Jarosinski, Mark A.Dhayalan, BalamuruganRege, NischayChatterjee, DeepakWeiss, Michael A.2022-10-272022-10-272021-05Jarosinski MA, Dhayalan B, Rege N, Chatterjee D, Weiss MA. 'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues. Diabetologia. 2021;64(5):1016-1029. doi:10.1007/s00125-021-05422-6https://hdl.handle.net/1805/30425Insulin 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.en-USPublisher PolicyArtificial pancreasGlucose sensorGlucose-responsive insulinGlucose-responsive polymersHormone-receptor recognitionArticle