108-LB: Sustained Glucagon Effect on Blood Glucose and Improvements of Insulin Resistance Mediated by a Novel Long-Acting Glucagon Analog, HM15136, in Animal Models

HM15136 is a novel long-acting glucagon (GCG) analog conjugated with human IgG FC fragment via a short PEG linker. Previously, HM15136 treatment led to body weight loss (BWL) in obese animal models while showing transient effect on blood glucose (BG). Insulin resistance (IR) can lead to imbalances in BG homeostasis in obesity, representing a key risk factor for T2DM. Considering the potential benefit of BWL in IR improvement, HM15136 could be a novel therapeutic option for obesity treatment. To assess this concept, the present study evaluated the effect of HM15136 on BG as well as BW, and investigated the mechanism leading to IR improvement in vitro and in vivo. In DIO rats, 4 weeks treatment of HM15136 led to remarkable BWL (-17 ∼ -42% vs. Veh). BG monitoring showed that an initial BG elevation was rapidly normalized and maintained normal thereafter, with no HbA1c increase (3.4 and 3.7% for Veh and HM15136). Similar results were also observed in DIO mice, showing no abnormal glycemic control by HM15136. Interestingly, BWL effect were correlated with free-fatty acid (FFA) and HOMA-IR reduction. In vitro studies in 3T3-L1 adipocytes further confirmed the deteriorating effect of FFA on insulin signaling. These results suggested that improvements in the lipotoxic milieu explains, at least in part, the IR improvement seen with HM15136. To further explore additional mechanism, inflammatory markers and adipokines affecting insulin signaling were evaluated. HM15136 not only inhibited F4/80 expression, but also increased FGF-21 and adiponectin expression in white adipose tissue and 3T3-L1 adipocytes. Our results demonstrated that BWL under by HM15136 therapy is accompanied by the reduction of 1) lipotoxicity, 2) inflammatory biomarkers, and the expression of 3) insulin-sensitizing adipokines, eventually leading to IR reversal and normal BG maintenance. Human studies are needed to confirm whether these findings will translate into humans.