GLP ‐ 1R biased cAMP agonism maintains glycemic control with reduced malaise and emesis in preclinical mammalian models

AIMS: Glucagon-like peptide-1 receptor (GLP-1R) agonists improve glycemic control and promote weight loss in diabetes and obesity but are also associated with gastrointestinal adverse events, including nausea and emesis in many patients. These concerns highlight the need for the development of novel GLP-1R agonists that minimize these side effects while maintaining beneficial metabolic outcomes. Here, we investigate the in vivo effects of exendin-4-Phe1 (Ex-Phe1), a GLP-1R biased agonist. MATERIALS AND METHODS: In three pre-clinical species, mice (n = 43), rats (n = 54), and musk shrews (n = 30), we examined in vivo glycemic control, feeding, and nausea/emesis following native Ex-4 and Ex-Phe1 administration. We also used cFos expression following Ex-4 and Ex-Phe1 administration to examine neural activation in regions involved in mediating nausea and emetic side effects of GLP-1R agonism. RESULTS: In vitro studies show Ex-Phe1 favors cAMP signaling with reduced β-arrestin recruitment. Compared to Ex-4, Ex-Phe1 produced fewer emetic episodes in musk shrews (Suncus murinus) and little to no pica, a proxy for nausea, in rats. Ex-Phe1 effects on food intake and body weight varied by species, while Ex-4 and Ex-Phe1 similarly enhanced glucose tolerance in all species. Ex-4 and Ex-Phe1 increased cFos expression within brain regions linked to nausea and emesis in all species. CONCLUSIONS: Collectively, Ex-Phe1 maintains glycemic benefits in all three species, but putatively blunts the ability of the CNS GLP-1R+ cells to drive anorexia and weight loss, as well as unwanted adverse events (nausea/emesis) in rats and musk shrews.