研究内容と概説

以下のテーマを中心に基礎研究・臨床研究を進めています。

 各個人の病因・病態・体質に応じたテーラーメイド医療構築へむけての研究

1. 遺伝素因に関する研究

糖尿病や甲状腺疾患の発症・進展に関与する遺伝子の解明を進めています。疾患に関与する遺伝子を明らかにすることにより、ハイリスク患者の予知・予防が可能となるばかりでなく、疾患の発症・進展メカニズムが分子レベルで明らかとなり、分子メカニズムに基づいた根本的予防法・治療法の構築にもつながるからです。下記の疾患に関して、ヒト・モデル動物の両面から研究を進めています。

2. 分子メカニズムに応じた最適の治療法構築に関する研究

糖尿病とひとくちに言っても、その成因・病態は不均一であり、個々の症例の成因・病態を的確に診断し、最適の治療法を構築する「テーラーメイド医療」が不可欠です。このために疾患の病因・病態を分子レベルで解明し、科学的根拠に基づいた臨床分類とそれに応じた最適療法の構築を進めています。

参考論文①

1. Kawabata Y, Nishida N, Awata T, Kawasaki E, Imagawa A, Shimada A, Osawa H, Tanaka S, Takahashi K, Nagata M, Yasuda H, Uchigata Y, Kajio H, Makino H, Yasuda K, Kobayashi T, Hanafusa T, Tokunaga K, Ikegami H:
   A genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in CSAD/lnc-ITGB7-1 on Chromosome 12q13.13 Associated with Susceptibility to Fulminant Type 1 Diabetes.
   Diabetes 68: 665-675, 2019
2. Noso S, Babaya N, Hiromine Y, Ito H, Taketomo Y, Yoshida S, Niwano F, Monobe K, Minohara T, Okada T, Tsugawa M, Kawabata Y, Ikegami H:
   Contribution of Asian haplotype of KCNJ18 to susceptibility to and ethnic differences in thyrotoxic periodic paralysis
   J Clin Endocrinol Metab. 104: 6338-6344, 2019
3. Taketomo Y, Noso S, Babaya N, Hiromine Y, Ito H, Kanto K, Niwano F, Oiso N, Kawada A, Kawabata Y, Ikegami H:
   Common phenotype and different non-HLA genes in Graves' disease and alopecia areata
   Hum Immunol. 78: 185-189, 2017
4. Noso S, Park C, Babaya N, Hiromine Y, Harada T, Ito H, Taketomo Y, Kanto K, Oiso N, Kawada A, Suzuki T, Kawabata Y, Ikegami H: Organ-specificity in autoimmune diseases: Thyroid and islet autoimmunity in alopecia areata.
   J Clin Endocrinol Metab 100:1976-1983, 2015
5. 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: Association study of MAFA and MAFB, genes related to organ-specific autoimmunity, with susceptibility to type 1 diabetes in Japanese and Caucasian populations.
   J Genet Syndr Gene Ther 4: 204, 2013
6. 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: Clinical and Genetic Characteristics of Patients with Autoimmune Thyroid Disease with Anti-islet Autoimmunity.
   Metabolism 60: 761-6, 2011
7. Noso S, Kataoka K, Kawabata Y, Babaya N, Hiromine Y, Yamaji K, Fujisawa T, Aramata S, Kudo T, Takahashi S, Ikegami H: Insulin transactivator MafA regulates intra-thymic expression of insulin and affects susceptibility to type 1 diabetes.
   Diabetes 59:2579-87, 2010
8. Kawabata Y, Ikegami H, Awata T, Imagawa A, Maruyama T, Kawasaki E, Tanaka S, Shimada A, Osawa H, Kobayashi T, Hanafusa T, Tokunaga K, Makino H on behalf of the the Committee on Type 1 Diabetes, Japan Diabetes Society: Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset.
   Diabetologia 52: 2513-2521, 2009
9. Ikegami H, Kawabata Y, Noso S, Fujisawa T, Ogihara T: Genetics of type 1 diabetes in Asian and Caucasian populations.
   Diab Res Clin Prac 77S:S116-S121, 2007
10. Ikegami H, Awata T, Kawasaki E, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Amemiya S, Kawabata Y, Kurihara S, Tanaka S, Kanazawa Y, Mochizuki M, Ogihara T, Japanese Study Group on Type 1 Diabetes Genetics: The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multi-center collaborative study in Japan.
    J Clin Endocrinol Metab 91:1087-92, 2006
11. Noso S, Ikegami H, Fujisawa T, Kawabata Y, Asano K, Hiromine Y, Tsurumaru M, Sugihara S, Lee I, Kawasaki E, Awata T, Ogihara T: Genetic heterogeneity in association of SUMO4 M55V variant with susceptibility to type 1 diabetes.
    Diabetes 54: 3582-3586, 2005
12. Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M, Nishino M, Uchigata Y, Lee I, Ogihara T: Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes.
    Diabetes 51:545-551, 2002
13. Ikegami H, Ogihara T: Genetics of insulin-dependent diabetes mellitus.
    Endocrine J 43:605-613, 1996
14. Ikegami H, Makino S, Yamato E, Kawaguchi Y, Ueda H, Sakamoto T, Takekawa K, Ogihara T: Identification of a new susceptibility locus for insulin-dependent diabetes mellitus by ancestral haplotype congenic mapping.
    J Clin Invest 96:1936-1942, 1995
15. Ikegami H, Kawaguchi Y, Ueda H, Fukuda M, Takekawa K, Fujioka Y, Fujisawa T, Uchida K, Ogihara T: MHC-linked diabtogenic gene of the NOD mouse: Molecular mapping of the 3' boundary of the diabtogenic region.
    Biochem Biophys Res Comm 192:677-682, 1993
16. Ikegami H, Kawaguchi Y, Yamato E, Kuwata S, Tokunaga K, Noma Y, Shima K, Ogihara T: Analysis by the polymerase chain reaction of histocompatibility leukocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus.
    J Clin Endocrinol Metab 75:1381-1385, 1992
17. Ikegami H, Eisenbarth GS, Hattori M: Major histocompatibility complex-linked diabetogenic gene of the nonobese diabetic mouse: analysis of genomic DNA amplified by the polymerase chain reaction.
    J Clin Invest 85:18-24, 1990
18. Ikegami H, Makino S, Harada M, Eisenbarth GS, Hattori M: The cataract Shionogi mouse, a sister strain of the non-obese diabetic mouse: similar class II but different class I gene products.
    Diabetologia 31:254-258, 1988

参考論文②

1. Babaya N, Ueda H, Noso S, Hiromine Y, Itoi-Babaya M, Kobayashi M, Fujisawa T, Ikegami H:
   Verification That Mouse Chromosome 14 Is Responsible for Susceptibility to Streptozotocin in NSY Mice.
   Int J Endocrinol. 2018: 7654979, 2018
2. Babaya N, Noso S, Hiromine Y, Ito H, Taketomo Y, Yamamoto T, Kawabata Y, Ikegami H.:
   Early-onset diabetes mellitus in a patient with a chromosome 13q34qter microdeletion including IRS2
   J Endocr Soc. 2:1207-1213, 2018
3. Babaya N, Ueda H, Noso S, Hiromine Y, Itoi-Babaya M, Kobayashi M,Fujisawa T and Ikegami H:Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains.
   BMC Genet 15:93,2014
4. Babaya N, Ueda H, Noso S, Hiromine Y, Nojima K, Itoi-Babaya M, Kobayashi M, Fujisawa T, Ikegami H: Dose effect and mode of inheritance of diabetogenic gene on mouse chromosome 11. J Diabetes Res 2013 (2013), Article ID 608923, 6 pages
5. Babaya N, Fujisawa T, Nojima K, Itoi-Babaya M, Yamaji K, Yamada K, Kobayashi M, Ueda H, Hiromine Y, Noso S, Ikegami H: Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14.
   Diabetologia 53:1362-1371, 2010
6. Noso S, Fujisawa T, Kawabata Y, Asano K, Hiromine Y, Fukai A, Ogihara T, Ikegami H: Association of small ubiquitin-like modifier 4 (SUMO4) valiant, located in IDDM5 locus, with type 2 diabetes in the Japanese population.
   J Clin Endocrinol Metab 92:2358-62, 2007
7. Itoi-Babaya M, Ikegami H, Fujisawa T, Ueda H, Nojima K, Babaya N, Kobayashi M, Noso S, Kawaguchi Y, Yamaji K, Shibata M, Ogihara T: Fatty liver and obesity: phenotypically correlated but genetically distinct traits in a mouse model of type 2 diabetes.
   Diabetologia 50:1641-1648, 2007
8. Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Nakura J, Abe M, Yamamoto M, Jin J, Wu Z, Miki T, Fukuda M, Ogihara T: Association of I27L polymorphism of hepatocyte nuclear factor 1alpha gene with high density lipoprotein cholesterol level.
   J Clin Endocrinol Metab 88:2548-2551, 2003
9. Shintani M, Ikegami H, Kawaguchi Y, Fujisawa T, Ohishi M, Katsuya T, Jitsuo H, Shimamoto K, Ogihara T: Leptin gene polymorphism is associated with hypertension independent of obesity.
   J Clin Endocrinol Metab 87:2909-2912, 2002
10. Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Yamato E, Shibata M, Ogihara T: Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait.
    Diabetes 48:1168-1174, 1999
11. Shen G-Q, Ikegami H, Kawaguchi Y, Fujisawa T, Hamada Y, Ueda H, Shintani M, Nojima K, Kawabata Y, Yamada K, Babaya N, Ogihara T: Asp905Tyr polymorphism of skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 gene in non-insulin-dependent diabetes mellitus.
    Diabetes Care 21:1086-1089, 1998
12. Fujisawa T, Ikegami H, Kawaguchi Y, Ogihara T: Meta-analysis of the association of Trp64Arg polymorphism of beta3-adrenergic receptor gene with body mass index.
    J Clin Endocrinol Metab 83:2441-2444, 1998
13. Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Oga T, Ueda H, Shintani M, Fukuda M, Ogihara T: Association of Trp64Arg mutation of beta3-adrenergic receptor with NIDDM and body weight gain.
    Diabetologia 39:349-352, 1996
14. Fujisawa T, Ikegami H, Kawaguchi Y, Hamada Y, Ueda H, Shintani M, Fukuda M, Ogihara T: Meta-analysis of the association of Insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy.
    Diabetologia 41:47-53, 1998
15. Shen GQ, Ikegami H, Fujisawa T, Hamada Y, Kamide K, Rakugi H, Higaki J, Murakami H, Shimamoto K, Ogihara T: Asp905Tyr polymorphism of protein phosphatase 1 G-subunit gene in hypertension.
    Hypertension 30:236-239, 1997

参考論文③

1. Noso S, Fujisawa T, Kawabata Y, Asano K, Hiromine Y, Fukai A, Ogihara T, Ikegami H: Association of small ubiquitin-like modifier 4 (SUMO4) valiant, located in IDDM5 locus, with type 2 diabetes in the Japanese population.
   J Clin Endocrinol Metab 92:2358-62, 2007
2. Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Ohno T, Shibata M, Ogihara T: Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11.
   Biochem Biophys Res Commun 328:158-164, 2005
3. Ikegami H, Fujisawa T, Ogihara T: Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes?
   ILAR Journal 45:267-276, 2004

