title: Identification of a novel variant in the phosphoenolpyruvate carboxykinase gene promoter in Japanese patients with type 2 diabetes.
abstract: Phospho enolpyruvate carboxykinase (PEPCK) plays an important role in gluconeogenesis and hepatic glucose production. To test the hypothesis that mutations of the PEPCK gene promoter contribute to the increased hepatic glucose production that leads to diabetes, we screened for polymorphisms of the PEPCK promoter region in 252 Japanese type 2 diabetic patients and 188 non-diabetic control subjects. A novel variant at position - 232 (C to G) was found at a similar frequency in type 2 diabetes patients (32 %) and control subjects (35 %) (p = 0.26). However, patients with the - 232 G/G genotype had an earlier age of onset than those with the - 232 C/C or - 232 C/G genotypes (p = 0.028). As the variant might well otherwise influence hormonal action, we transfected PEPCK-luciferase fusion gene constructs with the variant into human hepatoma cells and examined the response to dexamethasone, insulin, and cAMP. The reporter assay showed no significant difference in hormonal responses with the fusion gene containing the variant. Accordingly, the single-base variant at position - 232 of the PEPCK gene promoter is most probably not a major contributor to the pathogenesis of type 2 diabetes. However, this variation may be useful as a genetic marker for other metabolic disorders, especially in Japanese.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine B5, Osaka University, 2 - 2 Yamada-Oka, Suita, Osaka 565-0871, Japan. yhorikaw@showa.gunma-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Horikawa
authors.forename: T
authors.initials: T
authors.lastname: Yamasaki
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.forename: R
authors.initials: R
authors.lastname: Shingu
authors.forename: I
authors.initials: I
authors.lastname: Yoshiuchi
authors.forename: J
authors.initials: J
authors.lastname: Miyagawa
authors.forename: M
authors.initials: M
authors.lastname: Namba
authors.forename: T
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007564:Japan; D008297:Male; D008875:Middle Aged; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D003907:Dexamethasone; D010729:Phosphoenolpyruvate Carboxykinase (GTP)