Molecular and cellular mechanisms of GLP-1 receptor agonists and their emerging clinical applications
Mateusz Kurowski, Katarzyna Rekiel, Aleksandra Marcinkowska, Oskar Ratajczyk, Piotr Urbanowicz, Stanisław Iwankiewicz, Wojciech Grzelczak, Zuzanna Kaz mierczakAbstract
In the 21st century, obesity and type 2 diabetes mellitus represent some of the greatest challenges in modern medicine, affecting hundreds of millions of people worldwide and leading to systemic multiorgan dys-function caused by cellular stress, glucotoxicity, and lipotoxicity. Glucagon-like peptide-1 (GLP-1) receptor agonists represent a promising incretin-based based therapies, replacing the purely glucocentric model with an adipocentric approach that modulates the cellular mechanisms of metabolic diseases. By activating intracellular pathways dependent on cAMP, PKA, and Epac2, GLP-1RAs not only enhance glucose-dependent insulin secretion and suppress appetite but also actively reduce endoplasmic reticulum stress and protect pancreatic beta cells from apoptosis. Their pleiotropic effects extend significantly beyond glycemic control, demonstrating proven benefits in preventing pathological cardiac remodeling, improving vascular endothelial function, reducing oxidative stress in the kidneys, and modulating neuroinflammatory pathways. Despite substantial cardiometabolic and nephroprotective advantages, GLP-1 receptor agonist therapy is associated with safety concerns, such as gastrointestinal symptoms caused by delayed gastric emptying and an increased risk of biliary disorders. Given the complexity of these multiorgan effects, further studies with extended follow-up periods are essential to determine which benefits are direct receptor-mediated effects and which result secondarily from weight loss.