Figure 4From: Pancreatic islet cell therapy for type I diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantationGlucose 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.Back to article page