参考論文④

1. Babaya N, Noso S, Hiromine Y, Taketomo Y, Niwano F, Yoshida S, Yasutake S, Kawabata Y, Ikegami H:
   Flash glucose monitoring in type 1 diabetes: A comparison with Self-monitoring blood glucose.
   J Diabetes Investig. [in press]
2. Noso S, Kataoka K, Kawabata Y, Babaya N, Hiromine Y, Yamaji K, Fujisawa T, Aramata S, Kudo T, Takahashi S, Ikegami H: Insulin transactivator MafA regulates intra-thymic expression of insulin and affects susceptibility to type 1 diabetes.
   Diabetes 59:2579-87, 2010
3. Hotta M, Tashiro F, Ikegami H, Niwa H, Ogihara T, Yodoi J, Miyazaki J-I: Pancreatic beta-cell-specific expression of thioredoxin, an antioxidative and anti-apoptotic protein, prevents autoimmune and streptozotocin-induced diabetes.
   J Exp Med 188:1445-1451, 1998
4. Fukuda M, Ikegami H, Kawaguchi Y, Sano T, Ogihara T: Antioxidant, probucol, can inhibit the generation of hydrogen peroxide in islet cells induced by macrophages and prevent islet cell destruction in NOD mice.
   Biochem Biophys Res Comm 209:953-958, 1995

参考論文⑤

1. Yoshida Y, Kashiwabara K, Matsuyama Y, Hirakawa Y, Tanaka T, Nangaku M, Noso S, Ikegami H, Ohsugi M, Ueki K, Mita T, Watada H, Koya D, Wada J, Shimizu M, Wada T, Ito Y, Narita I, Kashihara N:
   The Conditions, Pathogenesis and Progression of Diabetic Kidney Disease and Early Decliner in Japan.
   BMJ Open Diabetes Res Care. 1: e000902, 2020
2. Sugimoto K, Tabara Y, Ikegami H, Takata Y, Kamide K, Ikezoe T, Kiyoshige E, Makutani Y, Onuma H, Gondo Y, Ikebe K, Ichihashi N, Tsuboyama T, Matsuda F, Kohara K, Kabayama M, Fukuda M, Katsuya T, Osawa H, Hiromine Y, Rakugi H:
   Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: The Multicenter Study for Clarifying Evidence for Sarcopenia in Patients with Diabetes Mellitus.
   J Diabetes Investig. 10: 1471-1479, 2019
3. Kanto K, Ito H, Noso S, Babaya N, Hiromine Y, Taketomo Y, Toma J, Niwano F, Yasutake S, Kawabata y, Ikegami H:
   Effects of dosage and dosing frequency on the efficasy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus.
   J Diabetes Investig. 9: 587-593, 2018
4. Ito H, Ohno Y, Yamauchi T, Kawabata Y, Ikegami H: Efficacy and safety of metformin for treatment of type 2 diabetes in elderly Japanese patients.Geriatr Gerontol Int 11:55-62, 2011
5. Kobayashi M, Ikegami H, Fujisawa T, Nojima K, Kawabata Y, Noso S, Babaya N, Itoi-Babaya M, Yamaji K, Hiromine Y, Shibata M, Ogihara T: Prevention and treatment of obesity, insulin resistance and diabetes by bile acid binding resin. Diabetes 56:239-247, 2007
6. Inoue K, Ikegami H, Fujisawa T, Shintani M, Kawabata Y, Nojima K, Ono M, Nisino M, Babaya M, Babaya N, Ogihara T: High degree of mitochondrial 3243 mutation in gastric biopsy specimen in a patient with MELAS and diabetes complicated by marked gastrointestinal abnormalities. Diabetes Care 26:2219, 2003
7. Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, Yamada K, Shibata M, Yamato E, Ogihara T: Age-dependent changese in phenotypes and candidate gene analysis in a polygenic animal model of type II diabetes; NSY mouse.
   Diabetologia 43:932-938, 2000
8. Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, Yamada K, Shibata M, Yamato E, Ogihara T: Age-dependent changese in phenotypes and candidate gene analysis in a polygenic animal model of type II diabetes; NSY mouse.
   Diabetologia 43:932-938, 2000
9. Yoneda H, Ikegami H, Yamamoto Y, Yamato E, Cha T, Kawaguchi Y, Tahara Y, Ogihara T: Analysis of early phase insulin responses in non-obese subjects with mild glucose intolerance.
   Diabetes Care 15:1517-1521, 1992

参考論文⑥

1. Niwano F, Hiromine Y, Noso S, Babaya N, Ito H, Yasutake S, Matsumoto I, Takeyama Y, Kawabata Y, Ikegami H:
   Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes.
   J Diabetes Investig.9: 1084-1090,2018