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Insulin Fibril Nucleation: The Role of Prefibrillar Aggregates

M. I. Smith ^*, J. S. Sharp ^* and C. J. Roberts 

^* School of Physics and Astronomy and Nottingham Nanotechnology and Nanoscience Centre, and Laboratory of Biophysics and Surface Analysis, School of Pharmacy and Nottingham Nanotechnology and Nanoscience Centre, University of Nottingham, Nottingham, United Kingdom

Correspondence: Address reprint requests to J. S. Sharp, Tel.: 44-0-115-951-5142; E-mail: james.sharp{at}nottingham.ac.uk.

Dynamic light scattering and Fourier transform infrared spectroscopy were used to study the formation of prefibrillar aggregates and fibrils of bovine pancreatic insulin at 60°C and at pH 1. The kinetics of disintegration of the prefibrillar aggregates were also studied using these techniques after a quench to 25°C. These experiments reveal that formation of prefibrillar aggregates is reversible under the solution conditions studied and show that it is possible to significantly reduce the nucleation (lag) times associated with the onset of fibril growth in bovine pancreatic insulin solutions by increasing the concentration of prefibrillar aggregates in solution. These results provide convincing evidence that less structured prefibrillar aggregates can act as fibril-forming intermediates.