Formation Mechanism of Insulin Fibrils and Structural Aspects of the Insulin Fibrillation Process

M.      Groenning; S.      Frokjaer; B.      Vestergaard

Abstract

The therapeutic importance of gaining a thorough knowledge on insulin fibrillation in relation to type I diabetes has lead to six decades of studies focusing on its formation kinetics and structural characteristics. Insulin fibrils feature characteristics common to amyloid fibrils such as an elongated morphology, characteristic cross-β diffraction pattern, Thioflavin T fluorescence, and Congo Red birefringence. A full understanding of the fibrillation process requires structural elucidation of every species and determination of the kinetics of interconversion between species on the reaction pathway. Therefore, describing the underlying mechanism is complicated and different mechanisms have been proposed. In the recent years increased knowledge has been obtained on the importance of prefibrillar oligomeric species present during the process. A solution structure of such a species and also low-resolution structures of mature insulin fibrils have been obtained as well as high-resolution structures of two insulin hexa-peptide segments forming cross-β sheet structures. However, it still remains to be elucidated whether these cross-β structures corresponds to the structure in the fibril formed from the full-length protein. Different morphologies of insulin fibrils are observed depending on the arrangement of the protofilament, and even circular amyloids and spherulites composed of a core with many fibrils extending from it have been observed. This review will mainly focus on the structure of the species present during the insulin fibrillation process such as the partially unfolded monomeric intermediate, prefibrillar oligomeric species, and the insulin fibrils. Furthermore, it will address the formation mechanism and potential inhibition of the fibrillation process.

Keywords: Insulin, amyloid, fibrillation, nucleus, structure, oligomer, monomeric intermediate, mechanism