FGF21 Response to Critical Illness: Effect of Blood Glucose Control and Relation With Cellular Stress and Survival
Steven E Thiessen1, Ilse Vanhorebeek1, Inge Derese1
1Clinical Division and Laboratory of Intensive Care Medicine, Department Cellular and Molecular Medicine, KU Leuven University, B-3000 Leuven, Belgium.
Context:
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.
Setting/Design:
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.
Interventions:
Insulin was infused to control blood glucose.
Main Outcome Measures And 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.
Conclusion:
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.
Insights
Critical illness significantly elevates fibroblast growth factor-21 (FGF21). Targeting normoglycemia lowered FGF21 and may improve survival by reducing mitochondrial damage and the integrated stress response (ISR).
Area of Science:
- Biochemistry and Molecular Biology
- Critical Care Medicine
- Endocrinology
Background:
- Critical illness is characterized by mitochondrial damage, a process potentially mitigated by maintaining normoglycemia.
- Mitochondrial dysfunction is known to induce fibroblast growth factor-21 (FGF21) through the integrated stress response (ISR).
Purpose of the Study:
- To investigate whether critical illness increases serum FGF21 levels.
- To determine if maintaining normoglycemia (80-110 mg/dL) with insulin, compared to hyperglycemia, reduces serum FGF21 by attenuating mitochondrial dysfunction and ISR.
Main Methods:
- Serum FGF21 concentrations were measured in 405 critically ill patients and 20 controls.
- Critically ill rabbits (n=26) and healthy rabbits (n=13) were studied for tissue analyses, including hepatic fgf21 expression, mitochondrial function, and ISR markers.
- Patients and rabbits were randomized to either hyperglycemia or normoglycemia, with insulin used to control blood glucose.
Main Results:
- Serum FGF21 was 8-fold higher in critically ill patients upon ICU admission compared to controls (P < .0001) and remained elevated in non-survivors.
- Maintaining normoglycemia significantly lowered serum FGF21 (P = .01), suggesting a contribution to the mortality benefit of glycemic control.
- In rabbits, hepatic fgf21 expression increased significantly (P < .0001) and correlated with mitochondrial dysfunction and ISR markers, with both being reduced by normoglycemia.
Conclusions:
- Critical illness potently induces serum FGF21 and hepatic fgf21 expression.
- Mitochondrial damage and the ISR likely contribute to FGF21 induction in critical illness.
- Targeting normoglycemia demonstrated an ability to attenuate FGF21, mitochondrial dysfunction, and ISR markers.
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