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Akira Shimada

Publications and source records attributed to Akira Shimada.

54 records · Page 3Linked to original sources
PubMed2003

Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) P22 Phox C242T gene polymorphism in type 1 diabetes.

Type 1 diabetes is caused by the immune-mediated destruction of insulin-secreting pancreatic beta cells and is thought to be an autoimmune disease resulting from a complex interaction of genetic and environmental factors. In animal models of type 1 diabetes, macrophages and their products, superoxides, have central roles in the beta cell destruction, but in humans their roles remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces superoxide in macrophages, and its essential component, p22 phox, is a critical enzyme for superoxide production. The C242T polymorphism in the p22 phox coding gene has been reported to be associated with reduced oxidase activity. We therefore investigated whether the p22 phox gene polymorphism affected the susceptibility to and clinical course of type 1 diabetes. We examined 287 Japanese type 1 diabetic patients and 425 unrelated nondiabetic subjects. In addition, we allocated the diabetic patients to the following three groups: (1) acute-onset type 1 diabetes with at least one autoantibody (GADA, IA-2, IAA); (2) acute-onset type 1 diabetes without autoantibodies; and (3) slow-onset type 1 diabetes with autoantibody. We could not find a significant difference in p22 phox genotype and T allele frequency between overall type 1 diabetic patients and control subjects. Regardless of the onset pattern and autoantibody positivity of type 1 diabetes, no difference in p22 phox genotype and T allele frequency was found among the groups. In conclusion, the p22 phox C242T gene polymorphism did not affect the susceptibility to and clinical course of Japanese type 1 diabetes.

Base Sequence↗
PubMed2003

Stromal cell-derived factor-1 chemokine gene polymorphism is not associated with onset age of Japanese type 1 diabetes.

Type 1 diabetes is characterized by cell-mediated autoimmune destruction of pancreatic beta cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. Recently, it was reported that a polymorphism of the stromal cell-derived factor-1 (SDF-1) (a kind of chemokine) gene was associated with early onset of type 1 diabetes in Caucasians. Therefore, we examined SDF-1 gene polymorphism in Japanese type 1 diabetes in this study. We examined the SDF-1 gene polymorphism (801G-->A) in 298 unrelated Japanese type 1 diabetic patients and 270 healthy subjects by the TaqMan PCR method. Allelic and genotypic frequencies of the SDF-1 A variants were similar in overall type 1 diabetic patients and healthy subjects. We then stratified the patients by their onset pattern (acute vs. slow onset) and islet-associated autoantibody positivity. However, no significant difference was found among each group of type 1 diabetes. Furthermore, unlike the previous report in "Caucasian" type 1 diabetics, the SDF-1 A variant was not associated with early onset of the disease in Japanese type 1 diabetics. The SDF-1 gene polymorphism was not associated with onset age (or onset pattern) of type 1 diabetes in Japanese. Further study is necessary to conclude whether SDF-1 gene polymorphism affects the onset age in type 1 diabetes in general.

Adult↗
PubMed2003

Two cases of "fulminant" type 1 diabetes suggesting involvement of autoimmunity.

Recently, a novel subtype of type 1 diabetes, so-called fulminant type 1 diabetes, has been proposed. One of the characteristics of this subtype is the absence of detectable "islet-associated" autoantibody, so it was originally proposed as being "nonautoimmune-mediated"; however, it has not yet been concluded whether autoimmunity is involved. We have previously shown that serum interferon-inducible protein-10 and glutamic acid decarboxylase-reactive CD4(+) interferon-gamma-producing cells in the peripheral blood are good markers for T cell-mediated autoimmunity in type 1 diabetes. Here, we report two cases of fulminant type 1 diabetes in which these markers were detected and in which the involvement of islet-associated autoimmunity is suggested.

Adult↗
PubMed2003

Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p < 0.001 vs. baseline). The summation operator CPR in the Ins group was unchanged. Among the SU group, 30% of subjects (9/30) progressed to IDDM, while 8.3% of Ins group subjects (2/24) progressed to IDDM (p = 0.087). With regard to the subjects who had a preserved C-peptide response ( summation operator CPR >/= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (>/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

Autoantibodies↗
PubMed2003

Detection of GAD-reactive CD4+ cells in so-called "type 1B" diabetes.

OBJECTIVE: Although the majority of type 1 diabetes is considered to be type 1A, some patients with type 1 diabetes have no islet-associated autoantibody in their serum. This type of type 1 diabetes has usually been diagnosed as type 1B on the basis of islet-associated autoantibody-negativity. In this study, we tried to demonstrate the existence of islet-associated antigen-specific T cells in type 1 diabetes without islet-associated autoantibody. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 110 Japanese diabetic patients, including 15 type 2 diabetic patients. Measurement of islet-associated antigen-specific cytokine response was performed by intracellular cytokine staining for flow cytometry. RESULTS: The number of GAD-reactive IFN-gamma-producing CD4+ cells in 50,000 CD4+ cells in diabetics with type 1B (113.6 +/- 34.6, median 45), type 1A (132.4 +/- 33.3, median 25), and LADA (154.4 +/- 44.1, median 20) was higher than that in type 2 diabetics (0.3 +/- 0.3, median 0) and control subjects (3.8 +/- 2.4, median 0). When the normal upper limit of the number of GAD-reactive CD4+ cells was set at the mean + 3SD of values in control subjects, at least half (52.4%) of the so-called "type 1B" patients were positive for GAD-reactive IFN-gamma-producing CD4+ cells, a significantly larger proportion than that in type 2 diabetics (0%; p < 0.001). CONCLUSIONS: Assessment of T cell reactivity against islet-associated antigen may contribute to the diagnosis of "autoimmune-related" type 1 diabetes.

