Inhibition of insulin amyloid fibril formation by cyclodextrins

Abstract

Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.

Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity

“…In vitro insulin amyloid fibrils are formed under certain destabilizing environments, such as high temperature, increased ionic strength, exposure to hydrophobic surface, low pH, and shaking (Jansen et al, 2005 ; Jayamani and Shanmugam, 2014 ; Kitagawa et al, 2015 ). It is still under argument that either an intermolecular hydrophobic force or electrostatic attraction is responsible for the amyloidogenesis.…”

A novel age‐related venous amyloidosis derived from EGF‐containing fibulin‐like extracellular matrix protein 1

“…EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process.We investigated the morphology of amyloid fibrils in ultra-thin sections with an electron microscope, as described previously [19] and explained in supplementary material, Supplementary materials and methods.…”

Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

“…[55] The effects of CyDs were investigated against the formation of amyloid fibrils derived from human insulina nd different insulin analogues (e.g.,a spart and detemir,r espectively,f ast and slow acting) with different hydrophobicities by the ThT assay and TEM. [56] In particular,H P bCyD and bCyDGlcAGlc were added to insulin during the formation of aggregates. HPbCyD inhibitedi nsulin detemira ggregation more effectively than bCyDGlgAGlc, whereas bCyDGlgAGlc was more effective in inhibiting insulin aspart aggregation.Both CyDs slightly inhibited human insulin aggregation.…”