The postprandial rise in plasma cortisol in men is mediated by macronutrient-specific stimulation of adrenal and extra-adrenal cortisol production

Abstract

Context: Circadian variation is a fundamental characteristic of plasma glucocorticoids, with a postprandial rise in cortisol an important feature. The diurnal rhythm is presumed to reflect alterations in hypothalamic-pituitary-adrenal axis activity; however, cortisol is produced not only by the adrenal glands but also by regeneration from cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue.

Objective: We tested the contribution of peripheral cortisol regeneration to macronutrient-induced circadian variation of plasma cortisol in humans.

Design: This was a randomized, single-blinded, crossover study.

Setting: The study was conducted at a hospital research facility.

Participants: Eight normal-weight healthy men participated in the study.

Interventions: Subjects were given isocaloric energy isodense flavor-matched liquid meals composed of carbohydrate, protein, fat, or low-calorie placebo during infusion of the stable isotope tracer 9,11,12,12-[2H]4-cortisol.

Outcome measures and results: Plasma cortisol increased similarly after all macronutrient meals (by ∼90 nmol/L) compared with placebo. Carbohydrate stimulated adrenal secretion and extra-adrenal regeneration of cortisol to a similar degree. Protein and fat meals stimulated adrenal cortisol secretion to a greater degree than extra-adrenal cortisol regeneration. The increase in cortisol production by 11β-hydroxysteroid dehydrogenase type 1 was in proportion to the increase in insulin. The postprandial cortisol rise was not accounted for by decreased cortisol clearance.

Conclusions: Food-induced circadian variation in plasma cortisol is mediated by adrenal secretion and extra-adrenal regeneration of cortisol. Given that the latter has the more potent effect on tissue cortisol concentrations and that effects on adrenal and extra-adrenal cortisol production are macronutrient specific, this novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and the contrasting effects of certain diets on postprandial metabolism.

Figure 1

Use of deuterated cortisol tracer to quantify the contribution of adrenal and extra-adrenal tissues to the circulating cortisol pool. The circulating cortisol pool (A) is determined by three sources: adrenal cortisol production, cortisol regeneration by 11β-HSD1, and cortisol clearance predominantly by the hepatic A-ring reductases and by 11β-HSD2. A rise in circulating cortisol may be due to either increased production by the adrenals or by 11β-HSD1 or to reduced cortisol clearance. The stable isotope tracer d4-cortisol can be used to determine the contribution of these three sources (B). On removal of the deuterium from the 11 position by 11β-HSD2, d4-cortisol is converted to d3-cortisone, which then forms d3-cortisol once regenerated by 11β-HSD1. d3-Cortisol can be formed only by 11β-HSD1 so can be used to quantify cortisol production by 11β-HSD1, whereas d4-cortisol cannot be regenerated and therefore can be used to quantify cortisol clearance.

Figure 2

Hormone concentrations before and after meals. Data are mean ± SEM for plasma cortisol (A), glucose (B) and insulin (C) concentrations prior to and after carbohydrate (CHO, filled squares), fat (filled circles), protein (filled triangles), and placebo (open diamonds) meals (n = 8 for all meals). A deuterated cortisol infusion was commenced at t = 0 minutes, with the meals each given at t + 210 minutes. Cortisol, glucose, and insulin were all similar prior to the meal. Plasma cortisol followed its usual circadian pattern and fell during the morning and then increased after all meals compared with placebo (all P < .05). Glucose and insulin significantly increased after CHO compared with the three other meals (both P < .001), and insulin levels were increased after protein compared with fat and placebo meals (P < .05).

Figure 3

Adrenal and extra-adrenal cortisol production. Data are mean ± SEM for Ra cortisol (A), rate of appearance of d3-cortisol (Ra d3-cortisol) (B), and d4-cortisol clearance (C) after carbohydrate (CHO, filled squares), fat (filled circles), protein (filled triangles), and placebo (open diamonds) meals (n = 8 for all meals). Ra cortisol was increased after all three meals vs placebo (P < .05). Ra d3-cortisol was increased by CHO compared with all other meals (P < .001) and by protein compared with placebo and fat meals (P < .05). d4-cortisol clearance was increased after the high-protein meal (P < .05 vs placebo).