A study led by Drs. Rosa Alén Alonso, Irma García Martínez, and Ángela Martínez Valverde of the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM, CSIC-UAM) and CIBERDEM (Networked Biomedical Research Centre in Diabetes and Associated Metabolic Diseases) demonstrates that extracellular vesicles released by hepatocytes under lipotoxic stress can trigger inflammation and dysfunction in the pancreas, thereby contributing both to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and to the onset of type 2 diabetes.
The work, recently published in Diabetologia, focuses on vesicles secreted by hepatocytes overloaded with lipids (termed Hep-sEV). Although these particles had previously been linked to liver inflammation and MASLD progression, their impact on extrahepatic tissues such as the pancreas had not been fully explored.
The results show that lipotoxic Hep-sEV are taken up by macrophages within pancreatic islets, where they activate Toll-like receptor 4 (TLR4) and trigger a local inflammatory response. This signaling leads to downregulation of genes essential for β-cell identity and impairs the cells’ ability to secrete insulin in response to glucose.
By specifically deleting TLR4 in macrophages, the authors protected pancreatic islets from inflammation and preserved β-cell function, suggesting that this receptor could serve as a novel therapeutic target to prevent or delay disease progression.
In animal models, chronic administration of lipotoxic Hep-sEV induced inflammation in both liver and pancreas, led to hepatic fibrosis, and triggered a systemic immunometabolic response characterized by insulin resistance. In this pre-diabetic phase, treated mice also exhibited compensatory insulin hypersecretion that maintained normal glucose tolerance.
The team also assessed the translational relevance of their findings: in human pancreatic islet cultures, treatment with lipotoxic Hep-sEV significantly reduced insulin secretion, confirming the clinical significance of the results. “This study highlights how toxic lipids released by the liver can drive the progression of MASLD and type 2 diabetes, and positions TLR4 as a promising therapeutic target for early intervention to halt disease advancement,” concludes Dr. Ángela Martínez Valverde.
This research was conducted in collaboration with investigators from CIBERDEM (Benoit Gauthier and Elisa Fernández-Millán), the Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), the Centro Nacional de Investigaciones Cardiovasculares (CNIC), the Universidad Complutense de Madrid (UCM), and the Instituto de Investigación del Hospital 12 de Octubre.
Effect of lipotoxic hepatocyte-derived extracellular vesicles in pancreas inflammation: essential role of macrophage TLR4 in beta cell functionality.
Alén R, Garcia-Martinez I, Cobo-Vuilleumier N, Fernández-Millán E, Gallardo-Villanueva P, Ferreira V, Izquierdo M, Moro MÁ, Lizasoain I, Nieto N, Gauthier BR, Valverde ÁM.
Diabetologia. 2025 May 19. doi: 10.1007/s00125-025-06445-z. PMID: 40387904