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Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

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.

SUBMITTER: Chou DH

PROVIDER: S-EPMC4345600 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

Chou Danny Hung-Chieh DH Webber Matthew J MJ Tang Benjamin C BC Lin Amy B AB Thapa Lavanya S LS Deng David D Truong Jonathan V JV Cortinas Abel B AB Langer Robert R Anderson Daniel G DG

Proceedings of the National Academy of Sciences of the United States of America 20150209 8

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 insu ...[more]

PMID: 25675515

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Project description:Phenylboronic acids have emerged as synthetic receptors that can reversibly bind to cis-diols of glucose molecules. The incorporation of phenylboronic acids in hydrogels offers exclusive attributes; for example, the binding process with glucose induces Donnan osmotic pressure resulting in volumetric changes in the matrix. However, their practical applications are hindered because of complex readout approaches and their time-consuming fabrication processes. Here, we demonstrate a microimprinting method to fabricate densely packed concavities in phenylboronic acid functionalized hydrogel films. A microengineered optical diffuser structure was imprinted on a phenylboronic acid based cis-diol recognizing motif prepositioned in a hydrogel film. The diffuser structure engineered on the hydrogel was based on laser-inscribed arrays of imperfect microlenses that focused the incoming light at different focal lengths and direction resulting in a diffused profile of light in transmission and reflection readout modes. The signature of the dimensional modulation was detected in terms of changing focal lengths of the microlenses due to the volumetric expansion of the hydrogel that altered the diffusion spectra and transmitted beam profile. The transmitted optical light spread and intensity through the sensor was measured to determine variation in glucose concentrations at physiological conditions. The sensor was integrated in a contact lens and placed over an artificial eye. Artificial stimulation of variation in glucose concentration allowed quantitative measurements using a smartphone's photodiode. A smartphone app was utilized to convert the received light intensity to quantitative glucose concentration values. The developed sensing platform offers low cost, rapid fabrication, and easy detection scheme as compared to other optical sensing counterparts. The presented detection scheme may have applications in wearable real-time biomarker monitoring devices at point-of-care settings.

Dataset Information

Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

Publications

Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.

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