Inhibition of amyloidal aggregation of insulin by amino acid conjugated bile acids: An insight into the possible role of biosurfactants in modulating the fibrillation kinetics and cytotoxicity

Insulin-induced amyloidosis, a typical example of protein fibrillation, reduces the effectiveness of insulin treatment in type-II diabetic patients, which demands intense investigations to mitigate insulin fibrillation. Herein, the inhibitory effect of two taurine conjugated bile acids [taurocholic acid (TCA) and taurodeoxycholic acid (TDCA)] towards insulin fibrillation has been elucidated using various biophysical, imaging and computational tools. TCA delays lag time of fibrillation while TDCA targets fibril elongation step and thus impeding insulin primary fibrillation. TDCA also inhibits the secondary fibrillation of insulin efficiently. The greater inhibition of both fibrillation processes is evidenced once insulin is kept with TDCA under fibrillogenic conditions. In silico studies reveal that these two bile acids interact with several aggregation-prone residues (e.g. Tyr16, Phe24, Tyr26) present at the C-terminal portion of insulin B-chain. Such interactions stabilize the native insulin structure, reduce the surface hydrophobicity and aggregate size as well as modulate the fibril morphology. Both these molecules are non-toxic and attenuate insulin fibril-induced hemolysis of erythrocytes and cytotoxicity in HepG2 cells. Overall, our findings provide novel insights to the study of amyloidal protein fibrillation and lay foundation towards the utilization of these two taurine conjugated bile acids as inhibitors of insulin fibrillation and insulin-induced amyloidosis.