Studies on human ialet amyloid polypeptide gene expression and non-insulin-dependent diabetes

人淀粉样多肽基因表达与非胰岛素依赖型糖尿病的研究

• 批准号: 05670838
• 负责人: KANATSUKA Azuma
• 金额: $ 1.41万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670838/
• 关键词: islet amyloid polypeptide; amylin; non-insulin-dependent diabetes mellitus; islet amyloid; insulin secretion; transformed pancreatic Beta-cells; transgenic mouse; transfection; 糖尿病; ヒト膵島アミロイド蛋白遺伝子

Islet amyloid the most significant pathological finding in human non-insulin-dependent diabetes mellitus (NIDDM) and islet amyloid polypeptide (IAPP) /amylin is a major component of the amyloid. We proposed to resolve the relationship between IAPP gene expression and onset or progression of NIDDM.1. We had developed transgenic mouse expressing human IAPP.In the transgenic mice, amyloid-like fibrils were formed in secretory granules of pancreatic Beta-cells, suggesting that IAPP-derived amyloid fibrils are formed in secretory granules, released and aggregated into amyloid deposits in human NIDDM.Glucose tolerance was normal in the transgenic mice. After long-term feeding with sucrose or high fat diet, glucose tolerance remained to be normal, suggesting that onset of diabets mellitus is not induced only by human IAPP expression.2. We tried to introduce human IAPP cDNA in transfomed mouse pancreatic Beta-cells by transfection method and succeeded in the development of pancreatic Beta-cell line expressing human IAPP.Although insulin synthesis was not influenced by human IAPP expression, glucose-induced insulin secretion was markedly depressed. From these results, we conclude that overexpression of IAPP might impaire insulin secretion in NIDDM.The present studies are useful to understand a relationship among IAPP gene expression, islet amyloid deposition and onset or progression of NIDDM.

胰岛淀粉样蛋白是人类非胰岛素依赖型糖尿病（NIDDM）最重要的病理改变，而胰岛淀粉样多肽（IAPP）/胰淀素是淀粉样蛋白的主要成分。本研究拟探讨IAPP基因表达与NIDDM发病或进展的关系。我们建立了表达人IAPP的转基因小鼠，在转基因小鼠中，胰岛β细胞分泌颗粒中有淀粉样纤维形成，提示人NIDDM时IAPP源性淀粉样纤维在分泌颗粒中形成、释放并聚集成淀粉样沉积物，转基因小鼠葡萄糖耐量正常。长期喂食蔗糖或高脂饲料后，葡萄糖耐量仍保持正常，提示糖尿病的发病并非仅由人IAPP表达诱导.我们尝试将人IAPP cDNA转染小鼠胰岛β细胞，成功地建立了表达人IAPP的胰岛β细胞系，虽然人IAPP的表达不影响胰岛素的合成，但明显抑制葡萄糖诱导的胰岛素分泌。这些结果提示，IAPP的过度表达可能影响NIDDM患者的胰岛素分泌，本研究有助于了解IAPP基因表达、胰岛淀粉样蛋白沉积与NIDDM发病或进展之间的关系。

项目成果

金塚東: "膵島アミロイドタンパク/アミリンとインスリン非依存型糖尿病発生工学を用いた病態動物モデル BIOmedica" 北隆館, 5 (1993)

东金冢：“BIOmedica，使用胰岛淀粉样蛋白/胰淀素和胰岛素非依赖性糖尿病开发工程的病理动物模型”Hokuryukan，5（1993）

Kazuo Yagui, Takahide Yamaguchi, Azuma Kanatsuka, Fumio Shimada, Choug I Huang, Yoshiharu Tokuyama, Haruhiko Ohsawa, Ken-ichi Yamamura, Jun-ichi Miyazaki, Atsuo Mikata, Sho Yoshida, Hideichi Makino: "Formation of islet amyloid fibrils in beta-secretory gr

Kazuo Yagui、Takahide Yamaguchi、Azuma Kanatsuka、Fumio Shimada、Choug I Huang、Yoshiharu Tokuyama、Haruhiko Ohsawa、Ken-ichi Yamamura、Jun-ichi Miyazaki、Atsuo Mikata、Sho Yoshida、Hideichi Makino：“β-淀粉样蛋白纤维的形成

Kazuo Yagui: "Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin." European Journal of Endocrinology. 12(in press). (1995)

Kazuo Yagui：“表达人胰岛淀粉样多肽/胰岛淀粉样多肽的转基因小鼠的β分泌颗粒中胰岛淀粉样原纤维的形成。”

Azuma Kanatsuka, Hideichi Makino, Kazuo Yagui, Chau I Huang, Masato Taira, Atsuo Mikata, Sho Yoshida: "Islet amyloid polypeptide and its N-terminal and C-terminal flanking peptides' immunoreactivity in islet amyloid of diabetic patients." Diabetic Researc

Azuma Kanatsuka、Hideichi Makino、Kazuo Yagui、Chau I Huang、Masato Taira、Atsuo Mikata、Sho Yoshida：“糖尿病患者胰岛淀粉样蛋白中的胰岛淀粉样多肽及其 N 末端和 C 末端侧翼肽的免疫反应性。”

Yoshiharu Tokuyama, Azuma Kanatsuka, Yoshihumi Suzuki, Takahide Yamaguchi, Masato Taira, Hideichi Makino, Sho Yoshida: "Islet amyloid polypeptide gene : no evidence of abnomal promoter region in thirty-five type 2 diabetic patients." Diabetes Research and

Yoshiharu Tokuyama、Azuma Kanatsuka、Yoshihumi Suzuki、Takahide Yamaguchi、Masato Taira、Hideichi Makino、Sho Yoshida：“胰岛淀粉样多肽基因：在 35 名 2 型糖尿病患者中没有异常启动子区域的证据。”