Fibroblast growth factor 21 (FGF21) is a liver-secreted protein playing an important role in the metabolic adaptation to energy deficit in mice and, at a lesser extent, in humans. Evidence also suggests FGF21 participates in the adaptation to energy excess induced by high carbohydrate/low protein supplies. We compared serum FGF21 in response to glucose deprivation (20-h fasting) and to glucose excess (euglycemic-hyperinsulinemic clamp) in humans.


Eighteen healthy, lean, young males were assessed during prolonged fasting (only water, minimal physical activity, 20 h) and a glucose clamp (2 mU/kg/min, 2 h). Fasting and clamp sessions were randomly assigned. Classical markers of metabolic adaptation (fuel oxidation, blood metabolites and insulin) and serum FGF21 concentration were measured before and after each intervention.


Prolonged fasting elevated average circulating FFA (108±72%), glycerol (63±52%), and beta-hydroxybutyrate (148±137%); while lowering circulating glucose (-7±5%), insulin (-22±57%) and respiratory quotient (-4±8%). In turn, glucose clamp suppressed circulating FFA (-64±23%), glycerol (-38±32%), and beta-hydroxybutyrate (-13±20%); while increasing circulating lactate (68±52%) and respiratory quotient (14±11%). These opposing metabolic scenarios were not accompanied by modifications in serum FGF21. Thus, median serum FGF21 before and after prolonged fasting were 72 (38-138) and 24 (5-63) pg/ml, respectively. Such change only reached borderline significance (-41 [-111-0] pg/ml; p=0.05). In turn, median serum FGF21 before and after clamp were 94 (40-141) and 83 (45-209) pg/ml, respectively (p=0.82). Clamp-induced serum FGF21 changes were unrelated to glucose disposal rate (r=-0.13; p=0.62).


Serum FGF21 does not respond to glucose deprivation or excess as do classical markers of these conditions.