Molecular Mechanisms on Pancreatic β cell Proliferation

胰腺β细胞增殖的分子机制

• 批准号: 18590978
• 负责人: MITSURU Ohsugi
• 金额: $ 2.49万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590978/
• 关键词: Diabetes Melitus; Signal Transduction; Pancreatic β cells

1. Molecuar mechanisms of IRS-2 mRNA and protein level determination. Utilizing mouse pancreatic islets in vivo as well as isolated islets, we discovered following experimental facts. (A) IRS-2 mRNA and protein levels were positively regulated chiefly by glucose stimulation. (B) This glucose-stimulated IRS-2 induction requires glucose metabolism and Ca2+ influx. (C) CREB phosphorylation/activation was required for Glucose-stimulated IRS-2 induction in the islets. (D) Calmodulin-dependent kinases, not PKA, play a major roles in CREB phoshorylation and subsequent IRS-2 induction by glucose2. Importance of intact Glucose-IRS-2 pathway in adaptive β cell growth in response to insulin resistance. By examining the pancreas islets of obese diabetic mice, including ob/ob, db/db, KK-Ay, and KK/Ta mice, we discovered that CREB phosphorylation was enhanced and IRS-2 mRNA and protein levels were elevated when these pancreatic islets were capable of proliferating in response to insulin resistance. These observations confirmed the importance of glucose-IRS-2 pathway in adaptive β cell growth.3. Importance of IRS-2 in adaptive β cell growth in response to insulin resistance. In addition to our previous publications (J Cline Invest. 2004; 114; 917-27 and Diabetes 2000; 49: 1880-9) we further confirmed the importance of IRS-2 in adaptive adaptive β cell growth in response to insulin resistance. Pancreatic specific glucokinase heterozygous knockout mice exhibited defective β cell growth and reduced IRS-2 protein in the islets when these mice were fed with a high fat diet. A transgenic expression of IRS-2 partially ameliorated the defective β cell growth in glucokinase heterozygous knockout mice.4. Identifying new genes involved in adaptive β cell growth. Gene expression profiles of the pancreatic islets of insulin resistant mice were surveyed with DNA microarrays. We identified more than 300 genes of which their expression levels were significantly altered.

1. IRS-2 mRNA和蛋白水平测定的分子机制。利用小鼠体内胰岛以及分离的胰岛，我们发现了以下实验事实。(A)IRS-2 mRNA和蛋白水平主要受葡萄糖刺激的正调控。(B)这种葡萄糖刺激的IRS-2诱导需要葡萄糖代谢和Ca 2+内流。(C)CREB磷酸化/活化是胰岛中葡萄糖刺激的IRS-2诱导所必需的。(D)钙调素依赖性激酶，而不是PKA，在CREB磷酸化和随后的IRS-2诱导葡萄糖2中发挥主要作用。完整的葡萄糖-IRS-2通路在响应胰岛素抵抗的适应性β细胞生长中的重要性。通过检查肥胖糖尿病小鼠（包括ob/ob、db/db、KK-Ay和KK/Ta小鼠）的胰岛，我们发现当这些胰岛能够响应于胰岛素抵抗而增殖时，CREB磷酸化增强，IRS-2 mRNA和蛋白水平升高。这些观察结果证实了葡萄糖-IRS-2通路在适应性β细胞生长中的重要性. IRS-2在响应胰岛素抵抗的适应性β细胞生长中的重要性。除了我们以前的出版物（J克莱恩投资。二○ ○四年;一百一十四; 917-27和Diabetes 2000; 49：1880-9），我们进一步证实了IRS-2在响应胰岛素抗性的适应性适应性β细胞生长中的重要性。胰腺特异性葡萄糖激酶杂合基因敲除小鼠在喂食高脂饲料时，胰岛中β细胞生长缺陷和IRS-2蛋白减少。IRS-2的转基因表达部分改善了葡萄糖激酶杂合敲除小鼠中缺陷β细胞的生长.鉴定参与适应性β细胞生长的新基因。应用基因芯片技术检测胰岛素抵抗小鼠胰岛的基因表达谱。我们鉴定了300多个基因，其中它们的表达水平发生了显着改变。

项目成果

Insulin Resistance and β cell proliferation

胰岛素抵抗和β细胞增殖

• 发表时间: 2007
• 期刊: In Kadowaki T, Ishibashi S, Sakura H, Tobe K, and Noda M(editors) Textbook of Diabetes Mellitus-Basic and Clinical Sciences, Nishimura shoten
• 作者: Zhou Y;Cras-Meneur C;Ohsugi M;Stormo GD;Permutt MA.;Ohsugi M
• 通讯作者: Ohsugi M

Exocytosis Complex Molecules Rab3 and SNAP25 in Islet β cells in Response to Systemic Insulin Resistance and Glucotoxicity

胰岛 β 细胞中胞吐复合分子 Rab3 和 SNAP25 响应全身胰岛素抵抗和糖毒性

• 发表时间: 2007
• 作者: Kobayashi M;Tobe K;Suzuki R;Ohsugi M;Kowatari-Otsuka N;Sakamoto K Kubota N;Terauchi Y;Nagamatsu S;and Kadowaki T
• 通讯作者: and Kadowaki T

Adipogenesis in Obesity Requires Close Interplay Between Differentiating Adipocytes, Stromal Cells, and Blood Vessels.

肥胖中的脂肪生成需要分化的脂肪细胞、基质细胞和血管之间的密切相互作用。

• 发表时间: 2007
• 期刊: Diabetes 56
• 作者: 島崎猛夫;他;Morita Y;森田圭紀;Nishimura S;Nishimura S
• 通讯作者: Nishimura S

ln vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue.

小鼠体内成像揭示了肥胖脂肪组织中的局部细胞动力学和炎症。

• 发表时间: 2008
• 期刊: J Clin Invest. 118
• 作者: Mihoko;Tsuji;Nishimura S
• 通讯作者: Nishimura S

インスリン抵抗性と膵B細胞の増殖 カラー版糖尿病学基礎と臨床

胰岛素抵抗和胰腺 B 细胞增殖 彩色版本 糖尿病学基础知识和临床研究

• 发表时间: 2007
• 作者: Kobayashi M;Tobe K;Suzuki R;Ohsugi M;Kowatari-Otsuka N;Sakamoto K Kubota N;Terauchi Y;Nagamatsu S;and Kadowaki T;Kamei N;亀井望;小林正稔;大杉満;大杉満
• 通讯作者: 大杉満