Natural Polyphenols as Modulators of the Fibrillization of Islet Amyloid Polypeptide

Diabetes mellitus type 2 (type-2 diabetes) is a metabolic disorder characterized by the increased blood glucose concentration and insulin resistance in peripheral tissues (e.g., muscles and adipose tissue). The initiation of the pathological cascade of events that lead to type-2 diabetes has been subject of debate; however, it has been commonly accepted that the oversecretion of human islet amyloid polypeptide (hIAPP, a hormone co-secreted with insulin) by the pancreatic 𝛽-cells is the main trigger of type-2 diabetes. In fact, 90% of the type-2 diabetes patients present hIAPP deposits in the extracellular space of the 𝛽-cells. These hIAPP supramolecular arrangements (both fibrillar and oligomeric) have been reported to be the origin of cytotoxicity, which leads to 𝛽-cell dysfunction through a series of different mechanisms, including the interaction of hIAPP oligomers with the cell membrane that leads to the influx of Ca²⁺ and increase in the cellular oxidative stress, among others. This overview shows the importance of developing type-2 diabetes treatment strategies able to (1) remodel of the secondary structure of cytotoxic hIAPP oligomers entrapping them into off-pathway nontoxic species and (2) reestablish physiological levels of oxidative stress. Natural polyphenols are a class of antioxidant compounds that are able to perform both functions. Herein we review the published literature of the most studied polyphenols, in particular for their ability to remodel the hIAPP aggregation pathway, to rescue the in vitro pancreatic 𝛽-cell viability and function, as well as to perform under a complex biological environment, i.e., in vivo animal models and clinical trials. Overall, natural polyphenols are able to control the cytotoxic hIAPP aggregation and minimize hIAPP-mediated cellular dysfunction and can be considered as important lead compounds for the treatment of type-2 diabetes.