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Tetsuro Kobayashi

Publications and source records attributed to Tetsuro Kobayashi.

At least 37 records · Page 2Linked to original sources
PubMed2004

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin.

Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.

Animals↗
PubMed2004

A case of invasive lobular carcinoma of the breast first manifesting with duodenal obstruction.

Lobular carcinoma of the breast presents with various clinical manifestations. Lobular carcinoma comprises about one fifth of cases of ductal carcinoma. Intestinal metastasis is dominant in cases of lobular carcinoma. Without a prior diagnosis of lobular carcinoma of the breast, the diagnosis of intestinal metastasis from breast cancer is difficult. A 52-year-old women underwent duodenogastrectomy for duodenal cancer. About 18 months later, she underwent mastectomy for lobular carcinoma of the breast. The duodenal cancer consisted mainly of malignant cells invading the submucosa that were identical to those in the breast. Immunohistochemical assays for estrogen receptor also confirmed breast cancer metastasis. Duodenal obstruction was the first sign of isolated metastatic lobular carcinoma of the breast in this case. The characteristic metastatic pattern of lobular carcinoma, which differs from that of ductal carcinoma, should be kept in mind to ensue proper diagnosis. Preceding breast surgery for lobular carcinoma should prompt investigation based on the typical metastatic pattern.

Breast Neoplasms↗
PubMed2004

Effects of a 4-week 70% high carbohydrate/15% low fat diet on glucose tolerance and on lipid profiles.

In order to investigate the effect of high carbohydrate/low fat diet on glucose tolerance and on lipid profiles, we performed a 4-week crossover study. Japanese subjects (30 patients with type 2 diabetes mellitus, 15 subjects with impaired glucose tolerance and 8 subjects with normal glucose tolerance) were allocated either 55% standard carbohydrate/30% fat (sc) or 70% high carbohydrate/15% low fat (hc) diet for four weeks, and evaluated by OGTT and various parameters. Then, the diet was crossed over to another diet, and identical parameters were re-evaluated after four weeks. Area under the glucose concentration-time curve (AUG) or triglyceride did not show significant changes between the two diets. HDL-Cholesterol and body mass index decreased significantly by hc diet. Free fatty acids and homeostasis model assessment insulin resistance index showed a tendency to be decreased by hc diet. AUG hc/sc ratio was inversely correlated with AUG or free fatty acids on standard carbohydrate diet. In conclusion, the present 4-week high carbohydrate/low fat diet may be useful to reduce body weight and insulin resistance. The 4-week high carbohydrate/low fat diet did not affect glucose tolerance as a whole. Although the 4-week high carbohydrate/low fat diet decreased HDL-Chol, it did not increase triglyceride.

Blood Glucose↗
PubMed2004

Distinct diagnostic criteria of fulminant type 1 diabetes based on serum C-peptide response and HbA1c levels at onset.

OBJECTIVE: Diagnostic criteria in fulminant type 1 diabetes, a novel subtype of type 1 diabetes, remain unclear. RESEARCH DESIGN AND METHODS: We analyzed basal and longitudinal changes of serum C-peptide levels during a 75-g oral glucose tolerance test (OGTT) in 125 consecutively recruited patients with type 1 diabetes including fulminant type 1 diabetes (n = 25) and acute-onset type 1 diabetes (n = 100). Discriminating criteria of fulminant type 1 diabetes were examined using receiver-operating characteristic curve analysis and multiple logistic regression analysis. RESULTS: The integrated values of serum C-peptide response during OGTT (SigmaC-peptide) in fulminant type 1 diabetes at onset, 1 year, and 2 years after onset were markedly lower than those in acute-onset type 1 diabetes. None of the patients with fulminant type 1 diabetes had improvement of C-peptide response to OGTT. Fasting C-peptide values at onset in fulminant type 1 diabetes were significantly lower than those in acute-onset type 1 diabetes. We established diagnostic criteria of serum C-peptide and HbA(1c) levels at onset that discriminate fulminant type 1 diabetes from acute-onset type 1 diabetes with high sensitivity and specificity: a criterion in which the levels of both the fasting C-peptide is <or=0.033 nmol/l and HbA(1c) is <or=8.0% or a criterion in which the levels of both the SigmaC-peptide is <or=0.540 nmol/l and HbA(1c) is <or=8.0%. CONCLUSIONS: Fulminant type 1 diabetes has extremely low beta-cell function at onset that rarely recovers after onset. Sensitive and specific diagnostic criteria were established for detection of fulminant type 1 diabetes based on serum C-peptide and HbA(1c) levels at onset.

