Structural, kinetic, and thermodynamic aspects of insulin aggregation

Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling the aggregation kinetics has been observed. Quantitative analysis of aggregation includes data of gradual monomeric depletion followed by the formation of subvisible particles. Kinetic and thermodynamic studies are essential to gain key insights into the aggregation process. Despite being the medical marvel in the world of diabetes, insulin suffers from the challenge of aggregation. Physicochemical stresses are experienced by insulin during industrial formulation, storage, delivery, and transport, considerably impacting product quality, efficacy, and effectiveness. The present review briefly describes the pathways, mathematical kinetic models, and thermodynamics of protein misfolding and aggregation. With a specific focus on insulin, further discussions include the structural heterogeneity and modifications of the intermediates incurred during insulin fibrillation. Finally, different model equations to fit the kinetic data of insulin fibrillation are discussed. We believe that this review will shed light on the conditions that induce structural changes in insulin during the lag phase of fibrillation and will motivate scientists to devise strategies to block the initialization of the aggregation cascade. Subsequent abrogation of insulin fibrillation during bioprocessing will ensure stable and globally accessible insulin for efficient management of diabetes.