2002 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細胞の転写因子NGN3、PAX6、NKX2.2、NKX6.1、BETA2遺伝子およびK_<ATP>チャネルを構成するSUR1とKir6.2遺伝子における計16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由来の約2万個のESTから開発したマイクロアレイを用いて、膵島、肝、小腸で共通に発現する11種類のMODY候補遺伝子を見出した。マウス膵島由来の約2万個のESTからマイクロアレイを開発した。1型糖尿病モデルKDPラットの解析から、新規の1型糖尿病感受性遺伝子としてCblbを同定した。 (研究班2)遺伝子機能解析 PiccoloがcAMP-GEFIIおよびRim2と複合体を形成し、膵β細胞におけるカルシウムセンサーとして機能することを明らかにした。アディポネクチンはAMPキナーゼを活性化することによって、骨格筋では脂肪酸燃焼と糖の取り込みを、肝臓では糖新生を抑制し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を膵β細胞に発現させるTgマウスではインスリン合成能が著明に低下し、糖尿病が発症することを見出した。 (研究班3)疾患遺伝子解析 GIPシグナルの遮断により高脂肪食負荷や過食による肥満・インスリン抵抗性・耐糖能障害が回避されることを示した。ウオルフラム症候群の原因遺伝子WFS1の欠損マウスは膵β細胞の脱落により糖尿病を発症することを見出した。肝臓においてPI3-キナーゼ活性を阻害すると、高血糖、高インスリン血症、脂質代謝異常を生じることを明らかにした。 (研究班4)遺伝疫学解析 MODY5の原因遺伝子HNF-1βにおける新たな変異を同定した。これらの研究成果は朝日、毎日、読売、日本経済新聞等に掲載された。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Wenyi, Z. et al.: "Role of urotensin II gene in the genetic susceptibility to type 2 diabetes mellitus in Japanese"Diabetologia. (in press).
[Publications] Horikawa, Y. et al.: "Genetic variations in CAPN10 are not a major factor in the occurrence of type 2 diabetes in Japanese"J. Clin. Endocrinol. Metab.. 88. 244-247 (2003)
[Publications] Yamauchi, T. et al.: "Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis"J. Biol. Chem.. 278. 2461-2468 (2003)
[Publications] Fujimoto, K. et al.: "Piccolo, a Ca(2+) sensor in pancreatic beta-cells. Involvement of cAMP-GEFII. Rim2. Piccolo complex in cAMP-dependent exocytosis"J. Biol. Chem.. 277. 50497-50502 (2002)
[Publications] Miki, T. et al.: "ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue"Am. J. Physiol. Endocrinol. Metab.. 283. E1178-E1184 (2002)
[Publications] Yokoi, N. et al.: "Cblb is a major susceptibility gene for rat type 1 diabetes mellitus"Nat. Genet.. 31. 391-394 (2002)
[Publications] Minami, K. et al.: "Normalization of intracellular Ca(2+) induces a glucose-responsive state in glucose-unresponsive beta-cells"J. Biol. Chem.. 277. 25277-25282 (2002)
[Publications] Zhang, Y. et al.: "Identification, tissue expression, and functional characterization of Otx3, a novel member of the Otx family"J. Biol. Chem. 277. 28065-28069 (2002)
[Publications] Miki, T. et al.: "Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1"Nat. Med.. 8. 466-472 (2002)
[Publications] Tonooka, N. et al.: "High frequencies of mutations in the HNF-1 alpha gene in non-obese patients with diabetes of youth in Japanese and identification of case of digenic inheritance"Diabetologia. 45. 1709-1712 (2002)
[Publications] Yamauchi, T. et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat. Med.. 8. 1288-1295 (2002)
[Publications] Kubota, N. et al.: "Disruption. of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 277. 25863-25866 (2002)
[Publications] Hara, K. et al.: "Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)
[Publications] Kajikawa, M. et al.: "Ouabain suppresses glucose-induced mitochondrial ATP production and insulin release by generating reactive oxygen species in pancreatic islets"Diabetes. 51. 2522-2529 (2002)
[Publications] Miyawaki, K. et al.: "Inhibition of gastric inhibitory polypeptide signaling prevents obesity"Nat. Med.. 8. 738-742 (2002)
[Publications] Iwamoto, K. et al.: "Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene"Diabetologia. 45. 1182-1195 (2002)
[Publications] Matsumoto, M. et al.: "Role of the IRS-1 and PI 3-kinase signaling pathway in insulin-induced expression of SREBP-1c and glucokinase genes in rat hepatocytes"Diabetes. 51. 1672-1680 (2002)
[Publications] Miyake, K. et al.: "Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver"J. Clin. Invest.. 110. 1483-1491 (2002)
[Publications] Tanizawa, Y. et al.: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion : Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH"Diabetes. 51. 712-717 (2002)
[Publications] Furuta, H. et al.: "Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese"J. Clin. Endocrinol. Metab.. 87. 3859-3863 (2002)

