STUDY OF ABNORMAL GLUCOSE METABOLISM ASSOCIATED WITH AGEING AND ESTABLISHMENT FOR AN ANIMAL MODEL OF NIDDM

衰老相关葡萄糖代谢异常的研究及NIDDM动物模型的建立

• 批准号: 09671022
• 负责人: UTSUGI Toshihiro
• 金额: $ 1.92万
• 依托单位: GUNMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671022/
• 关键词: Ageing; Ageing suppressing gene; klotho; Diabetes mellitus; Glucose transporter; Klotho

1. Klotho gene expression in the new animal model for human ageing and study for insulin deficiency in this model1) We have recently identified a novel gene, termed klotho (kl), which may suppress several ageing phenotypes. Defect of kl gene expression in the mouse results in a syndrome resembling human ageing, such as arteriosclerosis, skin atrophy, osteoporosis, and pulmonary emphysema. The klotho gene is expressed in the kidney, artery, and lung. The gene sequence was 40% similarity with β-glucosidase. The gene expression in the kidney was decreased-in model rats for hypertension and diabetes mellitus. As the dysfunction of endothelial cells were recovered after parabiosis experiment, we suggest that the klotho gene products can act as a fluid factor, such as hormones and cytokines.2) To see whether mouse homozygote for the kl mutation (kl/kl) show abnormal glucose metabolism and insulin deficiency, OGTT was performed at 6-8 weeks of age. Blood glucose levels during OGTT in kl/kl mi … More ce were significantly lower than those in wild mice. Whereas, insulin content of the pancreas in kl/kl mice-was significantly lower compared to that of control mice. The decreased insulin production was also supported by Northern blot analysis that showed lower levels of insulin mRNA in kl/kl mice.3) Histological findings showed that pancreatic β cells were selectively diminished, and α cells were slightly increased in number in the klotho mice. We could not find immunocytes in the islets of pancreas and apoptosis signals were not detectable, suggesting that the insulin deficiency could be due to direct effect by defect of kl gene expression in the klotho mouse.These findings were published in Nature 1997, Biochem Biophys Res Comm 1998, and reported in several national and international meetings, such as Japan diabetes association, European association for study of the diabetes, and so on.2. Establishment for the animal model for NIDDMThis study was initiated to see high calorie diet can induce NIDDM in mouse heterozygote for the kl mutation (kl/+) that has increased insulin sensitivity. So far, no animal developped NIDDM for one years.3. Study for prevention of abnormal glucose metabolism using the purified klotho proteinPurification of klotho protein is now on-going. Once purified and prepared for administration in vivo, this study can performed. Less

1. Klotho基因在新的人类衰老动物模型中的表达及其对胰岛素缺乏的研究1）我们最近发现了一种新的基因，称为Klotho（kl），它可以抑制几种衰老表型。小鼠kl基因表达缺陷导致类似人类衰老的综合征，如动脉硬化、皮肤萎缩、骨质疏松和肺气肿。klotho基因在肾脏、动脉和肺中表达。该基因序列与β-葡萄糖苷酶的同源性为40%。在高血压和糖尿病模型大鼠肾脏中的基因表达降低。实验结果表明，klotho基因产物可能是一种体液因子，如激素和细胞因子。2）为了观察kl突变纯合子（kl/kl）小鼠是否存在糖代谢异常和胰岛素缺乏，在6-8周龄时进行OGTT。OGTT期间的血糖水平，kl/kl mi ...更多信息 ce显著低于野生小鼠。而kl/kl小鼠胰腺胰岛素含量明显低于对照组。北方印迹分析显示kl/kl小鼠中胰岛素mRNA水平较低，也支持胰岛素产生减少。3）组织学结果显示，klotho小鼠中胰腺β细胞选择性减少，α细胞数量略有增加。这些结果发表在Nature 1997，Biochem Biophys Res Comm 1998，并在日本糖尿病协会，欧洲糖尿病研究协会等。NIDDM动物模型的建立本研究旨在观察高热量饮食可诱发胰岛素敏感性增加的k1突变（k1/+）杂合子小鼠NIDDM。到目前为止，一年内没有动物发生NIDDM。使用纯化的klotho蛋白预防糖代谢异常的研究klotho蛋白的纯化目前正在进行中。一旦纯化并制备用于体内给药，即可进行本研究。少

项目成果

OHYAMA Y, UTSUGI T, NAGAI R, ET AL: "INSULIN PRODUCTION AND INSULIN SENSITIVITY IN THE KLOTHO MUTANT MOUSE, THE NOVEL ANIMAL FOR HUMAN AGEING"DIABETES. 47. A393 (1998)

OHYAMA Y、UTSUGI T、NAGAI R 等人：“克洛托突变小鼠的胰岛素产生和胰岛素敏感性，人类衰老的新动物”糖尿病。

Aizawa H., Nagai R. et al: "Doun regulation of the klotho gene in the kidny under sustained clroulatory stress in rats"Biochem Biophys Res Comm. 249. 865-871 (1998)

Aizawa H.、Nagai R. 等人：“大鼠持续性循环应激下肾脏中 klotho 基因的 Doun 调节”Biochem Biophys Res Comm。

宇津木敏浩、永井良三、他: "老化抑制遺伝子klotho欠損マウスにおける糖代謝とインスリン抵抗性の検討"日本臨床代謝学会記録. 35. 84-84 (1998)

Toshihiro Utsugi、Ryozo Nagai 等：“衰老抑制基因 klotho 缺陷小鼠的葡萄糖代谢和胰岛素抵抗检查”日本临床代谢学会记录 35. 84-84 (1998)。

AIZAWA H, NAGAI R, ET AL: "DOWN REGULATION OF THE KLOTHO GENE IN THE KIDNEY UNDER SUSTAINED CIRCULATORY STRESS IN RATS"BIOCHEM BIOPHYS RES COMM. 249. 865-871 (1998)

AIZAWA H、NAGAI R 等人：“大鼠持续循环应激下肾脏中 KLOTHO 基因的下调”BIOCHEM BIOPHYS RES COMM。

Ohyama Y,Utsugi T,Nagai R. et al: "Inslin produet in and Insulin Sinsitivity in the Kloth mueant mnne,the roul animal for human ageing" Diaheres. 47. A393 (1998)

Ohyama Y、Utsugi T、Nagai R. 等人：“Kloth mueant mnne 中的胰岛素产品和胰岛素活性，人类衰老的主要动物”Diaheres。