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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.
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Abstract |
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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.
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Introduction |
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The concentrations of cortisol available within target cells to activate glucocorticoid receptors is determined not only by the plasma cortisol concentration, but also by the extent of local intracellular regeneration of cortisol from inactive cortisone, catalyzed by 11ß-hydroxysteroid dehydrogenase type 1 (11HSD1) (5). To date, interest in 11HSD1 has focused on its medium- and long-term effects on features analogous to Cushing’s syndrome. In mice, transgenic overexpression of 11HSD1 within adipose tissue (6) or liver (7) results in local glucocorticoid excess, whereas targeted deletion of 11HSD1 (8) or pharmacological inhibition of 11HSD1 (9, 10, 11) results in intracellular glucocorticoid deficiency, each with substantial effects on glucose and fatty acid metabolism. In humans, we and others have reported increased 11HSD1 expression and activity in sc adipose tissue in obesity (12, 13, 14, 15, 16, 17, 18). However, recent data suggest that variations in 11HSD1 are also important in the short term in humans. For example, "whole-body" generation of cortisol by 11HSD1 increased within 2–3 h after consumption of a mixed meal (19). Conversely, intra-adipose cortisol generation was markedly reduced within 1 h of introducing hyperinsulinemia in lean men, but not in obese men (20). These observations raise the important possibility that 11HSD1 plays a dynamic role in modifying the acute metabolic response to feeding.
The basis for acute changes in 11HSD1 activity is unknown. 11HSD1 transcription is subject to complex tissue-specific control by many factors that might change after feeding. In cells, these include insulin, peroxisome proliferator-activated receptor (PPAR)
and PPAR
agonists (putative receptors for fatty acid availability), liver X receptor agonists, cytokines, GH, and IGF-I (5). In animals, PPAR (21) and PPAR (22) agonists and high-fat feeding (23) selectively regulate adipose and liver 11HSD1 transcription. Posttranscriptional regulation of 11HSD1 may also occur. The rate of regeneration of cortisol may be limited by availability of reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the lumen of the endoplasmic reticulum (24), generated by the oxidation of glucose-6-phosphate by the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Complete loss of H6PDH appears to allow a "switch" in 11HSD1 from reductase to dehydrogenase activity (i.e. a switch from cortisol regeneration to cortisol inactivation) (25). However, the influence of physiological variations in oxidation of glucose-6-phosphate—such as might occur during hyperinsulinemia—on cortisol metabolism is unknown.
Against this background, we have explored the acute regulation of 11HSD1 in humans in detail in vivo. We have investigated whether: 1) increased cortisol regeneration by 11HSD1 can be induced directly by hyperinsulinemia and/or elevated free fatty acids; 2) acute variations in 11HSD1 in sc adipose tissue parallel changes in whole-body cortisol regeneration; and 3) variations in insulin and glucose flux allow "switching" of adipose 11HSD1 between reductase and dehydrogenase activity. To test these hypotheses in healthy men, we manipulated plasma glucose and insulin concentrations during a euglycemic hyperinsulinemic clamp, and triglyceride and free fatty acid concentrations during infusion of fat emulsion (Intralipid 20%), and measured whole-body and intraadipose cortisol metabolism using steroid tracers. These manipulations were introduced 5 h after the most recent meal, to mimick the usual intermeal interval and avoid potential stress associated with more prolonged fasting.
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Subjects and Methods |
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Nine male healthy volunteers were recruited by advertisement. Inclusion criteria were: age between 20–70 yr; body mass index between 20–30 kg/m2; normal thyroid, renal, and hepatic function; alcohol intake less than 28 U per week; no chronic disease (including hypertension or glucose intolerance); no chronic medication; and no glucocorticoid therapy in the previous 6 months. Local ethical approval and written informed consent were obtained.
Study design and protocol
Volunteers participated in a random-order three-phase crossover single-blind study comparing cortisol metabolism during: 1) iv insulin and glucose infusion; 2) iv lipid infusion; and 3) placebo saline infusion. Phases were separated by 7–14 d. To study the acute time course of effects of hyperinsulinemia and hyperlipidemia, tracer steroids were infused to steady-state before these manipulations were introduced.
In each phase, volunteers attended the Clinical Research Facility after an overnight fast and were given a standard light breakfast at 0700 h. Three iv cannulae were inserted: one for sampling arterialized blood was placed in a dorsal hand vein kept under a heated pad; an antecubital vein was cannulated in each arm for infusions. After cleaning with Betadine (SSL, Knutsford, UK) and injection of local anesthetic (5 ml Lignocaine 1%; Braun, Sheffield, UK), two microdialysis cannulae (containing 20-kDa permeable membranes; CMA Microdialysis, Solna, Sweden) were inserted in abdominal sc fat, approximately 10 cm lateral to the umbilicus on each side, as previously described (20).
At time zero (
0830 h), a primed iv infusion of cortisol (20% 9,11,12,12-[2H]4-cortisol and 80% hydrocortisone-21-succinate) was commenced (3.6 mg priming bolus, then continuous 1.74 mg/h infusion) (20, 26, 27, 28, 29). Through separate microdialysis cannulae (20), intraadipose infusions were commenced of 1) 1,2,6,7-[3H]4-cortisol (50 nmol/l) and 2) 1,2-[3H]2-cortisone (67 nmol/l) at a rate of 0.3 µl/min. After 3.5 h, a further iv infusion was commenced with either: 1) soluble human insulin (0.8 mU/kg·min) with variable rate 20% dextrose infusion to maintain arterialized blood glucose of 5 mmol/liter; 2) Intralipid 20% (Intralipid; Kabivitrum Inc., Stockholm, Sweden) (30 ml/h for 15 min then 50 ml/m2·h); or 3) 0.9% saline as placebo control (same rate as Intralipid). Measurements continued for a further 3.5 h. Volunteers were given 200 ml of water to drink every hour to encourage regular bladder emptying. Intralipid 20% contains 200 g/liter purified soybean oil, 12 g/liter purified egg phospholipids, and 22 g/liter glycerol in a proprietary emulsified suspension analogous to chylomicrons.
Arterialized blood glucose was measured every 5 min using a glucometer (Roche Accu-Check; Advantage 2). Arterialized blood samples were obtained at intervals indicated in the figures; plasma was separated promptly and stored at –80 C. Urine was collected at baseline and then every hour for analysis of tracer steroid metabolism; the volume was recorded, and aliquots were stored at –20 C. Microdialysis microvials were changed every hour and dialysate stored at –80 C.
Laboratory assays
Deuterated cortisol and its metabolites. Isotopomers of 9,11,12,12-[2H]4-cortisol (D4-cortisol); 9,12,12-[2H]3-cortisone (D3-cortisone); and 9,12,12-[2H]3-cortisol (D3-cortisol) were measured as described previously (26) in plasma and urine by gas chromatography mass spectrometry after formation of methoxime-trimethylsilyl derivatives. Epi-cortisol was added to plasma, and epi-cortisol and epi-5ß-tetrahydrocortisol were added to urine as internal standards. Analysis of isotopomers was performed on a Finnigan Voyager gas chromatography/mass spectrometry system with a CP-Sil 5CB (25 m x 0.25 mm id, 0.25 m ft; J&W Scientific, Folsom, CA). Enrichments were calculated from peak areas. Results for D4-cortisol were corrected for isotopic interference from endogenous mass + 4 cortisol and mass + 1 D3-cortisol. Results for D3-cortisol were corrected for isotopic interference from endogenous mass + 3 cortisol.
Cortisol kinetics were calculated as described previously (20). Rates of appearance of endogenous cortisol were calculated as [(rate of D4-cortisol infusion)/(D4-cortisol:cortisol ratio)] – (rate of infusion of cortisol). Clearance of cortisol and of D4-cortisol were calculated as (infusion rate)/(concentration). Rate of appearance of D3-cortisol was calculated as (rate of D4-cortisol infusion)/(D4-cortisol:D3-cortisol ratio).
Urinary excretion rates of deuterated steroids were calculated for each hour as (concentration of deuterated steroid) x (volume of urine).
Microdialysis. Steroids were extracted and separated by thin-layer chromatography as previously described (20). Tritiated steroids were quantified by liquid scintillation counting (to <2% error), and background counts were subtracted; counts in the sample were always at least 5-fold higher than background. Steroid recovery was calculated as the percentage of total counts in the infusate that were recovered in the effluent. 11HSD1 activities were expressed as percent conversion of labeled cortisone to cortisol (reductase activity) or cortisol to cortisone (dehydrogenase activity) per hour.
Other assays. Insulin was measured by enzyme immunoassay (Eurogenetics Tasah Corp. UK Ltd., Hampton, UK). Electrolytes were measured with a Vitras 950 (Ortho Diagnostics, Raritan, NJ), and glucose was determined on a Cobas Mira Plus (Roche, Mannheim, Germany). Free fatty acids were measured by a colorimetric technique (Wako, Neuss, Germany). Glycerol (blank without lipase) and triglycerides (with lipase and after subtraction of blank glycerol value) were measured by an enzymatic colorometric kit (Sigma, Poole, UK) on a Cobas Fara.
Statistics
Data are presented as mean ± SEM. Coefficients of variation (CVs) were calculated as SD/mean x 100%. The time course of effects of insulin and Intralipid was examined by repeated measures ANOVA using "placebo-corrected" data (i.e. values at each time point for insulin or Intralipid were subtracted from the values for saline infusion for each participant). Where ANOVA identified effects of infusion, post hoc paired t tests were performed to identify differences in absolute values. To reduce the variance of kinetic parameters derived from deuterated-steroid measurements, values were averaged for four measurements taken during steady-state in the final 30 min of the run-in period (180–210 min) and for three measurements taken in the final 40 min of each infusion (380–420 min).
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Results |
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The subjects were aged between 24–68 yr (mean ± SEM, 41 ± 4.3), with body mass index 19.7–30.2 kg/m2 (25.5 ± 1.2), waist to hip ratio 0.8–1.1 (0.9 ± 0.03), and systolic blood pressure 106–168 mm Hg (125 ± 6.2).
Effects of infusions on plasma fuel substrates and insulin
See Fig. 1
. After a light breakfast 90 min before the start of the study, insulin, glucose, and fatty acid concentrations returned to baseline values within 120 min. Insulin infusion from 210 min resulted in raised plasma insulin and reduced free fatty acid levels, whereas plasma glucose levels were maintained as intended at approximately 5.0 mmol/liter with dextrose infusion (Fig. 1). Intralipid infusion from 210 min resulted in raised free fatty acid levels and no change in plasma glucose or insulin levels. Plasma triglyceride levels fell slightly between 0–390 min with saline infusion (1.07 ± 0.36 to 0.98 ± 0.33 mmol/liter; P < 0.05), were suppressed by insulin infusion (from 1.15 ± 0.38 to 0.82 ± 0.27 mmol/liter; P < 0.01), and were increased by Intralipid infusion (from 1.17 ± 0.39 to 1.55 ± 0.52 mmol/liter; P < 0.05).
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See Table 1 and Fig. 2. As previously described (20, 26), D4-cortisol enrichment and D4-cortisol to D3-cortisol ratios were in steady-state at the end of the run-in period (i.e. values did not change between 180–210 min). Thereafter, insulin and dextrose infusion increased the rate of appearance of D3-cortisol in plasma (reflected in lower D4-cortisol to D3-cortisol ratios) and tended to increase the appearance of endogenous cortisol (ANOVA P = 0.07; reflected in lower D4-cortisol to cortisol ratios). Intralipid infusion did not significantly alter any of the measurements of whole-body deuterated cortisol metabolism. Neither insulin nor Intralipid infusion altered clearance rates of cortisol and D4-cortisol.
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). However, there were no differences in urinary deuterated cortisol metabolite excretion among saline, insulin, or Intralipid infusions. Adipose 11HSD1 activity (microdialysis)
The recovery of tritiated steroid during intraadipose infusion of [3H]2-cortisone and [3H]4-cortisol in the placebo (saline) phase of the study is shown in Fig. 3A. Recovery decreased during the first 3 h of perfusion but was in steady-state thereafter, consistent with a stable equilibrium between infusion into the intraadipose pool and clearance from the intraadipose pool. Recoveries were similarly stable between 180 and 420 min in the insulin and Intralipid phases of the study (data not shown; by repeated measures ANOVA, there were no significant changes in recovery between 180 and 420 min and no significant interaction with intervention group).
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). Intersubject CVs were calculated from results for nine subjects during each of the five measurements between 180–420 min in the placebo (saline) phase: CVs were 44 ± 2.5% for reductase and 108 ± 13% for dehydrogenase activities. Intrasubject CVs could only be calculated from three measurements at 180 min in each of the nine subjects (limitations of exposure to radioactive tracers precluded additional measurements in any one subject): CVs were 29 ± 7% for reductase and 59 ± 9% for dehydrogenase activities.
Given the very high intersubject variability, changes with insulin and Intralipid are presented as differences from placebo, rather than as absolute conversion rates (Fig. 4). During acute hyperinsulinemia in a euglycemic clamp, reductase activity increased by 3.5 h (Fig. 4; ANOVA P < 0.05); dehydrogenase activity showed similar changes that were not statistically significant. Intralipid infusion increased both reductase (ANOVA P < 0.01) and dehydrogenase (ANOVA P < 0.03) activities.
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Discussion |
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Hyperinsulinemia produced a highly statistically significant increase in whole-body regeneration of D3-cortisol by 11HSD1. This observation is novel because previous in vivo data are scarce, and those that rely upon measurement of urinary cortisol metabolites (30) probably have insufficient sensitivity and specificity to confirm or refute any effect of insulin on 11HSD1. In one previous study, D4-cortisol infusion was undertaken before and after hyperinsulinemia (28); effects on splanchnic D3-cortisol production were not reported in detail, although there was a small increase in D3-cortisol generation in the leg. Unlike this previous study, here we included a normoinsulinemic control group. Recent studies using arteriovenous sampling have suggested that the major source of extraadrenal production of cortisol is the splanchnic circulation (28), with contributions from both liver and other visceral tissues (most likely visceral adipose tissue) (27). Regeneration of cortisol in nonsplanchnic tissues has been detected, for example, in the leg (29), where it may still play an important role in determining local concentrations of cortisol, even if substantial cortisol is not released into the circulation. In the current experiments, however, we found only a small effect of insulin locally within sc adipose tissue (Fig. 4). We previously reported that acute hyperinsulinemia induces a rapid, but temporary, fall in intraadipose cortisol generation in lean but not obese men (20). Here, in a group with intermediate body mass indices, any immediate fall in 11HSD1 activity with hyperinsulinemia was insignificant (Fig. 4). However, there followed a minor increase in 11HSD1 activity, which appears unlikely to contribute substantially to the increase in whole-body D3-cortisol generation. These observations suggest that the acute effects of insulin extend beyond sc adipose tissue. In vitro, insulin has been reported to down-regulate 11HSD1 expression and activity in a number of cells, including hepatocytes, fibroblasts, and adipose cells (reviewed in Ref. 5). However, the in vitro effects may be confounded by the influence of insulin on cellular differentiation in cell culture, and it appears most likely that the up-regulation occurring after 2–3 h of hyperinsulinemia is transcriptional.
Intralipid infusion also influenced cortisol metabolism. However, in contrast with insulin, Intralipid induced substantial changes in sc adipose tissue 11HSD1 without altering systemic measurements of deuterated-cortisol metabolism. There was no accompanying change in serum insulin concentrations. These observations are consistent with one previous study that showed no effect of iv fatty acid infusion on liver 11HSD1 (measured by first pass metabolism of cortisone) (31). It may be that Intralipid affects 11HSD1 only in sc adipose tissue, where fatty acid turnover is high (32) and the contribution of cortisol regeneration to the systemic circulation is probably low (28). The time course of the Intralipid effect, being maximal at the end of a 3.5-h infusion, is consistent with transcriptional regulation and alterations in total 11HSD1 protein, albeit that free fatty acid concentrations were also rising steadily during the infusion (Fig. 1). However, mechanisms by which changes in fatty acid flux and concentration within the adipose cells might influence 11HSD1 transcription will need to be dissected in vitro. Intralipid contains a mixture of fatty acids derived from soya and chicken eggs; whether more typical meat or fish-derived fatty acids would have the same effect is uncertain and should now be tested by dietary manipulation.
Stewart and colleagues (24, 25) have recently proposed that variations in supply of NADPH cofactor for 11HSD1 by H6PDH may limit the capacity for reductase activity (regenerating cortisol from cortisone), allowing a switch in favor of dehydrogenase inactivation of cortisol by 11HSD1. We did find dehydrogenase activity within sc adipose tissue in vivo, as previously reported ex vivo (33), but there are several caveats. The insertion of the microdialysis cannulae causes significant local trauma so that it is possible that this reflects 11HSD1 favoring dehydrogenase activity only when it is dissociated from H6PDH in damaged tissues. 11HSD type 2 in the local vasculature may contribute to dehydrogenase activity (34). Notably, the dehydrogenase activity was of smaller magnitude than reductase activity in adipose tissue, consistent with previous arteriovenous sampling studies demonstrating net cortisone extraction from sc adipose (35). Importantly, there was no evidence from our data that acute regulation of 11HSD1 by insulin or Intralipid infusion is due to a switch in enzyme direction (from reductase to dehydrogenase or vice versa) because enzyme activities changed in parallel (Fig. 4). Because hyperinsulinemia is expected to alter the glucose-6-phosphate pool (the substrate for H6PDH) within adipose cells, this is probably as good a test as is currently available of the role of H6PDH in modifying 11HSD1 directionality in vivo in humans.
Both insulin and Intralipid infusions might alter intra-adipose blood flow, which we did not measure directly in this study, and might, in principle, have a differential effect on the rates of removal of cortisol and cortisone from the intraadipose pool. However, this explanation appears unlikely, because we did not observe changes in recovery of steroid during the intervention phase of the study (Fig. 3A), and alterations in dehydrogenase and reductase activities occurred in parallel rather than inversely as one would predict if blood flow had differential effects on cortisol and cortisone metabolism.
Although the effects on regeneration of cortisol were the most obvious in this study, there may also be effects of insulin and lipids on other enzymes that metabolize cortisol. Basu et al. (28) have reported that insulin increases splanchnic cortisol uptake, whereas, in the current study, in the face of increased peripheral regeneration of cortisol during hyperinsulinemia, there was no decrease in cortisol clearance rates. This suggests that insulin increases removal of cortisol by enzymes other than 11HSD1. The pathway responsible was not identified because rates of excretion of deuterated-cortisol metabolites in urine were not increased by insulin (Table 1).
These data have important implications in physiology and pathology. Physiologically, they highlight that the rate of local regeneration of cortisol is dynamic rather than static and may allow acute control of glucocorticoid action over and above alterations in the hypothalamic-pituitary-adrenal axis. The current experiments do not test whether postprandial hyperinsulinemia and/or hyperlipidemia are responsible for the recently reported rise in peripheral cortisol regeneration after a mixed meal (19); however, the time course and magnitude of effects observed are consistent with those observed after a meal. In pathology, the contrasting effects of insulin and lipid infusions on 11HSD1 in different tissues highlight the capacity for tissue-specific regulation, which presumably underlies the tissue-specific dysregulation in obesity (12). Indeed, we have shown that obese humans resist acute regulation of adipose 11HSD1 by hyperinsulinemia (20), whereas obesity-prone strains of mice resist down-regulation of adipose 11HSD1 by high-fat feeding (23). The current studies also illustrate that detailed dissection of cortisol metabolism within individual tissues in humans is now not only possible using these contemporary tools, but is likely to yield novel insights into glucocorticoid signaling in health and disease.
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Acknowledgments |
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Footnotes |
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Disclosure summary: D.J.W., N.Z.M.H., and R.A. have nothing to declare. B.R.W. consults for Incyte, Johnson & Johnson, Merck, Syrrx and Vitae, has received lecture fees from Abbott and Bristol Myers Squibb, and is an inventor on patents owned by the University of Edinburgh.
First Published Online September 5, 2006
Abbreviations: CV, Coefficient of variation; H6PDH, hexose-6-phosphate dehydrogenase; 11HSD1, 11ß-hydroxysteroid dehydrogenase type 1; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PPAR, peroxisome proliferator-activated receptor.
Received April 14, 2006.
Accepted August 25, 2006.
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ligands inhibit adipocyte 11ß-hydroxysteroid dehydrogenase type 1 expression and activity. J Biol Chem 276:12629–12635 agonists reduce 11ß-hydroxysteroid dehydrogenase type 1 in the liver. Biochem Biophys Res Commun 279:330–336[CrossRef][Medline]This article has been cited by other articles:
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  G. Banhegyi, M. Csala, and A. Benedetti Hexose-6-phosphate dehydrogenase: linking endocrinology and metabolism in the endoplasmic reticulum J. Mol. Endocrinol., April 1, 2009; 42(4): 283 - 289. [Abstract] [Full Text] [PDF]
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 C. Jang, V. R Obeyesekere, F. P Alford, and W. J Inder Skeletal muscle 11{beta} hydroxysteroid dehydrogenase type 1 activity is upregulated following elective abdominal surgery Eur. J. Endocrinol., February 1, 2009; 160(2): 249 - 255. [Abstract] [Full Text] [PDF]
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 A. Balachandran, H. Guan, M. Sellan, S. van Uum, and K. Yang Insulin and Dexamethasone Dynamically Regulate Adipocyte 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Endocrinology, August 1, 2008; 149(8): 4069 - 4079. [Abstract] [Full Text] [PDF]
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 D. P Macfarlane, S. Forbes, and B. R Walker Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome J. Endocrinol., May 1, 2008; 197(2): 189 - 204. [Abstract] [Full Text] [PDF]
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 S. Boullu-Ciocca, V. Achard, V. Tassistro, A. Dutour, and M. Grino Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet-Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood Diabetes, March 1, 2008; 57(3): 669 - 677. [Abstract] [Full Text] [PDF]
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 R. H. Stimson, A. M. Johnstone, N. Z. M. Homer, D. J. Wake, N. M. Morton, R. Andrew, G. E. Lobley, and B. R. Walker Dietary Macronutrient Content Alters Cortisol Metabolism Independently of Body Weight Changes in Obese Men J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4480 - 4484. [Abstract] [Full Text] [PDF]
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D. J. Wake, R. H. Stimson, G. D. Tan, N. Z. M. Homer, R. Andrew, F. Karpe, and B. R. Walker Effects of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} Agonists on 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1848 - 1856. [Abstract] [Full Text] [PDF]
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J. W. Tomlinson, M. Sherlock, B. Hughes, S. V. Hughes, F. Kilvington, W. Bartlett, R. Courtney, P. Rejto, W. Carley, and P. M. Stewart Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity in Vivo Limits Glucocorticoid Exposure to Human Adipose Tissue and Decreases Lipolysis J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 857 - 864. [Abstract] [Full Text] [PDF]
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, solid line), insulin (
, dotted line), or Intralipid (
, solid line). Insulin infusion increased plasma insulin and suppressed plasma free fatty acid concentrations (ANOVA, both P < 0.01). Intralipid infusion increased plasma free fatty acid concentrations (ANOVA, P < 0.01) without affecting plasma insulin. There were no differences in plasma glucose between the groups.
). In the other cannula, [3H]4-cortisol was infused to measure dehydrogenase activity (