A Human Biomimetic Liver Microphysiology System to Study the Pathophysiology of Metabolic Dysfunction-Associated Steatotic Liver Disease and Its Comorbidity With Type 2 Diabetes Mellitus
Abstract (summary)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant global health concern, especially prevalent among individuals with type 2 diabetes mellitus (T2DM) which has a comorbidity rate of 70%. A crucial aspect of this relationship is hepatic insulin resistance, which disrupts both lipogenesis and glucose production, particularly within the context of the metabolic syndrome. Research indicates that lipid-induced hepatic insulin resistance can lead to dysfunction in pancreatic islets, illustrating a complex interaction between the liver and pancreas that contributes to the coexistence of type 2 diabetes and MASLD. To better understand this connection, a human biomimetic microphysiological system (MPS) was developed, combining a vascularized liver acinus MPS (vLAMPS) with a pancreatic islet MPS (PANIS). This innovative approach enables comprehensive assessment of MASLD progression alongside its impact on pancreatic islet function. The liver acinus is the liver's fundamental unit, composed of hepatocytes and non-parenchymal cells organized in a complex three-dimensional structure that is essential for metabolic processing. Through tissue engineering and microfluidic techniques, vLAMPS has been designed to accurately simulate this complexity, mimicking the liver's microenvironment and facilitating the analysis of histological and functional parameters. Meanwhile, the PANIS replicates the functionality of the islets using a microfluidic system, preserving the pancreatic microenvironment. Connecting the vLAMPS and PANIS creates a robust platform for studying the pathophysiology of MASLD and T2DM. Under early metabolic syndrome conditions, the standalone vLAMPS exhibited characteristics of early-stage MASLD. When connected with PANIS, it revealed an altered islet secretome and a disrupted insulin secretion response, highlighting direct signaling from the liver to the islets. Finally, we examined the mechanisms behind hepatic insulin resistance exacerbated by excess glucose, free fatty acids, and insulin. Our findings demonstrated impaired insulin signaling and increased glucose and lipid production within the vLAMPS, particularly affecting gluconeogenesis and de novo lipogenesis pathways regulated by Akt phosphorylation. This study not only enhances our understanding of metabolic dysfunction but also sheds light on the interrelation of liver and pancreatic functions in the pathophysiology of MASLD and T2DM, providing insights into potential therapeutic targets.
Indexing (details)
Medicine;
Physiology;
Pathology
0564: Medicine
0719: Physiology
0571: Pathology
