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

• Published in: Diabetologia 2021-05, Vol.64 (5), p.1016-1029
• Main Authors: Jarosinski, Mark A., Dhayalan, Balamurugan, Rege, Nischay, Chatterjee, Deepak, Weiss, Michael A.
• Format: Article
• Language: English
• Subjects: Algorithms; Bioavailability; Blood glucose; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood Glucose Self-Monitoring - instrumentation; Blood Glucose Self-Monitoring - trends; Blood levels; Conformation; Control algorithms; Diabetes; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Glucose; Glucose - metabolism; Glucose - pharmacology; Glucose monitoring; Human Physiology; Humans; Hypoglycemia; Insulin; Insulin - administration & dosage; Insulin - analogs & derivatives; Insulin 100 – celebrating 100 years of insulin; Insulin Infusion Systems - trends; Internal Medicine; Inventions - trends; Medicine; Medicine & Public Health; Metabolic Diseases; Pancreas, Artificial - trends; Polymers; Review; Technological change
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-021-05422-6

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 insulin-delivery 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. Graphical abstract