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Association of the polymorphisms in the 5′‐untranslated region of PTEN gene with type 2 diabetes in a Japanese population
Author(s) -
Ishihara Hajime,
Sasaoka Toshiyasu,
Kagawa Syota,
Murakami Shihou,
Fukui Kazuhito,
Kawagishi Yukio,
Yamazaki Katsuya,
Sato Akira,
Iwata Minoru,
Urakaze Masaharu,
Ishiki Manabu,
Wada Tsutomu,
Yaguchi Saori,
Tsuneki Hiroshi,
Kimura Ikuko,
Kobayashi Masashi
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)01225-0
Subject(s) - pten , tensin , type 2 diabetes , gene , biology , insulin resistance , population , exon , cancer research , phosphatase , endocrinology , insulin , genetics , pi3k/akt/mtor pathway , phosphorylation , medicine , diabetes mellitus , signal transduction , environmental health
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known to act as a lipid phosphatase hydrolyzing phosphatidylinositol (PI)(3,4,5)P 3 to PI(4,5)P 2 . Since the PI3‐kinase product, PI(3,4,5)P 3 , is an important second messenger leading to the metabolic action of insulin, PTEN functions as a potent negative regulator of insulin signaling and its gene is one of the possible candidates involved in susceptibility to the development of type 2 (non‐insulin‐dependent) diabetes. In the present study, we investigated the polymorphisms of the PTEN gene in Japanese patients with type 2 diabetes and non‐diabetic control subjects. We identified three mutations of the gene in the type 2 diabetes patients. Among these mutations, the frequency of the substitution of C with G at position −9 (−9C→G) (SNP1), located in the untranslated region of exon 1, was significantly higher in type 2 diabetic patients than in control subjects. In addition, transfection of the PTEN gene with SNP1 resulted in a significantly higher expression level of PTEN protein compared with that of the wild‐type PTEN gene in Cos1 and Rat1 cells. Furthermore, insulin‐induced phosphorylation of Akt in HIRc cells was decreased more greatly by transfection of SNP1 PTEN gene than that of wild‐type PTEN gene. These findings suggest that the change of C to G at position −9 of the PTEN gene is associated with the insulin resistance of type 2 diabetes due possibly to a potentiated hydrolysis of the PI3‐kinase product.