Molecular Crosstalk between Artificial Sweetener Aspartame and Diabetes-Linked Insulin Hormone Unveils Possible Amyloidosis Risks

An important adaptation for diabetes patients is the consumption of artificial sweetener aspartame, which is present in more than thousands of food products and medicines. Several studies have shown diverse side effects of aspartame, and it is also known to form amyloid-like cytotoxic and cross-seeding-competent nanostructures. Here, we reveal a direct crosstalk between aspartame and insulin that induces their cross-seeding and coaggregation events. Insulin’s cross-β structure possesses high affinity for aspartame and triggers its self-assembly into cytotoxic nanostructures. Likewise, aspartame nanostructures were found to trigger the amyloid aggregation of insulin. The coaggregates of aspartame and insulin display amyloid-like structural and biophysical characteristics, and possess potential to initiate cross-seeding reactions. Importantly, unlike insulin fibrils, the aspartame–insulin coassembled fibrils were found to be peptidase-resistant and cytotoxic. The results indicate the interplay between insulin fibrillation and aspartame aggregation, which signifies a possible link between the progression of diabetes-associated complications and the consumption of aspartame.