2002 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] Wenyi, Z. et al.: "Role of urotensin II gene in the genetic susceptibility to type 2 diabetes mellitus in Japanese"Diabetologia. (in press).

[Publications] Horikawa, Y. et al.: "Genetic variations in CAPN10 are not a major factor in the occurrence of type 2 diabetes in Japanese"J. Clin. Endocrinol. Metab.. 88. 244-247 (2003)

[Publications] Yamauchi, T. et al.: "Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis"J. Biol. Chem.. 278. 2461-2468 (2003)

[Publications] Fujimoto, K. et al.: "Piccolo, a Ca(2+) sensor in pancreatic beta-cells. Involvement of cAMP-GEFII. Rim2. Piccolo complex in cAMP-dependent exocytosis"J. Biol. Chem.. 277. 50497-50502 (2002)

[Publications] Miki, T. et al.: "ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue"Am. J. Physiol. Endocrinol. Metab.. 283. E1178-E1184 (2002)

[Publications] Yokoi, N. et al.: "Cblb is a major susceptibility gene for rat type 1 diabetes mellitus"Nat. Genet.. 31. 391-394 (2002)

[Publications] Minami, K. et al.: "Normalization of intracellular Ca(2+) induces a glucose-responsive state in glucose-unresponsive beta-cells"J. Biol. Chem.. 277. 25277-25282 (2002)

[Publications] Zhang, Y. et al.: "Identification, tissue expression, and functional characterization of Otx3, a novel member of the Otx family"J. Biol. Chem. 277. 28065-28069 (2002)

[Publications] Miki, T. et al.: "Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1"Nat. Med.. 8. 466-472 (2002)

[Publications] Tonooka, N. et al.: "High frequencies of mutations in the HNF-1 alpha gene in non-obese patients with diabetes of youth in Japanese and identification of case of digenic inheritance"Diabetologia. 45. 1709-1712 (2002)

[Publications] Yamauchi, T. et al.: "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase"Nat. Med.. 8. 1288-1295 (2002)

[Publications] Kubota, N. et al.: "Disruption. of adiponectin causes insulin resistance and neointimal formation"J. Biol. Chem.. 277. 25863-25866 (2002)

[Publications] Hara, K. et al.: "Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population"Diabetes. 51. 536-540 (2002)

[Publications] Kajikawa, M. et al.: "Ouabain suppresses glucose-induced mitochondrial ATP production and insulin release by generating reactive oxygen species in pancreatic islets"Diabetes. 51. 2522-2529 (2002)

[Publications] Miyawaki, K. et al.: "Inhibition of gastric inhibitory polypeptide signaling prevents obesity"Nat. Med.. 8. 738-742 (2002)

[Publications] Iwamoto, K. et al.: "Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene"Diabetologia. 45. 1182-1195 (2002)

[Publications] Matsumoto, M. et al.: "Role of the IRS-1 and PI 3-kinase signaling pathway in insulin-induced expression of SREBP-1c and glucokinase genes in rat hepatocytes"Diabetes. 51. 1672-1680 (2002)

[Publications] Miyake, K. et al.: "Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver"J. Clin. Invest.. 110. 1483-1491 (2002)

[Publications] Furuta, H. et al.: "Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese"J. Clin. Endocrinol. Metab.. 87. 3859-3863 (2002)

清野進千葉大学, 大学院・医学研究院, 教授 (80236067)