Fructosylation of human insulin causes AGEs formation, structural perturbations and morphological changes: an in silico and multispectroscopic study

Fructosylation of proteins results in the formation of advanced glycation end-products (AGEs). A diet rich in fructose along with hyperglycemia can cause fructose mediated glycation (fructosylation) of proteins, which results in AGEs formation. Insulin is a peptide hormone that is glycated when exposed to carbohydrates such as glucose. In this study, we have analysed the interaction of insulin with fructose and biophysically characterized fructose modified insulin. In silico studies performed through molecular docking and molecular dynamics simulation revealed that fructose binds to insulin with strong affinity resulting in the formation of insulin-fructose complex. Fructosylation of insulin caused hyperchromicity, loss of intrinsic fluorescence, gain in AGEs specific fluorescence and elevated the carbonyl and fructosamine content. Enhanced thioflavin T fluorescence suggested the presence of fibrillar structures at higher concentrations of fructose. Electron microscopy revealed the formation of characteristic amorphous and amyloid like aggregates at lower and higher concentrations of fructose, respectively. These findings show that fructosylation of insulin causes AGEs production, aggregation and alters its gross structural integrity. These changes may reduce the biological activity of insulin that can aggravate conditions like type II diabetes mellitus. Communicated by Ramaswamy H. Sarma

Automated summary

Protein fructosylation leads to the formation of advanced glycation end-products (AGEs). A diet high in fructose, combined with hyperglycemia, can cause fructose-mediated glycation of proteins, resulting in AGEs formation. This study analyzed the interaction of insulin with fructose and characterized the modified insulin. In silico studies showed that fructose strongly binds to insulin, forming an insulin-fructose complex. Fructosylation of insulin led to changes in its structural integrity, including the formation of aggregates and the production of AGEs, potentially reducing the biological activity of insulin and exacerbating conditions like type II diabetes mellitus.