Recycling Between Cortisol and Cortisone in Human Splanchnic, Subcutaneous Adipose, and Skeletal Muscle Tissues In Vivo

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) is a therapeutic target in metabolic syndrome because it catalyses reductase regeneration of cortisol from cortisone in adipose and liver. 11βHSD1 can also catalyze the reverse dehydrogenase reaction in vitro (e.g., if cofactor is limited). We used stable isotope tracers to test the hypothesis that both 11βHSD1-reductase and -dehydrogenase activities occur in human metabolic tissues in vivo. 1,2-[2H]2-Cortisone (d2-cortisone) was validated as a tracer for 11β-dehydrogenase activity and its inhibition by licorice. d2-Cortisone and 9,11,12,12-[2H]4-cortisol (d4-cortisol) (to measure 11β-reductase activity) were coinfused and venous samples obtained from skeletal muscle, subcutaneous adipose (n = 6), and liver (n = 4). Steroids were measured by liquid chromatography–tandem mass spectrometry and arteriovenous differences adjusted for blood flow. Data are means ± SEM. 11β-Reductase and -dehydrogenase activities were detected in muscle (cortisol release 19.7 ± 4.1 pmol/100 mL/min, d3-cortisol 5.9 ± 1.8 pmol/100 mL/min, and cortisone 15.2 ± 5.8 pmol/100 mL/min) and splanchnic (cortisol 64.0 ± 11.4 nmol/min, d3-cortisol 12.9 ± 2.1 nmol/min, and cortisone 19.5 ± 2.8 nmol/min) circulations. In adipose, dehydrogenase was more readily detected than reductase (cortisone release 38.7 ± 5.8 pmol/100 g/min). Active recycling between cortisol and cortisone in metabolic tissues in vivo may facilitate dynamic control of intracellular cortisol but makes consequences of dysregulation of 11βHSD1 transcription in obesity and diabetes unpredictable. Disappointing efficacy of 11βHSD1 inhibitors in phase II studies could be explained by lack of selectivity for 11β-reductase.

Diminished adrenal sensitivity and ACTH efficacy in obese premenopausal women

“…A drawback of these studies is that locally produced cortisol from cortisone and vice versa by 11b-HSD1, facilitating oxidation or reduction determined by local cell conditions, and subsequent release from fat, muscle, or splanchnic organs into the circulation, was not quantitated. However, recently a new stable isotope method in which 1,2-[ 2 H] 2 -cortisone and 9,11,12,12-[H 2 ] 4 -cortisol were infused has revealed that in human subjects active recycling between cortisol and cortisone occurs in subcutaneouos fat, muscle, and splanchnic organs (38). Comparable data in obesity and diabetes mellitus are not yet available.…”

The modulation of corticosteroid metabolism by hydrocortisone therapy in patients with hypopituitarism increases tissue glucocorticoid exposure

“…Previous studies have been performed in either healthy control subjects, obese subjects or diabetic subjects (42,43,44,45). In order to accurately assess cortisol metabolism patients are infused with deuterated cortisol and metabolic products measured, which allows a more direct assessment of the relative activity of 11b-HSD1 and 2 in vivo than can be inferred by urinary metabolite assessment.…”

Cibler la voie métabolique du cortisol comme action thérapeutique dans le diabète de type 2

“…Cet échec relatif pourrait résulter d'un manque de sélectivité des inhibiteurs de la 11βHSD1 utilisés jusqu'à présent, qui exercent aussi une action sur la 11β-réductase [35]. De plus, la régulation de l'activité de la 11βHSD1 est particulièrement complexe et est conditionnée par la disponibilité en NADPH tissulaire, de telle sorte qu'il peut exister, selon les circonstances, un recyclage entre cortisol et cortisone [35]. Une autre explication pourrait se trouver dans des différences inter-espèces.…”