Acute in vivo regulation of 11β-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans

Context: Extraadrenal regeneration of cortisol by 11 beta-hydroxysteroid dehydrogenase type 1 (11HSD1) is increased after a mixed meal. It is unknown which tissue is responsible and whether this reflects the complex transcriptional control of 11HSD1 or posttranscriptional control exerted by supply of reduced nicotinamide adenine dinucleotide phosphate from hexose-6-phosphate dehydrogenase. Objective: The objective of this study was to test whether hyperinsulinemia and/or increased serum free fatty acids increase wholebody and intraadipose 11HSD1, and whether adipose 11HSD1 switches from dehydrogenase to reductase activity. Methods: In nine healthy men, we measured whole-body cortisol regeneration (by iv infusion of 9,11,12,12-[H-2](4)-cortisol) and intraadipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [H-3](4)-cortisol and [H-3](2)-cortisone in separate cannulae) during: 1) a hyperinsulinemic euglycemic clamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and 3) saline infusion, each for 3.5 h. Results: Hyperinsulinemia increased rate of appearance of 9,12,12[H-2](3)-cortisol (9.3 +/- 0.8 vs. 16.7 +/- 1.1 nmol/min with saline, P < 0.001), indicating increased whole-body 11HSD1. Within adipose, the predominant reaction was reductase conversion of cortisone to cortisol (after 3.5 h of saline infusion, reaching 11.0 +/- 2.7% per hour reductase vs. 5.2 +/- 1.3 dehydrogenase, P < 0.02); insulin increased reductase (reaching 15.8 +/- 3.0, P < 0.05) and tended to increase dehydrogenase activity. Intralipid infusion had no effects on wholebody deuterated cortisol metabolism, but increased both dehydrogenase and reductase (reaching 16.7 +/- 1.8, P < 0.01) activities in adipose. Conclusions: Hyperinsulinemia and increased free fatty acids induce acute increases in 11HSD1 activity in adipose tissue that are not attributable to a switch from dehydrogenase to reductase. Hyperinsulinemia also increases systemic cortisol regeneration. These effects may enhance intracellular cortisol concentrations after a meal.