Analysis of genetic basis for islet-specific autoimmunity and the applecation to prevention and treatment of type 1 diabetes

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591327
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kinki University
• Principal Investigator: NOSO Shinsuke 近畿大学, 医学部, 講師 (90460849)
• Co-Investigator(Kenkyū-buntansha): IKEGAMI Hiroshi 近畿大学, 医学部, 教授 (20221062) ; KAWABATA Yumiko 近畿大学, 医学部, 准教授 (80423185) ; BABAYA Naru 近畿大学, 医学部, 講師 (10449837)
• Project Period (FY): 2011 – 2013
• Keywords: エネルギー・糖質代謝異常

Research Abstract

Type 1 diabetes is a tissue-specific autoimmune disease against insulin-producing beta cells in pancreatic islets. To clarify the mechanisms of beta cell-specific destruction and the application of treatment for type 1 diabetes, we identified genetic factors, including Mafa gene, for islet-specific autoimmune response by association studies of candidate genes for type 1 diabetes with multiple organ-specific autoimmune diseases (type 1 diabetes, Graves' disease, Hashimoto thyroiditis and alopecia areata). Then, we established the Mafa knockout NOD mouse by speed congenic protocol. The cumulative incidence of type 1 diabetes in Mafa knockout NOD mouse was significantly protected in homozygotes of knockout allele in comparison with heterozygotes and wild type, suggesting the critical role of Mafa gene on the development of type 1 diabetes in vivo.

Research Products

• [Journal Article] Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse (2014)
  • Author(s): Wang X, Sugimoto K, Fujisawa T, Shindo N, Minato S, Kamada Y, Hamano M, Ohishi M, Ikegami H, Rakugi H
  • Journal Title: Hepatol Res Volume: 44 Pages: 102-13
  • Peer Reviewed
• [Journal Article] Association study of MAFA and MAFB, genes related to organ-specific autoimmunity, with susceptibility to type 1 diabetes in Japanese and Caucasian populations (2013)
  • Author(s): Noso S, Kawabata Y, Babaya N, Hiromine Y, Kawasaki E, Awata T, Maruyama T, Sunanda B, Oiso N, Kawada A, Suzuki T, Eisenbarth GS, Ikegami H
  • Journal Title: J Genet Syndr Gene Ther Volume: 4 Pages: 204
  • Peer Reviewed
• [Journal Article] Dose effect and mode of inheritance of diabetogenic gene on mouse chromosome 11 (2013)
  • Author(s): Babaya N, Ueda H, Noso S, Hiromine Y, Nojima K, Itoi-Babaya M, Kobayashi M, Fujisawa T, Ikegami H
  • Journal Title: J Diabetes Res Volume: Article ID 608923 Pages: 6
  • Peer Reviewed
• [Journal Article] Analysis of hepatic gene expression profile in a spontaneous mouse model of type 2 diabetes under a high sucrose diet (2013)
  • Author(s): Nojima K, Sugimoto K, Ueda H, Babaya N, Ikegami H, Rakugi H
  • Journal Title: Endocrine J Volume: 60 Pages: 261-74
  • Peer Reviewed
• [Journal Article] A low-frequency GLIS3 variant associated with resistance to Japanese type 1 diabetes (2013)
  • Author(s): Awata T, Yamashita H, Kurihara S, Morita-Ohkubo T, Miyashita Y, Katayama S, Kawasaki E, Tanaka S, Ikegami H, Maruyama T, Shimada A, Takahashi K, Kawabata Y, Kobayashi T, Nishida N, Mawatari Y; on behalf of the Japanese Study Group on Type 1 Diabetes Genetics
  • Journal Title: Biochem Biophys Res Commun Volume: 437 Pages: 521-5
  • Peer Reviewed
• [Journal Article] 円形脱毛症に併存する甲状腺および膵島自己免疫に関する臨床的・遺伝的研究 (2013)
  • Author(s): 朴忠勇、能宗伸輔、川畑由美子、山内孝哲、馬場谷成、原田剛史、廣峰義久、伊藤裕進、村田佳織、武友保憲、貫戸幸星、當間純子、末吉功治、吉田左和、大磯直毅、川田暁、池上博司
  • Journal Title: 近畿大学医学雑誌 Volume: 38(3,4) Pages: 107-114
  • Peer Reviewed
• [Journal Article] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians (2012)
  • Author(s): Ikegami H (他名65名)
  • Journal Title: Nat Genet Volume: 44 Pages: 67-73
  • Peer Reviewed
• [Journal Article] Prolonged hyperinsulinemia after subcutaneous injection of 2400 U regular insulin in a suicide attempt : Time course of serum insulin with frequent measurements (2012)
  • Author(s): Hiromine Y, Kawabata Y, Yamauchi T, Noso S, Babaya N, Harada T, Ito H, Ikegami H
  • Journal Title: J Diabetes Invest Volume: 3 Pages: 468-470
  • Peer Reviewed
• [Journal Article] ClassIIHLA genotype in fluminant type 1 diabetes : A nationwide survey with reference to glutamic acid decarboxylase antibodies (2012)
  • Author(s): Tsutsumi C, Imagawa A, Ikegami H, Makino H, Kobayashi T, Hanafusa T, on behalf of the Japan Diabetes Society Committee on Type 1 diabetes Mellitus Research
  • Journal Title: J Diabetes Invest Volume: 3 Pages: 62-69
  • Peer Reviewed
• [Journal Article] Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 diabetes Mellitus : New diagnostic criteria of fluminant ytpe 1 diabetes mellitus (2012) (2012)
  • Author(s): Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, Shimizu I, Takahashi K, Nagata M, Makino H, Maruyama T
  • Journal Title: J Diabetes Invest Volume: 3 Pages: 536-539
  • Peer Reviewed
• [Journal Article] Association of Genetic Variation in FTO with Risk of Obesity and Type 2 Diabetes with Date from 96,551 East and South Asians (2012)
  • Author(s): Ikegami H,(他64名)
  • Journal Title: Diabetologia Volume: 55 Pages: 981-995
  • Peer Reviewed
• [Journal Article] Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute-onset Type 1 diabetes Mellitus : New diagnostic criteria of fluminant ytpe 1 diabetes mellitus (2012) (2012)
  • Author(s): Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, Shimizu I, Takahashi K, Nagata M, Makino H, Maruyama T
  • Journal Title: Diabetol Int Volume: 3 Pages: 179-183
  • Peer Reviewed
• [Journal Article] Genetics and Pathogenesis of Type 1 Diabetes : Prospects for Prevention and Intervention (2011)
  • Author(s): Ikegami H, Noso S, Babaya N, Kawabata Y
  • Journal Title: J Diabetes Invest Volume: 2 Pages: 415-420
  • Peer Reviewed
• [Journal Article] Clinical and Genetic Characteristics of Patients with Autoimmune Thyroid Disease with Anti-islet Autoimmunity (2011)
  • Author(s): Moriguchi M, Noso S, Kawabata Y, Yamauchi T, Harada T, Komaki K, Babaya N, Hiromine Y, Ito H, Yamagata S, Murata K, Higashimoto T, Park CY, Yamamoto A, Ohno Y, Ikegami H
  • Journal Title: Metabolism Volume: 60 Pages: 761-6
  • Peer Reviewed
• [Journal Article] Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals (2011)
  • Author(s): Takeuchi F, Yamamoto K, Katsuya T, Nabika T, Sugiyama T, Fujioka A, Isono M, Ohnaka K, Fujisawa T, Nakashima E, Ikegami H, Nakamura J, Yamori Y, Yamaguchi S, Kobayashi S, Ogihara T, Takayanagi R, Kato N
  • Journal Title: Diabetologia Volume: 54 Pages: 1350-1359
  • Peer Reviewed
• [Journal Article] Efficacy and safety of low-dose metformin for treatment of type 2 diabetes in elderly Japanese patients (2011)
  • Author(s): Ito H, Ohno Y, Yamauchi T, Kawabata Y, Ikegami H
  • Journal Title: Geriatr Gerontol Int Volume: 11 Pages: 55-62
  • Peer Reviewed
• [Journal Article] Attenuated food anticipatory actibity and abnormal circadian locomotor rhythms in Rgs16 knockdown mice (2011)
  • Author(s): Hayasaka N, Aoki K, Kinoshita S, Yamaguchi S, Wakelield JK, Tsuji-Kawahara S, Horikawa K, Ikegami H, Wakana S, Murakami T, Ramabhadran R, Miyazawa M, Shibata S
  • Journal Title: Pros ONE Volume: 6 Pages: e17655
  • Peer Reviewed
• [Journal Article] the Research Committee on Type 1 Diabetes of the Japan Diabetes Society : Type 1 Diabetes and Interferon Therapy : A nationwide survey in Japan (2011)
  • Author(s): Nakamura K, Kawasaki E, Imagawa A, Awata T, Ikegami H, Uchigata Y, Kobayashi T, Shimada A, Nakanishi K, Makino H, Maruyama T, Hanafusa T
  • Journal Title: Diabetes Care Volume: 34 Pages: 2084-2089
  • Peer Reviewed
• [Journal Article] Analysis of the HLA and non-HLA susceptibility loci in Japanese type 1 diabetes (2011)
  • Author(s): Yamashita H, Awata T, Kawasaki E, Ikegami H, Tanaka S, Maruyama T, Shimada A, Nakanishi K, Takahashi K, Kobayashi T, Kawabata Y, Miyashita Y, Kurihara S, Morita-Ohkubo T, Katayama S; on behalf of The Japanese Study Group on Type 1 Diabetes Genetics
  • Journal Title: Diabetes Metab Res Rev Volume: 27 Pages: 844-848
  • Peer Reviewed
• [Presentation] A search for susceptibility genes contributing to islet-specific autoimmunity in type 1 diabetes by association studies with multiple autoimmune diseases (2013)
  • Author(s): Noso S, Kawabata Y, Babaya N, Hiromine Y, Moriguchi M, Murata K, Choongyong Park, Taketomo Y, Ikegami H
  • Organizer: 13th International Congress of the Immunology of Diabetes
  • Place of Presentation: Lorne, Australia
  • Year and Date: 20131207-11
• [Presentation] Low expression level of Peripheral CD4+PD-1+T-cells in Japanese Patients with Type 1A Diabetes (2013)
  • Author(s): Fujisawa R, Haseda F, Tsutsumi C, Hiromine Y, Noso S, Kawabata Y, Mitsui S, Terasaki J, Ikegami H, Imagawa A, Hanafusa T
  • Organizer: 13th International Congress of the Immunology of Diabetes
  • Place of Presentation: Lorne, Australia
  • Year and Date: 20131207-11
• [Presentation] Low Expression of PD-1 in Peripheral CD4+ T-cells in Japanese Patients with Type 1A Diabetes (2013)
  • Author(s): Fujisawa R, Haseda F, Tsutsumi C, Hiromine Y, Noso S, Kawabata Y, Mitsui S, Terasaki J, Ikegami H, Imagawa A, Hanafusa T
  • Organizer: 73rd Scientific Session of America Diabetes Association
  • Place of Presentation: Chicago, USA
  • Year and Date: 20130621-25
• [Presentation] Mafa knockout NOD mice are protected from type 1 diabetes despite accelerated infiltration of lymphocytes into islets (2013)
  • Author(s): Noso S, Babaya N, Hiromine Y, Kawabata Y, Ikegami H
  • Organizer: 49th European Association for the Study of Diabetes Annual Meeting
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2013-09-25
• [Presentation] Symposium 8 "Islet biology" Genetics and pathogenesis of beta-cell destruction in type 1 diabetes (2013)
  • Author(s): Ikegami H
  • Organizer: 26th Spring Congress of Korean Diabetes Association, 1st Korea-Japan Diabetes Forum
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2013-05-10
• [Presentation] Basic Science 13, MDIA Symposium "GeneticsII" A search for susceptibility genes contributing to islet-specific autoimmunity in type 1 diabetes (2012)
  • Author(s): Noso S, Ikegami H
  • Organizer: 4th Scientific Meeting of the Asian Association for the Study of Diabetes
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2012-11-27
• [Presentation] Susceptibility genes for type 2 diabetes and related phenotypes cluster on mouse chromosome 14 (2012)
  • Author(s): Babaya N, Noso S, Hiromine Y, Ueda H, Ikegami H
  • Organizer: 48th European Association for the Study of Diabetes Annual Meeting
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-10-03
• [Presentation] Plenary Lecture⑫Genetics of type 1 diabetes : HLA and non-HLA genes (2012)
  • Author(s): Ikegami H
  • Organizer: ISPAD Science School for Physicians 2012 in Kyoto
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2012-09-03
• [Presentation] Association of a functional polymorphism MAFA Gly346Cys with susceptibility to type 1 diabetes (2012)
  • Author(s): Noso S, Kawabata Y, Babaya N, Hiromine Y, Kawasaki E, Awata T, Maruyama T, Babu S, Eisenbarth GS, Ikegami H
  • Organizer: 12th International Congress of the Immunology of Diabetes
  • Place of Presentation: Victoria, Canada
  • Year and Date: 2012-06-18
• [Presentation] Association of PDCD-1 (programmed cell death-1) polymorphisms in Japanese Patients with Fulminant and Type 1A diabetes (2012)
  • Author(s): Tsutsumi C, Hiromine Y, Imagawa A, Mitsui S, Noso S, Kawabata Y, Terasaki J, Ikegami H, Hanafusa T
  • Organizer: 12th International Congress of the Immunology of Diabetes
  • Place of Presentation: Victoria, Canada
  • Year and Date: 2012-06-18
• [Presentation] Heterogenetiy of classIIHLA genotypes in patients with fulminant type 1 diabetes in Japan (2011)
  • Author(s): Tsutsumi C, Imagawa A, Ikegami H, Makino H, Kobayashi T, Hanafusa T
  • Organizer: The 3rd Scientific Meeting of the Asian Association for the Study of Diabetes
  • Place of Presentation: Beijing, China
  • Year and Date: 20110722-24
• [Presentation] Susceptibility to insulin resistance, adiposity and obesity is mapped to proximal region of mouse chromosome 14 (2011)
  • Author(s): Babaya N, Noso S, Hiromine Y, Kobayashi M, Ueda H, Ikegami H
  • Organizer: The 16th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-10-21
• [Presentation] Main Symposium 5 / Type 1diabetes in East Asia「Genetics of Type 1 diabetes in East Asia」 (2011)
  • Author(s): Ikegami H
  • Organizer: The 16th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2011-10-21
• [Book] 糖尿病学2011「胸腺における新たなインスリン発現調節因子としてのMafAの役割と1型糖尿病発症への関与」 (2011)
  • Author(s): 能宗伸輔、池上博司
  • Total Pages: 81-88
  • Publisher: 診断と治療社
• [Remarks]
  • URL: http://emdm.med.kindai.ac.jp/index.php