Study of impaired insulin exocytosis in diabetes mellitus by imaging technique

糖尿病胰岛素胞吐作用受损的影像学研究

• 批准号: 15390108
• 负责人: NAGAMATSU Shinya
• 金额: $ 8.83万
• 依托单位: Kyorin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390108/
• 关键词: Insulin; TIRF; exocytosis; imaging; pancreatic β cell; diabetes mellitus; insulin secretion; TIRFM

In these years the number of diabetic patients significantly increased worldwide and caused cerebrovascular disorder and heart vascular events, therefore, the onset prevention and restricted blood sugar levels control of diabetic patients are regarded as urgent business for both human health and medical economy. Because impaired insulin release is characteristics in type 2 diabetes, to elucidate the mechanism of normal and impaired insulin exocytosis is important. In this study, we developed the imaging system of total internal reflection fluorescence(TIRF) and applied this imaging system to pancreatic beta cells. Our system is a powerful tool for disclosure of insulin docking and fusion system by monitoring the dynamic motion of insulin granules on the plasma membrane. We found that granules fusing during the first phase insulin release originated mostly from morphologically previously docked granules, whereas granules fusing during the second phase arose from newcomers that were originally stored intracellulary. We also found that previously docked granules were colocalized with syntaxin 1A clusters in the plasma membrane, and fused from them. Finally we found that in diabetic beta cells, syntaxin 1A clusters decreased, thereby, docked granules decreased, as a result, first phase of insulin release decreased in the diabetic status.

近年来，世界范围内糖尿病患者数量显著增加，并引发脑血管疾病和心血管事件，因此，糖尿病患者的发病预防和限制血糖水平控制被视为人类健康和医疗经济的当务之急。由于胰岛素释放受损是2型糖尿病的特点，因此阐明正常和受损的胰岛素胞吐的机制非常重要。在本研究中，我们开发了全内反射荧光(TIRF)成像系统，并将该成像系统应用于胰岛β细胞。我们的系统通过监测胰岛素颗粒在质膜上的动态运动，是揭示胰岛素对接和融合系统的有力工具。我们发现，在胰岛素释放的第一阶段融合的颗粒主要来自形态上先前对接的颗粒，而在第二阶段融合的颗粒来自最初储存在细胞内的新来者。我们还发现，以前停靠的颗粒与Synaxin 1A簇在质膜上共定位，并与它们融合。最后我们发现，在糖尿病的β细胞中，Synaxin 1A簇减少，从而对接的颗粒减少，从而导致糖尿病状态下胰岛素释放的第一时相减少。

项目成果

Osteoclastic function is accelerated in male patients with type 2 diabetes mellitus: the preventive role of osteoclastogenesis inhibitory factor/osteoprotegerin (OCIF/OPG) on the decrease of bone mineral density

• DOI: 10.1016/j.diabres.2004.08.006
• 发表时间: 2005-05-01
• 期刊: DIABETES RESEARCH AND CLINICAL PRACTICE
• 影响因子: 5.1
• 作者: Suzuki, K;Kurose, T;Ishida, H
• 通讯作者: Ishida, H

Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-L1 adipocytes

• DOI: 10.1152/ajpendo.00456.2004
• 发表时间: 2005-10-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
• 影响因子: 5.1
• 作者: Yamaguchi, S;Katahira, H;Ishida, H
• 通讯作者: Ishida, H

Ohara-Imaizumi M, Nagamatsu S et al.: "Site of docking and fusion of insulin secretory granules in live MIN6 β cells analyzed by TAT-conjugated anti-syntaxin 1 antibody and total internal reflection fluorescence microscopy."J Biol Chem. 279. 8403-8408 (20

Ohara-Imaizumi M、Nagamatsu S 等人：“通过 TAT 缀合的抗突触蛋白 1 抗体和全内反射荧光显微镜分析活 MIN6 β 细胞中胰岛素分泌颗粒的对接和融合位点。”J Biol Chem 279。 8403-8408 (20

Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation.

• DOI: 10.1172/jci22955
• 发表时间: 2005-02
• 期刊: The Journal of clinical investigation
• 作者: K. Kasai;M. Ohara-Imaizumi;N. Takahashi;Shin Mizutani;Shengli Zhao;T. Kikuta;H. Kasai;S. Nagamatsu-S.-N

Nakamichi Y, Nagamatsu S et al.: "PPAR-gamma overexpression suppresses glucose-induced proinsulin biosynthesis and insulin release synergistically with pioglitazone in MIN6 cells."Biochem Biophys Res Commun. 306. 832-836 (2003)

Nakamichi Y、Nagamatsu S 等人：“PPAR-γ 过表达可抑制 MIN6 细胞中葡萄糖诱导的胰岛素原生物合成和胰岛素释放，与吡格列酮协同作用。”Biochem Biophys Res Commun。