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teris AlbertsBiovitrum SE12, SE-112 76, Stockholm, Sweden
Address all correspondence and requests for reprints to: Dr. P. Alberts, Pharmacology 2, Department of Biology, Biovitrum SE12, SE-112 76 Stockholm, Sweden. E-mail: peteris.alberts{at}biovitrum.com.
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Introduction |
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Glucocorticoids exert their tissue effects by binding to the glucocorticoid and mineralocorticoid receptors, both members of the nuclear receptor superfamily of ligand-activated transcription factors. Administration of the glucocorticoid receptor antagonist RU 486 decreases blood glucose in db/db mice and in patients with Cushing’s syndrome (6, 7). However, the specific effects on target tissues depend not only on receptor type and density, but also on the availability and metabolic conversion of glucocorticoid by intracellular enzymes (8). Two 11ß-hydroxysteroid dehydrogenases (11ß-HSD) catalyze the interconversion between active and inactive glucocorticoids (9). The enzyme 11ß-HSD1 is widely expressed and yields increased local tissue concentration of active glucocorticoid by converting cortisone into cortisol in humans, and 11-dehydrocorticosterone into corticosterone in rodents. In contrast, the enzyme 11ß-HSD2 catalyzes the opposite reaction, the inactivation of active glucocorticoid (10, 11).
The phenotype of mice having a targeted disruption of the 11ß-HSD1 gene substantiates the role of 11ß-HSD1 in the liver where it is highly expressed (12, 13). These mice have slightly lower plasma glucose levels on high-fat diet and show attenuated activation of key enzymes for hepatic gluconeogenesis after 24-h starvation combined with stress. Furthermore, 11ß-HSD1 knockout mice exhibit improved glucose tolerance, which is displayed despite modestly elevated plasma corticosterone levels. This shows the pivotal role of 11ß-HSD1 for enhancing intracellular glucocorticoid action in vivo.
BVT.2733 is a selective inhibitor of murine 11ß-HSD1 shown to decrease blood glucose levels and gluconeogenic enzymes after 7-d continuous sc administration to hyperglycemic KKAy mice (14). In the present study the effect of oral administration twice a day (b.i.d.) on glucose and insulin levels was tested in both KKAy mice and two other established animal models of type 2 diabetes, the ob/ob and the db/db mice. Furthermore, the effect of BVT.2733 on endogenous glucose production, and insulin sensitivity was assessed in euglycemic, hyperinsulinemic clamp studies and glucose tolerance tests in conscious ob/ob and KKAy mice.
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Animals
Male mice, C57BL/6J, C57BL/6JBom-ob/ob (Lepob; ob/ob; age 17–20 wk), and C57BL/KSBom-db/db (Leprdb; db/db; age 12–17 wk), from Taconic Farms (Ry, Denmark) were given a normal diet (R34, Lactamin, Vadstena, Sweden) and water ad libitum. Male KK-Ay/Ta Jcl (KKAy) mice (age, 8–14 wk; 10–12 wk old at the time of clamp) from Clea Japan (Tokyo, Japan) were given a high-fat diet (purified version of Sweetened Condensed Milk Diet, catalog no. D12266B; 32 kcal% fat, 
0.01% cholesterol; Research Diets, New Brunswick, NJ) and water ad libitum. The animals were kept one per cage at 22 ± 1 C, 50 ± 20% humidity, and a 12-h light, 12-h dark cycle with lights on at 0500–0630 h. They were grouped based on 4-h fasting blood glucose values, 4-h fasting blood glucose and plasma insulin (clamp studies), or body weight (normal, wild-type C57BL/6J mice). The procedures involving animals were in conformity with national and international laws for the care and use of laboratory animals and were approved by the local animal ethical committee.
Serum and plasma preparation
Serum was prepared from trunk blood samples that were kept 30 min at 4 C before centrifugation at 2000–3000 x g for 10–15 min and stored in tubes at -70 C until analysis.
Plasma was prepared from tail blood samples (10–20 µl) that were collected in heparinized hematocrit capillary tubes (Kebo-Lab, VWR, Solna, Sweden) on ice, centrifuged (24,000 x g, 10 min, 4 C), transferred to a microtiter 96-well plate, and stored at -20 C until analysis.
