Molecular variants and derivatives of insulin for improved glycemic control in diabetes

Insulin is a historic molecule. It presents many first instances, such as the first protein to be fully sequenced, one of the first proteins to be crystallized in pure form, one among the early proteins whose structure was investigated using X-ray crystallography, the first protein to be chemically synthesized and the first Biotech drug. Therefore, the development of insulin in the early years is intricately intertwined with the progress in molecular and structural biology. In recent years, development of a range of insulin analogs has led to better control of glucose levels, thus preventing secondary complications and improving the quality of life in diabetic patients. Such analogs were obtained by modification of the native insulin sequence. They vary with regard to their pharmacokinetic profile, stability, tissue specificity and mode of administration. In addition, alterations involving incorporation of various chemical moieties in insulin and its co-crystallization with insoluble derivatives are used to modulate the time-action profile of the drug. This article traces the development of molecular variants and derivatives of insulin. It discusses future directions for further improvement in their properties to produce still better insulin therapeutics for tight glycemic control.