842-P: A Novel CRFR2-Selective UCN2 Analog, HM17321, Improves Glycemic Control across Multiple Preclinical Models
Abstract
Introduction and Objective: Obesity is a major cause of various metabolic diseases, particularly type 2 diabetes (T2D), and most of the T2D patients are overweight or obese. Thus, glycemic control efficacy becomes to be recognized as one of the essential features of anti-obesity medication. HM17321, a novel CRFR2-selective UCN2 was developed for high quality weight management, and its proof of concept was demonstrated in animal models of obesity. Here, the potential benefits of HM17321 on glucose homeostasis and related mode of action was further investigated.
Methods: ipGTT was performed in normal mice after single drug administration. In DIO mice, HOMA-IR was determined after 8 weeks treatment of HM17321. To evaluate overall glycemic control effect, db/db mice were administered with HM17321 for 4 weeks, followed by HbA1c measurement and ipGTT. Semaglutide (Sema) was included as a comparative control.
Results: In normal mice, single administration of HM17321 significantly reduced BG during ipGTT, indicating its rapid glucose tolerance improvement effects. Similarly, chronic treatment of HM17321 significantly reduced HOMA-IR in DIO mice (8.8 ~ 11.8 vs. 65.7 for DIO vehicle; 11.2 for normal vehicle), indicating its improvement effect on insulin resistance. In line with these findings, 4 weeks treatment of HM17321 in diabetic db/db mice significantly decreased HbA1c and ipGTT AUCBG compared to vehicle. Notably, overall glycemic control effect in db/db mice was comparable to…
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