Graduate Student Incheon National University, Republic of Korea
Abstract: The prevalence of obesity-related metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2DM) is rising. Understanding the metabolic pathways underlying these diseases is crucial for drug development, which requires advanced in vitro models of key organs involved in metabolism, particularly the liver-pancreas axis. While existing liver-pancreas axis models are useful for studying glucose regulation, they fall short in replicating an in vivo-like liver-pancreas axis due to the slow transport of metabolic substrates and suboptimal organ function in mixed media cultures. To address these limitations, we developed a multi-organoid device (MOD) that enables convective transport of metabolites between separated organoids. This device significantly enhances metabolic substrate transport compared to passive diffusion-based systems and improves organoid function. To model MASLD on this platform, liver organoids were treated with palmitate (PA), a fatty acid, which induced characteristic lipotoxicity, lipid accumulation, and increased secretion of Fetuin A (FetA), a key signaling molecule. Moreover, our device successfully replicated MASLD-induced T2DM, characterized by FetA-mediated β-cell apoptosis, impaired pancreatic glucose sensitivity, glucose intolerance, and hyperinsulinemia. Additionally, the widely used T2DM drug metformin exhibited clinically relevant efficacy within the system, underscoring its potential for drug screening applications. Overall, this MOD provides a robust platform for modeling the interactions between MASLD and T2DM and holds promise for the development of effective therapeutic strategies for metabolic diseases.
Funding Source: Supported by NRF-2022R1C1C1008610 and KFRM (24A0105L1, 22A0105L1-11).
