Insulin is a key hormone regulating glucose homeostasis, intimately associated with glycemia and is exposed to glycation by glucose, reducing sugars and other highly reactive carbonyls, particularly in diabetes. Glycation of insulin has been reported to differentially affect protein structure, stability and aggregation depending on the glycating agent and experimental conditions. Under reducing conditions glycation produces higher insulin oligomerization thus accelerating amyloid formation whereas, in non-reducing conditions, glycation inhibits amyloid formation. To better detail the effect of glycation on insulin malfunction and toxicity, we investigated the effect of another glycating agent, the D-ribose. Recently, ribosylation has received great interest due to its role in protein glycation and its consequential effects such as protein aggregation, oxidative stress and cell death. Moreover, unusual high concentration of D-ribose has been detected in the urine of type II diabetics. Our results showthat, using ribose, as glycating agent, the insulin conformation is preserved and does not evolve in amyloid aggregates because of the block of the a helix to ß-sheet transition, which initiates the aggregation process, maintaining the protein in a soluble state. At the same time, ribose-glycated insulin strongly affects the cell viability, starting a death pathway consisting in the activation of caspases 9 and 3/7, intracellular ROS production and activation of the transcription factor NF kB.
Iannuzzi, C., Borriello, M., Carafa, V., Altucci, L., Vitiello, M., Balestrieri, M. L., … Sirangelo, I. (2016). D-ribose-glycation of insulin prevents amyloid aggregation and produces cytotoxic adducts. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1862(1), 93–104. https://doi.org/10.1016/j.bbadis.2015.10.021