title: Examination of the phosphoenolpyruvate carboxykinase gene promoter in patients with noninsulin-dependent diabetes mellitus.
abstract: Expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis, is under dominant negative regulation by insulin. In this study, we sought to test the hypothesis that mutations in the PEPCK gene promoter may impair the ability of insulin to suppress hepatic glucose production, thereby contributing to both the insulin resistance and increased rate of gluconeogenesis characteristic of NIDDM. The proximal PEPCK promoter region in 117 patients with noninsulin-dependent diabetes mellitus and 20 obese Pima Indians was amplified by PCR and analyzed with single strand conformation polymorphism techniques. In addition, limited direct DNA sequencing was performed on the insulin response sequence and flanking regions. No DNA sequence polymorphisms were found in any patient. This result suggests that mutations in cis-acting PEPCK gene regulatory elements do not constitute a common cause of noninsulin-dependent diabetes mellitus. The significance of genetic variation in promoter regions to human disease is discussed.
authors.affiliation: Division of Endocrinology and Metabolism, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Ludwig
authors.forename: A
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: R M
authors.initials: RM
authors.lastname: O'Brien
authors.forename: R L
authors.initials: RL
authors.lastname: Printz
authors.forename: D K
authors.initials: DK
authors.lastname: Granner
authors.forename: D E
authors.initials: DE
authors.lastname: Moller
authors.forename: J S
authors.initials: JS
authors.lastname: Flier
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D005943:Gluconeogenesis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D007328:Insulin; D010729:Phosphoenolpyruvate Carboxykinase (GTP)