1997 年度実績報告書

膵β細胞の分子マップ作成に関する国際共同研究

研究課題

研究課題/領域番号	08044248
研究機関	千葉大学
研究代表者	清野進千葉大学, 医学部, 教授 (80236067)
研究分担者	THORENS Bern ローザンヌ大学, 薬理学研究所, 助教授 STOFFEL Mark ロックフェラー大学, 代謝疾患研究部門, 助教授 BELL Graeme シカゴ大学, ハワードヒューズ研究所, 教授五ノ井透千葉大学, 真菌医学研究センター, 助手 (30134365) 稲垣暢也秋田大学, 医学部, 教授 (30241954)
キーワード	糖尿病 / インスリン / 遺伝子 / スルホニール尿素受容体 / 開口放出 / ATP感受性K^+-チャネル / 家族性低血糖症
研究概要	平成8〜9年度には以下に示すような膵β細胞に発現する分子の単離と機能解析を行った。 1) ATP感受性K^+チャネル(K_<ATP>)の構造・機能解析膵β細胞のK_<ATP>チャネルはインスリン分泌の調節に重要であると考えられている。我々は内向き整流性K^+チャネルメンバーであるKir6.2を単離し、膵β細胞のK_<ATP>チャネルがスルホニール尿素受容体(SUR1)とKir6.2から構成されていることを明らかにした。さらに、心筋、骨格筋、脳に発現しているスルホニール尿素受容体のイソフォーム(SUR2)を単離し、心筋骨格筋のK_<ATP>チャネルがSUR2とKir6.2により構成されることを示した。また、膵β細胞のK_<ATP>チャネルの生体内での機能を明らかにする目的でKir6.2のdominant-negative変異体を膵β細胞に特異的に発現する遺伝子導入マウス(Tgマウス)を作製した。Tgマウスは新生仔期にヒトの新生児家族性低血糖症と類似した低血糖を示し、6週令以降では糖尿病を発症した。これらの結果から、膵β細胞のK_<ATP>チャネルがグルコースによるインスリン分泌の調節に重要な役割を果たしていることが示された。さらにSUR1あるいはKir6.2の遺伝子異常は家族性低血糖症の原因となることを証明した。 2) Noc-2の単離と機能解析膵β細胞からのインスリン開口放出に関与する分子は糖尿病発症の候補遺伝子である。われわれは、膵β細胞および内分泌細胞に発現し、ホルモンの開口放出に関与すると考えられる新たな分子Noc-2を単離した。Noc-2を副腎細胞株であるPC12に成長ホルモンとともに共出現すると、高濃度K^+による成長ホルモン分泌を有意に促進させることから、Noc-2は膵β細胞からのインスリン分泌を制御している可能性が示唆された。

研究成果

(25件)

すべてその他

すべて文献書誌 (25件)