Aged↗
PubMed2003

Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.

Acute Disease↗
PubMed2003

Fulminant type 1 diabetes: a nationwide survey in Japan.

OBJECTIVE: To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey. RESEARCH DESIGN AND METHODS: History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan. RESULTS: In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P < 0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti-islet antigen 2 antibodies. CONCLUSIONS: Fulminant type 1 diabetes is a distinct subtype and accounts for approximately 20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.

Adolescent↗
PubMed2003

[The attempt to standardize treatment protocols for cancer-related hypercalcemia: developing a data-based flowchart].

We developed a flowchart for the treatment of cancer-related hypercalcemia based on the review of previous reports. The treatment protocols were standardized in each group of four different ranges of serum calcium concentration (< 12, 12-14, 14-16, < 16 mg/dl). In each Ca range, specific treatment was adjusted according to the clinical evaluation of symptoms and progression of illness of the patients.

Calcium↗
PubMed2002

Insulin intervention to preserve beta cells in slowly progressive insulin-dependent (type 1) diabetes mellitus.

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is characterized by (1) late age of onset, with initial features of NIDDM and subsequent progression to insulin-dependent stage; (2) high predictive value of autoantibodies against glutamic acid decarboxylase (GADAb) and islet cell antibodies (ICA) for progression of beta cell failure; (3) less predominant T cell response, which may attack and eventually destroy beta-cells in affected pancreas. These findings may suggest a rationale for intervention to prevent slowly progressive beta cell dysfunction in this type of diabetes. We identified three independent risk factors for progression of beta cell failure in SPIDDM: (1) sulfonylurea treatment; (2) ICA-positive periods; and (3) initial body weight. We hypothesized that removal of the risk factors for further progression of beta cell dysfunction will have beneficial effects on intervention strategy in treating SPIDDM. In our pilot study, we used a small dose of insulin instead of sulfonylurea in the early stage of treatment of patients with SPIDDM. Insulin-treated SPIDDM patients had a sustained C peptide response (CPR), while most of sulfonylurea-treated patients progressed to an insulin-dependent state. We organized a randomized multicenter clinical trial to study early treatment to prevent the progression of beta cell dysfunction in SPIDDM (the Tokyo Study). It was demonstrated that early intervention with insulin therapy is an effective treatment modality in the early stage of SPIDDM patients who had preserved beta cell function at entry (integrated value of serum C peptide values at 0, 30, 60, 90, and 120 minutes; Sigma CPR >or= 10 ng/mL) and high GADAb (>10 U/mL). Preventive insulin treatment was ineffective in the patients who had diminished insulin reserve at entry (Sigma CPR < 10 ng/mL). Insulin intervention to preserve beta cell dysfunction in SPIDDM is effective and safe in patients with preserved beta cell function and high GADAb titers at the initiation of insulin.

Age of Onset↗
PubMed2002

Anti-insulin-like growth factor-1 autoantibodies in type 1 diabetes.

Insulin-like growth factor-1 (IGF-1) reportedly suppresses the development of type 1 diabetes in NOD mice, suggesting that IGF-1 is possibly a candidate for the autoantigens in type 1 diabetes. We therefore examined the anti-IGF-1 autoantibodies (IGF-1 Ab) in sera from patients with type 1 diabetes using radioimmunoassay. However, we were unable to demonstrate the existence of anti-IGF-1 autoantibodies in type 1 diabetes with our method. Further study is necessary to clarify whether anti-IGF-1 autoantibodies are existent in human type 1 diabetes and to determine the significance of IGF-1 in the pathogensesis of type 1 diabetes.

Adult↗
PubMed2002

Detection of ATM gene mutation in human glioma cell line M059J by a rapid frameshift/stop codon assay in yeast.

A yeast-based frameshift/stop codon assay for examining ATM (ataxia telangiectasia mutated) mutations was established. Each of six fragments of a PCR-amplified coding sequence for ATM is inserted in frame by homologous recombination into a yeast URA3 fusion protein gene, and the transformants are assayed for growth in the absence of uracil. The usefulness of this assay was verified in a panel of cell lines derived from individuals with homozygous and heterozygous ATM mutations. The assay was also shown to distinguish between specimens with wild-type alleles and those with truncating mutations: a frameshift mutation or an inserted stop codon. Using this assay M059J cells, which fail to express the catalytic subunit of DNA-dependent protein kinase (PRKDC, also known as DNA-PKcs) and are hypersensitive to ionizing radiation, were found to express two different aberrant ATM transcripts: one characterized by 4776 del 133, which corresponds to the deletion of exon 33, and the other by 4909 ins 116. Subsequent analysis of the intron sequences revealed that 4909 ins 116 is comprised of a nucleotide sequence corresponding to 84013-84128 in intron 33 with a cryptic splice site. Thus the radiosensitive phenotype of M059J cells appears to be due to a defect in PRKDC and a truncating ATM mutation.