Adolescent↗
PubMed2003

Association of the SNP-19 genotype 22 in the calpain-10 gene with elevated body mass index and hemoglobin A1c levels in Japanese.

BACKGROUND: An association of variations in the calpain-10 gene (CAPN10) with type 2 diabetes was originally reported in Mexican Americans. However, some studies in other racial groups were contradictory. METHODS: We studied the influence of genotypes and haplotype combinations (haplogenotypes) of CAPN10 on the metabolic traits in 286 Japanese subjects who visited a General Health Check-up Center. RESULTS: As for single nucleotide polymorphism (SNP)-19, subjects with genotype 22 had higher body mass index (BMI) and hemoglobin A(1c) (HbA(1c)) levels than those with genotypes 11 and 12 (p=0.003 and p=0.024, respectively). In SNP-63, subjects with genotype 11 had higher BMI and HbA(1c) levels than those with genotypes 12 and 22 (p=0.003 and p=0.045, respectively). Subjects who had genotype 22 at SNP-19 always had genotype 11 at SNP-63. Subjects with haplogenotype 121/121 had higher BMI levels (p=0.021) and tended to have higher HbA(1c) levels (p=0.08) than those with other haplogenotypes. All things considered, SNP-19 genotype 22, which was composed of haplogenotype 121/121 and 121/221, had highest significance level of association with elevated HbA(1c) levels. SNP-43 did not affect metabolic traits in our subjects. Subjects with haplogenotype 112/121 rather showed lower BMI and HbA(1c) levels (p=0.016 and p=0.008) than those with all other haplogenotypes. CONCLUSIONS: These results indicate the contribution of SNP-19 in CAPN10 to mild obesity and glucose intolerance in Japanese.

Blood Glucose↗
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

Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes.

Disease-specific epitope profiles of glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) were studied in slowly progressive type 1 (insulin-dependent) diabetes mellitus (SPIDDM) and acute onset type 1 (insulin-dependent) diabetes mellitus (AIDDM) using seven kinds of GAD65/67 chimeric molecules. Sera obtained from Japanese SPIDDM (n = 17) and AIDDM (n = 46) patients followed prospectively were analyzed by immunoprecipitation, ELISA, and Western blotting. GAD65Ab in all SPIDDM samples reacted specifically with an N-terminal linear epitope located on the membrane anchoring domain between amino acids 17-51 and C-terminal conformational epitope between amino acids 443-585 of GAD65. The binding of GAD65Ab with N-terminal 83 residues in SPIDDM inversely correlated with the period in which insulin was not required. GAD65Ab in AIDDM did not react with N-terminal epitope located between amino acids 1-83, irrespective of the titer of GAD65Ab. A novel epitope of GAD65Ab in AIDDM residing between amino acids 244-360 was identified in 17% (8 of 46) of patients whose age of onset was younger than other AIDDM patients. In conclusion, GADAb in SPIDDM has unique N-terminal linear epitopes that are located on the anchoring domain of GAD65 molecules. Association is suggested between GAD65Ab targeted to this region and slowly progressive beta-cell failure in SPIDDM.

Autoantibodies↗
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↗
PubMed2002

Expression of intercellular adhesion molecule-1 (ICAM-1) during hypoxia-reoxygenation by sinusoidal endothelial cells (SECs) in an obstructive jaundice model.

BACKGROUND/PURPOSE: The aim of the present study was to investigate the expression of intercellular adhesion molecule-1 (ICAM-1) by sinusoidal endothelial cells (SECs) during hypoxia-reoxygenation in an obstructive jaundice model. METHODS: Male Wistar rats aged 6 to 8 weeks were assigned to an obstructive jaundice group (group OJ; n = 8) and a sham-operated control group (group S; n = 8). Using flow cytometry, we determined the percentage of ICAM-1-positive cells and the mean fluorescence intensity (MFI) of ICAM-1 per cell in each group during hypoxia-reoxygenation. RESULTS: The percentage of ICAM-1-positive cells in group OJ did not change significantly under successive incubation conditions. However, the MFI in group OJ differed significantly between normoxia and 24-h renormoxia. The present study investigated the function of isolated SECs from rats with obstructive jaundice and hypoxia-reoxygenation. The percentage of ICAM-1-positive cells and the MFI of ICAM-1-positive cells showed quite similar changes caused by hypoxia-reoxygenation stress in group S and Group OJ. The ICAM-1 expression increased with hypoxia-reoxygenation in both normal and OJ SECs, and the amount of ICAM-1, on the whole, increased. Obstructive jaundice increased the percentage of ICAM-1-positive cells from the normal state. CONCLUSIONS: The amount of ICAM-1 increased with hypoxia-reoxygenation in obstructive jaundice than normal state.

