Human Islet Amyloid Polypeptide: From Physiological Hormone to Amyloid Pathology and Therapeutic Target in Type 2 Diabetes Mellitus

Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37 residue hormone co-secreted with insulin by pancreatic β cells that regulates glucose homeostasis. In persistent hyperglycemic and insulin resistant conditions, hIAPP is overexpressed, leading to its misfolding and aggregation into oligomers and fibrils. These amyloid fibrils are strongly associated with β cell dysfunction and apoptosis. Islet amyloid deposits have been reported in about 90% of people with Type 2 Diabetes Mellitus (T2DM), highlighting the association between hIAPP aggregation and disease progression. Although current treatments improve glycemic control and reduce diabetic complications, they do not directly address hIAPP amyloid formation or the underlying progressive β-cell pathology. Consequently, blocking or modulating hIAPP aggregation has become a highly relevant therapeutic strategy, although no anti-hIAPP therapy has yet been approved. This review discusses the biosynthesis and processing of hIAPP, and its physiological functions. The mechanisms proposed to contribute to hIAPP-mediated β-cell toxicity, including membrane damage, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction, are then considered. Current approaches to interfere with hIAPP aggregation are reviewed, including peptide analogues, polyphenols and other small molecules, nanochaperones, antibodies, and nanobodies. Additionally included amylin-based treatments, such as pramlintide and novel dual-agonist approaches. The review further discusses the challenges of translating hIAPP inhibitors toward clinically relevant anti diabetic therapies, such as pharmacokinetic limitations, target specificity, off-target interactions with other amyloid proteins, and the complexity of T2DM pathophysiology. Finally, future perspectives for proceeding with hIAPP-targeted interventions from preclinical models to clinical efficacy.