Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion.

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 [HbA <42 mmol/l (<6.0%)], glucose intolerance [HbA 42-47 mmol/l (6.0-6.4%)] and type 2 diabetes [HbA ≥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 HbA. Mechanistic investigations used tanycyte-specific GLP-1R knockdown (GLP-1R) 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 HbA (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-1R 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.