EXAMINATION OF THE PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE PROMOTER INPATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS

Expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiti ng enzyme in gluconeogenesis, is under dominant negative regulation by insulin. In this study, we sought to test the hypothesis that mutatio ns in the PEPCK gene promoter may impair the ability of insulin to sup press hepatic glucose production, thereby contributing to both the ins ulin resistance and increased rate of gluconeogenesis characteristic o f NIDDM. The proximal PEPCK promoter region in 117 patients with nonin sulin-dependent diabetes mellitus and 20 obese Pima Indians was amplif ied by PCR and analyzed with single strand conformation polymorphism t echniques. In addition, limited direct DNA sequencing was performed on the insulin response sequence and flanking regions. No DNA sequence p olymorphisms were found in any patient. This result suggests that muta tions in cis-acting PEPCK gene regulatory elements do not constitute a common cause of noninsulin-dependent diabetes mellitus. The significa nce of genetic variation in promoter regions to human disease is discu ssed.