Accumulated Cytotoxicity Induced by Islet Amyloid Polypeptide Oligomers in Type 2 Diabetes

Type 2 diabetes is characterized by progressive aggregation of islet amyloid polypeptide (IAPP) within the islets of Langerhans, a process strongly implicated in beta-cell dysfunction and loss. Although oligomeric IAPP intermediates are widely considered the principal cytotoxic species, the relative contributions of the many biological and kinetic processes governing their formation, clearance, and conversion into fibrils remain poorly quantified. Here, a mathematical model of IAPP aggregation is developed that incorporates the physiology of beta-cell secretion and the microanatomy of the islet, including capillary-mediated clearance, enzymatic degradation, and the kinetics of oligomer and fibril formation within a well-mixed control volume. Building on the hypothesis that oligomers are the major cytotoxic species, the concept of accumulated cytotoxicity is introduced, defined as the time integral of the oligomer concentration, and a systematic sensitivity analysis of this quantity with respect to all model parameters is performed. The results reveal a striking hierarchy: only two parameters, the basal rate of IAPP monomer secretion and the rate constant for spontaneous oligomer dissociation, exert a first-order influence on long-term accumulated cytotoxicity, with dimensionless sensitivities approaching +1 and -1, respectively, while the effect of all other parameters remains subordinate and decays at long times. The model further shows that capillary clearance, owing to the physical exclusion of oligomers from fenestrated capillaries, selectively reduces fibril accumulation and amyloid deposition without affecting oligomer-mediated cytotoxicity, indicating that amyloid area fraction, the standard histological metric of disease severity, may not be a reliable surrogate for cytotoxic burden. The model predicts that approximately 48% of the islet area is replaced by amyloid after 30 years, broadly consistent with histological observations of advanced disease. These findings identify monomer secretion and oligomer dissociation as the most promising therapeutic targets to limit cytotoxic damage in type 2 diabetes and provide a quantitative framework for evaluating candidate intervention strategies.