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.

Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.

Details

Title
Elevated circulating follistatin associates with an increased risk of type 2 diabetes
Author
Wu Chuanyan 1 ; Borné Yan 2 ; Gao, Rui 3 ; López Rodriguez Maykel 4 ; Roell, William C 5 ; Wilson, Jonathan M 5   VIAFID ORCID Logo  ; Regmi Ajit 5 ; Cheng, Luan 2 ; Aly, Dina Mansour 2 ; Andreas, Peter 6 ; Machann Jürgen 7   VIAFID ORCID Logo  ; Staiger Harald 6 ; Fritsche, Andreas 6 ; Birkenfeld, Andreas L 6   VIAFID ORCID Logo  ; Rongya, Tao 8 ; Wagner, Robert 6   VIAFID ORCID Logo  ; Canouil Mickaël 9   VIAFID ORCID Logo  ; Mun-Gwan, Hong 10   VIAFID ORCID Logo  ; Schwenk, Jochen M 10   VIAFID ORCID Logo  ; Ahlqvist Emma 2   VIAFID ORCID Logo  ; Kaikkonen, Minna U 11   VIAFID ORCID Logo  ; Nilsson, Peter 2   VIAFID ORCID Logo  ; Shore, Angela C 12   VIAFID ORCID Logo  ; Khan Faisel 13 ; Natali, Andrea 14 ; Melander Olle 2 ; Orho-Melander Marju 2 ; Nilsson, Jan 2   VIAFID ORCID Logo  ; Hans-Ulrich, Häring 6 ; Renström, Erik 2 ; Wollheim, Claes B 15 ; Engström Gunnar 2 ; Weng Jianping 16 ; Pearson, Ewan R 17 ; Franks, Paul W 2   VIAFID ORCID Logo  ; White, Morris F 8 ; Duffin, Kevin L 5 ; Vaag Allan Arthur 18 ; Laakso Markku 19   VIAFID ORCID Logo  ; Stefan, Norbert 6   VIAFID ORCID Logo  ; Groop Leif 20   VIAFID ORCID Logo  ; De Marinis Yang 21   VIAFID ORCID Logo 

1  Lund University, Department of Clinical Sciences, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); School of Control Science and Engineering, Shandong University, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); School of Intelligent Engineering, Shandong Management University, Jinan, China (GRID:grid.495260.c) (ISNI:0000 0004 1791 7210) 
2  Lund University, Department of Clinical Sciences, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
3  School of Control Science and Engineering, Shandong University, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174) 
4  Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490); University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
5  Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA (GRID:grid.417540.3) (ISNI:0000 0000 2220 2544) 
6  Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology; and Department for Diagnostic Laboratory Medicine, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); German Center for Diabetes Research (DZD), Tübingen, Germany (GRID:grid.452622.5) 
7  Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); German Center for Diabetes Research (DZD), Tübingen, Germany (GRID:grid.452622.5); University of Tübingen, Section of Experimental Radiology, Department of Radiology, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447) 
8  Boston Children’s Hospital, Harvard Medical School, Division of Endocrinology, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
9  Inserm U1283 / CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille; University of Lille, Lille University Hospital, Lille, France (GRID:grid.410463.4) (ISNI:0000 0004 0471 8845) 
10  Affinity Proteomics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden (GRID:grid.5037.1) (ISNI:0000000121581746) 
11  University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
12  NIHR Exeter Clinical Research Facility, Royal Devon and Exeter Hospital and University of Exeter Medical School, Exeter, Devon, UK (GRID:grid.477603.1) 
13  University of Dundee, Ninewells Hospital & Medical School, Division of Systems Medicine, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
14  University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy (GRID:grid.5395.a) (ISNI:0000 0004 1757 3729) 
15  Lund University, Department of Clinical Sciences, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); University Medical Centre, Department of Cell Physiology and Metabolism, Geneva, Switzerland (GRID:grid.150338.c) (ISNI:0000 0001 0721 9812) 
16  University of Science and Technology of China, Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639) 
17  School of Medicine, University of Dundee, Division of Population Health & Genomics, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
18  Steno Diabetes Center Copenhagen, Gentofte, Denmark (GRID:grid.419658.7) (ISNI:0000 0004 0646 7285) 
19  Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490); Kuopio University Hospital, Department of Medicine, Kuopio, Finland (GRID:grid.410705.7) (ISNI:0000 0004 0628 207X) 
20  Lund University, Department of Clinical Sciences, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
21  Lund University, Department of Clinical Sciences, Malmö, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); School of Control Science and Engineering, Shandong University, Jinan, China (GRID:grid.27255.37) (ISNI:0000 0004 1761 1174); University of Science and Technology of China, Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-26536-w
ProQuest document ID
2595779034
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.