamic acid decarboxylase 65 (GAD65Ab) was also higher in the patients than in the control subjects (70% and 0%, respectively), but 7 out of 9 GAD65Ab-negative patients had ICA512AA and/or 37KAb. Since 93% of the IDDM patients had at least one of these antibodies, combined analysis with 37KAb, ICA512AA, and GAD65Ab facilitates diagnosis of Japanese IDDM.

Adolescent↗
PubMed1996

Depression of dehydroepiandrosterone in Japanese diabetic men--comparison between non-insulin-dependent diabetes mellitus and impaired glucose tolerance.

Hyperglycemia is known to reduce dehydroepiandrosterone (DHEA) circulating levels; however, the mechanism by which hyperglycemia decreases DHEA is not elucidated. In this study, serum DHEA and DHEA sulfate (DHEA-S) levels were compared in 50 men with non-insulin-dependent diabetes mellitus (NIDDM) and 50 age-matched men with impaired glucose tolerance (IGT) receiving only diet therapy. Serum concentrations of DHEA and DHEA-S in the NIDDM group were significantly lower than in the IGT group (7.8 and 9.7 nmol/l vs 3.4 and 4.9 mumol/l, respectively; p < 0.01) but there was no significant difference in immunoreactive insulin between the two groups. When the results from both groups were combined, HbA1C was significantly inversely related to DHEA (r = -0.243, p < 0.01) and DHEA-S (r = -0.305, p < 0.01). Immunoreactive insulin showed no correlation with DHEA and DHEA-S. Multiple regression analysis showed that HbA1C was independently negatively related to both DHEA and DHEA-S. We conclude that hyperglycemia may decrease serum DHEA and DHEA-S in Japanese men with NIDDM, but the depression of DHEA(-S) is independent of serum insulin level.

Dehydroepiandrosterone↗
PubMed1996

Myasthenia-like syndrome induced by overdosage of cibenzoline.

A case of cibenzoline-induced myasthenia-like syndrome is reported. A 67-year-old woman with renal failure and no previous disorder of neuromuscular junction complained of fatigue during climbing up a flight of stairs and experiencing heavy eyelids after administration of 100 mg/day of cibenzoline. Repetitive nerve stimulation tests revealed decrement at 5-10 Hz. After reduction of the dosage, myasthenia-like signs and symptoms disappeared. The peak cibenzoline concentration was still high even after the dose reduction (666.4 ng/ml). In conclusion, cibenzoline, at a high plasma level, may induce myasthenia-like syndrome without any disorder of the neuromuscular junction.

Aged↗
PubMed1996

Immune response to heat-shock protein correlates with induction of insulitis in I-E alpha d transgenic NOD mice.

To evaluate the correlation between heat-shock protein (HSP) and insulitis, we compared lymphocyte proliferative response to Mycobacterium leprae HSP65 of NOD mice with that of I-E alpha d transgenic NOD (I-E+NOD) mice, which show no insulitis. We found that splenocytes from 15-week-old NOD mice showed a more marked proliferative response to HSP than did those from age-matched I-E+NOD mice (P < 0.05). We then transferred splenocytes from 12-week-old NOD mice into I-E+NOD mice to induce insulitis in the recipients and examined antibody levels against HSP. By 6 weeks posttransfer, insulitis was successfully transferred to four out of five recipients of NOD splenocytes and antibody levels against HSP were significantly higher in the NOD splenocyte-transferred group than in controls, which showed no insulitis (P < 0.01). These results suggest that immune response to HSP correlates with insulitis in NOD mice. Our results support the assertion that HSP is a useful antigen for investigating the etiology of IDDM.

Animals↗
PubMed1995

Nitric oxide is important for mouse beta-cell line killing by peritoneal exudate cells obtained from cyclophosphamide treated non-obese diabetic mice.

Macrophages from recent onset non-obese diabetic (NOD) mice showed cytotoxicity against the NOD mouse derived beta-cell line, MIN6N-9a. In this report, we examined whether nitric oxide is associated with beta-cell destruction. Peritoneal exudate cells (PEC), obtained from cyclophosphamide treated NOD mice showed higher cytotoxicity against MIN6N-9a compared to PECs from saline injected NOD mice (P < 0.01). This effect was suppressed in cells incubated with 0.5 mmol/l NG-methyl-L-arginine, a nitric oxide synthase inhibitor (P < 0.001). In addition, the nitrite concentration of the co-culture medium, as an index of nitric oxide production, increased in MIN6N-9a cells co-cultured with peritoneal exudate cells from cyclophosphamide injected NOD mice but not in co-culture with saline injected NOD mice (P < 0.05). Thus, nitric oxide plays an important role in beta-cell line destruction of macrophages obtained from NOD mice.

