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

Abstract

Insulin replacement therapy for diabetes mellitus seeks to minimise excursions in blood glucose concentration above or below the therapeutic range (hyper-or hypoglycaemia). To mitigate acute and chronic risks of such excursions, glucose-responsive insulindelivery technologies have long been sought for clinical application in type 1 and long-standing type 2 diabetes mellitus. Such 'smart' systems or insulin analogues seek to provide hormonal activity proportional to blood glucose levels without external monitoring. This review highlights three broad strategies to co-optimise mean glycaemic control and time in range: (1) coupling of continuous glucose monitoring (CGM) to delivery devices (algorithm-based 'closed-loop' systems); (2) glucose-responsive polymer encapsulation of insulin; and (3) mechanism-based hormone modifications. Innovations span control algorithms for CGM-based insulin-delivery systems, glucose-responsive polymer matrices, bio-inspired design based on insulin's conformational switch mechanism upon insulin receptor engagement, and glucose-responsive modifications of new insulin analogues. In each case, innovations in insulin chemistry and formulation may enhance clinical outcomes. Prospects are discussed for intrinsic glucose-responsive insulin analogues containing a reversible switch (regulating bioavailability or conformation) that can be activated by glucose at high concentrations.

Structural principles of insulin formulation and analog design: A century of innovation

“…Such glucose-responsive insulins (GRIs) thus define a major and long-standing goal in molecular pharmacology (for recent reviews, see [ [173] , [174] , [175] ]. Intrinsic (or unimolecular) GRIs envisage a modified hormone whose bioavailability or activity is glucose-dependent [ 25 ]. Potential technologies include sequestration of the insulin analog within a glucose-dependent SQ depot or circulating inactive complex, released under conditions of hyperglycemia.…”

“…We envisage that in the next decade, a continuing interplay between foundational and translational studies will enable new therapeutic approaches and treatment technologies for Type 1 and Type 2 diabetes mellitus (T1D and T2D) [ 23 ]. These frontiers promise to integrate protein engineering with systems biology and molecular physiology to address yet-unmet clinical needs [ 24 , 25 ].…”

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

“…Using glucose-responsive insulin (GRI), which only acts in the hyperglycemic milieu without causing hypoglycemia, would be the most ideal option for insulin treatment. However, developing ‘smart’ insulin requires advances in various fields, such as formulation chemistry, protein engineering, glucose-sensing technology, and delivery devices, and many challenges still exist [ 83 ]. Because blood glucose levels fluctuate rapidly, a fast-responding system without a time lag is necessary.…”

“…There are two broad classes of molecular GRIs: (1) polymer-based systems, which consist of insulin contained within a glucose-responsive polymeric matrix-based vesicle or hydrogel composed of glucose-binding proteins, glucose oxidase, or boronate- based chemistries, and (2) molecular-based bioconjugation systems, which introduce a glucose-sensitive motif (phenylboronic acid, glucosamine, or mannose) to the insulin molecule or its formulation. The characteristics of various GRIs have been extensively reviewed in recently published papers [ 83 , 86 ]. Although these elegant strategies remain in the early stage of development, continued progress is expected.…”

Celebrating 100 years of insulin

“…Developing the 'technology' theme, Weiss and colleagues [10] take us into the fascinating world of 'smart' insulindelivery devices and molecular technologies designed to exploit feedback regulation. Whilst current pump-based closed-loop systems exploit algorithmic control based on the output of a continuous glucose monitor, the authors highlight the promise of molecular strategies to provide intrinsic in vivo feedback based on glucose-regulated insulin bioavailability or bioactivity.…”