Deficiency of glucokinase gene expression and NIDDM

葡萄糖激酶基因表达缺陷与 NIDDM

• 批准号: 06671034
• 负责人: MATSUTANI Akira
• 金额: $ 1.15万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671034/
• 关键词: NIDDM; Glucokinase gene; Promoter; GLUT1; GLUT2

We evaluated the promoter activity of islet GCK promoter variants and implicated its patho-physiological role in glucose metabolism. The promoter region containing polymorphic region at -30 (G to A) from the islet transcription initiation site, were PCR amplified from genomic DNA of 60 NIDDM patients and 56 non-diabetic subjects, whose genotypes were determined by SSCP and direct sequence. The frequency of the rare promoter with the sequence A at -30 was not different between NIDDM and the non-diabetic. The human islet promoter activity was assessed by transfecting HIT cells with the luciferase expression plasmid. The luciferase activity in the cells transfected with the promoter-luciferase plasmids containing the sequence A at -30 was significantly lower than that with the plasmids containing the sequence G.Oral glucose tolerance test (OGTT) was carried out in 22 non-diabetic subjects ; 8 subjects with G/G,10 with G/A,and 4 with A/A.Subjects with the sequence A showed higher plasma glucose levels on OGTT than subjects with the sequence G.Insulin levels were not significantly different among groups. All 8 subjects with G/G showed normal glucose tolerance, but 6 of 10 subjects with G/A and 3 of 4 subjects with A/A had impaired glucose tolerance. These data suggest that the promoter function is affected in the individual with the sequence A at -30, resulting in impaired glucose tolerance associated with GCK dysfunction. The present results thus suggest the possibility that a naturally occurring variant of the GCK promoter may contribute to the susceptibility to NIDDM in Japanese.GLUT1, GLUT2 genes does not seem to have a major in the development of NIDDM.

我们评估了胰岛GCK启动子变体的启动子活性，并暗示其在葡萄糖代谢中的病理生理作用。从60例NIDDM患者和56例非糖尿病患者的基因组DNA中PCR扩增出含有胰岛转录起始位点-30（G → A）多态性的启动子区，用SSCP和直接测序法检测基因型。在NIDDM组和非糖尿病组中，-30位序列为A的罕见启动子的频率没有差异。通过用荧光素酶表达质粒转染HIT细胞来评估人胰岛启动子活性。在-30的A序列的启动子-荧光素酶质粒转染的细胞中的荧光素酶活性显著低于G序列的质粒转染的细胞。8例G/G受试者，10例G/A受试者，A/4 A.序列A的受试者在OGTT时的血糖水平高于序列G的受试者。胰岛素水平无显著差异在群体之间。所有8例G/G受试者均显示正常糖耐量，但10例G/A受试者中有6例和4例A/A受试者中有3例存在糖耐量受损。这些数据表明，在具有-30处的序列A的个体中，启动子功能受到影响，导致与GCK功能障碍相关的葡萄糖耐量受损。本研究结果提示GCK启动子的天然变异可能与日本人NIDDM的易感性有关，而GLUT 1、GLUT 2基因在NIDDM的发生发展中似乎并不起主要作用。

项目成果

Tao T, Tanizawa Y. Matsutani A. Matsubara A. Kaneko T. Kaku: "K-HepG2/erythrocyte glucose transporter (GLUT1) gene in NIDDM : a population association study and molecular scanning in Japanese subjects." Diabetologia. 38. 942-947 (1995)

Tai T、Tanizawa Y. Matsutani A. Matsubara A. Kaneko T. Kaku：“NIDDM 中的 K-HepG2/红细胞葡萄糖转运蛋白 (GLUT1) 基因：日本受试者的群体关联研究和分子扫描。”

Tao T,Tanizawa Y,Matsutani A,Matsubara A,Kaneko T,Kaku K: "HepG2/erythrocyte glucose transporter (GLUT1) gene in NIDDM" a population association study and molecular scanning in Japanese subjects. Diabetologia. 38. 942-947 (1995)

Tai T、Tanizawa Y、Matsutani A、Matsubara A、Kaneko T、Kaku K：“NIDDM 中的 HepG2/红细胞葡萄糖转运蛋白 (GLUT1) 基因”是日本受试者的群体关联研究和分子扫描。

Matsubara A. Tanizawa Y. Matsutani A. Kaneko T. Kaku K :"Seqeuence variadons of the pancreatic islet/liver glucose transporter (GLUT2) gene in Japanese subjects with non- insulin-dependent diabetes mellitus." J Clin Endocrinol Metab. 80. 3131-3135 (1995)

Matsubara A. Tanizawa Y. Matsutani A. Kaneko T. Kaku K：“日本非胰岛素依赖型糖尿病受试者胰岛/肝脏葡萄糖转运蛋白 (GLUT2) 基因的序列变化。”

松谷 朗、野田 薫、松原 淳、綾目 秀夫、田尾 健、加来浩平、兼子俊男: "ヒトGK遺伝子 プロモーター領域の多型性の意義 -プロモーター活性の検討.糖尿病記録号 1993 : 46〜50" 豊田 隆謙編, 296 (1994)

Akira Matsutani、Kaoru Noda、Jun Matsubara、Hideo Ayame、Ken Tao、Kohei Kaku、Toshio Kaneko：“人类 GK 基因启动子区域多态性的意义 - 启动子活性的检查。糖尿病记录 1993 年：46-50”编辑丰田高研，296 (1994)

Matsubara A,Tanizawa Y,Matsutani A,Kaneko T,Kaku K: "Seqeuence variations of the pancreatic islet/liver glucose transporter (GLUT2) gene in Japanese subjects with non-insulin-dependent diabetes mellitus." J Clin Endocrinol Metab. 80. 3131-3135 (1995)

Matsubara A、Tanizawa Y、Matsutani A、Kaneko T、Kaku K：“日本非胰岛素依赖型糖尿病受试者中胰岛/肝脏葡萄糖转运蛋白 (GLUT2) 基因的序列变异。”