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.