@article{0a53c75edc1d4c97811a091cc48a4e18,
title = "Elevated circulating follistatin associates with an increased risk of type 2 diabetes",
abstract = "The 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.",
keywords = "Genome-wide association studies, Type 2 diabetes",
author = "Chuanyan Wu and Yan Born{\'e} and Rui Gao and {L{\'o}pez Rodriguez}, Maykel and Roell, {William C.} and Wilson, {Jonathan M.} and Ajit Regmi and Cheng Luan and Aly, {Dina Mansour} and Andreas Peter and J{\"u}rgen Machann and Harald Staiger and Andreas Fritsche and Birkenfeld, {Andreas L.} and Rongya Tao and Robert Wagner and Micka{\"e}l Canouil and Hong, {Mun Gwan} and Schwenk, {Jochen M.} and Emma Ahlqvist and Kaikkonen, {Minna U.} and Peter Nilsson and Shore, {Angela C.} and Faisel Khan and Andrea Natali and Olle Melander and Marju Orho-Melander and Jan Nilsson and H{\"a}ring, {Hans Ulrich} and Erik Renstr{\"o}m and Wollheim, {Claes B.} and Gunnar Engstr{\"o}m and Jianping Weng and Pearson, {Ewan R.} and Franks, {Paul W.} and White, {Morris F.} and Duffin, {Kevin L.} and Vaag, {Allan Arthur} and Markku Laakso and Norbert Stefan and Leif Groop and {De Marinis}, Yang",
note = "Funding Information: This study was supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039; and the Swedish Foundation for Strategic Research Dnr IRC15-0067. The authors acknowledge the information provided by the National Diabetes Register of Sweden, the Malm{\"o} HbA1c register, the Diabetes 2000 registry, and the registers provided by the Swedish Board of Health and Welfare. The research leading to these results has received funding from the European Community{\textquoteright}s Seventh Framework Programme (FP7/ 2007-2013) for the Innovative Medicines Initiative under grant agreement n° 115006, the SUMMIT consortium. Furthermore, the research was supported with a project grant from the Swedish Research Council to LG (2015-02558), and a European Foundation for the Study of Diabetes (EFSD) grant and Hjelt Foundation grant to YDM. The study was also funded by the Swedish Heart–Lung Foundation (Grant No. 2017-0626, 20170520 and 20180640), the Swedish Research Council (VR 201502811, 2017-02688), the Novo Nordisk Foundation (NNF18OC0034408), and Diabetes Wellness Sweden (25-420 PG). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115974 (BEAt-DKD). This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and EFPIA with JDRF. The IMI-DIRECT cohorts were supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115317 (DIRECT), resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in-kind contribution. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and EFPIA. This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 16.0097. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies. Financial support has been given to the Malm{\"o} Diet and Cancer Study by the Swedish Cancer Foundation, the Swedish Medical Research Council, the European Commission, the City of Malm{\"o}, the Swedish Dairy Association and the Albert P{\aa}hlsson Foundation. We also acknowledge support from a Lund University Infrastructure grant: “Malm{\"o} Population-Based cohorts” (STYR 2019/2046). This study included data from register linkage with the National Diabetes Register (NDR) of Sweden, a register containing data from both hospital care and primary health care for patients with diabetes. CW and RG were supported by the National Natural Scientific Foundation of China (NSFC) under Grant U1806202 and 61533011. ACS was supported by the NIHR Exeter Clinical Research Facility; the views expressed here are those of the authors and not those of the UK Department of Health or NIHR. NS is currently supported by a Heisenberg-Professorship of the Deutsche For-schungsgemeinschaft (STE 1096/3-1) and a Visiting Professorship from the Harvard Medical School. European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (Grant No. 802825 to M.U.K) and Jane and Aatos Erkko Foundation (MUK). We would like to thank the Clinical Biomarker Facility at SciLifeLab, Sweden, for providing assistance in protein analyses; and Matilda Dale and Dr. Ragna H{\"a}ussler for their work on Olink for the IMI-DIRECT. We also thank AstraZeneca for suggestions on implementation of the research. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = nov,
day = "10",
doi = "10.1038/S41467-021-26536-w",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}
