title: Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes.
abstract: Hepatokines have emerged as liver-derived hormone-like factors. Plasma fibroblast growth factor (FGF)-21 and follistatin increase with a high glucagon to insulin ratio and exercise, and resting levels are elevated in patients with type 2 diabetes (T2D).
  
  
  
  The objective of the study was to investigate the regulatory roles of glucagon to insulin ratio and T2D on exercise-induced FGF21 and follistatin secretion. Design /Interventions: Young healthy males performed a 2-hour bicycle exercise bout followed by 5 hours of rest in supine position with and without a pancreatic clamp blocking the increase in the glucagon to insulin ratio. In addition, we evaluated exercise-induced plasma FGF21 and follistatin in patients with T2D compared with healthy controls in response to 1 hour of bicycle exercise followed by a 3-hour recovery period.
  
  
  
  In healthy individuals, we observed a 10-fold (P < .002) increase in the glucagon to insulin ratio during exercise, which was abolished by the pancreatic clamp. Exercise with the pancreatic clamp completely blunted the exercise-induced increase in FGF21 (P = .007), whereas the induction of follistatin was approximately 50% reduced (P = .04). Exercise-induced FGF21 secretion was completely absent in patients with T2D, whereas the exercise-induced follistatin increase was impaired.
  
  
  
  Exercise-induced increases in plasma FGF21 and follistatin are attenuated by the pancreatic clamp, indicating important roles for glucagon and insulin as upstream regulators. For follistatin, an additional regulatory mechanism must exist. Our data further show that exercise-induced FGF21 and follistatin secretion are impaired in patients with T2D. The magnitude of changes in glucagon and insulin or the sensitivity to these hormones seems central in the regulation of FGF21 and follistatin in humans.
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Jakob Schiøler
authors.initials: JS
authors.lastname: Hansen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Bente Klarlund
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Guowang
authors.initials: G
authors.lastname: Xu
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehmann
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (J.S.H., B.K.P., P.P.) and Department of Clinical Biochemistry (J.S.H., P.P.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Key Laboratory of Separation Science for Analytical Chemistry (G.X.), Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Division of Pathobiochemistry and Clinical Chemistry (R.L., C.W.), Department of Internal Medicine IV and Institute for Diabetes Research and Metabolic Diseases (R.L., C.W.), Helmholtz Zentrum München, University Tuebingen, D-72074 Tuebingen, Germany; and German Center for Diabetes Research (R.L., C.W.), D-85764 Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Plomgaard
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015444:Exercise / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D038681:Follistatin / Q000097:blood / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D055815:Young Adult
chemical_list: D038681:Follistatin; D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon