Glucose-sensitive insulin with attenuation of hypoglycaemia
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Abstract
Abstract The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes. Insulin doses must be adjusted to ensure blood glucose values within normal range, but matching insulin doses to fluctuating glucose levels is difficult since even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence which can be anything from uncomfortable to life-threatening. It has thus been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to glucose over the physiological range as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle and a glucoside to insulin, thereby introducing a “switch” that can open and close in response to glucose and thereby equilibrate insulin between active and less active conformations. The insulin receptor affinity of NNC2215 increased 12-fold when glucose concentration was increased from 0 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions.
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These agents remain in early stages of development, being used only in preclinical models.
“However, these agents remain in early stages of development, being used only in preclinical models [165, 166].”
From Diabetic gastroparesis: pathophysiology and impact on insulin timing choices (2026) · cites this paper as [165]
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- Authors
- Hoeg-Jensen, T., Kruse, T., Brand, C. L., Sturis, J., Fledelius, C., Nielsen, P. K., Nishimura, E., Madsen, A. R., Lykke, L., Halskov, K. S., Koščová, S., Kotek, V., Davis, A. P., Tromans, R. A., Tomsett, M., Peñuelas-Haro, G., Leonard, D. J., Orchard, M. G., Chapman, A., Invernizzi, G., Johansson, E., Granata, D., Hansen, B. F., Pedersen, T. A., Kildegaard, J., Pedersen, K.-M., Refsgaard, H. H. F., Alifrangis, L., Fels, J. J., Neutzsky-Wulff, A. V., Sauerberg, P., & Slaaby, R.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Apigenex (Czechia) (CZ)
- University of Bristol (GB)
- Corresponding author
- Slaaby, Rita
- ORCID
- Hoeg-Jensen, Thomas
- Kruse, Thomas
- Brand, Christian L.
- Sturis, Jeppe
- Nishimura, Erica
- Madsen, Alice R.
- Davis, Anthony P.
- Tromans, Robert A.
- Tomsett, Michael
- Peñuelas-Haro, Guillem
- Leonard, Daniel J.
- Orchard, Michael G.
- Invernizzi, Gaetano
- Johansson, Eva
- Granata, Daniele
- Kildegaard, Jonas
- Pedersen, Karen-Margrethe
- Refsgaard, Hanne H. F.
- Alifrangis, Lene
- Fels, Johannes J.
- Neutzsky-Wulff, Anita V.
- Slaaby, Rita
- Venue
- Nature
- Published
- 2024-10-16
- Volume
- 634
- Issue
- 8035
- Pages
- 944-951
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11499270
- OpenAlex
- W4403450838
- Cited by
- 65
- References
- 39
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 5 · 2023: 1 · 2021: 1 · 2014: 1
- FWCI
- 20.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by-nc-nd)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- hypoglycemia prevention, glucosides, insulin receptor affinity, diabetes mellitus, glycemic control, glucose-responsive insulin
- MeSH terms
- Animals, Blood Glucose, Female, Glucose, Glucosides, Humans, Hypoglycemia, Insulin, Male, Receptor, Insulin, Swine, Rats, Sprague-Dawley, Macrocyclic Compounds, Mice, Rats
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