File(s) under permanent embargo
Treatment of type 2 diabetes with the designer cytokine IC7Fc
journal contribution
posted on 2019-10-01, 00:00 authored by M Findeisen, T L Allen, D C Henstridge, H Kammoun, A E Brandon, L L Baggio, K I Watt, M Pal, L Cron, E Estevez, C Yang, Greg KowalskiGreg Kowalski, L O’Reilly, C Egan, E Sun, L M Thai, G Krippner, T E Adams, R S Lee, J Grötzinger, C Garbers, S Risis, M J Kraakman, N A Mellet, J Sligar, E T Kimber, R L Young, M A Cowley, Clinton BruceClinton Bruce, P J Meikle, P A Baldock, P Gregorevic, T J Biden, G J Cooney, D J Keating, D J Drucker, S Rose-John, M A FebbraioThe gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
History
Journal
NatureVolume
574Pagination
63 - 68Publisher
NatureLocation
London, Eng.Publisher DOI
ISSN
0028-0836eISSN
1476-4687Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2019, The Author(s), under exclusive licence to Springer Nature Limited.Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC