Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion.
Saponaro C., Imbernon M., Louvet I., Deligia E., Chen S., Davies I., Acosta-Montalvo A., Moreno-Lopez M., Wemelle E., Kothegala L., Porteiro B., Auger F., Zubiaga L., Dellalau N., Thevenet J., Mühlemann M., Pasquetti G., Gmyr V., Pfrieger FW., Nogueiras R., Schwaninger M., Rorsman P., Staels B., Kerr-Conte J., Knauf C., Jones B., Pattou F., Prevot V., Bonner C.
AIMS/HYPOTHESIS: Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist for type 2 diabetes and obesity management, shows variable patient responses. We investigated the metabolic state-dependent mechanisms underlying this heterogeneity and how liraglutide's mode of action shifts across stages of metabolic dysfunction. METHODS: We employed human pancreatic islets from donors across metabolic states (normoglycaemic [HbA1c <42 mmol/l (<6.0%)], glucose intolerance [HbA1c 42-47 mmol/l (6.0-6.4%)] and type 2 diabetes [HbA1c ≥48 mmol/l (≥6.5%)]) using dynamic perifusion and static incubation techniques to assess glucose-stimulated insulin secretion. GLP-1R mRNA levels were measured in 112 donor islets stratified by HbA1c. Mechanistic investigations used tanycyte-specific GLP-1R knockdown (GLP-1RTanycyteKD) mice and botulinum toxin B-expressing (iBot) mice to distinguish between central and peripheral pathways. Oral glucose tolerance tests, pyruvate tolerance tests and positron emission tomography were performed to assess in vivo metabolic effects. RESULTS: Liraglutide (25 nmol/l) enhanced glucose-stimulated insulin secretion specifically in donors with glucose intolerance (n=7, p=0.021), with no effect in normoglycaemic islets (n=7), despite preserved GLP-1 (7-36) responsiveness. In type 2 diabetes islets, GLP-1R mRNA levels progressively decreased with rising HbA1c (p=0.015, normoglycaemic [n=48] vs type 2 diabetes [n=10]). In chow-fed mice, liraglutide's insulin-stimulating effects required tanycyte-mediated hypothalamic access, as demonstrated by abolished responses in GLP-1RTanycyteKD mice. However, during metabolic dysfunction (a 12-week high-fat diet), direct islet responsiveness was restored independent of tanycyte function. Advanced metabolic disease (a 27-week high-fat diet) maintained islet responsiveness ex vivo while losing in vivo insulin enhancement, revealing insulin-independent glucose-lowering mechanisms involving hepatic gluconeogenesis suppression and enhanced peripheral glucose uptake. CONCLUSIONS/INTERPRETATION: Liraglutide operates through complementary, metabolic state-dependent pathways: tanycyte-mediated brain actions predominate in healthy conditions, direct islet effects emerge during glucose intolerance and insulin-independent mechanisms maintain efficacy across metabolic states. This mechanistic framework enables potential patient stratification in type 2 diabetes therapy, suggesting that matching liraglutide's predominant mechanism to individual metabolic profiles could optimise treatment outcomes.