FGF21 Response to Critical Illness: Effect of Blood Glucose Control and Relation With Cellular Stress and Survival.
BACKGROUND
Critical illness is hallmarked by mitochondrial damage, which is attenuated by targeting normoglycemia. Mitochondrial dysfunction induces fibroblast growth factor-21 (FGF21) via the integrated stress response (ISR).


OBJECTIVE
We evaluated whether critical illness elevates serum FGF21 concentrations and whether targeting normoglycemia (80-110 mg/dL) with insulin vs tolerating hyperglycemia may lower serum FGF21 by attenuating mitochondrial dysfunction and the ISR.


METHODS
We quantified serum FGF21 concentrations in critically ill patients. To allow tissue analyses, including hepatic fgf21 expression in relation with mitochondrial function and ISR markers, we studied critically ill rabbits. Patients and rabbits were randomized to hyper- or normoglycemia. Patients/Other Participants: We studied 405 fed critically ill patients vs 20 matched non-critically ill control subjects as well as 26 critically ill rabbits vs 13 healthy rabbits.


METHODS
Insulin was infused to control blood glucose.


RESULTS
Serum FGF21 concentrations upon intensive care unit admission were 8-fold higher than in control subjects (P < .0001), decreased with time, but always remained higher in nonsurvivors than survivors (P ≤ .006). Maintaining normoglycemia lowered serum FGF21 (P = .01), statistically explaining at least part of its mortality benefit. In ill rabbits, hepatic fgf21 expression was substantially increased (P < .0001) and was tightly correlated with mitochondrial dysfunction (all R(2) ≥ 0.49; all P ≤ .0006 for complex I and V) and ISR markers on day 3 (R(2) ≥ 0.73; P ≤ .0001), all lowered by targeting normoglycemia.


CONCLUSIONS
Critical illness is a potent inducer of serum FGF21 and of liver fgf21 expression, possibly driven at least in part by mitochondrial damage and the ISR, which were all attenuated by targeting normoglycemia.
Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Steven E
SE
Thiessen
Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Ilse
I
Vanhorebeek
Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Inge
I
Derese
Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Jan
J
Gunst
Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Greet
G
Van den Berghe
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D016638:Critical Illness / Q000401:mortality*; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D007328:Insulin / Q000627:therapeutic use; D007362:Intensive Care Units; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011817:Rabbits
D001786:Blood Glucose; D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors