Glucagon-like peptide 1 increases glucose-dependent activity of the homeoprotein IDX-1 transactivating domain in pancreatic beta-cells

Both glucose and glucagon-like peptide 1 (GLP-1) stimulate insulin gene transcription in endocrine pancreatic beta-cells within the islets of Langerhans. The effects of glucose are mediated by the homeodomain transcription factor islet duodenum homeobox -1 (IDX-1) that binds to two adenine thymidine-rich (A1 and A2/3) motifs within the rat insulin promoter. Glucose stimulates the activity of the transactivation domain of IDX-1 that lies within the first 80 amino acids of the IDX-1 protein. The effects of GLP-1 on insulin gene expression are primarily conferred by the cAMP responsive element (CRE) within the insulin promoter. GLP-1 stimulates glucose-dependent insulin release from beta-cells. We hypothesize that GLP-1 may augment the effects of glucose on insulin gene transcription. Here we show that GLP-1 stimulates insulin gene transcription independent of the CRE and is glucose-dependent. Furthermore, we show that GLP-1 stimulates the transactivational activity of IDX-1.