2001 Fiscal Year Annual Research Report

糖尿病の遺伝素因の総合的解析

Research Project

Project/Area Number	10NP0201
Research Institution	Chiba University
Principal Investigator	清野進千葉大学, 大学院・医学研究院, 教授 (80236067)
Co-Investigator(Kenkyū-buntansha)	清野裕京都大学, 大学院・医学研究科, 教授 (40030986) 門脇孝東京大学, 大学院・医学系研究科, 助教授 (30185889) 岡芳知東北大学, 大学院・医学系研究科, 教授 (70175256) 南條輝志男和歌山県立医科大学, 医学部, 教授 (40164511) 武田純群馬大学, 生体調節研究所, 教授 (40270855)
Keywords	多因子疾患 / 糖尿病 / 原因遺伝子解析 / インスリン / 遺伝子機能 / 遺伝子構造 / 相関解析
Research Abstract	(総括班) 全班員の共同研究として膵β細胞の主要な転写因子のうち、HNF-1α、HNF-1β、HNF-4α、Isl-1、PDXの5つの遺伝子における17個のSNPsについて、1758名の2型糖尿病患者と1260名の非糖尿病対照者のタイピングを終了した。 (研究班1)遺伝子構造解析ヒト膵島に加え、ヒトインスリノーマ、ヒト小腸、ラット膵ラ氏島、ラット海馬、ラット視床下部、ラット網膜、RIN細胞、マウスMIN6細胞、マウス小腸について各々約2万個のESTを集積した。膵β細胞におけるPKAリン酸化によらないcAMP依存性シグナル伝達を担うcAMP-GEFII, Rim2ヒト遺伝子の構造を決定し、SNPsを集積した。 (研究班2)遺伝子機能解析 K_<ATP>チャネル欠損マウスの解析から、視床下部のK_<ATP>,チャネルは脳のグルコースセンサーであることを明らかにした。アディポネクチンは骨格筋において脂肪酸燃焼に関わる遺伝子の発現を上昇させることによりインスリン抵抗性を改善することを明らかにした。転写因子ICERのトランスジェニックマウスの解析から、CREB/ATFファミリーが糖尿病発症に関わることを示した。 (研究班3)疾患遺伝子解析 GIP受容体欠損マウスとob/obマウスとのダブル欠損マウスではレプチン以外の系を介する肥満抑制効果が認められることを示した。ウオルフラム症候群の原因遺伝子WFS1の発現がERストレスにより変化することを見出した。肝臓におけるPI3-キナーゼがインスリン作用の伝達に重要な働きをしていることを明らかにした。 (研究班4)遺伝疫学解析 Pax4遺伝子およびSyntacxin 1A遺伝子が日本人2型糖尿病の危険因子であることを示した。これらの研究成果は朝日、毎日、読売、日本経済、科学新聞等に掲載された。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Ban, N.: "Hepatocyle nuclear factor-1a recruits the transcriptional Co-activator p300 on the GLUT2 gene promoter"Diabetes.. (in press).
[Publications] Nishizawa, H.: "Small heterodimer partner, an orphan nuclear receptor, augments PPARg transactivation"J.Biol.Chem.. 277. 1586-1592 (2002)
[Publications] Yoshiuchi, I.: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY."Diabetolosia. 45. 154-155 (2002)
[Publications] Suzuki, Y.: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271"Diabetes Care. 25. 407-408 (2002)
[Publications] Fujimoto, S.: "Prior exposure to high glucose augments depolarization-induced insulin release by mitigating the decline of ATP level in rat islets"Endocrinology. 143. 213-221 (2002)
[Publications] Yamauchi, T.: "Increased insulin sensitivity despite lipodystrophy in heterozygous CBP deficient mice"Nature Genetics. 30. 221-226 (2002)
[Publications] Miki, T.: "Roles of the K_<ATP> channels in cell survival and differentiation of endocrine pancreas"Diabeles.. 50. S48-S51 (2001)
[Publications] Beguin, P.: "Regulation of Ca^<2+> channel expression at the face by the small G-protein kir/Gem."Nature. 411. 701-706 (2001)
[Publications] Yamada, K.: "Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure"Science. 292. 1543-1546 (2001)
[Publications] Kashima, Y.: "Critical role of cAMP-GFEII・Rim2 complex in in cretin -potentiated insulin secretion"J.Biol.Chem.. 276. 46046-46053 (2001)
[Publications] Yamauchi, T.: "Inhibition of RXR and PPARg ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108. 1001-1013 (2001)
[Publications] Yamada, T.: "3-phosphoinositide-dependent protein kinase 1, an Akt1 kinase, is involved in dephosphorylation of Thr308 of Akt1 in Chinese hamster ovary cells"J.Biol.Chem.. 276. 5339-5345 (2001)
[Publications] Shimajiri, Y.: "A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese"Diabetes. 50. 2864-2869 (2001)
[Publications] Tsunoda, K.: "Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic Patients"Diabetologia. 44. 2092-2097 (2001)
[Publications] Yamauchi, T.: "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7. 941-946 (2001)
[Publications] Yamauchi, T.: "Inhibition of RXR and PPARg ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108. 1001-1013 (2001)
[Publications] Emoto, M.: "Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes"Diabetes. 50. 1166-1170 (2001)
[Publications] Mori, H.: "A polymorphism in the 5' untranslated region and a Met^<229>→Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type 2 diabetes melltitus"Diabetologia. 44. 373-376 (2001)
[Publications] Matsumoto, M.: "Inhibition of insulin-induced Activtion of Akt by a kinase-deficient mutant of the e isozyme of protein kinas C."J.Biol.Chem.. 276. 14400-14406 (2001)
[Publications] Nakae, J.: "Insulin regulation of gene expression through the forkhead transcription factor foxo1 (fkhr) requires kinases distinct from Akt."Biochemistry. 40. 11768-11776 (2001)