Glucose analysis
Blood glucose concentrations (Figs. 1–3
and Tables 2 and 3) were measured immediately using microcuvettes and test strips (Hemocue, Ängelholm, Sweden; or Accu-Chek, Roche, Basel, Switzerland). Both methods are based on glucose dehydrogenase conversion of glucose to gluconolactone. The measurable range is 0–22.2 mM for Hemocue and 0.6–33.3 mM for Accu-Chek. The reported within-run precision is SD 
0.3 mM with coefficients of variation of 3.5%, 2.6%, 1.9%, 1.6%, and 2.2% at 4.3, 7.7, 12.5, 18.2, and 21.0 mM glucose, respectively (Hemocue), and with a coefficient of variation less than 4.0% at 9.2 mM and less than 2.9 SD at 3.3 mM glucose (Accu-Chek). When glucose concentrations exceeded the measurable range, samples were diluted with heparin (LEO, Lövens, Ballerup, Denmark; final concentration, 10 IU/ml in physiological saline) or physiological saline.
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) were measured with an UV method (Roche) using a Cobas Mira instrument. Glucose was oxidized to gluconolactone by glucose dehydrogenase in the presence of NAD+ and mutarotase that accelerates the reaction. The formation of NADH was measured photometrically at 340 nm.
Insulin, cholesterol, triglyceride, and free fatty acid analysis
Serum insulin was analyzed with a rat insulin RIA (Linco Research, Inc., St. Louis, MO). In the oral glucose tolerance test (OGTT) and clamp experiments, plasma insulin was analyzed with a rat insulin ELISA (Mercodia, Uppsala, Sweden).
Serum cholesterol was analyzed with an enzymatic colorimetric method (MPR2, Roche). Serum triglycerides were analyzed with an enzymatic colorimetric method after elimination of free glycerol (Triglycerides/GB, Roche). Serum nonesterified, free fatty acids were determined with an enzymatic colorimetric method using oleic acid as a standard (NEFA C, Wako Chemicals, Neuss, Germany).
mRNA analysis
Real-time PCR was used to quantify mRNA levels (TaqMan, PE Applied Biosystems, Foster City, CA) of 11ß-HSD1 (EC 1.1.1.146), PEPCK (EC 4.1.1.32), and G6Pase (EC 3.1.3.9) isolated from liver, mesenteric fat, and epididymal fat (14). Levels were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA and 18S rRNA. Plasmid containing cloned reference DNA was used to construct standard curves for 11ß-HSD1and GAPDH levels (PE Applied Biosystems).
OGTT
All animals were administered BVT.2733 or vehicle b.i.d.; ob/ob mice BVT.2733 (200 mg/kg·d; for 4 d) and KKAy mice BVT.2733 (400 mg/kg·d; for 3 d). D-Glucose (2 g/kg; 200 mg/ml stock solution, Fresenius Kabi, Uppsala, Sweden) was given p.o. after overnight fasting and 2 h after the last administration of vehicle or BVT.2733. Blood samples were taken immediately before the glucose load and after 15, 30, 60, and 120 min.
Euglycemic, hyperinsulinemic clamp
Surgery and drug treatment before clamp.
A microrenathane implantation tubing catheter (Braintree Scientific, Inc., Braintree, MA) was inserted into the right jugular vein under isoflurane (Forene, Abbott, Chicago, IL) anesthesia at least 4 d before administration of drug or vehicle and at least 8 d before the clamp. The catheter was tunneled under the skin, extracted in the neck, and filled with glycerol containing heparin to prevent blood from clotting. BVT.2733 (200 mg/kg·d) or vehicle was administered for 3 d (KKAy mice) and 4 d (ob/ob mice).
Clamp protocol.
The clamps were performed in conscious mice (16). After administration of the last BVT.2733 dose the animals were fasted for 5 h before start of the clamp procedure. The animals were connected to a liquid swivel via the venous catheter and acclimatized for 45 min.