Animals↗
PubMed2002

A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy.

Four apolipoprotein (apo) E variants have been reported to be associated with lipoprotein glomerulopathy (LPG), which is characterized by type III hyperlipoproteinemia (type III HLP) and proteinuria and frequently leads to nephrotic syndrome. We report the histologic findings in the kidneys of a type III HLP patient with an apo E variant, apo E Toranomon, in which the glutamine at residue 187 in apo E is substituted by glutamic acid (Q187E). The patient also had type 2 diabetes mellitus. No evidence of lipoprotein thrombi suggestive of LPG was detected, however, and the histologic diagnosis was diabetic nephrosclerosis. This unique case illustrates that not all apo E variants result in LPG, and the location of mutations in the apo E protein is one of the important determinants for the development of LPG.

Apolipoproteins E↗
PubMed2002

Multistep carcinogenesis in anaplastic thyroid carcinoma: a case report.

We previously established an anaplastic thyroid carcinoma cell line (KOA2) that had double mutations: an N-ras mutation and a p53 gene mutation. To clarify multistep carcinogenesis, we analysed surgical material from the patient from whom KOA2 was derived for abnormalities in the N-ras and p53 genes. The resected material had two histologically different lesions: a follicular neoplasm and an anaplastic carcinoma. The N-ras mutation was observed in both lesions, but the p53 gene mutation only in the anaplastic lesion. These facts indicate that an N-ras mutation may induce follicular neoplasm and a subsequent p53 mutation may have caused the follicular neoplasm to transform to anaplastic carcinoma in this patient. This report suggests direct evidence for multistep carcinogenesis in anaplastic thyroid carcinoma.

Adenocarcinoma, Follicular↗
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

Association of HLA-DQ genotype in autoantibody-negative and rapid-onset type 1 diabetes.

OBJECTIVE: Some type 1 diabetic patients have a distinct phenotype characterized by the absence of pancreatic autoantibodies and fulminant clinical symptoms at onset, including marked hyperglycemia, severe diabetic ketoacidosis, and normal to near-normal HbA(1c) levels with complete destruction of beta-cells. However, little is known about genetic factors of this distinct subtype of diabetes (fulminant autoantibody-negative type 1 diabetes). RESEARCH DESIGN AND METHODS: We analyzed HLA-DQ genotypes in fulminant autoantibody-negative type 1 diabetes (n = 22) and autoantibody-positive type 1 diabetes (immune-mediated type 1 diabetes, n = 78) recruited from a cohort between 1980 and 2000. RESULTS: Fulminant autoantibody-negative type 1 diabetes had a significantly high prevalence of the HLA-DQA1*0303-DQB1*0401 haplotype in a homozygous manner (RR 39) or in a heterozygous manner with the HLA-DQA1*0302-DQB1*0303 haplotype (RR 13). In contrast, autoantibody-positive type 1 diabetic patients had a high prevalence of the HLA-DQA1*0302-DQB1*0303 haplotype in a homozygous manner (RR 10) or in a heterozygous manner with the HLA-DQA1*0303-DQB1*0401 haplotype (RR 12). CONCLUSIONS: Pathogenic roles of genotypic combinations of specific HLA-DQ haplotypes in a homozygous manner are suggested as causative mechanisms of aggressive beta-cell damage in a subtype of autoantibody-negative type 1 diabetes with fulminant clinical features.

Autoantibodies↗
PubMed2002

Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis: pathological examinations of the endocrine and exocrine pancreas.

Histopathological changes of biopsied pancreata were examined in three diabetic patients with autoimmune chronic pancreatitis (ACP). We found intra- and periinsular mononuclear cell (MNC)-mainly CD8+ T cell-infiltration as well as MNC infiltration around the ductal cells. Islet beta cell volume decreased significantly. Some ductal cells expressed insulin and insulin promoter factor-1 concomitantly in the affected pancreas. These findings provide new insight toward understanding the pathological mechanisms of corticosteroid treatment-responsive diabetes associated with ACP.

Adrenal Cortex Hormones↗