MECHNISMS OF PANCREATIC BETA CELL DEATH BY Ca^<2+>/CALMODULIN; USING TRANSGENIC MICE

Ca^2/钙调蛋白导致胰腺β细胞死亡的机制；

• 批准号: 13671183
• 负责人: NIKI Ichiro
• 金额: $ 2.18万
• 依托单位: OITA MEDICAL UNIVERSITY (2002)Nagoya University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671183/
• 关键词: type 2 diabetes mellitus; calmodulin; transgenic mouse; apoptosis; insulin; pancreatic beta cell; sulphonylureas; NO (nitric oxide)

We investigated the mechanisms of the pancreatic beta cell death at the onset of diabetes mellitus using transgenic mice overexpressing calmodulin in a beta cell specific manner. We found the transgenic mice experienced the beta cell death in as early stage of the onset, which was worsened by the anti-diabetic sulphonylurea tolbutamide. This means that Ca^<2+> influx by tolbutamide via closure of the ATP-sensitive K^+-channel may cause the beta cell death. Ca^<2+>, the central second messenger for insulin secretion, may possess a toxic effect on the beta-cell life as an inducer of apoptosis. We also found L-NAME, an inhibitor of nitric oxide synthase (NOS), retarded the onset of hyperglycemia in the transgenic mice. Isoform-specific immunostaining of pancreata demonstrated neural NOS might participate in the beta cell apoptosis. Prevention of hyperglycemia in the mouse model occurred partially, suggesting other mechanisms are involved. Because glucose-induced this transgenic mouse is a model to investigate beta cell exhaustion under diabetic conditions.

我们利用以β细胞特异性方式过度表达钙调蛋白的转基因小鼠，研究了糖尿病发病时胰岛β细胞死亡的机制。我们发现转基因小鼠在发病早期就经历了β细胞死亡，抗糖尿病药物甲苯磺脲加重了这种死亡。这意味着，甲苯丁胺通过关闭ATP敏感的K~(++)通道，使Ca~(2+)~(2+)内流，可能导致β细胞死亡。作为胰岛素分泌的第二信使，作为细胞凋亡的诱导者，钙离子可能对胰岛β细胞的寿命有毒性作用。我们还发现，一氧化氮合酶抑制剂L-NAME可以延缓转基因小鼠高血糖的发生。胰腺异构体特异性免疫组织化学染色显示神经型一氧化氮合酶可能参与了胰岛β细胞的凋亡。在小鼠模型中发生了部分高血糖的预防，这表明其他机制也参与其中。由于葡萄糖诱导，这只转基因小鼠是研究糖尿病条件下β细胞衰竭的模型。

项目成果

Yu W, Niwa T, Miura Y, Horio F, Teradaira S, Ribar TJ, Means AR, Hasegawa Y, Senda T, Niki I: "Calmodulin overexpression causes Ca^<2+>-dependent apoptosis of pancreatic beta cells which can be prevented by inhibition of nitric oxide synthase"Lab Invest.

Yu W、Niwa T、Miura Y、Horio F、Teradaira S、Ribar TJ、Means AR、Hasekawa Y、Senda T、Niki I：“钙调蛋白过度表达会导致胰腺 β 细胞的 Ca^2 依赖性细胞凋亡，这是可以预防的

仁木一郎: "プロテインキナーゼによるインスリン顆粒動態の制御.分子糖尿病学の進歩2002"矢崎義雄監修、門脇 孝春日雅人、清野 進、渥美義仁、編集(金原出版). 16-19 (2002)

Ichiro Niki：“蛋白激酶对胰岛素颗粒动力学的控制。2002 年分子糖尿病的进展”，Yoshio Yazaki 监督，Masato Kadowaki、Susumu Kiyono 和 Yoshihito Atsumi 编辑（Kanehara Publishing）16-19（2002 年）。

Niwa T, Nimura Y, Niki I: "Lack of effects of incretin hormones on insulin release from pancreatic islets in the bile duct-ligated rats"Am J Physiol. 280. E59-E64 (2001)

Niwa T、Nimura Y、Niki I：“肠促胰岛素激素对胆管结扎大鼠胰岛胰岛素释放缺乏影响”Am J Physiol。

Niki I, Senda T: "Regulation of insulin release at pre-exocytotic stages of the secretory machinery"Current Medicinal Chemistry. 2. 219-231 (2002)

Niki I，Senda T：“分泌机制前胞吐阶段胰岛素释放的调节”当前药物化学。