Regulation of gluconeogenic gene expression by glucocorticoids, cAMP and cytokines

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate dehydrogenase kinase 4 (PDK4) regulate steps in the pathway of gluconeogenesis and pyruvate oxidation respectively. In the liver, the expression of the genes encoding these proteins is induced during starvation and diabetes. Two primary mediators of this induction are glucocorticoids and glucagon (via cAMP). In type II diabetes, hepatic insulin resistance is associated with increased glucose output by the liver and elevated PEPCK and PDK4 gene expression. Several cytokines including tumor necrosis factor alpha (TNFa) and interleukin 6 (IL-6) have been suggested as factors that contribute to insulin resistance. We have examined the mechanisms by which cAMP and glucocorticoids induce the PEPCK and PDK4 genes. Insulin will block the stimulatory actions of these hormones on the gluconeogenic genes. Insulin will inhibit the PDK4 gene in part through the forkhead/FoxO1 transcription factors. In these studies, we report that TNFa and IL6 will alter the expression of PEPCK and PDK4 genes and impact the insulin regulation of these genes.