[文献書誌] Mizuno, N. et al.: "Altered Bcl-2 and Bax expression and intracellular Ca^<2+> signaling in apoptosis of pancreatic β-cells and the impairement of glucose-induced insulin secretion." Endocrinology. (in press). (1998)
[文献書誌] Sanchez J. A. et al.: "Modulation of reconstituted ATP-sensitive K^+ channels by GTP-binding proteins." J. Physiol.(in press). (1998)
[文献書誌] Suzuki, M. et al.: "Kir6.2 : a subunit of ATP-sensitive K^+ channels in mitochondria." Biochem. Biophys. Res. Commun.241. 693-637 (1997)
[文献書誌] Kotake, K. et al.: "Noc2 : a putative zinc finger protein involved in excytosis in endocrine cells." J. Biol. Chem.272. 29407-29410 (1997)
[文献書誌] Nestorowicz, A. et al.: "A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism." Diabetes. 46. 1743-1748 (1997)
[文献書誌] Mizuta, M. et al.: "Localization and functional role of synaptotagmin III in insulin secretory vesicles in pancreatic β-cells." Diabetes. 46. 2002-2006 (1997)
[文献書誌] Miki, T. et al.: "Abnormalities of pancreatic islets by targeted expression of a dominant-negative K_<ATP> channel." Proc. Natl. Acad. Sci. USA. 94. 11969-11973 (1997)
[文献書誌] Ueda, K. et al.: "MgADP antagonism to Mg-independent ATP binding of the sulfonylurea receptor SUR1." J. Biol. Chem.272. 22983-22986 (1997)
[文献書誌] Inagaki, N. et al.: "Subunit stoichiometry of the pancreatic β-cell ATP-sensitive K^+ channel." FEBS lett.409. 232-236 (1997)
[文献書誌] Suzuki, M. et al.: "Localization of the ATP-sensitive K^+ channel subunit, Kir6.2, in mouse pancreas." Diabetes. 46. 1440-1444 (1997)
[文献書誌] Komatsuzaki, K. et al.: "A novel system that reports the G-proteins linked to a given receptor : a study of type 3 somatostatin receptor." FEBS Lett.406. 165-170 (1997)
[文献書誌] Kuromi, H. et al.: "Suramin inhibits glucose-induced Ca^<2+> response in single rat pancreatic β cell." Jpn. J. Pahrmacol.73. 179-182 (1997)
[文献書誌] Inoue, H. et al.: "Sequence variants in the pancreatic islet β-cell inwardly rectifying K^+ channel Kir6.2 (Bir) gene : identification and lack of role in caucasian patients with NIDDM." Diabetes. 46. 502-507 (1997)
[文献書誌] Dunne, M. J. et al.: "Familial persistent hyperinsulinemic hypoglycaemia of infancy, and mutations in the sulfonylurea receptor." New Engl. J. Med.336. 703-706 (1997)
[文献書誌] Yoshitomi, H. et al.: "Involvement of MAP kinase and c-fos signaling in the inhibition of cell growth by somatostatin." Am. J. Physiol.272. E769-E774 (1997)
[文献書誌] Stoffel, M. et al: "The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism." Proc. Natl. Acad. Sci. USA. 94. 13209-13214 (1997)
[文献書誌] Guillam, M. T. et al.: "Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2." Nature genet.17. 327-330 (1997)
[文献書誌] Tanaka, J. et al.: "Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats." Arch. Histol. Cytol.46. 485-490 (1996)
[文献書誌] Kubota, A. et al.: "Effector coupling of somatostatin receptor subtypes on human endocrine tumors." Metabolism. 45. 42-45 (1996)
[文献書誌] Watabe, Y. et al.: "dentification of histone H2A. X as a growth factor secreted by an androgen-independent subline of mouse mammary carcinoma cell." J. Biol. Chem.271. 25126-25130 (1996)
[文献書誌] Namba, N. et al.: "Kir2.2v : a possible negative regulator of the inwardly rectifying K^+ channel Kir2.2." FEBS lett.386. 211-214 (1996)
[文献書誌] Inagaki, N. et al.: "A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K^+ channls." Neuron. 16. 1011-1017 (1996)
[文献書誌] Wang, C-Z. et al.: "Cloning and pharmacological characterization of a fourth P2X receptor subtype widely expressed in brain and peripheral tissues including various endocrine tissues." Biochem. Biophys. Res. Commun.220. 196-202 (1996)
[文献書誌] Yamagata, K. et al.: "Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)." Nature. 384. 455-457 (1996)
[文献書誌] Yamagata, K. et al.: "Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1)." Nature. 384. 458-460 (1996)

1997 年度 実績報告書

膵β細胞の分子マップ作成に関する国際共同研究

研究代表者

清野 進 千葉大学, 医学部, 教授 (80236067)

研究成果

[文献書誌] Mizuno, N. et al.: "Altered Bcl-2 and Bax expression and intracellular Ca^<2+> signaling in apoptosis of pancreatic β-cells and the impairement of glucose-induced insulin secretion." Endocrinology. (in press). (1998)

[文献書誌] Sanchez J. A. et al.: "Modulation of reconstituted ATP-sensitive K^+ channels by GTP-binding proteins." J. Physiol.(in press). (1998)

[文献書誌] Suzuki, M. et al.: "Kir6.2 : a subunit of ATP-sensitive K^+ channels in mitochondria." Biochem. Biophys. Res. Commun.241. 693-637 (1997)

