Engineering synthetically modified insulin for glucose-responsive diabetes therapy

Abstract

Though a suite of different insulin variants have been used clinically to provide greater control over pharmacokinetics, no clinically used insulin can tune its potency and/or bioavailability in a glucose-dependent manner. In order to improve therapy for diabetic patients, a vision has been the development of autonomous closed-loop approaches. Toward this goal, insulin has been synthetically modified with glucose-sensing groups or groups that can compete with free glucose for binding to glucose-binding proteins and evaluated in pre-clinical models. Specifically, it was demonstrated that site-specific modification of insulin with phenylboronic acid can result in glucose-responsive activity, leading to faster recovery in diabetic mice following a glucose challenge but with less observed hypoglycemia in healthy mice. This strategy, along with several others being pursued, holds promise to improve the fidelity in glycemic control with routine insulin therapy.

Keywords:

• bioartificial pancreas
• bionic pancreas
• concanavalin A
• diabetes
• drug delivery
• fully synthetic pancreas
• lectin
• phenylboronic acid

Financial & competing interests disclosure

This work was supported by a grant from Helmsley Charitable trust (award 2014PG-T1D002) received by R Langer and D Anderson along with a generous gift from the Tayebati Family Foundation received by D Anderson. It was also supported by the National Institutes of Health (NIDDK) through a Ruth L Kirschstein National Research Service Award (F32DK101335) received by M Webber. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• A number of clinically used insulin variants have demonstrated controllable pharmacokinetics, though none have activity that is tunable based on blood glucose levels.

• More closely matching natural blood glucose dynamics may reduce both the acute and chronic complications associated with diabetes.

• Multifarious efforts toward autonomous closed-loop insulin therapy have been evaluated in preclinical and clinical settings.

• Synthetic modification of the insulin protein to afford glucose-responsive insulin activity is one approach to affording glucose-responsive therapy.

• Insulin with glucose-mediated potency could be useful in both improving response to a glucose insult (i.e., meal) and limiting hypoglycemia.

• Significant efforts remain in clinical translation of glucose-responsive modified insulin to ensure safety and efficacy and to determine strategies for predictable and reliable therapy.

• There is great promise for the vision of glucose-responsive modified insulin in improving disease management, with subsequent benefits in improving quality of life and reducing co-morbidity associated with diabetes.

Notes