Emerging roles for ß-arrestin-1 in the control of the pancreatic ß-cell function and mass: new therapeutic strategies and consequences for drug screening.

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in ß-cell mass, decreased ß-cell survival and impaired glucose-dependent insulin release. Pancreatic ß-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. ß-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that ß-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for ß-arrestin-1 in the regulation of insulin secretion and ß-cell survival by GPCRs.