Glucose control of insulin gene transcription. Glucose metabolism in beta cells generates upstream signals that are responsible for the activation of factors involved in insulin transcription. (1) Glucose metabolism causes a shift of transcription factor PDX-1 from the cytoplasm to the nucleus, increases its activation domain and binding to A3 element. The effects are in part, due to the activity of phosphatidylinositol 3-kinase (PI3-K); another kinase stress-activated protein kinase 2 (SAPK2/P38) might be involved in this process. An alternative pathway involves histone and PDX-1. When glucose levels are low, PDX-1 interacts with histone deacetylases Hdac-1 and Hdac-2 and recruits them to insulin gene promoter, which causes the deacetylation of histone H4 and results in down-regulation of insulin gene expression. High concentrations of glucose diminish this inhibiting activity. (2) Stimulatory concentrations of glucose can activate ERK1/2, which promotes BETA2 and E47 heterodimerization and binding to E-box sites. (3) Glucose affects MafA at the mRNA level. Stimulatory glucose levels increase MafA transcription and result in increased MafA protein.