Glucorticoids: an investigation into a possible mechanism for their metabolic consequences and their prognostic role in acute illness

Abstract

Background: Chronic exposure to glucocorticoids leads to Cushing’s syndrome (CS) with its metabolic consequences. AMPK is involved in many metabolic processes. Cortisol circulates largely bound to binding proteins, with the smaller amount of unbound hormone responsible for its metabolic effects. In acute illness binding proteins fall and total cortisol (TC) no longer reflects free cortisol (FC) levels. Hypothesis: I hypothesized that 1) AMPK has an important role in metabolic consequences of CS and 2) FC, as compared to TC, offers a better reflection of the degree of stress and is a better prognostic measure in acute illness. Methods: Wistar rats were implanted with corticosterone or placebo pellets and tissues collected. Adipose tissue of patients with CS and controls was sampled and AMPK measured by AMPK assay. Experiments were confirmed in vitro. FC was measured by a specially developed assay in two prospective clinical studies in acutely ill patients. Results: In the animal model, AMPK was decreased in adipose tissue and heart, and increased in liver and hypothalamus. This was confirmed in vitro in the respective cell lines. In visceral adipose tissue of patients with CS, AMPK was lower compared to controls. During acute illness, the increase above basal FC was higher than the increase in TC and fell more markedly. After ACTH stimulation, TC increased to a similar and FC to a lesser extent as in major stress. The value of cortisol in predicting outcome was higher as compared to routinely measured parameters. The predictive value of FC was not superior to TC. Conclusion: Glucocorticoid-induced changes in AMPK constitute a novel mechanism possibly explaining some of the metabolic consequences of CS. The more pronounced increase in FC seen during stress as compared to the ACTH test suggests that this test does not adequately anticipate FC levels needed during severe stress. The prognostic accuracy of FC is not superior to TC.