Elevated circulating follistatin associates with an increased risk of type 2 diabetes
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Published:2021-11-10
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wu Chuanyan, Borné Yan, Gao Rui, López Rodriguez Maykel, Roell William C., Wilson Jonathan M.ORCID, Regmi Ajit, Luan Cheng, Aly Dina Mansour, Peter Andreas, Machann JürgenORCID, Staiger Harald, Fritsche Andreas, Birkenfeld Andreas L.ORCID, Tao Rongya, Wagner RobertORCID, Canouil MickaëlORCID, Hong Mun-GwanORCID, Schwenk Jochen M.ORCID, Ahlqvist EmmaORCID, Kaikkonen Minna U.ORCID, Nilsson PeterORCID, Shore Angela C.ORCID, Khan Faisel, Natali Andrea, Melander Olle, Orho-Melander Marju, Nilsson JanORCID, Häring Hans-Ulrich, Renström Erik, Wollheim Claes B., Engström Gunnar, Weng Jianping, Pearson Ewan R., Franks Paul W.ORCID, White Morris F., Duffin Kevin L., Vaag Allan Arthur, Laakso MarkkuORCID, Stefan NorbertORCID, Groop LeifORCID, De Marinis YangORCID
Abstract
AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
Funder
Vetenskapsrådet Stiftelsen för Strategisk Forskning European Foundation for the Study of Diabetes
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference36 articles.
1. Hansen, J. et al. Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation. Diabetes Metab. Res Rev. 29, 463–472 (2013). 2. Yndestad, A. et al. A complex role of activin A in non-alcoholic fatty liver disease. Am. J. Gastroenterol. 104, 2196–2205 (2009). 3. Jones, K. L. et al. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc. Natl Acad. Sci. USA 104, 16239–16244 (2007). 4. Lee, S. J. Quadrupling muscle mass in mice by targeting TGF-beta signaling pathways. PLoS One 2, e789 (2007). 5. Medeiros, E. F., Phelps, M. P., Fuentes, F. D. & Bradley, T. M. Overexpression of follistatin in trout stimulates increased muscling. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R235–R242 (2009).
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