The role of glucagon and endocrine FGFs in orchestrating the complex endocrine and metabolic responses to critical illness

Critically ill patients who need vital organ support to avoid imminent death develop remarkable endocrine and metabolic changes that have been related with morbidity and risk of death. Neuroendocrine changes affect growth hormone, thyroid hormone and cortisol, among others. Metabolic changes include mitochondrial dysfunction, low cholesterol, high triglyceride and bile acid levels, and disturbed glucose homeostasis manifested by insulin resistance and elevated blood glucose. Several factors have been implicated in the rise of glucose, including glucagon that normally raises blood glucose levels when these drop too low.

The action radius of glucagon appeared much wider, with a vital role in the adaptive response to physiological stress conditions in which hypoglycemia is not typically present. To name a few actions, glucagon enhances “self-eating” and substrate availability, decreases cholesterol and increases bile acids. Recent studies demonstrated that several effects of glucagon are mediated by fibroblast growth factor 21 (FGF21), that increasing FGF21 in mice mimics several endocrine and metabolic changes of critical illness and that FGF19 may be important for bile acid metabolism.

Using human samples, we will thoroughly characterize glucagon, FGF21, FGF19, and their regulators and receptors during critical illness in relation to endocrine and metabolic changes. Causal involvement in these changes will be addressed in several mechanistic studies in critically ill mice.