Abstract
With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) + /− hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action.
Highlights
Intracellular glucocorticoid receptors are widely expressed and affect energy metabolism, cardiovascular control and innate immunity[1,2,3,4,5]
The clearest effect where insulin and hydrocortisone oppose each other is with regard to an effect on the metabolism of branched chain amino acids and their metabolites
This observation links to the role of branched chain amino acids (BCAs) in obesity and insulin resistance observed in the literature[14,15,16]
Summary
In order to reduce any danger of overfitting a further OPLS-DA model (Fig. 6) was built on the 10 variables having the highest AUC values among the metabolites significantly affected by the HC dose (Table 4) in plasma samples of 38 subjects (low = 19, high = 19). All these metabolites showed varying degrees of positive correlation (0.54 ≤ r ≤ 0.85) except for the steroid conjugates androsterone glucuronide (|r| = 0.7) and pregnenolone sulfate (|r| = 0.85) which were negatively correlated with HC dose.
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