Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates
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Chou-2015-Glucose-responsive i.pdf
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Author(s)
Chou, Danny Hung-Chieh
Tang, Benjamin C.
Lin, Amy B.
Thapa, Lavanya S.
Deng, David
Truong, Jonathan V.
Webber, Matthew
Cortinas, Abel Bryan
Anderson, Daniel Griffith
Langer, Robert S
Date Issued
February 2015
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Chou, Danny Hung-Chieh, Matthew J. Webber, Benjamin C. Tang, Amy B. Lin, Lavanya S. Thapa, David Deng, Jonathan V. Truong, Abel B. Cortinas, Robert Langer, and Daniel G. Anderson. “Glucose-Responsive Insulin Activity by Covalent Modification with Aliphatic Phenylboronic Acid Conjugates.” Proc Natl Acad Sci USA 112, no. 8 (February 9, 2015): 2401–2406.
Version
Final published version
Abstract
Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1073/pnas.1424684112
