Insulin complexation with curcumin derivative mitigates the protein amyloidosis and efficiently manages diabetes in Drosophila melanogaster

Abstract

Insulin, a peptide hormone commonly used in the therapeutic management of diabetes mellitus, is anticipated to aggregate at sites of recurrent injections in diabetic patients. These aggregates are comprised of insoluble insulin fibrils, which can lead to localized inflammatory reactions and impaired insulin uptake. Therefore, it is essential to formulate strategies inhibiting the insulin fibrillation for better therapeutic applications. The phytochemicals, that exhibit anti-fibrillating properties, have shown a promising efficacy in mitigating insulin amyloidosis. Hence, the effects of Mangiferin (Mg), Rosmarinic Acid (RA), and Curcumin Cysteine Complex (CCC) are explored for insulin anti-fibrillating potentials at physiological pH. CCC and RA efficiently inhibit insulin fibrillation in a dose-dependent manner by binding to the aggregation-prone regions of the protein, suggesting a plausible mechanism for their anti-fibrillating potentials. In vivo findings revealed that treatments with the insulin-phytochemical formulations are more therapeutically effective in mitigating diabetic traits in Drosophila than monomeric insulin alone. Among the studied phytochemicals, insulin formulation with CCC showed the most pronounced efficacy in restoring the normal physiology in HSF-induced diabetic flies. Thus, CCC presence in insulin formulation offers a promising strategy to further stabilize the formulations against in vitro and in vivo insulin amyloidosis.