Modulating human IAPP aggregation in type 2 diabetes: inhibitors, mechanisms, and translational challenges

Islet amyloid polypeptide (IAPP) aggregation is a characteristic pathological feature of type 2 diabetes (T2D), driving pancreatic β-cell dysfunction and loss through the formation of toxic oligomeric and fibrillar species. In recent years, significant advances in structural biology and chemical biology have deepened our understanding of the molecular basis of IAPP misfolding and enabled the development of various molecular strategies to modulate its aggregation pathway. This review summarizes recent advances in IAPP aggregation inhibitors, encompassing natural products, small synthetic molecules, peptide mimetics, antibody-based inhibitors, and supramolecular modulators. Specifically, the ability to modulate human insulin-like amyloid polypeptide aggregation is discussed in terms of mechanistic insights, representative inhibitors, and translational potential. Eventually, we discuss the current challenges and future directions for the clinical translation of IAPP aggregation inhibitors, providing perspective for the development of next-generation therapeutics for type 2 diabetes.