Mutation/Polymorphism Scanning of Glucose-6-Phosphatase Gene Promoter in Noninsulin-Dependent Diabetes Mellitus Patients1

Abstract

Glucose-6-phosphatase (G6Pase) catalyzes the rate-limiting step of gluconeogenesis, and hepatic G6Pase activity is increased in diabetes. We have cloned and analyzed the human G6Pase gene promoter region and identified putative regulatory sequences for insulin, cAMP, glucocorticoid, and hepatocyte nuclear factors. The promoter region of the G6Pase gene was analyzed in 154 noninsulin-dependent diabetes mellitus patients and 90 control subjects by PCR-single strand conformation polymorphism and direct sequencing methods. Polymorphisms were not found in any subjects. The results suggested that in noninsulin-dependent diabetic patients, the major cause of the hepatic glucose overproduction was not attributed to dysregulation of the G6Pase gene due to mutation/polymorphism of its promoter region.

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

“…Although the molecular mechanisms of GC-induced side effects are complex and often not yet well understood, it appears justified to assume that some of these undesired effects, such as steroid diabetes, require GR-DNA interaction and transactivation. For example, the two most important enzymes of gluconeogenesis, an essential pathway in the development of diabetes, phosphoenolpyruvate carboxykinase (13,14) and glucose-6-phosphatase (15), are both induced by GCs. In contrast, a key mechanism for suppression of the hypothalamo-pituitary-adrenal axis, the decreased release of adrenocorticotropic hormone (ACTH) by corticotrophinreleasing hormone, is mediated by the GR via a transrepression mechanism (8).…”