On the environmental factors affecting the structural and cytotoxic properties of IAPP peptides

Pancreatic islets in type 2 diabetesmellitus (T2DM) patients are characterized by reduced ?-cells mass, increased ?-cells apoptosis, and diffuse extracellular amyloidosis.Amyloid deposition involves the aggregation of the islet amyloid polypeptide (IAPP) which is a neuropancreatic hormone cosecreted with insulin by ?-cells. IAPP is physiologically involved in glucose homeostasis, but it may turn toxic to ?-cells owing to its tendency to misfold giving rise to oligomers and amyloid fibrils. Despitemany studies dealing with this issue, the process by which the natively unfolded IAPP starts to self-assemble and the overall factors promoting this conversion are still poorly understood. The process of IAPP aggregation in vivo is harmful to pancreatic ?-cells but the nature of the IAPP toxic species, what exactly causes ?-cell damage and how ?-cells die, remains elusive. Over the last decades, there has been growing consensus about the notion that early stage molecular assemblies, notably small hIAPP oligomers, are the culprit of ?-cells decline. Some studies have pointed out how numerous environmental factors might affect "in vivo" the conformational features, as well as the aggregation and the cytotoxic properties of IAPP. Herein we review recent progress in the field, focusing our attention on the influences that membranes, pH, and metal ions may have on the conformational conversion and cytotoxicity of full-length IAPP as well as some peptide fragments. Thereafter, current theories proposed for the mechanisms of toxicity will be also summarized together with an outline of the underlying molecular links between IAPP and amyloid beta (A?) misfolding.