The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies.

Abstract

Proteotoxicity plays a key role in many devastating human disorders, including Alzheimer's, Huntington's and Parkinson's diseases; type 2 diabetes; systemic amyloidosis; and cardiac dysfunction, to name a few. The cellular mechanisms of proteotoxicity in these disorders have been the focus of considerable research, but their role in prevalent and morbid disorders, such as diabetes, is less appreciated. There is a large body of literature on the impact of glucotoxicity and lipotoxicity on insulin-producing pancreatic β-cells, and there is increasing recognition that proteotoxicty plays a key role. Pancreatic islet amyloidosis by the hormone IAPP, the production of advanced glycation endproducts (AGE), and insulin misprocessing into cytotoxic aggregates are all sources of β-cell proteotoxicity in diabetes. AGE, produced by the reaction of reducing sugars with proteins and lipids are ligands for the receptor for AGE (RAGE), as are the toxic pre-fibrillar aggregates of IAPP produced during amyloid formation. The mechanisms of amyloid formation by IAPP in vivo or in vitro are not well understood, and the cellular mechanisms of IAPP-induced β-cell death are not fully defined. Here, we review recent findings that illuminate the factors and mechanisms involved in β-cell proteotoxicity in diabetes. Together, these new insights have far-reaching implications for the establishment of unifying mechanisms by which pathological amyloidoses imbue their injurious effects in vivo.