2000 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・医学研究科, 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, 医学系大学院, 助教授 (30185889) 岡芳知山口大学, 医学部, 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) 前年度に引き続きインフォームドコンセントの得られた糖尿病患者、非糖尿病対照者からサンプルを収集し、それぞれ2,000例を越えるDNAサンプルを収集している。さらに全班員の共同研究として、アミリン遺伝子S20G多型を1556名の糖尿病患者と1108名の対照者で解析した結果、この変異は2型糖尿病発症進展のリスクファクターになることを示した。本研究は我が国で初めての多施設共同研究による糖尿病遺伝素因解析研究である。定量的データの検定を中心とする統計手法の系統樹を決定した。 (研究班1)遺伝子構造解析若年発症成人型糖尿病MODYの原因遺伝子であるHNF-4aの結合蛋白(SHP)遺伝子をスクリーニングしたところ、多数の変異を見い出した。家系調査の結果、同変異は糖尿病ではなく肥満との連鎖が示唆された。そこで非糖尿病の肥満児グループを解析した結果、SHP遺伝子は「小太り遺伝子」であること、さらに2型糖尿病発症のリスク因子となることを明らかにした。日本人の連鎖解析に耐えるようなマイクロサテライトパネルを作成した。グルコース応答性のインスリン分泌に関与する遺伝子をDNAマイクロアレイによって検索し、検索した6,500遺伝子のうち、82個の候補遺伝子を同定した。 (研究班2)遺伝子機能解析膵β細胞でcAMPセンサーを同定し、この分子がcAMPに依存するがPKAに依存しないインスリン分泌を担っていることを証明し、全く新しいインスリン分泌機構を発見した。IRS-1欠損マウス、IRS-2欠損マウスの結果からIRS-2の欠損は膵β細胞形成障害により糖尿病を発症することを明らかにした。CREβ/ATFファミリーの転写因子ATF-2のリン酸化がインスリン遺伝子発現を調節することを明らかにした。 (研究班3)疾患遺伝子解析 GIPレセプター欠損マウスは高脂肪食では全く肥満がおこらず、GIP遺伝子か倹約遺伝子であることを示した。Wolfram症候群の原因遺伝子WFS1の遺伝子産物は脳では、海馬CA1領域、アミグダラ、olfactory tubercleなど、辺縁系の神経細胞に強く発現し細胞レベルではendoplasmic reticulum(ER)に存在することを示した。atypical PKC特異的結合タンパクであるASIP/PAR3がPKCλと特異的に作用することによりインスリンによる糖輸送を抑制することを見い出した。 (研究班4)遺伝疫学解析アミリン遺伝子の変異(S20G)が正常アミリンに比しアミロイド形成能が高く,アポトーシスを強く誘導することを証明し,そのことが糖尿病の進展・増悪に関与することを示した。Isl-1遺伝子異常による若年発症成人病型糖尿病(MODY)を発見した。 SHP遺伝子と肥満(武田純)、cAMPセンサーの新たなインスリン分泌のメカニズム(清野進)、倹約遺伝子としてのGIP遺伝子(清野裕)は朝日新聞、毎日新聞、読売新聞の全国版にそれぞれ掲載された。

Research Products
(21 results)

All Other

All Publications (21 results)

[Publications] The study group of comprehensive analysis of genetic factors in diabetes mellitus.: "S20G mutation of the amylin gene is associated with type 2 diabetes in Japanese."Diabetologia. (in press). (2001)
[Publications] Miki,T. et al.: "The ATP-sensitive potassium channels in hypothalamic neurons are essential in the maintenance of glucose homeostasis by controlling glucagon release and food intake."Nature Neurosci.. (in press). (2001)
[Publications] Takeda,K. et al.: "WFS1 (Wolfram syndrome 1) gene product : Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain."Hum Mol Genet. (in press). (2001)
[Publications] Shiraishi. A et al.: "A novel glucokinase regulator in pancreatic beta cells. precursor of propionyl-coA carboxylase beta subunit interacts with glucokinase and augments its activity."J Biol Chem.. 276. 2325-2328 (2001)
[Publications] Yamada,T. et al.: "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] Nishigori,, H. et al.: "Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese."Proc.Natl.Acad.Sci.USA. 98. 575-580 (2001)
[Publications] Tsubamoto,Y. et al: "Hexamminecobalt (III) chloride inhibits glucose-induced insulin secretion at the Exocytotic process."J.Biol.Chem.. 276. 2979-2985 (2001)
[Publications] Wang,CZ. et al.: "The Na+-driven Cl-/HCO3- exchanger. Cloning, tissue distribution, and functional characterization."J.Biol.Chem.. 275. 35486-93540 (2000)
[Publications] Minami,K. et al.: "Insulin secretion and differential gene expression in responsive and -unresponsive MIN6 sublines."Am.J.Physiol.Endocrinol Metab.. 279. E773-781 (2000)
[Publications] Fujimoto,S.et al.: "Augmentation of basal insulin release from rata islets by preexposure to a high concentration of glucose."Am.J.Physiol.Endocrinol Metab.. 279. E927-940 (2000)
[Publications] Ban,N. et al.: "Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression."Diabetes. 49. 1142-1148 (2000)
[Publications] Ozaki,N. et al.: "cAMP-GEFII is a direct target of cAMP in regulated exocytosis."Nature Cell Biol.. 2. 805-811 (2000)
[Publications] Terauchi,Y. et al.: "Insulin effect during embryogenesis determines fetal growth. : a possible molocular link between birth weight and susceptibility to type 2 diabetes."Diabetes. 40. 82-86 (2000)
[Publications] Ueki,K. et al.: "Normalisation of insulin resistance in IRS-1 deficient mice by adenovirus-mediated gene therapy-potential role of protein kinase B in liver for the systemic glucose homeostasis-"J.Clin.Invest.. 105. 1437-1445 (2000)
[Publications] Kubota,N. et al.: "Disruption of insulin receptor substrate-2 causes type 2 diabetes due to liver insulin resistance and lack of compensatory b-cell hyperplasia."Diabetes. 49. 1880-1889 (2000)
[Publications] Fukunaga,K. et al.: "Requirement for Protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH2-terminal kinase."J.Biol.Chem.. 275. 5208-5213 (2000)
[Publications] Kawanishi,M. et al.: "Role of SNAP23 in insulin-induced translocation of GLUT4 in 3T3-L1 adipocytes."J.Biol.Chem.. 275. 8240-8247 (2000)
[Publications] Kotani,K. et al.: "Inhibition of insulin- induced glucose uptake by atypical protein kinase C isotype-specific interacting protein in 3T3-L1 adipocytes."J.Biol.Chem.. 275. 26390-26395 (2000)
[Publications] Shimomura,H. et al.: "Nonsense mutation of Islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history."Diabetes. 49. 1597-1600 (2000)
[Publications] Sakagashira,S. et al.: "S20G mutatnt amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin."Am.J.Pathol.. 157. 22019-22024 (2000)
[Publications] Gonoi,T.and Seino,S: "Pharmacology of Ionic Channel Function : Activators and Inhibitors. Handbook of Experimental Pharmacology"Springer-Verlng,Heidelberg. 662 (2000)

