Elucidating the pathological axis of hIAPP-mediated β-cell toxicity: A MATLAB-based network modelling

Human islet amyloid polypeptide (hIAPP) oligomers are increasingly recognized as central mediators of β-cell dysfunction and toxicity in type 2 diabetes mellitus (T2DM). Islet amyloidosis is a chronic condition developed during the course of T2DM and it is characterized by the deposition of toxic hIAPP aggregates in pancreatic β-cells. Although, islet amyloidosis in not a condition that has gone unaddressed however, the intricate mechanisms that the toxic hIAPP oligomers intervene with to mediate β-cell toxicity are yet to be fully elucidated. In this study, we employed systems metabolism and computational biology approach to mathematically reconstruct and investigate the dynamics and hIAPP-mediated β-cell toxicity axis using SimBiology MATLAB. The signalling network was reconstructed using a number of enzyme kinetics and parameters which provided a computable framework of all the signalling components giving us valuable insights to predict and replicate the best behavioural outcomes. Sensitivity analysis, Principal Component Analysis (PCA), Flux analysis, Model reduction and cross-talk point determination accurately captured the dynamics of the entire system and identified key components (RAGE, PKC, ROS, CytoC, PERK, IRE1, ATF6, Ca ₂₊ influx), interactions, and processes (insulin resistance, glycation, autophagy defect, ER and mitochondrial stress, apoptosis) driving its pathogenic behaviour.