2001 Fiscal Year Annual Research Report

糖尿病の遺伝素因の総合的解析

Principal Investigator

清野 進 千葉大学, 大学院・医学研究院, 教授 (80236067)

Research Products

[Publications] Ban, N.: "Hepatocyle nuclear factor-1a recruits the transcriptional Co-activator p300 on the GLUT2 gene promoter"Diabetes.. (in press).

[Publications] Nishizawa, H.: "Small heterodimer partner, an orphan nuclear receptor, augments PPARg transactivation"J.Biol.Chem.. 277. 1586-1592 (2002)

[Publications] Yoshiuchi, I.: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY."Diabetolosia. 45. 154-155 (2002)

[Publications] Suzuki, Y.: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271"Diabetes Care. 25. 407-408 (2002)

[Publications] Fujimoto, S.: "Prior exposure to high glucose augments depolarization-induced insulin release by mitigating the decline of ATP level in rat islets"Endocrinology. 143. 213-221 (2002)

[Publications] Yamauchi, T.: "Increased insulin sensitivity despite lipodystrophy in heterozygous CBP deficient mice"Nature Genetics. 30. 221-226 (2002)

[Publications] Miki, T.: "Roles of the K_<ATP> channels in cell survival and differentiation of endocrine pancreas"Diabeles.. 50. S48-S51 (2001)

[Publications] Beguin, P.: "Regulation of Ca^<2+> channel expression at the face by the small G-protein kir/Gem."Nature. 411. 701-706 (2001)

[Publications] Yamada, K.: "Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure"Science. 292. 1543-1546 (2001)

[Publications] Kashima, Y.: "Critical role of cAMP-GFEII・Rim2 complex in in cretin -potentiated insulin secretion"J.Biol.Chem.. 276. 46046-46053 (2001)

[Publications] Yamauchi, T.: "Inhibition of RXR and PPARg ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108. 1001-1013 (2001)

[Publications] Yamada, T.: "3-phosphoinositide-dependent protein kinase 1, an Akt1 kinase, is involved in dephosphorylation of Thr308 of Akt1 in Chinese hamster ovary cells"J.Biol.Chem.. 276. 5339-5345 (2001)

[Publications] Shimajiri, Y.: "A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese"Diabetes. 50. 2864-2869 (2001)

[Publications] Tsunoda, K.: "Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic Patients"Diabetologia. 44. 2092-2097 (2001)

[Publications] Yamauchi, T.: "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"Nature Medicine. 7. 941-946 (2001)

[Publications] Yamauchi, T.: "Inhibition of RXR and PPARg ameliorates diet-induced obesity and type 2 diabetes"J.Clin.Invest.. 108. 1001-1013 (2001)

[Publications] Emoto, M.: "Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes"Diabetes. 50. 1166-1170 (2001)

[Publications] Mori, H.: "A polymorphism in the 5' untranslated region and a Met^<229>→Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type 2 diabetes melltitus"Diabetologia. 44. 373-376 (2001)

[Publications] Matsumoto, M.: "Inhibition of insulin-induced Activtion of Akt by a kinase-deficient mutant of the e isozyme of protein kinas C."J.Biol.Chem.. 276. 14400-14406 (2001)

[Publications] Nakae, J.: "Insulin regulation of gene expression through the forkhead transcription factor foxo1 (fkhr) requires kinases distinct from Akt."Biochemistry. 40. 11768-11776 (2001)

清野進千葉大学, 大学院・医学研究院, 教授 (80236067)