Glucose-responsive insulin by molecular and physical design

  • An Erratum to this article was published on 19 December 2017

Abstract

The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.

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Figure 1: Evaluating parameters in a physiological model.
Figure 2: A schematic of a microneedle patch loaded with hypoxia-sensitive polymeric vesicles for glucose-responsive insulin delivery.
Figure 3: Designed engineered constructs.

Change history

  • 24 November 2017

    In the version of this Perspective originally published, the affiliations for authors Zhen Gu and Sanjoy Dutta were not correct, they should have read: Zhen Gu3,4,5, Sanjoy Dutta6. 3Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, USA. 4Pharmacoengineering and Molecular Pharmaceutics Division, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. 5Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA. 6JDRF International, New York, New York 10004, USA.

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Acknowledgements

The authors would like to acknowledge the Joint JDRF and Helmsley Charitable Trust sponsored Workshop on 'Design and Development of Glucose Responsive Insulins' held in New York, April 2016. The American Diabetes Association (ADA; 1-15-ACE-21) and the JDRF Diabetes Foundation (3-SRA-2015-117-Q-R; 2-SRA-2016-269-A-N); the Leona M. and Harry B. Helmsley Charitable trust (Award 2014PG-T1D002). All correspondence and requests for materials should be addressed to M.S.S.

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N.B. and A.C. compiled and edited the paper. N.B. and M.S. contributed to the mathematical modelling. Z.G. contributed to the section of Biomimetic GRI formulations. A.C., M.W., S.D., D.A. and R.L. contributed to the section on engineered insulins with glucose recognition. All authors discussed and commented on the manuscript.

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Correspondence to Michael S. Strano.

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Bakh, N., Cortinas, A., Weiss, M. et al. Glucose-responsive insulin by molecular and physical design. Nature Chem 9, 937–944 (2017). https://doi.org/10.1038/nchem.2857

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