Proinsulin C-peptide interferes with insulin fibril formation

Abstract

Insulin aggregation can prevent rapid insulin uptake and cause localized amyloidosis in the treatment of type-1 diabetes. In this study, we investigated the effect of C-peptide, the 31-residue peptide cleaved from proinsulin, on insulin fibrillation at optimal conditions for fibrillation. This is at low pH and high concentration, when the fibrils formed are regular and extended. We report that C-peptide then modulates the insulin aggregation lag time and profoundly changes the fibril appearance, to rounded clumps of short fibrils, which, however, still are Thioflavine T-positive. Electrospray ionization mass spectrometry also indicates that C-peptide interacts with aggregating insulin and is incorporated into the aggregates. Hydrogen/deuterium exchange mass spectrometry further reveals reduced backbone accessibility in insulin aggregates formed in the presence of C-peptide. Combined, these effects are similar to those of C-peptide on islet amyloid polypeptide fibrillation and suggest that C-peptide has a general ability to interact with amyloidogenic proteins from pancreatic beta-cell granules. Considering the concentrations, these peptide interactions should be relevant also during physiological secretion, and even so at special sites post-secretory or under insulin treatment conditions in vivo. (C) 2012 Elsevier Inc. All rights reserved.

Keywords

Proinsulin C-peptide; Amyloid formation; Diabetes type 1; Mass spectrometry

Published in

Biochemical and Biophysical Research Communications
2012, volume: 418, number: 3, pages: 489-493
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE

SLU Authors

• Willander, Hanna

  • Karolinska Institute

• Johansson, Jan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Biochemistry
Molecular Biology

Publication identifier

• DOI: https://doi.org/10.1016/j.bbrc.2012.01.051

Permanent link to this page (URI)

https://res.slu.se/id/publ/45747