INSULIN FIBRILLATION AND ROLE OF PEPTIDES AND SMALL MOLECULES IN ITS INHIBITION PROCESS

Insulin is a peptide hormone produced in the pancreas and plays a vital role in the metabolism of fats and carbohydrates in the human body. Like many other proteins, insulin can undergo slow structural transition from α-helix-rich conformation to a β-sheet form forming fibrillar association structures. Such association, however, leads to loss of function of the proteins. Fibrillation of insulin can seriously limit its therapeutic efficacy against type 2 diabetes. Fibrils are usually toxic, and insulin fibrillation can also lead to toxicity in humans. In order to reduce fibril-associated toxicity and enhance therapeutic potential of insulin, it is highly desirable to develop strategies to reduce the fibrillation potential of insulin. Detailed mechanistic study of insulin fibrillation revealed that the key step in the fibrillation process is the dissociation of the various oligomeric forms to the monomeric form. Attempts have therefore been made to identify molecules that can interfere with the dissociation process and thus delay the fibrillation kinetics. Several hybrid peptides could delay such fibrillation process of insulin. Using a hydrophobic peptide NK9, structural insight into the peptide-binding region of the insulin was obtained. Many other molecules such as polycyclic aromatic compounds and trifluoroethanaol were also found to be effective in delaying the fibrillation of insulin.