Ataxia Telangiectasia↗
PubMed2002

High frequency of valpha24(+) vbeta11(+) T-cells observed in type 1 diabetes.

OBJECTIVE: Natural killer T-cells (NKT cells) are believed to play an important role in the regulation of immune response, and a numerical and functional deficit of NKT cells has been reported to be associated with the pathogenesis of autoimmune diseases. Thus far, it has been shown that subjects with type 1 diabetes have a lower frequency of NKT cells than nondiabetic subjects. In this study, we measured the frequency of peripheral Valpha24(+) Vbeta11(+) T-cells, which include human NKT cells, in Japanese diabetic patients. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 164 Japanese diabetic patients and 67 healthy subjects. The diabetic patients were classified into four categories as follows: islet-associated autoantibody-positive (Ab(+)) and -negative (Ab(-)) classic type 1 diabetes, latent autoimmune diabetes in adults (LADA), and type 2 diabetes. We measured the frequency of peripheral Valpha24(+) Vbeta11(+) CD3(+) triple-positive cells. RESULTS: Unexpectedly, a higher frequency of Valpha24(+) Vbeta11(+) T-cells was observed in Ab(+) and Ab(-) patients compared with LADA patients (P = 0.0294 and P = 0.0021), type 2 diabetic patients (P < 0.0001 and P < 0.0001), and healthy subjects (P = 0.0046 and P = 0.0001). Moreover, an inverse correlation between Valpha24(+) Vbeta11(+) T-cell frequency and disease duration was observed in Ab(+) (rho = -0.455; P = 0.0023) and Ab(-) (rho = -0.432; P = 0.0162) patients. CONCLUSIONS: Our findings indicate that a high frequency of Valpha24(+) Vbeta11(+) T-cells is a unique finding in recent-onset classic type 1 diabetes, and measurement of Valpha24(+) Vbeta11(+) T-cell frequency may be useful to assess the disease activity of classic type 1 diabetes.

Adult↗
PubMed2002

[Serum lactate dehydrogenase and CD4+/CD8+ lymphocyte ratio predict survival in terminally ill cancer patients].

Accurate estimation of survival is important for effective palliative medicine of patients with cancer. In most clinical practice, however, the life expectancy has been predicted based on subjective evaluations. The purpose of this study was to find objective biological markers that can contribute to accurate prediction of survival in terminally ill cancer patients. Consecutive terminally ill cancer patients admitted to the Palliative Care Center in Tohoku University hospital from January to May 2001 were approached for this study. Forty-eight blood samples were obtained from 25 patients who provided a written informed consent. Common serum enzyme markers were determined using standard hospital laboratory methods. Cellular immunity status was evaluated by peripheral blood lymphocyte-subset analysis using flow cytometry. Mean patient survival was 33.5 +/- 21.6 (1-80) days. Multiple regression analysis revealed that lactate dehydrogenase (LDH) and the CD4+/CD8+ ratio were significantly associated with survival (r = 0.64, p < 0.0001). Further prospective studies are warranted to validate the usefulness of these determinants for accurate prediction of survival.

Adult↗
PubMedDate not supplied

Insulin-like growth factor-1 (IGF-1)-derived peptide protects against diabetes in NOD mice.

Spontaneous diabetes in non-obese diabetic (NOD) mice results from beta-cell destruction by autoreactive T lymphocytes. Here, we report the significance of insulin-like growth factor-1 (IGF-1) peptide as a tool for the prevention of type 1 diabetes. Female NOD mice were immunized with a subcutaneous injection of IGF-1, glutamic acid decarboxylase (GAD), insulin or IGF-1-derived peptides (residues 8-23, 24-41 or 50-70) in incomplete Freund's adjuvant (IFA) or with IFA only as the control group at 4 weeks of age, and observed up to 36-37 weeks of age. Diabetes onset was significantly suppressed and delayed in the IGF-1 group as compared to the GAD, insulin and control groups (p<0.05), and it was significantly suppressed and delayed in the (50-70)IGF-1 group as compared to the (8-23)IGF-1 and control groups (p<0.02). Although the degree of insulitis in all treated mice was not significantly different, a significant number of IL-4-producing cells in response to IGF-1 peptides were detected in (50-70)IGF-1-treated mice in intracellular cytokine assay. In conclusion, IGF-1 peptide 50-70 immunizations of NOD mice suppressed and delayed diabetes onset, probably through amplification of the Th2-type response. It was suggested that IGF-1 peptide 50-70 immunization can be used as a tool for prevention of type 1 diabetes.

Age Factors↗