Turn, Rachel

In the twenty-first century one of the most widespread and challenging human disorders is Type 2 Diabetes Mellitus (T2DM). Standard therapies are effective in achieving glycemic control but have undesired side effects, such as hypoglycemia and weight gain. As a result, there is an urgent need to develop novel therapeutics to treat this devastating disease. The Glucagon-like peptide receptor (GLP-1R) plays a critical role in glucose homeostasis and is therefore an attractive target for treatment of T2DM. GLP-1R exhibits pleiotropic signaling, so to determine if activation of one signaling pathway to the exclusion of others will provide improved therapeutics, we sought to identify GLP-1R biased ligands. Screening of large lentivirus-encoded combinatorial peptide libraries identified a novel GLP-1R ligand (peptide SR) exhibiting functional selectivity. Here, we describe the in vitro and in vivo pharmacological characterization of peptide SR and highlight the differences observed between this treatment and the reference ligand, Exendin-4.