Strategies for Interference of Insulin Fibrillogenesis: Challenges and Advances

Abstract

The discovery of insulin came with very high hopes for diabetic patients. In 2021, the world celebrated the 100th anniversary of the discovery of this vital hormone. However, external use of insulin is highly affected by its aggregating tendency that occurs during its manufacturing, transportation, and improper handling which ultimately leads to its pharmaceutically and biologically ineffective form. In this review, we aim to discuss the various approaches used for decelerating insulin aggregation which results in the enhancement of its overall structural stability and usage. The approaches that are discussed are broadly classified as either a measure through excipient additions or by intrinsic modifications in the insulin native structure.

Peptide Inhibitors of Insulin Fibrillation: Current and Future Challenges

“…In addition to the development of small molecule inhibitors of amyloid fibrillation, several approaches are being investigated to improve the stability of insulin formulations, including the use of variants, glycosylation, active surfaces, additives, and so on [ 115 ]. One of the remaining challenges is that although infusion pumps are becoming more popular, they do have drawbacks.…”

Amyloid Fibrillation of Insulin: Amelioration Strategies and Implications for Translation

“…16 Such a tendency toward amyloid degeneration and formation of fibrils in vitro is also noticed when insulin is subjected to physicochemical alterations (e.g., fluctuations in pH, temperature, ionic strength), stirring/agitation, or exposure to hydrophobic surfaces (e.g., Teflon, polystyrene) due to a loss of secondary backbone. 17,18 Insulin even elicits such degeneration after coming in contact with infusion apparatus, implantable pumps, and injectable pens. 19 The insulin amyloid, although not an in vivo deposit in a strict sense, demonstrates a β-pleated structure, enhanced emission with a characteristic right shift with thioflavin-T (Th-T) fluorescence, and apple-green birefringence under polarized light upon staining with Congo Red dye.…”

Study of the kinetics and mechanism of ferrocene-tripeptide inhibiting insulin aggregation

“…In contrast, Fc-FFD and Fc-FFK show scant contact with insulin, with the spatial distribution mainly divergent away from insulin, and thus show lower ability to inhibit insulin fibrils formation. Since residues F24 B and F25 B could be crosslinked and thus promote the aggregation process 16 (proved by a 1 H-NMR study 44 ), Fc-FFY and Fc-FFF which interacted with the hydrophobic tripeptide motif (F24 B -F25 B -Y26 B ) were more efficient to hinder the intermolecular aromatic p-p interactions and prevent the hydrophobic core formation, and finally inhibit the formation of insulin fibrils.…”