3-D-[3H]Glucose tracer (PerkinElmer, Boston, MA) dissolved in 0.9% saline was infused throughout the clamp to determine the glucose disposal rate (GDR). A priming bolus dose of 25 µCi/kg (925 kBq/kg) was given, followed by a continuous infusion of 2.5 µCi/kg·min (infusion rate, 50 µl/min·kg) by a microinjection pump (CMA/Microdialysis, Solna, Sweden). Blood samples (10 µl) were collected after 50, 60, and 70 min of D-[3H]glucose infusion and were used to determine the basal GDR. At the same time points, basal blood glucose levels were measured, and at 70 min a 20-µl blood sample was taken for basal plasma insulin measurement.
Insulin infusion (Actrapid, Novo Nordisk, Bagsværd, Denmark) was started 70 min after initiation of D-[3H]glucose infusion and continued for 90 min at a constant rate. A relatively low insulin concentration (12.5 mU/kg·min) was used to prevent complete suppression of endogenous glucose production (EGP) and therefore optimized to evaluate hepatic insulin sensitivity. Blood samples (10 µl) were taken after 70, 80, and 90 min of insulin infusion for determination of GDR. At 90 min, a 20-µl blood sample was taken for determination of circulating insulin levels during insulin infusion.
D-Glucose (300 mg/ml; Fresenius Kabi) was administered by an adjustable infusion pump (model 100, KD Scientific, New Hope, PA) to maintain blood glucose at the same level as before insulin infusion. The glucose infusion rate (GIR) was guided by blood glucose concentration measurements every 10 min. Blood glucose was clamped at the individual basal blood glucose level.
Blood [3H]D-glucose.
Barium hydroxide (50 µl, 0.3 M) and zinc sulfate (50 µl, 0.3 M) were added to blood samples (10 µl) and mixed. After centrifugation, supernatant (25-µl) samples in duplicate were transferred to scintillation vials and allowed to evaporate to dryness overnight to eliminate [3H]water. Next day, D-[3H]glucose was dissolved in water (0.5 ml), scintillation fluid (3 ml Ultima Gold, Packard, Meriden, CT) was added, and radioactivity was measured in a liquid scintillation spectrometer (TriCarb, Packard, Meriden, CT).
Calculations.
Blood glucose specific activity was calculated as the D-[3H]glucose divided by the measured blood glucose levels. Steady-state conditions for blood glucose specific activity were achieved during basal and clamp periods in both ob/ob mice and KKAy mice, as determined by linear regression analysis. The slopes were not significantly different from zero for all groups (P > 0.05; data not shown). GDR was calculated by dividing the rate of D-[3H]glucose infusion by the average specific activity of blood glucose. During basal conditions, EGP is assumed to be equal to the GDR. Under steady-state insulin infusion conditions (at 70–90 min), it is assumed that EGP = GDR - GIR.
Results are expressed as the mean ± SEM, except in Figs. 1 and 4, where the box extends from the 25th to the 75th percentile, with a line at the median, and the error bars show the highest and lowest values (PRISM 3.0 software, GraphPad, San Diego, CA).
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). In contrast, BVT.2733 (200 mg/kg·d) did not alter the blood glucose concentration in normal C57BL/6J mice (Fig. 1).
Serum insulin concentrations were lowered by the BVT.2733 treatment in ob/ob and db/db mice and tended to be lowered in KKAy mice, but were not altered in C57BL/6J mice (Table 1A).
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). The fasting blood glucose was 69% of the control value. Daily food intake was not affected in C57BL/6J and db/db mice by BVT.2733 (200 mg/kg·d). In ob/ob and KKAy mice, food intake was decreased by 25–39% and 14–19% compared with vehicle. Body weight was not altered in C57BL/6J, KKAy, and db/db mice, but was reduced by 5% in ob/ob mice compared with vehicle.
