Keiko Fukushima

Nagasaki University Hospital, Nagasaki, Nagasaki, Japan

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Publications (11)29.47 Total impact

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    ABSTRACT: Interferon-alpha (IFN-α) is widely used in the treatment of viral hepatitis, however, it is known that IFN-α therapy may induce type 1 diabetes. We report here on two cases of chronic viral hepatitis C who developed autoimmune type 1 diabetes during Peg-IFN-α plus ribavirin (RBV) therapy. Case 1: a 48-year-old male with chronic hepatitis C with chronic thyroiditis. The patient's plasma glucose level was normal and anti-islet autoantibody tests were negative before Peg-IFN-α+RBV therapy. The emergence of glutamic acid decarboxylase 65 autoantibody (GAD65Ab) was observed after five months of treatment. Autoantibodies to insulin and insulinoma-associated antigen-2 (IA-2) also became positive. Eleven months later, thirst and polydipsia occurred with increased fasting plasma glucose level and the patient was diagnosed with type 1A diabetes. Zinc transporter-8 autoantibody (ZnT8Ab) was not detectable at any point. The patient has type 1 diabetes-susceptible HLA-DRB1-DQB1 haplotypes *0405-*0401 and *0901-*0303. Case 2: a 65-year-old male with chronic hepatitis C with type 2 diabetes on insulin treatment. GAD65Ab and IA-2Ab were negative before Peg-IFN-α+RBV therapy, however, nine months later, a single appearance of GAD65Ab was observed. After twelve months, his plasma glucose control worsened rapidly, and he was diagnosed with type 1A diabetes. IA-2Ab and ZnT8Ab were negative throughout the clinical course. His HLA-DRB1-DQB1 haplotypes were *0410-*0402 and *1407-*0503. Both cases showed a unique GAD65Ab epitope (amino acids 360-442). These clinical courses suggest that IFN-α therapy provoked acute islet autoimmunity and onset of type 1 diabetes. Therefore, during IFN-α therapy, patients should be closely monitored for the occurrence of type 1 diabetes.
    Endocrine Journal 01/2010; 57(11):947-51. · 2.23 Impact Factor
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    ABSTRACT: In this study, we evaluated autoantibodies to IA-2 (IA-2As), glutamic acid decarboxylase 65 (GADAs), and islet cell antibodies (ICAs) in 233 patients with type 1 diabetes (M:F = 90:143, mean duration 4.0 +/- 6.7 yr) as a cross-sectional study. Of 233 patients with type 1 diabetes, IA-2A was detected in 58% of patients with duration within 2 weeks, 61% of patients with duration <1 yr, 41% of patients with diabetes for 1-3 yr, 29% for 4-9 yr, and 21% for >or=10 yr. These prevalences were similar to those of ICA, while the prevalence of GADA was not influenced by duration of diabetes with positivity of 63-74%. Thus, as the duration of diabetes became longer, the frequency of GADA(+)/IA-2A(-) patients increased and the frequency of GADA(+)/IA-2A(+) patients decreased. However, the frequency of GADA(-)/IA-2A(+) patients was not influenced by duration of diabetes. The prevalence of IA-2A was significantly higher in abrupt-onset group (68%, n= 79) compared to the slowly progressive group (23%, n= 22) in new-onset patients (P= 0.0001). However, there was no difference in the IA-2A frequency between these two groups (abrupt-onset 26%, n= 53 vs. slowly progressive 24%, n= 21) in patients with long-standing disease, suggesting that IA-2A positivity might persist in patients with slowly progressive type 1 diabetes. These results emphasize the heterogeneity of humoral autoimmunity to protein tyrosine phosphatase-like molecules, but not to GAD, in patients with type 1 diabetes.
    Annals of the New York Academy of Sciences 12/2008; 1150:248-51. · 4.38 Impact Factor
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    ABSTRACT: Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes. Combined treatment with B:9-23 peptide and polyinosinic-polycytidylic acid (poly I:C), but neither alone, induce insulitis in normal BALB/c mice. In contrast, the combined treatment accelerated insulitis, but prevented diabetes in NOD mice. Our immunofluorescence study with anti-CD4/anti-Foxp3 revealed that the proportion of Foxp3 positive CD4(+)CD25(+) regulatory T cells (Tregs) was elevated in the islets of NOD mice treated with B:9-23 peptide and poly I:C, as compared to non-treated mice. Depletion of Tregs by anti-CD25 antibody hastened spontaneous development of diabetes in non-treated NOD mice, and abolished the protective effect of the combined treatment and conversely accelerated the onset of diabetes in the treated mice. These results indicate that poly I:C combined with B:9-23 peptide promotes infiltration of both pathogenic T cells and predominantly Tregs into the islets, thereby inhibiting progression from insulitis to overt diabetes in NOD mice.
    Biochemical and Biophysical Research Communications 04/2008; 367(4):719-24. · 2.28 Impact Factor
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    ABSTRACT: Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that contains two distinct CD4 epitopes (B:9-16 and B:13-23). One of the two epitopes, B:13-23, overlaps with a CTL epitope (B:15-23). In this study, we report that the elimination of the CTL epitope from the B:9-23 peptide by amino acid substitution (with alanine) at positions B:16 and 19 (A16,19 altered peptide ligand) or truncation of the C-terminal amino acids from the peptide (B:9-21), neither of which stimulated the proliferation of insulin B:15-23 reactive CD8 T cells, provided significant intranasally induced suppression of diabetes when coadministered with a potent mucosal adjuvant cholera toxin (CT). Intranasal treatment with A16,19 resulted in the elimination of spontaneous insulin autoantibodies, significant inhibition of insulitis and remission from hyperglycemia, and prevented the progression to diabetes. Intranasal administration of native B:9-23/CT or B:11-23/CT resulted in a significant enhancement of insulin autoantibody expression and severity of insulitis and failed to prevent diabetes. Our present study indicates that elimination of the CTL epitope from the B:9-23 peptide was critically important for mucosally induced diabetes prevention. The A16,19 altered peptide ligand, but not other native insulin peptides, suppresses insulin autoantibodies associated with protection from and remission of diabetes.
    The Journal of Immunology 09/2007; 179(4):2082-8. · 5.52 Impact Factor
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    ABSTRACT: Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-gamma, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-gamma.
    Biochemical and Biophysical Research Communications 05/2007; 356(4):1024-30. · 2.28 Impact Factor
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    ABSTRACT: Recently, an association of a single nucleotide polymorphism, 163A>G encoding M55V, in the gene SUMO4, which has been shown to be a negative feedback regulator for nuclear factor kappaB, has been reported in type 1 diabetes. To establish whether SUMO4 locus contributes to the genetic susceptibility to other autoimmune disorders, a case-control analysis was carried out using genomic DNA from type 1 diabetes, autoimmune thyroid disease (AITD), rheumatoid arthritis (RA), and primary Sjögren's syndrome. A total of 1480 samples, including 929 cases (411 patients with type 1 diabetes, 292 AITD, 172 RA, and 54 primary Sjögren's syndrome) and 551 healthy control subjects of Japanese origin participated in the study. The 163A>G (rs237025, M55V) polymorphism of SUMO4 was genotyped. SUMO4 M55V variant was associated not only with type 1 diabetes [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.09-1.84; P = 0.0072], but also with increased risk of other autoimmune diseases, AITD (OR, 1.52; 95% CI, 1.14-2.03; P = 0.0041) and RA without amyloidosis (OR, 1.53; 95% CI, 1.65-2.24; P = 0.027), but not primary Sjögren's syndrome. Furthermore, the association of SUMO4 M55V variant was stronger in type 1 diabetic patients complicated with AITD (OR, 1.62; 95% CI, 1.06-2.47; P = 0.023) and in patients who have neither type 1 diabetes-susceptible class II HLA, DRB1*0405 nor DRB1*0901 (OR, 2.28; 95% CI, 1.34-3.87; P = 0.0018). These results indicate that the SUMO4 is a more common autoimmune disease gene and a supplementary risk factor to type 1 diabetes in conjunction with class II HLA.
    Journal of Clinical Endocrinology &amp Metabolism 08/2006; 91(8):3138-43. · 6.43 Impact Factor
  • Clinical Immunology - CLIN IMMUNOL. 01/2006; 119.
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    ABSTRACT: Adiponectin, an adipose tissue-specific plasma protein, is involved in insulin sensitizing and has anti-atherosclerotic properties. Plasma levels of adiponectin are decreased in obese individuals and patients with type 2 diabetes with insulin resistance. Tumor necrosis factor-alpha (TNF-alpha) decreases the expression of adiponectin in adipocytes. The aims of the present study were: (1) to identify the promoter region responsible for basal transcription of the human adiponectin gene, and (2) to investigate the mechanism by which adiponectin was regulated by TNF-alpha. The human adiponectin promoter (2.1kb) was isolated and used for luciferase reporter analysis by transient transfection into 3T3-L1 adipocytes. Deletion analysis demonstrated that the promoter region from -676 to +41 was sufficient for basal transcriptional activity. Mutation analysis of putative response elements for sterol regulatory element binding protein (SREBP) (-431 to -423) and CCAAT/enhancer binding protein (C/EBP) (-230 to -224) showed that both elements were required for basal promoter activity. Adiponectin transcription was increased 3-fold in cells that over-expressed constitutively active C/EBP-beta. Electrophoretic mobility shift assay, using nuclear extract from 3T3-L1 cells and the -258 to -199 region as a probe, demonstrated specific DNA-protein binding, which was abolished by TNF-alpha treatment. The present data indicate that the putative response elements for SREBP and C/EBP are required for human adiponectin promoter activity, and that suppression by TNF-alpha may, at least in part, be associated with inactivation of C/EBP-beta.
    Biochemical and Biophysical Research Communications 07/2005; 331(2):484-90. · 2.28 Impact Factor
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    ABSTRACT: To elucidate the mechanism of the high incidence of lower respiratory tract infections in patients with diabetes mellitus, we investigated the kinetics of production of macrophage inflammatory protein 2 (MIP-2), an important mediator of lung neutrophil recruitment, using mice with streptozotocin-induced diabetes. Intratracheal challenge with 1 mg of lipopolysaccharide (LPS), an endotoxin, per kg of body weight resulted in a time-dependent increase in the levels of MIP-2 protein in bronchoalveolar lavage (BAL) fluid, with the peak concentration (49.4 +/- 13 ng/ml) occurring at 3 h and significant neutrophil accumulation becoming apparent by 3 h in normal mice. In diabetic mice, the peak level of MIP-2 protein in BAL fluid did not occur until 6 h and was reduced to 21.9 +/- 10 ng/ml. Immunohistochemical studies using anti-MIP-2 antibody confirmed that the main cellular source of MIP-2 in the lung after LPS challenge was alveolar macrophages (AMs) in normal mice. The lungs in diabetic mice, however, showed no AMs staining for MIP-2 within 3 h after LPS challenge. PCR analysis using whole-lung RNA showed a time-dependent increase in MIP-2 mRNA levels after LPS instillation. The level of MIP-2 mRNA in diabetic mice was markedly decreased compared to that in normal mice. Our results indicate that impairment of MIP-2 mRNA expression in the AMs in diabetic mice resulted in delayed neutrophil recruitment in the lungs, and this may explain the development and progression of pulmonary infection in diabetes mellitus.
    Infection and Immunity 06/2000; 68(5):2925-9. · 4.07 Impact Factor
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    ABSTRACT: 症例は28歳,男性.1994年(18歳時)に健康診断でFPG 111 mg/dlを指摘されたが放置していた.1996年2月(20歳時),FPG 165 mg/dl, HbA1c 7.8%にて糖尿病と診断され,精査・加療目的にて当科受診した.初診時,身長177 cm, 体重69 kgと肥満はなく,HbA1c 6.9%, GAD抗体63.7 U/ml, 尿中CPR 34.8 μg/日,75 gOGTT時のΣ CPR(0~180分)23.3 ng/mlと内因性インスリン分泌の保たれたGAD抗体陽性インスリン非依存状態糖尿病(NIDDM)と診断された.IA-2抗体,インスリン自己抗体,TPO抗体はいずれも陰性で,HLA-DRB1*0405/*1502-DQB1*0401/*0601 と日本人1型糖尿病の疾患感受性および抵抗性ハプロタイプを有していた.膵β細胞機能を保持させる目的でNPHインスリン4単位/日を開始,その後8年間にわたり内因性インスリン分泌能を追跡した.その結果,75 gOGTTにおけるΣCPR(0~180分)は,2年後33.4 ng/ml, 4年後25.4 ng/ml, 6年後14.2 ng/ml, 8年後4.7 ng/mlと4年目以降に低下し,インスリン必要量は26単位/日まで増加した.GAD抗体は8年後も9.7 U/mlと陽性である.GAD抗体陽性NIDDMにおける少量インスリン治療の有効性を考えるうえで貴重な症例と考えられる.
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    ABSTRACT: Insulin is a major autoantigen responsible for the pathogenesis of type 1 diabetes, and its B-chain peptide B:9-23 has been suggested to contain critically important epitopes in the NOD mouse. We have previously demonstrated that the altered peptide ligand of B:9-23 peptide with alanine substitutions at positions 16 and 19 (A16,19 APL) suppresses insulitis and reduces the incidence of diabetes when administered intranasally together with cholera toxin (CT). In this study, we extended the previous findings to determine whether mucosal administration of the A16,19APL without the use of toxic CT is efficacious for diabetes prevention. To this end,we linked the A16,19APL to the C-terminus of non-toxic cholera toxin (CTB) B subunit and the chimeric fusion protein was produced in methyloprophic yeast Pichia pastoris. Although intranasal administration of the recombinant CTB-A16,19APL fusion protein extracted fromthe yeast cells failed to prevent the progression to diabetes, oral administration of the live yeast cells producing the chimeric protein resulted in more than 50% reduction of the development of diabetes, albeit the fact that protective efficacy did not reach the significance level by life table analysis (P= 0.08). Furthermore, the expression of insulin autoantibodies was not altered throughout the course of oral immunization experiment. These results demonstrated that the efficacy of recombinant CTB-A16,19APL for oral immunization has much room for improvement. Nevertheless, oral administration of recombinant yeast or other edible materials such as food plants engineered to produce altered autoantigenic peptide could potentially become a novel non-invasive immunotherapeutic strategy for type 1 diabetes. (250 word)

Publication Stats

106 Citations
29.47 Total Impact Points


  • 2006–2010
    • Nagasaki University Hospital
      Nagasaki, Nagasaki, Japan
  • 2005–2008
    • Nagasaki University
      • • Department of Endocrinology and Metabolism
      • • Graduate School of Biomedical Sciences
      Nagasaki-shi, Nagasaki-ken, Japan
  • 2000
    • Kanazawa Medical University
      Kanazawa, Ishikawa, Japan