Effects of confinement on insulin amyloid fibrils formation.
Insulin, a 51-residue protein universally used in diabetes treatment, is known to produce amyloid fibrils at high temperature and acidic conditions. As for other amyloidogenic proteins, the mechanisms leading to nucleation and growth of insulin fibrils are still poorly understood. We here report a study of the fibrillation process for insulin confined in a suitable polymeric hydrogel, with the aim of ascertain the effects of a reduced protein mobility on the various phases of the process. The results indicate that, with respect to standard aqueous solutions, the fibrillation process is considerably slowed down at moderately high concentrations and entirely suppressed at low concentration. Moreover, the analysis of the initial stages of the fibrillation process in aqueous solutions revealed a large spatial heterogeneity, which is completely absent when the fibrillation is carried out in the hydrogel. We attribute this heterogeneity to the diffusion in solution of large amyloidal aggregates, which must be formed very fast compared to the average times for the whole sample. These findings are interpreted in the framework of recently suggested heterogeneous nucleation mechanisms. Moreover, they may be useful for the development of new insulin pharmaceutical formulations, more stable against adverse conditions.
Librizzi
Fabio
F
Dipartimento di Scienze Fisiche e Astronomiche, Università di Palermo, Via Archirafi 36, Palermo, Italy. librizzi@fisica.unipa.it
Foderà
Vito
V
Vetri
Valeria
V
Lo Presti
Caterina
C
Leone
Maurizio
M
D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000737:chemistry*; D011142:Polyvinyl Alcohol / Q000737:chemistry; D013696:Temperature
D000682:Amyloid; D007328:Insulin; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011142:Polyvinyl Alcohol