Obesity is a major risk factor for a number of metabolic disorders such as hyperlipidemia, glucose intolerance, and T2DM. Recent researches indicated a stimulatory effect of glucagon (GCG) on energy expenditure and appetite inhibition, suggesting the utilization of GCG as a pharmacological therapy for obesity and related metabolic disorders. In line with this, we previously observed that chronic treatment of HM15136, a novel long-acting glucagon analog, conferred efficient body weight loss (BWL) in DIO mice. Here, we further investigated the potential benefits of HM15136 in obesity-related metabolic disorders. In DIO mice, time-course change in fat mass, liver triglyceride (TG), and fasting blood glucose (FBG) was determined. Chronic treatment of HM15136 was associated with progressive BWL (-37.5% vs. vehicle (Veh) at day17) and fat mass reduction with little effect on lean mass, confirming its potent anti-obesity effect. Interestingly, despite marginal BWL at initial drug treatment period, significant reduction in blood TG (-56.5% vs. Veh at day2) and subsequent liver TG (-41.5% vs. Veh at day7) was achieved, and maintained thereafter. Moreover, the TG lowering both in blood and liver was followed by sustainable FBG lowering, suggesting that rapid depletion of lipid, the main sources for gluconeogenesis, might contribute to FBG control by HM15136. To evaluate the potential effect on post-prandial glucose control, oral glucose tolerance test (oGTT) was performed, and reduced BG level during oGTT was observed as BWL occurred. Time-dependent reduction in HOMA-IR evidenced the insulin sensitivity improvement. To our knowledge, this is the first study demonstrating the potential benefits of chronic GCG engagement in the management of BW, blood lipid, and even BG. Based on these results, HM15136 may be a novel option for the management of obesity and related metabolic disorders. Human study is ongoing for the clinical relevance of these findings.


J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Spouse/Partner; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.

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