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

Type 2 diabetes is characterized by the 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 numerous 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 conducted. The results reveal a clear 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 effects of all other parameters remain subordinate and diminish 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, a commonly used histological metric of disease severity, may not be a reliable surrogate for cytotoxic burden. At the highest secretion rate, the model predicts approximately 48% islet replacement by amyloid after 30 years, substantially below the >85% reported in some end-stage histological studies; this discrepancy is consistent with the omission of late-stage processes such as beta-cell death and release of intracellular IAPP from the present model. These findings identify monomer secretion and oligomer dissociation as potentially promising therapeutic targets for limiting cytotoxic damage in type 2 diabetes and provide a quantitative framework for evaluating candidate intervention strategies.