Inhibition of GSK-3 selectively reduces glucose-B-phosphatase and phosphoenolpyruvate carboxykinase gene expression

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 dia betes. For example, the expression of two hepatic genes, glucose-6-phosphat ase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, th eir expression is insensitive to insulin. An agent that mimics the effect o f insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The re pressive actions of insulin on these genes are dependent on phosphatidylino sitol (PI) 3-kinase. However, the molecules that lie between this lipid kin ase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK -3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongl y reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expressio n. In addition, GSK-3 inhibition does not result in the subsequent activati on of protein kinase B or inhibition of the transcription factor FKHR, whic h are candidate regulatory molecules for these promoters. Thus, GSK-3 activ ity is required for basal activity of each promoter. Inhibitors of GSK-3 sh ould therefore reduce hepatic glucose output, as well as increase the synth esis of glycogen from L-glucose. These findings indicate that GSK-3 inhibit ors may have greater therapeutic potential for lowering blood glucose level s and treating type 2 diabetes than previously realized.