Amino Acid Oxidoreductases↗
PubMed1994

Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay.

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.

Adolescent↗
PubMed1994

Acceleration of diabetes in young NOD mice with peritoneal macrophages.

To elucidate the roles of macrophages in the pathogenesis of NOD murine diabetes, peritoneal macrophages from NOD mice were injected into young NOD mice. We used 12 to 20 week-old NOD mice of both sexes as donors, and sex-matched 2-week-old NOD mice as recipients. Cyclophosphamide (CY), 200 mg/kg, was intraperitoneally injected into the donors. Two weeks later, peritoneal exudate cells (PEC) were collected from the diabetic donors. Macrophage-rich fractions (MRF) were collected by adherence. Then PEC(5-8 x 10(6)) or MRF(3-7 x 10(6)) were transferred, intraperitoneally, to the recipients. Two weeks later, some of the recipients were killed in order to perform immunofluorescent analysis of splenocytes and to assess pancreatic histology. Mac 1 positive splenocytes were increased in PEC- and in MRF-injected recipient mice. Insulitis was seen in PEC- and MRF-injected mice, but not in controls. Some of the recipients were injected with CY, 200 mg/kg, intraperitoneally, at two weeks post cell transfer. Two weeks after CY injection, the animals were examined for the presence of diabetes. The incidences of diabetes were 67% in PEC-injected mice, 40% in the MRF-injected group, and 3% in the controls. These results suggest that peritoneal macrophages accelerate the disease process in NOD mice.

Animals↗
PubMed1994

Radioimmunoassay detects the frequent occurrence of autoantibodies to the Mr 65,000 isoform of glutamic acid decarboxylase in Japanese insulin-dependent diabetes.

Glutamic acid decarboxylase antibodies (GAD65Ab) are common in new onset Caucasian insulin-dependent diabetic (IDDM) patients but it is unclear if this marker is also prevalent in patients of other ethnic backgrounds. We determined antibodies against human recombinant GAD in Japanese diabetic patients using a radioimmunoassay with competition between in vitro translated 35S-GAD65 and non-labelled recombinant human GAD65 (rhGAD65). GAD67 antibodies (GAD67Ab) were similarly analyzed but without antigen competition. In 73 Japanese diabetic patients, GAD65Ab were found in 11/16 (69%) of patients with short-duration (less than 5 yrs) IDDM, 6/23 (26%) with long-duration (5 or more yrs) IDDM and 10/20 (50%) with slowly progressive diabetes. High GAD65Ab levels were associated with concomitant autoimmune diseases (p = 0.021). GAD67Ab were found in 4/16 (25%) of patients with short-duration IDDM, 3/23 (13%) with long-duration IDDM and 2/20 (10%) with slowly progressive diabetes. In 14 non-insulin dependent diabetic (NIDDM) patients, GAD65Ab and GAD67Ab were not found (0/14) and 1/50 (2%) healthy controls were positive in either assay. Among the GAD67Ab-positive samples, 8/9 (88%) were also high level GAD65Ab positive, 7/9 (77%) were displaced by an excess of rhGAD65 and the antibody levels correlated (r2 = 0.573; p = 0.003). Our data are consistent with a strong association of GAD65Ab also in Japanese IDDM, and suggest that, when present, GAD67Ab are frequently directed to epitope(s) common to GAD65 and GAD67.

Asian People↗
PubMed1994

Resistance to cyclophosphamide-induced diabetes in transgenic NOD mice expressing I-Ak.

Transgenic expression of the MHC (major histocompatibility complex) class II I-Ak molecule was previously shown to effectively reduce the incidence of insulitis in non-obese diabetic (NOD) mice at the age of 20 weeks. We have further characterized the expression and function of the I-Ak molecule and examined its effects on the incidence of diabetes in NOD mice. The newly expressed I-Ak molecule was recognized as an alloantigen by the T lymphocytes of normal NOD mice as shown by mixed lymphocyte reaction (MLR). The levels of endogenous I-Ag7 expression on peripheral blood lymphocytes were not affected by the transgene expression. Transgenic NOD mice were completely resistant to spontaneous diabetes, but the treatment by cyclophosphamide, which effectively induces diabetes in normal NOD mice, caused diabetes, although at a much lower incidence than that of normal NOD mice. On the basis of these findings, we discuss the role of I-Ak in the prevention of diabetes in NOD mice.

Animals↗