Glucose-sensitive insulin with attenuation of hypoglycaemia
The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes<sup>1,2</sup>. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because 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 therefore 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<sup>3</sup>. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle<sup>4</sup> 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 for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 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.
Authors
- Daniele Granata (ORCID: https://orcid.org/0000-0001-6539-5400)
- Lene Alifrangis (ORCID: https://orcid.org/0000-0002-5356-6484)
- Michael Tomsett (ORCID: https://orcid.org/0009-0009-3246-4540)
- Christian L. Brand (ORCID: https://orcid.org/0000-0002-7355-4448)
- Simona Koščová
- A.V. Neutzsky-Wulff (ORCID: https://orcid.org/0000-0002-0577-3374)
- Bo F. Hansen
- Per Sauerberg
- Eva Johansson (ORCID: https://orcid.org/0000-0001-9330-5169)
- Michael G. Orchard (ORCID: https://orcid.org/0000-0002-0651-2571)
- Gaetano Invernizzi (ORCID: https://orcid.org/0000-0002-5737-4754)
- Christian Fledelius
- Jeppe Sturis (ORCID: https://orcid.org/0000-0001-9938-5278)
- Hanne H. F. Refsgaard (ORCID: https://orcid.org/0000-0002-4996-4084)
- Thomas Åskov Pedersen (ORCID: https://orcid.org/0000-0003-0437-9188)
- Thomas Høeg-Jensen (ORCID: https://orcid.org/0000-0003-3882-6345)
- Jonas Kildegaard (ORCID: https://orcid.org/0000-0003-0946-5587)
- Johannes Josef Fels (ORCID: https://orcid.org/0000-0002-6616-6746)
- Robert A. Tromans
- Kim Halskov (ORCID: https://orcid.org/0000-0001-7448-7577)
- Anthony P. Davis (ORCID: https://orcid.org/0000-0001-5213-624X)
- Rita Slaaby (ORCID: https://orcid.org/0000-0002-2038-8466)
- Lennart Lykke
- Daniel J. Leonard (ORCID: https://orcid.org/0000-0003-2503-0890)
- Erica Nishimura (ORCID: https://orcid.org/0000-0001-5741-3648)
- Karen‐Margrethe Pedersen (ORCID: https://orcid.org/0009-0004-0386-2391)
- Vladislav Kotek
- Guillem Peñuelas-Haro
- Thomas Kruse (ORCID: https://orcid.org/0000-0002-5756-753X)
- Andy Chapman
- Alice R. Madsen
- Peter Kresten Nielsen
Institutions
- Novo Nordisk (Denmark) (DK)
- University of Bristol (GB)
- Novametrics (United Kingdom) (GB)
- Novo Nordisk (Switzerland) (CH)
- Apigenex (Czechia) (CZ)
- Novo Nordisk (Germany) (DE)
Publication Details
- Journal
- Nature
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1038/s41586-024-08042-3
- Citations
- 43
- Primary Topic
- Diabetes Management and Research
- Type
- article
- Field-Weighted Citation Impact
- 14.67
Funders
- Novo Nordisk