TY - JOUR TI - Elevated circulating follistatin associates with an increased risk of type 2 diabetes AU - Wu, Chuanyan AU - Borné, Yan AU - Gao, Rui AU - López Rodriguez, Maykel AU - Roell, William C. AU - Wilson, Jonathan M. AU - Regmi, Ajit AU - Luan, Cheng AU - Aly, Dina Mansour AU - Peter, Andreas AU - Machann, Jürgen AU - Staiger, Harald AU - Fritsche, Andreas AU - Birkenfeld, Andreas L. AU - Tao, Rongya AU - Wagner, Robert AU - Canouil, Mickaël AU - Hong, Mun-Gwan AU - Schwenk, Jochen M. AU - Ahlqvist, Emma AU - Kaikkonen, Minna U. AU - Nilsson, Peter AU - Shore, Angela C. AU - Khan, Faisel AU - Natali, Andrea AU - Melander, Olle AU - Orho-Melander, Marju AU - Nilsson, Jan AU - Häring, Hans-Ulrich AU - Renström, Erik AU - Wollheim, Claes B. AU - Engström, Gunnar AU - Weng, Jianping AU - Pearson, Ewan R. AU - Franks, Paul W. AU - White, Morris F. AU - Duffin, Kevin L. AU - Vaag, Allan Arthur AU - Laakso, Markku AU - Stefan, Norbert AU - Groop, Leif AU - De Marinis, Yang T2 - Nature Communications AB - 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. DA - 2021/12// PY - 2021 DO - 10.1038/s41467-021-26536-w DP - DOI.org (Crossref) VL - 12 IS - 1 SP - 6486 J2 - Nat Commun LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-021-26536-w Y2 - 2021/12/06/15:18:24 KW - WP3 ER -