Effect of Pressure on Islet Amyloid Polypeptide Aggregation: Revealing the Polymorphic Nature of the Fibrillation Process

Type II diabetes mellitus is a disease which is characterized by peripheral insulin resistance coupled with a progressive loss of insulin secretion that is associated with a decrease in pancreatic islet β-cell mass and the deposition of amyloid in the extracellular matrix of β-cells, which lead to islet cell death. The principal component of the islet amyloid is a pancreatic hormone called islet amyloid polypeptide (IAPP). High-pressure coupled with FT-IR spectroscopic and AFM studies were carried out to elucidate further information about the aggregation pathway as well as the aggregate structures of IAPP. To this end, a comparative fibrillation study of IAPP fragments was carried out as well. As high hydrostatic pressure (HHP) is acting to weaken or even prevent hydrophobic self-organization and electrostatic interactions, application of HHP has been used as a measure to reveal the importance of these interactions in the fibrillation process of IAPP and its fragments. IAPP preformed fibrils exhibit a strong polymorphism with heterogeneous structures, a large population of which are rather sensitive to high hydrostatic pressure, thus indicating a high percentage of ionic and hydrophobic interactions and loose packing of these species. Conversely, fragments 1−19 and 1−29 are resistant to pressure treatment, suggesting more densely packed aggregate structures with less void volume and strong cooperative hydrogen bonding. Furthermore, the FT-IR data indicate that fragment 1−29 has intermolecular β-sheet conformational properties different from those of fragment 1−19, the latter exhibiting polymorphic behavior with more disordered structures and less strongly hydrogen bonded fibrillar assemblies. The data also suggest that hydrophobic interactions and/or less efficient packing of amino acids 30−37 region leads to the marked pressure sensitivity observed for full-length IAPP.