Glucose-sensitive insulin with attenuation of hypoglycaemia

Thomas Hoeg-Jensen, Thomas Kruse, Christian L. Brand, Jeppe Sturis, Christian Fledelius, Peter K. Nielsen, Erica Nishimura, Alice R. Madsen, Lennart Lykke, Kim S. Halskov, Simona Koščová, Vladislav Kotek, Anthony P. Davis, Robert A. Tromans, Michael Tomsett, Guillem Peñuelas-Haro, Daniel J. Leonard, Michael G. Orchard, Andy Chapman, Gaetano Invernizzi, Eva Johansson, Daniele Granata, Bo F. Hansen, Thomas A. Pedersen, Jonas Kildegaard, Karen-Margrethe Pedersen, Hanne H. F. Refsgaard, Lene Alifrangis, Johannes J. Fels, Anita V. Neutzsky-Wulff, Per Sauerberg and Rita Slaaby ()
Additional contact information
Thomas Hoeg-Jensen: Novo Nordisk
Thomas Kruse: Novo Nordisk
Christian L. Brand: Novo Nordisk
Jeppe Sturis: Novo Nordisk
Christian Fledelius: Novo Nordisk
Peter K. Nielsen: Novo Nordisk
Erica Nishimura: Novo Nordisk
Alice R. Madsen: Novo Nordisk
Lennart Lykke: Novo Nordisk
Kim S. Halskov: Novo Nordisk
Simona Koščová: APIGENEX
Vladislav Kotek: APIGENEX
Anthony P. Davis: University of Bristol
Robert A. Tromans: Carbometrics
Michael Tomsett: Carbometrics
Guillem Peñuelas-Haro: Carbometrics
Daniel J. Leonard: Carbometrics
Michael G. Orchard: Carbometrics
Andy Chapman: Carbometrics
Gaetano Invernizzi: Novo Nordisk
Eva Johansson: Novo Nordisk
Daniele Granata: Novo Nordisk
Bo F. Hansen: Novo Nordisk
Thomas A. Pedersen: Novo Nordisk
Jonas Kildegaard: Novo Nordisk
Karen-Margrethe Pedersen: Novo Nordisk
Hanne H. F. Refsgaard: Novo Nordisk
Lene Alifrangis: Novo Nordisk
Johannes J. Fels: Novo Nordisk
Anita V. Neutzsky-Wulff: Novo Nordisk
Per Sauerberg: Novo Nordisk
Rita Slaaby: Novo Nordisk

Nature, 2024, vol. 634, issue 8035, 944-951

Abstract: Abstract The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes1,2. 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 hypoglycaemia3. 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 macrocycle4 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.

Date: 2024
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DOI: 10.1038/s41586-024-08042-3

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