MON-591 Effect of Liraglutide Treatment on Proglucagon-Derived Peptides

Liraglutide is a glucagon-like peptide 1 receptor agonist (GLP-1ra) and has 97% homology to native GLP-1. Native GLP-1 derives from proglucagon, which is also a prohormone for other peptides including GLP-2, glucagon, oxytomodulin, glicentin, and major proglucagon fragment. Aside from GLP-1 and glucagon, the actions and roles of the other proglucagon-derived peptides remain unclear. In addition, the effect of liraglutide treatment on these peptides are unknown. The aim of this study was to evaluate the effect of treatment with liraglutide compared with placebo on proglucagon-derived peptides. Adults who were overweight/obese (BMI 27-40 kg/m(2)) with prediabetes were randomized to liraglutide 1.8mg daily vs placebo for 14 weeks. All participants met regularly with a registered dietitian and were advised to decrease calorie intake by 500 kcal/day. Proglucagon-derived peptides were measured during mixed-meal tolerance test (MMTT) at baseline and after 14 weeks in a subset of individuals with saved samples (n=16 on liraglutide, n=19 on placebo). The MMTT involved eating breakfast at 08:00 (20% of daily energy intake) and lunch at 12:00 (40% of daily energy intake). Blood was collected before breakfast and hourly from 08:00 to 16:00. The area-under-the curve (AUC) was calculated for all proglucagon-derived peptides using the trapezoidal method. Individuals treated with liraglutide lost twice as much weight as those assigned to placebo injections (mean ± SD, 6.1 ± 1.9 vs 3.2 ± 2.2 kg, p<0.002). Treatment with liraglutide also was associated with a significant (p < 0.01) decrease in all proglucagon-derived peptides. In the placebo group, only glucagon AUC significantly decreased after 14-weeks (P=0.002). Our study demonstrates for the first time that liraglutide treatment is associated with decrease in proglucagon-derived peptides, suggesting downregulation of endogenous proglucagon. The effects of this downregulation are unknown and need further study.