Chemical modifications of insulin: Finding a compromise between stability and pharmaceutical performance

Insulin, a key peptide hormone that conjointly with its receptor regulates blood glucose levels, is used as the major means to treat diabetes. This therapeutic hormone may undergo different chemical modifications during industrial processes, pharmaceutical formulation, and through its endogenous storage in the pancreatic β-cells. Insulin is highly sensitive to the environmental stresses and easily undergoes structural changes, being also able to unfold and aggregate. Even small changes altering the structural integrity of insulin may have important impact on the biological efficacy in relation to the physiological and pharmacological activities of this hormone. The chemical modifications of insulin may occur either randomly or based on the well-planned strategies to enhance its pharmaceutical properties. A plethora of studies have attempted to answer the fundamental questions of how chemical modifications and which environmental conditions may have either destructive effects or improve structural stability and pharmaceutical performance of insulin. The aim of this review is to highlight the impact of different modifications on structure, stability, biological activity, and pharmaceutical properties of insulin.