Glucose-sensitive insulin – one step closer towards the “holy grail” of insulin research
With current insulin therapy there is still a risk of hypoglycemia, which in certain circumstances can be life-threatening. The quest for discovering a true glucose-sensitive insulin – an insulin, which can auto-adjust its bioactivity depending on actual glucose levels in vivo – has been a long-standing aspiration in pharmaceutical research. Sometimes it is even reflected as the “holy grail” of insulin research.
Several research strategies have been tried, including the release of insulin or insulin analogs from glucose responsive biomaterials as well as bioengineered insulins binding to glucose itself or glucose dependent proteins – so far with limited success and limited translatability from in vitro to in vivo systems. Very recently researchers from Novo Nordisk reported the discovery of a novel, smartly engineered insulin, NNC2215, which is reversibly glucose responsive to a glucose range relevant for diabetes, not only in vitro but also in vivo. “(https://www.nature.com/articles/s41586-024-08042-3)” This exciting new insulin was engineered by attaching a selective glucose binding macrocycle to the B29 Lys side chain and a glycoside to the B1 amino-terminus of DesB30 human insulin. These modifications enable the molecule to adopt distinct conformations depending on the glucose level – a bioactive “open” conformation at higher glucose levels (20 mM) and a less bioactive “closed” conformation at lower glucose levels (3 mM). Excitingly, NNC2215 could also demonstrate glucose responsiveness and protection from hypoglycemia when tested in diverse animal models (rats & pigs).
The approach reported here to engineer a truly reversible, glucose responsive insulin is one of the most promising achievements in the field and should be a “must read” for every peptide & diabetes researcher, from a drug discovery but also peptide design perspective.
Open access article: (https://www.nature.com/articles/s41586-024-08042-3)
Hoeg-Jensen T, Kruse T, Brand CL, Sturis J, Fledelius C, Nielsen PK, Nishimura E, Madsen AR, Lennart L, Halskov K, Koščová S, Kotek V, Davis AP, Tromans RA, Tomsett M, Peñuelas-Haro G, Leonard DJ, Orchard MG, Chapman A, Invernizzi G, Johansson E, Granata D, Hansen BF,
Pedersen TA, Kildegaard J, Pedersen KM, Refsgaard HHF, Alifrangis L, Fels JJ, Neutzsky-Wulff, Sauerberg P & Slaaby R. Glucose-sensitive insulin with attenuation of hypoglycemia Nature 634, 944 -951 (2024).
Michael Wagner
Dewpoint Therapeutics
Member, BPF Scientific Advisory Board
https://www.linkedin.com/in/michael-wagner-a086bb15/
Read previous editions of the BPF Journal Club series: https://www.boulderpeptide.org/journal-club