Insulin is a small protein with 51 residues that mediates glucose uptake, and an interesting model for studying protein misfolding and aggregation. The aggregated forms of insulin undergo loss of activity and can provoke unwanted immune responses. Use of small molecules is considered to be an affordable method to counteract this aggregation process and stabilize insulin. In this study, aggregated forms of human recombinant insulin have been produced following exposure to high temperature. Aggregation process was followed over time by checking absorbance with spectrophotometry in presence and absence of various concentrations of small phenolic compounds including eugenol and epinephrine. Effects of these compounds on the structure and function of incubated insulin were evaluated by spectrofluorimetry, melting temperature (Tm) measurement and insulin tolerance test on Wistar rats. Formation of heat-induced insulin aggregation can be effectively inhibited by 1 mM eugenol and epinephrine and both compounds were found to preserve insulin activity to a considerable extent. In conclusion, simple aromatic compounds could be tailored to act as potent anti-aggregation compounds for insulin. (C) 2019 Elsevier Inc. All rights reserved.