title: Acute in vivo regulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans.
abstract: BACKGROUND
  Extraadrenal regeneration of cortisol by 11beta-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 whole-body 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-[2H]4 -cortisol) and intra-adipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [3H]4 -cortisol and [3H]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-[2H]3 -cortisol (19.3 +/- 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 whole-body 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.
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Wake
authors.forename: Natalie Z M
authors.initials: NZ
authors.lastname: Homer
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D003903:Deuterium / Q000493:pharmacokinetics; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007260:Infusion Pumps; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D016037:Single-Blind Method; D014915:Whole-Body Counting
chemical_list: D001786:Blood Glucose; D005217:Fat Emulsions, Intravenous; D007328:Insulin; D003903:Deuterium; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone