Exenatide Blocks JAK1-STAT1 in Pancreatic Beta Cells.

Exenatide (Ex-4) is an anti-diabetic drug that acts through the glucagon-like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes. Ex-4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type I diabetes, but the mechanisms are not fully understood. We therefore analyzed the pathways affected by Ex-4 in human islets using oligonucleotide microarrays and the PathwayStudio™ software. We identified the JAK1-STAT1 pathway as a novel target of Ex-4 and confirmed the Ex-4-mediated downregulation of JAK1 and STAT1 by quantitative RT-PCR in human islets and INS-1 cells. JAK1-STAT1 is the major signaling pathway mediating the IFN-γ effects on beta cell apoptosis in type 1 diabetes. Thus, these findings suggest that Ex-4 treatment may also be beneficial in type 1 diabetes, where it may help protect beta cells from cytokine-induced cell death by inhibiting JAK1-STAT1. [ABSTRACT FROM AUTHOR]