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

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. Publication Link

GLP-1R-biased agonist, Ex-Phe1 in musk shrews significantly enhances glycemic control, reduces body weight and food intake, while producing substantially reduced nausea and emesis compared to the GLP-1R receptor agonist, Ex-4.

Effects of acute treatment with Ex-Phe1 in musk shrews. (A) Ex-4 dose-dependently reduces body weight and (B) suppresses food intake. (C) The number of single emetic episodes in 120 min following systemic administration of vehicle and various doses of Ex-4. (D) Ex-Phe1 modestly reduces body weight and (E) suppresses food intake at 210 μg/kg and 2.1 mg/kg, however to a lesser magnitude than Ex-4. (F) The number of single emetic episodes in 120 min following systemic administration of vehicle and various doses of Ex-Phe1. (G) Ex-Phe1 and Ex-4 show equal potency in enhancing glucose clearance during IPGTT (2 g/kg). (H) AUC analyses from 0 to 120 min. Ex-4 and Ex-Phe1 treated animals had lower AUC 0-120 compared to vehicle treated animals. For (A)–(E) n = 10, for (F), (G) n = 9). All data are expressed as mean SEM. In the emetic studies, the number of animals exhibiting emesis, expressed as a fraction of the total number of animals tested, is indicated above each treatment group. Data in (A)–(G) were analysed with two-way repeated-measures ANOVA followed by Tukey's post hoc test. Data in (H) were analysed with one-way repeated measures ANOVA followed by Tukey's post hoc test. Means with different letters are significantly different from each other (p <0.05). Vehicle versus 21 μg/kg Ex-Phe1: *p <0.05, ***p <0.0001; Vehicle versus 210 μg/kg Ex-Phe1: ###p <0.0001; Vehicle versus 21 μg/kg Ex-4: @@@p <0.0001; Vehicle versus 210 μg/kg Ex-4: ∋p <0.05, ∋ ∋ ∋p <0.001; 210 μg/kg Ex-Phe1 versus 21 μg/kg Ex-4: ∞p <0.05.