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 glucosebinding modified insulin molecule with glucose-responsive activity verified in vivo.diabetes | protein modification | molecular engineering | glucose sensing | smart therapy

Supramolecular PEGylation of biopharmaceuticals

“…All insulin formulations reduced average blood glucose to a normoglycemic level (<200 mg/dL for a mouse) following a single s.c. administration. The slope of this initial drop in blood glucose appears independent of formulation and likely arises from the reported dose-independent sensitivity of the streptozotocin (STZ) mouse model for administered insulin at short time intervals following administration (38). Animals that received either recombinant insulin or insulin formulated with CB [7] became hyperglycemic again ∼2 h following administration.…”

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

“…The matrix can undergo structural transformations (i.e., shrink, swell, dissociate) regulated by glucose concentration changes, leading to glucose-stimulated insulin release (11)(12)(13)(14). The typical glucose-sensing moieties include phenylboronic acid (PBA), glucose-binding protein (GBP), and glucose oxidase (GO x ) (12)(13)(14)(15)(16)(17)(18)(19)(20). Despite these available sensing chemistries, the majority of existing synthetic closed-loop systems have only been studied in vitro, with relatively few showing applicability in vivo due to specific challenges for each glucose-sensing strategy.…”

Smart nanosystems: Bio-inspired technologies that interact with the host environment

“…These technologies are able to tune the blood glucose levels to desirable levels for longer periods of time relative to nonresponsive insulin delivery in a diabetic mouse model (48,49). Finally, insulin itself has been engineered with a glucose-binding switch, allowing for glucose-mediated activation of insulin in the blood in a single molecule formulation (50).…”