Insulin in disguise

People with type I diabetes need regular doses of insulin to control their blood-sugar levels. At present, insulin is administered with a pump or by daily injection, although much research has focused on developing more convenient methods of delivery. Writing in Proceedings of the National Academy of Sciences, Jerrold Olefsky, Richard Lerner and colleagues now describe preliminary studies on an insulin delivery technique that might greatly increase the interval between doses. Chemically attached masking groups are used to inactivate insulin, but the activity can be fully restored with a catalytic antibody that selectively removes the masking groups. In theory, administering the antibody with modified insulin could allow a gradual release of active insulin.

The catalytic antibody and the masking group it specifically cleaves from modified molecules were developed previously. Olefsky and colleagues compared the activity of insulin modified with the masking groups, named insulin^D, with native insulin. The affinity of insulin^D for the insulin receptor was reduced by 90%, and its ability to stimulate glucose transport in insulin-sensitive cells was reduced by 96%. These results were mirrored to some extent in a test of the ability to stimulate glucose disposal in rats, with insulin^D being 55% less effective than insulin. In all cases, pre-treatment of insulin^D with the catalytic antibody completely reversed the defect.

Much work is needed before this approach becomes therapeutically practical, in particular on the kinetics of the possible system in which insulin^D is administered in parallel with the catalytic antibody. Importantly, the versatility of the chemical modification could allow the creation of fomulations that are slowly susceptible to antibody cleavage, thus mimicking endogenous basal insulin secretion. Furthermore, the approach is generally applicable — reversible chemical modifications of a wide range of proteins could potentially be used to manipulate their half-life, distribution or activity for therapeutic advantage.