Review: Glucose-sensitive insulin

Abstract

Background Hypoglycemia, the condition of low blood sugar, is a common occurance in people with diabetes using insulin therapy. Protecting against hypoglycaemia by engineering an insulin preparation that can auto-adjust its biological activity to fluctuating blood glucose levels has been pursued since the 1970s, but despite numerous publications, no system that works well enough for practical use has reached clinical practise. Scope of review This review will summarise and scrutinise known approaches for producing glucose-sensitive insulin therapies. Notably, systems described in patent applications will be extensively covered, which has not been the case for earlier reviews of this area. Major conclusions The vast majority of published systems are not suitable for product development, but a few glucose-sensitive insulin concepts have recently reached clinical trials, and there is hope that glucose-sensitive insulin will become available to people with diabetes in the near future.

The future of insulin therapy

“…Glucose-responsive insulins (GRIs) that only act when blood glucose levels are high are considered to be the ''holy grail" of insulin therapy [35]. Indeed, an insulin that would ''automatically" keep blood glucose in a target range of about 4 to 10 mmol/l and would safely avoid hypoglycaemia without the need of tedious and error-prone dose titration would abolish most of the adverse effects of insulin.…”

“…These challenges include the narrow blood glucose target range and the required high affinity and selectivity (e.g. towards fructose and lactate) of the glucose-binding moiety to a relatively small and polar molecule [35]. In addition, activation and inactivation of insulin needs to happen very fast to avoid hypoglycaemia and pronounced hyperglycaemia.…”

“…A critical review of all these developments are beyond the scope of this paper, but excellent reviews on this topic are already available, e.g. [35,39,40]. In general, GRIs often use glucose-oxidase, glucose-binding proteins (e.g., lectins like concanavalin A (ConA) or oligomannosyl-insulin conjugates) or other glucose-blinding molecules (e.g., boronate-based entities like phenylboronic acid [PBA]) for glucose sensing [41].…”

“…For instances, microneedle patches for transdermal delivery have been proposed [42] which would solve potential toxicity issues. However, lag time of glucose and insulin transport from the blood compartment to the patch might be an issue with this approach as well as insulin capacity and mechanical robustness [35].…”

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

“…Like endogenous beta cells, such systems (broadly designated GRIs) would provide insulin activity proportionate to the metabolic state. Accordingly, the GRI concept has attracted the attention of the research community [24][25][26][27] and funders [28,29] alike.…”