Metabolic State Determines Central and Peripheral Mechanisms of Liraglutide-Enhanced Insulin Secretion

Abstract

While liraglutide effectively treats type 2 diabetes (T2D) and obesity, its mechanism of action across disease progression remains poorly understood. Liraglutide selectively enhances GSIS in islets from glucose-intolerant donors and in islets exposed to prediabetic conditions, but not in normoglycemic or T2D islets. In healthy mice, liraglutide's insulinotropic effect requires tanycyte-mediated central transport, whereas in glucose intolerance it acts directly on islets. Additionally, liraglutide reduces blood glucose in normoglycemic mice through insulin-independent mechanisms involving decreased gluconeogenesis and enhanced peripheral glucose uptake. These findings demonstrate that the therapeutic window for liraglutide's pancreatic effects may be optimal during prediabetes, while its central and insulin-independent actions predominate in other metabolic states.