2004 Fiscal Year Final Research Report Summary
Identification of type 2 diabetes susceptibility genes in the Japanese population by genome mapping and candidate gene approach and functional analysis
| Project/Area Number |
14013008
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | University of Tokyo |
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Principal Investigator |
KADOWAKI Takashi University of Tokyo Hospital, Department of Metabolic Diseases, Professor, 医学部附属病院糖尿病・代謝内科, 教授 (30185889)
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| Co-Investigator(Kenkyū-buntansha) |
HARA Kazuo University of Tokyo Hospital, Department of Metabolic Diseases, Assistant, 医学部附属病院糖尿病・代謝内科, 助手 (50359600)
YAMAUCHI Toshimasa University of Tokyo Hospital, Department of Metabolic Diseases, Special Associate Professor, 医学部附属病院糖尿病・代謝内科, 客員助教授 (40372370)
KUBOTA Naoto University of Tokyo Hospital, Department of Metabolic Diseases, Special Assistant, 医学部附属病院糖尿病・代謝内科, 客員助手 (50396719)
TOBE Kazuyuki University of Tokyo Hospital, Department of Metabolic Diseases, Special Assistant, 医学部附属病院糖尿病・代謝内科, 講師 (30251242)
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| Project Period (FY) |
2000 – 2004
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| Keywords | SNP / Haplotype / diabetes / affected sib pair / adiponectin |
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| Research Abstract |
We have mapped type 2 diabetes susceptibility genes to the 9 chromosomal regions 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 9p, llp13-p12, 15q13-q21, and 20q12-q13) in the Japanese population. In 3q26-q28, the gene encoding adiponectin which is adipocyte-derived insulin sensitizing hormone, is located. We found that SNP276 in the adiponectin gene was associated with plasma level of adiponectin, insulin resistance, and risk of type 2 diabetes, suggesting that the adiponectin gene is a type 2 diabetes susceptibility gene. In1q36-32, the AMPKa2 subunit gene is located ant we found that polymorphism in the AMPKa2 subunit gene is associated with insulin resistance and type 2 diabetes. In 20q12-q13 we found we found verystrong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene, although none of the individual polymorphisms examined showed any significant association with type 2 diabetes. In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as yet unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene directly influencing the susceptibility to type 2 diabetes. We are performing association studies using dense map of SNP in the remaining 6 chromosomal regions we have mapped to identify type 2 diabetes susceptibility genes in the Japanese population.
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[Journal Article] Absence of an association between the polymorphisms in the genes encoding adiponectin receptors and type 2 diabetes.2005
Author(s)
Hara K, Horikoshi M, Kitazato H, Yamauchi T, Ito C, Noda M, Ohashi J, Froguel P, Tokunaga K, Nagai R, Kadowaki T.
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Journal Title
Diabetologia 48
Pages: 1307-14
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeastthrough a homolog of mammalian adiponectin receptor.2005
Author(s)
Narasimhan ML, Coca MA, Jin J, Yamauchi T, Ito Y, Kadowaki T, Kim KK, Pardo JM, Damsz B, Hasegawa PM, Yun DJ, Bressan RA.
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Journal Title
Molecular Cell 17
Pages: 171-80
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis.2005
Author(s)
Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y, Takashima Y, Nakamura K, Nakamura T, Yamauchi T, Kubota N, Kadowaki T, Matsuki Y, Ogawa W, Hiramatsu R, Kasuga M.
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Journal Title
J. Biol. Chem. 280
Pages: 12867-12875
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Expression of DGAT2 in white adipose tissue is regulated by central leptin action.2005
Author(s)
Suzuki R, Tobe K, Aoyama M, Sakamoto K, Ohsugi M, Kamei N, Nemoto S, Inoue A, Ito Y, Uchida S, Hara K, Yamauchi T, Kubota N, Terauchi Y, Kadowaki T.
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Journal Title
J. Biol. Chem. 280
Pages: 3331-7
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Kruppel-like transcription factor KLF5 is a key_regulator of adipocyte differentiation.2005
Author(s)
Oishi Y, Manabe I, Tobe K, Tsushima K, Shindo T, Fujiu K, MD; Nishimura, Maemura K, Yamauchi T, Kubota N, Suzuki R, Kitamura T, Akira S, Kadowaki T, Nagai R.
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Journal Title
Cell Metabolism 1
Pages: 27-39
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Angiopoietin-related growth factor antagonizes obesity and insulin resistance.2005
Author(s)
Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y, Urano T, Kimura Y, Kubota Y, Maekawa H, Miyamoto T, Miyata K, Matsumoto SI, Sakai J, Nakagata N, Takeya M, Koseki H, Ogawa Y, Kadowaki T, Suda T.
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Journal Title
Nature Medicine 11
Pages: 400-8
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Insulin/Foxol pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity.2004
Author(s)
Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S, Kamon J, Kobayashi M, Suzuki R, Ham K, Kubota N, Terauchi Y, Froguel P, Nakae J, Kasuga M, Accili D, Tobe K, Ueki K, Nagai R, Kadowaki T.
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Journal Title
J. Biol. Chem. 279
Pages: 30817-30822
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel IKK beta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance.2004
Author(s)
Kamon J, Yamauchi T, Muto S, Takekawa S, Ito Y, Hada Y, Ogawa W, Itai A, Kasuga M, Tobe K, Kadowaki T.
