Acute In Vivo Regulation of 11ß-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans
Deborah J. Wake,
Natalie Z. M. Homer,
Ruth Andrew and
Brian R. Walker
Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom
Address all correspondence and requests for reprints to: Prof. Brian R. Walker, University of Edinburgh, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: B.Walker{at}ed.ac.uk.
Context: Extraadrenal regeneration of cortisol by 11ß-hydroxysteroiddehydrogenase type 1 (11HSD1) is increased after a mixed meal.It is unknown which tissue is responsible and whether this reflectsthe complex transcriptional control of 11HSD1 or posttranscriptionalcontrol exerted by supply of reduced nicotinamide adenine dinucleotidephosphate from hexose-6-phosphate dehydrogenase.
Objective: The objective of this study was to test whether hyperinsulinemiaand/or increased serum free fatty acids increase whole-bodyand intraadipose 11HSD1, and whether adipose 11HSD1 switchesfrom dehydrogenase to reductase activity.
Methods: In nine healthy men, we measured whole-body cortisolregeneration (by iv infusion of 9,11,12,12-[2H]4-cortisol) andintra-adipose interconversion of cortisol and cortisone (bysc microdialysis infusion of [3H]4-cortisol and [3H]2-cortisonein separate cannulae) during: 1) a hyperinsulinemic euglycemicclamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and3) saline infusion, each for 3.5 h.
Results: Hyperinsulinemia increased rate of appearance of 9,12,12-[2H]3-cortisol(19.3 ± 0.8 vs. 16.7 ± 1.1 nmol/min with saline,P < 0.001), indicating increased whole-body 11HSD1. Withinadipose, the predominant reaction was reductase conversion ofcortisone to cortisol (after 3.5 h of saline infusion, reaching11.0 ± 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 whole-body deuteratedcortisol metabolism, but increased both dehydrogenase and reductase(reaching 16.7 ± 1.8, P < 0.01) activities in adipose.
Conclusions: Hyperinsulinemia and increased free fatty acidsinduce acute increases in 11HSD1 activity in adipose tissuethat are not attributable to a switch from dehydrogenase toreductase. Hyperinsulinemia also increases systemic cortisolregeneration. These effects may enhance intracellular cortisolconcentrations after a meal.
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