title: Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity.
abstract: BACKGROUND
  Fibroblast growth factor (FGF) 21, a novel member of the FGF family, plays a role in a variety of endocrine functions, including regulation of glucose and lipid metabolism. The role of FGF21 in skeletal muscle is currently not known.
  
  
  METHODS
  Serum levels and skeletal muscle mRNA of FGF21 were determined in normal glucose tolerant (n = 40) and type 2 diabetic (T2D; n = 40) subjects. We determined whether FGF21 has direct effects on glucose metabolism in cultured myotubes (n = 8) and extensor digitorum longus skeletal muscle.
  
  
  RESULTS
  Serum FGF21 levels increased 20% in T2D versus normal glucose tolerant subjects (p < 0.05), whereas skeletal muscle mRNA expression was unaltered. Fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), waist circumference, and body mass index (BMI) significantly correlated with serum FGF21 levels in T2D (p < 0.01), but not in normal glucose tolerant subjects. Serum FGF21 concentrations were greater in T2D patients in the highest tertile of fasting insulin (p < 0.05) and BMI (p < 0.05). Stepwise regression analysis identified BMI as the strongest independent variable correlating with FGF21. FGF21 exposure increased basal and insulin-stimulated glucose uptake in human myotubes, coincident with increased glucose transporter 1 mRNA, and enhanced glucose transporter 1 abundance at the plasma membrane. In isolated extensor digitorum longus muscle, FGF21 potentiated insulin-stimulated glucose transport, without altering phosphorylation of Akt or AMP-activated protein kinase.
  
  
  CONCLUSIONS
  Plasma FGF21 is increased in T2D patients, and positively correlated with fasting insulin and BMI. However, FGF21 has direct effects in enhancing skeletal muscle glucose uptake, providing additional points of regulation that may contribute to the beneficial effects of FGF21 on glucose homeostasis. Whether increased plasma FGF21 in T2D is a compensatory mechanism to increase glucose metabolism remains to be determined.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredirick L
authors.initials: FL
authors.lastname: Mashili
authors.forename: Reginald L
authors.initials: RL
authors.lastname: Austin
authors.forename: Atul S
authors.initials: AS
authors.lastname: Deshmukh
authors.forename: Tomas
authors.initials: T
authors.lastname: Fritz
authors.forename: Kenneth
authors.initials: K
authors.lastname: Caidahl
authors.forename: Katrin
authors.initials: K
authors.lastname: Bergdahl
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Chibalin
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
mesh_terms: D000818:Animals; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051272:Glucose Transporter Type 1; D007328:Insulin; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose