The chronic administration of two novel long-acting Xenopus glucagon-like peptide-1 analogs xGLP159 and xGLP296 potently improved systemic metabolism and glycemic control in rodent models

We here reported 2 novel Xenopus glucagon-like peptide-1 (xGLP-1) analogs, xGLP159 and xGLP296, whose therapeutic effects on metabolic efficacy and glycemic control were evaluated in rodents. The in vitro potency of xGLP159 and xGLP296 were investigated on human embryonic kidney 293 cells. The acute glucose-lowering and insulinotropic effects of xGLP159 and xGLP296 were assessed in the Institute of Cancer Research, Kunming, and diabetic (db/db) mice. The pharmacokinetic profiles of xGLP159 and xGLP296 were confirmed on Sprague-Dawley (SD) rats and their long-acting hypoglycemic and anorectic effects were evaluated in db/db mice. Chronic treatment effects of xGLP159 and xGLP296 were evaluated in diet-induced obese (DIO) mice and db/db mice. The results showed that xGLP159 and xGLP296 exhibited comparable receptor activation potency, hypoglycemic effect, and insulinotropic activity to liraglutide. The enhanced half-lives of xGLP159 and xGLP296 in SD rats (5.1 and 5.8 h, respectively) resulted in prolonged anti-db/db durations in db/db mice. Three weeks' administration of xGLP159 and xGLP296 normalized glucose tolerance and adiposity in DIO mice. Furthermore, 11-wk treatment of xGLP159 and xGLP296 corrected hyperglycemia and improved pancreatic function in db/db mice. These preclinical studies supported xGLP159 and xGLP296 as promising candidates for the treatment of metabolic diseases.-Han, J., Meng, T., Chen, X., Han, Y., Fu, J., Zhou, F., Fei, Y., Li, C. The chronic administration of two novel long-acting Xenopus glucagon-like peptide-1 analogs xGLP159 and xGLP296 potently improved systemic metabolism and glycemic control in rodent models.