2000 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・医学研究科, 教授 (80236067)

Research Products

[Publications] The study group of comprehensive analysis of genetic factors in diabetes mellitus.: "S20G mutation of the amylin gene is associated with type 2 diabetes in Japanese."Diabetologia. (in press). (2001)

[Publications] Miki,T. et al.: "The ATP-sensitive potassium channels in hypothalamic neurons are essential in the maintenance of glucose homeostasis by controlling glucagon release and food intake."Nature Neurosci.. (in press). (2001)

[Publications] Takeda,K. et al.: "WFS1 (Wolfram syndrome 1) gene product : Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain."Hum Mol Genet. (in press). (2001)

[Publications] Shiraishi. A et al.: "A novel glucokinase regulator in pancreatic beta cells. precursor of propionyl-coA carboxylase beta subunit interacts with glucokinase and augments its activity."J Biol Chem.. 276. 2325-2328 (2001)

[Publications] Yamada,T. et al.: "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] Nishigori,, H. et al.: "Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese."Proc.Natl.Acad.Sci.USA. 98. 575-580 (2001)

[Publications] Tsubamoto,Y. et al: "Hexamminecobalt (III) chloride inhibits glucose-induced insulin secretion at the Exocytotic process."J.Biol.Chem.. 276. 2979-2985 (2001)

[Publications] Wang,CZ. et al.: "The Na+-driven Cl-/HCO3- exchanger. Cloning, tissue distribution, and functional characterization."J.Biol.Chem.. 275. 35486-93540 (2000)

[Publications] Minami,K. et al.: "Insulin secretion and differential gene expression in responsive and -unresponsive MIN6 sublines."Am.J.Physiol.Endocrinol Metab.. 279. E773-781 (2000)

[Publications] Fujimoto,S.et al.: "Augmentation of basal insulin release from rata islets by preexposure to a high concentration of glucose."Am.J.Physiol.Endocrinol Metab.. 279. E927-940 (2000)

[Publications] Ban,N. et al.: "Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression."Diabetes. 49. 1142-1148 (2000)

[Publications] Ozaki,N. et al.: "cAMP-GEFII is a direct target of cAMP in regulated exocytosis."Nature Cell Biol.. 2. 805-811 (2000)

[Publications] Terauchi,Y. et al.: "Insulin effect during embryogenesis determines fetal growth. : a possible molocular link between birth weight and susceptibility to type 2 diabetes."Diabetes. 40. 82-86 (2000)

[Publications] Ueki,K. et al.: "Normalisation of insulin resistance in IRS-1 deficient mice by adenovirus-mediated gene therapy-potential role of protein kinase B in liver for the systemic glucose homeostasis-"J.Clin.Invest.. 105. 1437-1445 (2000)

[Publications] Kubota,N. et al.: "Disruption of insulin receptor substrate-2 causes type 2 diabetes due to liver insulin resistance and lack of compensatory b-cell hyperplasia."Diabetes. 49. 1880-1889 (2000)

[Publications] Fukunaga,K. et al.: "Requirement for Protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH2-terminal kinase."J.Biol.Chem.. 275. 5208-5213 (2000)

[Publications] Kawanishi,M. et al.: "Role of SNAP23 in insulin-induced translocation of GLUT4 in 3T3-L1 adipocytes."J.Biol.Chem.. 275. 8240-8247 (2000)

[Publications] Kotani,K. et al.: "Inhibition of insulin- induced glucose uptake by atypical protein kinase C isotype-specific interacting protein in 3T3-L1 adipocytes."J.Biol.Chem.. 275. 26390-26395 (2000)

[Publications] Shimomura,H. et al.: "Nonsense mutation of Islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history."Diabetes. 49. 1597-1600 (2000)

[Publications] Sakagashira,S. et al.: "S20G mutatnt amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin."Am.J.Pathol.. 157. 22019-22024 (2000)

[Publications] Gonoi,T.and Seino,S: "Pharmacology of Ionic Channel Function : Activators and Inhibitors. Handbook of Experimental Pharmacology"Springer-Verlng,Heidelberg. 662 (2000)

清野進千葉大学, 大学院・医学研究科, 教授 (80236067)