2. Academic Validation
  3. Elevated circulating follistatin associates with an increased risk of type 2 diabetes

Elevated circulating follistatin associates with an increased risk of type 2 diabetes

  • Nat Commun. 2021 Nov 10;12(1):6486. doi: 10.1038/s41467-021-26536-w.
Chuanyan Wu  # 1 2 3,  Yan Borné  # 1,  Rui Gao 2,  Maykel López Rodriguez 4 5,  William C Roell 6,  Jonathan M Wilson 6,  Ajit Regmi 6,  Cheng Luan 1,  Dina Mansour Aly 1,  Andreas Peter 7 8 9,  Jürgen Machann 8 9 10,  Harald Staiger 7 8 9,  Andreas Fritsche 7 8 9,  Andreas L Birkenfeld 7 8 9,  Rongya Tao 11,  Robert Wagner 7 8 9,  Mickaël Canouil 12,  Mun-Gwan Hong 13,  Jochen M Schwenk 13,  Emma Ahlqvist 1,  Minna U Kaikkonen 5,  Peter Nilsson 1,  Angela C Shore 14,  Faisel Khan 15,  Andrea Natali 16,  Olle Melander 1,  Marju Orho-Melander 1,  Jan Nilsson 1,  Hans-Ulrich Häring 7 8 9,  Erik Renström 1,  Claes B Wollheim 1 17,  Gunnar Engström 1,  Jianping Weng 18,  Ewan R Pearson 19,  Paul W Franks 1,  Morris F White 11,  Kevin L Duffin 6,  Allan Arthur Vaag 20,  Markku Laakso 4 21,  Norbert Stefan 7 8 9,  Leif Groop 1 22,  Yang De Marinis 23 24 25
Affiliations

Affiliations

  • 1 Department of Clinical Sciences, Lund University, Malmö, Sweden.
  • 2 School of Control Science and Engineering, Shandong University, Jinan, Shandong, China.
  • 3 School of Intelligent Engineering, Shandong Management University, Jinan, Shandong, China.
  • 4 Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
  • 5 A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
  • 6 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
  • 7 Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology; and Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, University of Tübingen, Tübingen, Germany.
  • 8 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany.
  • 9 German Center for Diabetes Research (DZD), Tübingen, Germany.
  • 10 Section of Experimental Radiology, Department of Radiology, University of Tübingen, Tübingen, Germany.
  • 11 Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 12 Inserm U1283 / CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille; University of Lille, Lille University Hospital, Lille, France.
  • 13 Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
  • 14 NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital and University of Exeter Medical School, Exeter, Devon, UK.
  • 15 Division of Systems Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK.
  • 16 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • 17 Department of Cell Physiology and Metabolism, University Medical Centre, Geneva, Switzerland.
  • 18 Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, University of Science and Technology of China, Hefei, China.
  • 19 Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.
  • 20 Steno Diabetes Center Copenhagen, Gentofte, Denmark.
  • 21 Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
  • 22 Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
  • 23 Department of Clinical Sciences, Lund University, Malmö, Sweden. yang.de_marinis@med.lu.se.
  • 24 School of Control Science and Engineering, Shandong University, Jinan, Shandong, China. yang.de_marinis@med.lu.se.
  • 25 Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, University of Science and Technology of China, Hefei, China. yang.de_marinis@med.lu.se.
  • # Contributed equally.
PMID: 34759311 DOI: 10.1038/s41467-021-26536-w
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.

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