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Journal Title
Biochem. Biophys. Res. Commun. 323
Pages: 242-8
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Insulin receptor substrate-2 plays a crucial role in p cells and the hypothalamus.2004
Author(s)
Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K, Takamoto I, Satoh H, Maki T, Kubota T, Moroi M, Okada-Iwabu M, Ezaki O, Naigi R, Ueta Y, Kadowaki T, Noda T.
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Journal Title
J. Clin. Invest 114
Pages: 917-927
Description
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[Journal Article] Pioglitazone reduces islet triglyceride content and restores impaired glucose-stimulated insulin secretion in heterozygous PPARγ-deficient mice on a high-fat diet.2004
Author(s)
Matsui J, Terauchi Y, Kubota N, Takamoto I, Eto K, Yamashita T, Komeda K, Yamauchi T, Kamon J, Kita S, Noda M, Kadowaki T.
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Journal Title
Diabetes 53
Pages: 2844-2854
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in IRS2-/- mice.2004
Author(s)
Suzuki R, Tobe K, Aoyama M, Yamauchi T, Kamon J, Kubota N, Terauchi Y, Yoshimitsu H, Matsuhisa M, Nagasaka S, Ogata H, Tokuyama K, Nagai R, Kadowaki T.
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Journal Title
J. Biol. Chem. 279
Pages: 25039-25049
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] SH2-containing inositol phosphatase 2 predominantly regulates akt2, and not akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes.2004
Author(s)
Sasaoka T, Wada T, Fukui K, Murakami S, Ishihara H, Suzuki R, Tobe K, Kadowaki T, Kobayashi M.
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Journal Title
J. Biol. Chem. 279
Pages: 14835-14843
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Impairment of bone healing by insulin receptor substrate-1 deficiency.2004
Author(s)
Shimoaka T, Kamekura S, Chikuda H, Hoshi K, Chung U, Akune T, Maruyama Z, Komori T, Matsumoto M, Ogawa W, Terauchi Y, Kadowaki T, Nakamura K, Kawaguchi H.
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Journal Title
J. Biol. Chem. 279
Pages: 15314-15322
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Globular adiponectin protected ob/ob mice from diabetes and apoE deficient mice from atherosclerosis.2003
Author(s)
Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Matsui J, Eto K, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T.
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Journal Title
J. Riot Chem. 278
Pages: 2461-2468
Description
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[Journal Article] Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin.2003
Author(s)
Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T.
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Journal Title
J. Biol. Chem. 278
Pages: 40352-40363
Description
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[Journal Article] Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.2003
Author(s)
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Ham K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T.
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Journal Title
Nature 423
Pages: 762-769
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Froguel P. Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p.2002
Author(s)
Mori Y, Otabe S, Dina C, Yasuda K, Populaire C, Lecoeur C, Vatin V, Durand E, Ham K, Okada T, Tobe K, Boutin P, Kadowaki T
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Journal Title
Diabetes 51
Pages: 1247-1255
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.2002
Author(s)
Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Tomita M, Kimura S, Ito C, Froguel P, Kadowaki T.
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Journal Title
Diabetes 51
Pages: 536-540
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Disruption of adiponectin causes insulin resistance and neointimal formation.2002
Author(s)
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T.
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Journal Title
J. Biol. Chem 277
Pages: 25863-25866
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.2002
Author(s)
Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T.
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Journal Title
Nature Medicine 8
Pages: 1288-1295
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.2002
Author(s)
Yamauchi T, Oike Y, Kamon J, Waki H, Komeda K, Tsuchida A, Date Y, Li MX, Miki H, Akanuma Y, Nagai R, Kimura S, Saheki T, Nakazato M, Naitoh T, Yamamura K, Kadowaki T.
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Journal Title
Nature Genetics 30
Pages: 221-226
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.2002
Author(s)
Vasseur F, Helbecque N, Dina C, Lobbens S, Delannoy V, Gaget S, Boutin P, Vaxillaire M, Lepretre F, Dupont S, Hara K, Clement K, Bihain B, Kadowaki T, Froguel P.
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Journal Title
Hum Mol Genet 11
Pages: 2607-2614
Description
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[Journal Article] Maturity-onset diabetes of the young resulting from a novel mutation in the HNF-4alpha gene.2002
Author(s)
Hara K, Noda M, Waki H, Tobe K, Yamauchi T, Kadowaki H, Satou H, Tsukamoto K, Nagamatsu S, Yamagata K, Matsuzawa Y, Akanuma Y, Kimura S, Kadowaki T.
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Journal Title
Intern Med 41
Pages: 848-852
Description
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[Journal Article] The role of PPAR gamma in high-fat diet-induced obesity and insulin resistance.2002
Author(s)
Kadowaki T, Hara K, Kubota N, Tobe K, Terauchi Y, Yamauchi T, Eto K, Kadowaki H, Noda M, Hagura R, Akanuma Y.
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Journal Title
J Diabetes Complications 16
Pages: 41-45
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Pro12→Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population : possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.2002
Author(s)
Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, Inoue I, Seino Y, Yasuda K, Hanafusa T, Yamagata K, Awata T, Kadowaki T, Hara K, Yamada N, Gotoda T, Iwasaki N, Iwamoto Y, Sanke T, Nanjo K, Oka Y, Matsutani A, Maeda E, Kasuga M.
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Journal Title
Diabetes 50
Pages: 891-894
Description
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[Journal Article] The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.2001
Author(s)
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, AkanumaY, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T.
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Journal Title
Nature Medicine 7
Pages: 941-946
Description
「研究成果報告書概要(欧文)」より
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