GLUCOCORTICOIDS REGULATE THE INDUCTION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP) GENE-TRANSCRIPTION DURING DIABETES

The hormonal regulation of transcription of the phosphoenolpyruvate ca rboxykinase (GTP) (4.1.1.32) (PEPCK) gene during diabetes was studied using transgenic mice containing a chimeric gene consisting of segment s of the PEPCK promoter (-2000/+73, -460/+73, -355/+73) linked to bovi ne growth hormone (bGH) reporter gene. The effect of diabetes and insu lin on transgenic mice containing a mutation in cAMP regulatory sequen ces at -90/-82 and -250/-234 was also studied. In addition, we analyze d the transcriptional response of the PEPCK gene to adrenalectomy, the administration of glucocorticoids, and alterations in dietary protein and carbohydrate. Our results indicate that deletion of the insulin r egulatory sequence of the PEPCK promoter did not affect dietary contro l of PEPCK gene expression. However, glucocorticoids and the glucocort icoid regulatory unit appear to be essential for induction of PEPCK ge ne transcription by diabetes. By contrast, mutation of cAMP regulatory elements of the PEPCK promoter did not limit induction of PEPCK trans cription by diabetes, nor did it affect negative regulation of transcr iption by insulin. These results provide evidence for the interaction of insulin and glucocorticoid regulatory elements in the control of PE PCK gene transcription and suggest an important role of glucocorticoid s as a gluconeogenic activator during diabetes.