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.

Keywords: Glucose binders; Hypoglycaemia; Insulin conjugates; Polymers; Stability; Time lag; Toxicity.

Figure 1

Carbohydrate-sensitive insulin multihexamers. Reprinted with permission from J. Am. Chem. Soc. 2005, 127, 6158–6159. Copyright 2005 American Chemical Society.

Figure 2

MK-2640 and its balanced clearance between MR and HIR. Reprinted with permission from Diabetes 2018, 678, 299–30. Copyright 2018 American Diabetes Association.

Figure 3

Early diagram of how a glucose-sensitive switch might work.

Figure 4

Davis' glucose-binding macrocycles 1 and 2.

Figure 5

Boronate fatty acid insulin for glucose-sensitive albumin binding.

Figure 6

Glucose exists in water as 99% hemiacetal and 1% aldehyde.