[文献書誌] Kotake, K. et al.: "Noc2 : a putative zinc finger protein involved in excytosis in endocrine cells." J. Biol. Chem.272. 29407-29410 (1997)

[文献書誌] Nestorowicz, A. et al.: "A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism." Diabetes. 46. 1743-1748 (1997)

[文献書誌] Mizuta, M. et al.: "Localization and functional role of synaptotagmin III in insulin secretory vesicles in pancreatic β-cells." Diabetes. 46. 2002-2006 (1997)

[文献書誌] Miki, T. et al.: "Abnormalities of pancreatic islets by targeted expression of a dominant-negative K_<ATP> channel." Proc. Natl. Acad. Sci. USA. 94. 11969-11973 (1997)

[文献書誌] Ueda, K. et al.: "MgADP antagonism to Mg-independent ATP binding of the sulfonylurea receptor SUR1." J. Biol. Chem.272. 22983-22986 (1997)

[文献書誌] Inagaki, N. et al.: "Subunit stoichiometry of the pancreatic β-cell ATP-sensitive K^+ channel." FEBS lett.409. 232-236 (1997)

[文献書誌] Suzuki, M. et al.: "Localization of the ATP-sensitive K^+ channel subunit, Kir6.2, in mouse pancreas." Diabetes. 46. 1440-1444 (1997)

[文献書誌] Komatsuzaki, K. et al.: "A novel system that reports the G-proteins linked to a given receptor : a study of type 3 somatostatin receptor." FEBS Lett.406. 165-170 (1997)

[文献書誌] Kuromi, H. et al.: "Suramin inhibits glucose-induced Ca^<2+> response in single rat pancreatic β cell." Jpn. J. Pahrmacol.73. 179-182 (1997)

[文献書誌] Inoue, H. et al.: "Sequence variants in the pancreatic islet β-cell inwardly rectifying K^+ channel Kir6.2 (Bir) gene : identification and lack of role in caucasian patients with NIDDM." Diabetes. 46. 502-507 (1997)

[文献書誌] Dunne, M. J. et al.: "Familial persistent hyperinsulinemic hypoglycaemia of infancy, and mutations in the sulfonylurea receptor." New Engl. J. Med.336. 703-706 (1997)

[文献書誌] Yoshitomi, H. et al.: "Involvement of MAP kinase and c-fos signaling in the inhibition of cell growth by somatostatin." Am. J. Physiol.272. E769-E774 (1997)

[文献書誌] Stoffel, M. et al: "The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism." Proc. Natl. Acad. Sci. USA. 94. 13209-13214 (1997)

[文献書誌] Guillam, M. T. et al.: "Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2." Nature genet.17. 327-330 (1997)

[文献書誌] Tanaka, J. et al.: "Cellular distribution of the P2X4 ATP receptor mRNA in the brain and non-neuronal organs of rats." Arch. Histol. Cytol.46. 485-490 (1996)

[文献書誌] Kubota, A. et al.: "Effector coupling of somatostatin receptor subtypes on human endocrine tumors." Metabolism. 45. 42-45 (1996)

[文献書誌] Watabe, Y. et al.: "dentification of histone H2A. X as a growth factor secreted by an androgen-independent subline of mouse mammary carcinoma cell." J. Biol. Chem.271. 25126-25130 (1996)

[文献書誌] Namba, N. et al.: "Kir2.2v : a possible negative regulator of the inwardly rectifying K^+ channel Kir2.2." FEBS lett.386. 211-214 (1996)

[文献書誌] Inagaki, N. et al.: "A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K^+ channls." Neuron. 16. 1011-1017 (1996)

[文献書誌] Wang, C-Z. et al.: "Cloning and pharmacological characterization of a fourth P2X receptor subtype widely expressed in brain and peripheral tissues including various endocrine tissues." Biochem. Biophys. Res. Commun.220. 196-202 (1996)

[文献書誌] Yamagata, K. et al.: "Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3)." Nature. 384. 455-457 (1996)

[文献書誌] Yamagata, K. et al.: "Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1)." Nature. 384. 458-460 (1996)

1997 年度実績報告書

清野進千葉大学, 医学部, 教授 (80236067)