A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in pancreatic islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with primary islets on a chip (PANIS) enabling MASLD progression and islet dysfunction to be quantitatively assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion (GSIS) response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived secreted factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient–specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying complex disease mechanisms, and advancing precision medicine. ### Competing Interest Statement D.Lansing Taylor, Albert Gough, and Mark E. Schurdak have equity in Nortis, a company supplying MPS chips/some automation and EveAnalytics (accessing, analyzing, and computationally modeling data on patient-derived microphysiology systems). * α-SMA : alpha-actin, alpha-actin-2 CCL2 : C-C motif chemokine ligand 2 CCL3 : C-C motif chemokine ligand 3 COL1A1 : Collagen type I alpha 1 chain CXCL1 : C-X-C motif chemokine ligand 1 EMS : Early metabolic syndrome G-CSF : Granulocyte colony-stimulating factor GLP-1 : Glucagon like peptide 1 GM-CSF : Granulocyte-macrophage colony-stimulating factor GSIS : Glucose-stimulated insulin secretion HGF : Hepatocyte growth factor IGFBP-7 : Insulin like growth factor binding protein 7 IL-1β : Interleukin 1 beta IL-6 : Interleukin 6 IL-8 : Interleukin 8 ISI : Insulin stimulation index NF : Normal fasting IRS-2 : Insulin receptor substrate 2 PDGF-AA : Platelet-derived growth factor subunit A PP : Pancreatic polypeptide RBP4 : Retinol binding protein 4 ROS : Reactive oxygen species TIMP1 : TIMP metallopeptidase inhibitor 1 TNF-α : Tumor necrosis factor alpha VEGF : Vascular endothelial growth factor A