Molecular mechanism on the development of type 2 diabetes

2型糖尿病发生的分子机制

• 批准号: 20390058
• 负责人: TOMIZAWA Kazuhito
• 金额: $ 12.48万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390058/
• 关键词: 糖尿病; tRNA; 化学修飾; インスリン; 遺伝子改変マウス; Cdk5; 細胞内情報伝達; 修飾酵素; リン酸化; 蛋白質相互作用

Cdkal1 has been associated with an impaired insulin response and increased risk of type 2 diabetes (T2D), but its molecular function has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N^6- threonylcarbamoyladenosine (ms^2t^6A) in tRNA^<Lys>(UUU) and that it is required for the accurate translation of AAA and AAG codons. Pancreatic?-cell-specific Cdkal1 knockout mice showed pancreatic islet hypertrophy, a decrease in insulin secretion and impaired blood glucose control. In Cdkal1-deficient?-cells, glucose-stimulated proinsulin synthesis was reduced. Moreover, the expression of endoplasmic reticulum (ER) stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Cdkal1 knockout mice were hypersensitive to high-fat diet-induced ER stress. These findings suggest that the induced translation of proinsulin may require fully modified tRNA^<Lys>(UUU), potentially explaining the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

Cdkal 1与胰岛素反应受损和2型糖尿病（T2 D）风险增加有关，但其分子功能尚未确定。在这里，我们发现Cdkal 1是一种哺乳动物甲硫基转移酶，它可以生物合成tRNA^（UUU）中的2-甲硫基-N^6-苏氨酰氨基甲酰基腺苷（ms^2t^6A）<Lys>，并且它是AAA和AAG密码子准确翻译所必需的。胰腺癌？细胞特异性Cdkal 1敲除小鼠显示胰岛肥大、胰岛素分泌减少和血糖控制受损。在Cdkal 1缺乏症中？细胞，葡萄糖刺激的胰岛素原合成减少。此外，内质网（ER）应激相关基因的表达上调，在这些细胞中，观察到异常结构的ER。Cdkal 1基因敲除小鼠对高脂饮食诱导的内质网应激高度敏感。这些发现表明，胰岛素原的诱导翻译可能需要完全修饰的tRNA^<Lys>（UUU），这可能解释了携带cdkal 1风险等位基因的患者中T2 D的分子发病机制。

项目成果

ヒトtRNA修飾と2型糖尿病発症

人类 tRNA 修饰与 2 型糖尿病发病

• 发表时间: 2010
• 作者: Feng B.;Tomizawa K.;et al.;富澤一仁
• 通讯作者: 富澤一仁

Effects of purified newly developed botulinum neurotoxin type A in rat prostate.

纯化的新开发的 A 型肉毒杆菌神经毒素对大鼠前列腺的影响。

• 发表时间: 2009
• 期刊: Urology. 74巻
• 作者: Nishiyama Y.;Yokoyama T.;Tomizawa K.;Okamura K.;Yamamoto Y.;Matsui H.;Oguma K.;Nagai A.;Kumon H.
• 通讯作者: Kumon H.

ヒトtRNA修飾と疾患

人类 tRNA 修饰与疾病

• 发表时间: 2010
• 作者: 磯貝純夫;木村英二;人見次郎;木村宏;Chiba H;富澤一仁
• 通讯作者: 富澤一仁

Functional characterization of CDKAL1, a risk factor of T2DM

T2DM 危险因素 CDKAL1 的功能特征

• 发表时间: 2010
• 作者: Isogai S;Deguchi T;Yaniv K;Hitomi J;Weinstein BM;富澤一仁
• 通讯作者: 富澤一仁

CaM kinase 1a-induced phosphorylation of DRP1 regulates mitochondrial morphology

CaM 激酶 1a 诱导的 DRP1 磷酸化调节线粒体形态

• 发表时间: 2008
• 期刊: J. Cell Biol. 182
• 作者: Han XJ.;et. al
• 通讯作者: et. al