2002-P: A Long-Acting GLP-1 and Y2-Receptor Dual Agonist Improves Body Weight and Glucose Control in Obese and Diabetic Rodent Models

Bariatric surgery can result in profound weight loss and remission of type 2 diabetes. Following meal consumption post-surgery, patients exhibit an exaggerated increase in the circulating levels of the enteroendocrine L-cell peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). We have developed a long-acting PYY Y2 and GLP-1 receptor agonist (GLP-1-Fc-PYY), which exerted potent effects on improving glucose metabolism and body weight loss in diabetic db/db mice and diet-induced obese (DIO) mice. Administration of GLP-1-Fc-PYY to diabetic db/db mice for 28 days normalized HbA1_c levels (4.3%) compared to vehicle controls (9.1%), and exceeded that observed with Fc-GLP-1 monotherapy treatment (7.2%). GLP-1-Fc-PYY administration also preserved circulating insulin levels and increased pancreatic insulin content in db/db mice, which was not observed in mice treated with Fc-GLP-1. Administration of GLP-1-Fc-PYY for 21 days in DIO mice resulted in a 28% (p<0.0001) decrease in body weight, whereas vehicle-treated mice gained 13% and Fc-GLP-1-treated mice only exhibited a 13% reduction in body weight. To further characterize the GLP-1-Fc-PYY molecule, DIO GLP-1R knockout (KO) mice were treated for 13 days, and effects on body weight loss were partially attenuated in GLP-1R KO mice (10% BW loss), compared to wild type mice (32% BW loss). Additionally, when GLP-1R KO DIO mice were challenged with an IP glucose bolus following sub-chronic GLP-1-Fc-PYY treatment, the improvement in glucose excursion was lost compared to wild type mice. DIO Y2R KO mice treated for 11 days with GLP-1-Fc-PYY had attenuated BW loss (9%) compared to wild type mice (32%). These data suggest that GLP-1-Fc-PYY is a balanced dual agonist with in vivo activity at both the GLP-1 and Y2 receptors. GLP-1-Fc-PYY therefore represents a PYY/GLP-1 long-acting dual agonist that produces robust bariatric surgery-like weight loss and antidiabetic efficacy in relevant rodent models.