Aims/hypothesis <p>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.</p> Methods <p>We employed human pancreatic islets from donors across metabolic states (normoglycaemic [HbA_1c &lt;42 mmol/l (&lt;6.0%)], glucose intolerance [HbA_1c 42–47 mmol/l (6.0–6.4%)] and type 2 diabetes [HbA_1c ≥48 mmol/l (≥6.5%)]) using dynamic perifusion and static incubation techniques to assess glucose-stimulated insulin secretion. <i>GLP-1R</i> mRNA levels were measured in 112 donor islets stratified by HbA_1c. Mechanistic investigations used tanycyte-specific GLP-1R knockdown (GLP-1R^TanycyteKD) 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.</p> Results <p>Liraglutide (25 nmol/l) enhanced glucose-stimulated insulin secretion specifically in donors with glucose intolerance (<i>n</i>=7, <i>p</i>=0.021), with no effect in normoglycaemic islets (<i>n</i>=7), despite preserved GLP-1 (7–36) responsiveness. In type 2 diabetes islets, <i>GLP-1R</i> mRNA levels progressively decreased with rising HbA_1c (<i>p</i>=0.015, normoglycaemic [<i>n</i>=48] vs type 2 diabetes [<i>n</i>=10]). In chow-fed mice, liraglutide’s insulin-stimulating effects required tanycyte-mediated hypothalamic access, as demonstrated by abolished responses in GLP-1R^TanycyteKD 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.</p> Conclusions/interpretation <p>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.</p> Graphical Abstract <p></p>