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Treatment of type 2 diabetes with the designer cytokine IC7Fc

Findeisen, M, Allen, TL, Henstridge, DC ORCID: 0000-0003-4988-767X, Kammoun, H, Brandon, AE, Baggio, LL, Watt, KL, Pal, M, Cron, L, Estevez, E, Yang, C, Kowalski, GM, O'Reilly, L, Egan, C, Sun, E, Thai, LM, Krippner, G, Adams, TE, Lee, RS, Grotzinger, J, Garbers, C, Risis, S, Kraakman, MJ, Mellet, NA, Sligar, J, Kimber, ET, Young, RL, Cowley, MA, Bruce, CR, Meikle, PJ, Baldock, PA, Gregorevic, P, Biden, TJ, Cooney, GJ, Keating, DJ, Drucker, DJ, Rose-John, S and Febbraio, MA 2019 , 'Treatment of type 2 diabetes with the designer cytokine IC7Fc' , Nature, vol. 574, no. 7776 , pp. 63-68 , doi: 10.1038/s41586-019-1601-9.

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The 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.

Item Type: Article
Authors/Creators:Findeisen, M and Allen, TL and Henstridge, DC and Kammoun, H and Brandon, AE and Baggio, LL and Watt, KL and Pal, M and Cron, L and Estevez, E and Yang, C and Kowalski, GM and O'Reilly, L and Egan, C and Sun, E and Thai, LM and Krippner, G and Adams, TE and Lee, RS and Grotzinger, J and Garbers, C and Risis, S and Kraakman, MJ and Mellet, NA and Sligar, J and Kimber, ET and Young, RL and Cowley, MA and Bruce, CR and Meikle, PJ and Baldock, PA and Gregorevic, P and Biden, TJ and Cooney, GJ and Keating, DJ and Drucker, DJ and Rose-John, S and Febbraio, MA
Keywords: diabetes, drug, IL-6
Journal or Publication Title: Nature
Publisher: Nature Publishing Group
ISSN: 0028-0836
DOI / ID Number: 10.1038/s41586-019-1601-9
Copyright Information:

© The Author(s), under exclusive licence to Springer Nature Limited 2019

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