TOWARD UNDERSTANDING INSULIN FIBRILLATION

Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear agg regates. Shielding of hydrophobic domains is the main driving force fo r this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues , including A2, A3, B11, and B15, plays a crucial role in the fibrilla tion process. Recent crystal analyses and molecular modeling studies h ave suggested that when insulin fibrillates this exposed domain intera cts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils d id not elicit an increased immune response with respect to formation o f IgG insulin antibodies when compared with native insulin. In contras t, the IgE response increased with increasing content of insulin in fi brillar form. Strategies and practical approaches to prevent insulin f rom forming fibrils are reviewed. Stabilization of the insulin hexamer ic structure and blockage of hydrophobic interfaces by addition of sur factants are the most effective means of counteracting insulin fibrill ation.