Effect of the 11ß-HSD1 inhibitor BVT.2733 on hepatic mRNA concentrations
Treatment of KKAy mice with BVT.2733 resulted in a dose-dependent reduction of PEPCK mRNA levels in the liver from 2.12 ± 0.16 for vehicle to 1.95 ± 0.10 and 1.51 ± 0.14 (P < 0.01; n = 8) after the administration of 100 and 200 mg/kg·d, respectively (relative units from normalization to GAPDH mRNA). The levels of 11ß-HSD1 mRNA and G6Pase mRNA also tended to decrease. The level of 11ß-HSD1 mRNA was 2.45 ± 0.44 for vehicle and 2.33 ± 0.25 and 1.75 ± 0.21 for BVT.2733 (100 and 200 mg/kg·d; n = 8). The level of G6Pase mRNA was 1.09 ± 0.19 for vehicle and 1.55 ± 0.19 and 0.78 ± 0.13 for BVT.2733 (100 and 200 mg/kg·d; n = 8). Similar results were obtained when data were normalized to 18S rRNA (not shown).
Effect of the 11ß-HSD1 inhibitor BVT.2733 on OGTT
OGTTs were performed in ob/ob and KKAy mice. In mice from both strains BVT.2733 treatment resulted in decreased blood glucose concentrations at early time points compared with vehicle treatment (Fig. 2). In the KKAy mouse this was accompanied by lower insulin concentrations both before and after glucose administration, but in the ob/ob mice no differences in the effect on insulin levels were seen. ANOVAs using repeated measurements did not yield any significant differences between drug-treated and vehicle-treated mice. Also, the baseline adjusted AUCs (data not shown) for glucose and insulin in the KKAy and ob/ob BVT.2733-treated and vehicle-treated mice did not differ significantly (independent sample t tests). In the KKAy mice BVT.2733 (400 mg/kg·d) was used, because at 200 mg/kg·d no effect on the OGTT was observed in a pilot experiment (data not shown).
Effect of the 11ß-HSD1 inhibitor BVT.2733 on insulin sensitivity
Blood glucose concentrations during steady-state insulin infusion in the euglycemic, hyperinsulinemic clamp were similar to basal levels in ob/ob mice and vehicle-treated KKAy mice, but lower than basal levels in BVT.2733-treated KKAy mice (Table 2). Plasma insulin was increased approximately 2- to 4-fold by the insulin (12.5 mU/kg·min) infusion (Table 2).
The GIR in BVT.2733-treated mice was higher than that in vehicle-treated mice at all time points in both ob/ob and KKAy mice (Fig. 3 and Table 3). In ob/ob mice the corresponding AUCs between BVT.2733- and vehicle-treated mice were also significantly different (P < 0.01; data not shown).
The GDR was increased during insulin infusion in both vehicle- and BVT.2733-treated KKAy mice, but was not different between vehicle- and BVT.2733-treated ob/ob mice (Table 3). Under basal conditions no difference was observed between vehicle- and BVT.2733-treated groups in any of the strains.
EGP under basal conditions tended to be lower in BVT.2733-treated than in vehicle-treated ob/ob and KKAy mice (Table 3). During insulin infusion, however, EGP was more suppressed in both ob/ob and KKAy mice treated with BVT.2733 compared with vehicle-treated mice (Table 3).
Comparison of 11ß-HSD1 mRNA levels in liver and two different fat depots
The two hyperglycemic models in which the effects of 11ß-HSD1 inhibition were studied most extensively were further characterized in terms of 11ß-HSD1 mRNA levels. The levels of 11ß-HSD1 mRNA (normalized to GAPDH mRNA) in the liver, mesenteric fat, and epididymal fat were determined in C57BL/6J, KKAy, and ob/ob mice (Fig. 4). In liver and epididymal fat, the levels were higher in C57BL/6J and ob/ob than in KKAy mice. In mesenteric fat the levels in ob/ob mice were higher than those in C57BL/6J and KKAy mice.
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Discussion |
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The present results show that oral BVT.2733 administration decreased circulating glucose levels in ob/ob, db/db, and KKAy mice, with a parallel decrease in insulin levels. Analysis of hepatic mRNA in the KKAy mouse showed reduced levels of PEPCK mRNA. Thus, the results using oral administration confirm and extend the results obtained after osmotic minipump administration in the KKAy mouse (14). In the current study a larger effect of 11ß-HSD1 inhibition on blood glucose was seen in ob/ob and KKAy mice compared with db/db and normal mice. The ob/ob mice displayed the same concentration of 11ß-HSD1 mRNA in the liver as normal mice, whereas KKAy mice had only 25%. Furthermore, it has been reported that both the 11ß-HSD1 activity and mRNA levels are elevated in livers of db/db mice (17). Thus, the magnitude of the reduction of hepatic glucose production and blood glucose levels depends not only on the level of the target enzyme, but on other factors as well. In accordance, no blood glucose decrease was observed in normal mice despite high levels of 11ß-HSD1 expression in the liver. The lack of hypoglycemic effect in normal mice is in agreement with previous data showing that the nonspecific 11ß-HSD1 inhibitor carbenoxolone does not yield decreased blood glucose in healthy human volunteers (18, 19). Furthermore, 11ß-HSD1 knockout mice display normal fasting glucose levels (12, 20). Thus, inhibition and lack of the enzyme yield similar results. Taken together, the data support a fine-tuning effect of 11ß-HSD1 on blood glucose levels, where inhibition leads to a decrease in excessive, but not basal, levels.
After a 4-h fast, blood glucose as well as serum cholesterol, triglycerides, and free fatty acids were decreased in KKAy mice given BVT.2733. However, samples taken under ad libitum-fed conditions did not consistently alter serum cholesterol, triglyceride, or free fatty acid concentrations. As the fasting samples were obtained 4 h after administration, whereas samples from ad libitum-fed animals were collected 12 h post treatment, higher levels of inhibitor may have contributed to the decreases in lipids. Thus, lipid lowering might have a beneficial effect on hepatic insulin sensitivity and contribute to the reduced blood glucose levels. A lipid-lowering effect from 11ß-HSD1 inhibition was expected based on the lipolysis-inducing properties of glucocorticoids (19, 21). Similarly, selective overexpression of 11ß-HSD1 in white adipose tissue leads to increased adipose levels of corticosterone, lipoprotein lipase mRNA, and circulating free fatty acids (22). These transgenic mice develop visceral obesity similar to the human metabolic syndrome, supporting the hypothesis that 11ß-HSD1 inhibition might prevent or reduce omental obesity in human metabolic syndrome and type 2 diabetes. Clinical data suggest that overexpression of 11ß-HSD1 might contribute to development of the metabolic syndrome, because increased obesity correlates with higher expression of the enzyme (23, 24). However, in humans only sc adipose tissue has been investigated, not the more metabolically active and glucocorticoid receptor-rich visceral adipose tissue, where fat accumulation has been shown to correlate with increased morbidity and mortality (25).
Hyperglycemia and hyperphagia appear to depend on glucocorticoids in both man (23) and the commonly used models for type 2 diabetes ob/ob, db/db, and KKAy mice and fa/fa Zucker rats (26, 27, 28). In ob/ob and db/db mice, adrenalectomy slows and cortisone treatment increases weight gain (29). Likewise, the glucocorticoid receptor antagonist RU 486 prevents development of hyperphagia, obesity, and fat deposition in fa/fa Zucker rats with no effect in lean rats (30, 31). Moreover, mice exhibiting enhanced glucocorticoid activity due to selective overexpression of 11ß-HSD1 in white adipose tissue are both hyperglycemic and hyperphagic (22). In accordance, the present study shows that 11ß-HSD1 inhibition yielded slightly decreased food intake in ob/ob and KKAy mice. This is expected to contribute to reduced blood glucose levels. However, in KKAy mice the reduction in food intake was smaller than that in blood glucose, and in db/db mice glucose levels were reduced, with no concomitant effect on food intake. Thus, a beneficial reduction in food intake may contribute to the blood glucose-lowering effect of 11ß-HSD1 inhibition, although to a different degree in different models of type 2 diabetes.
Glucocorticoids contribute to increased hepatic glucose output in diabetes (4) and counteract the actions of insulin (1). The enzyme 11ß-HSD1 enhances the effect by generating active glucocorticoid in target tissues (9). We have previously shown that BVT.2733 inhibits 11ß-HSD1 in the liver and reduces hepatic levels of mRNA corresponding to key gluconeogenic enzymes (14). The present results support the hypothesis that selective 11ß-HSD1 inhibition yields enhanced insulin sensitivity and agrees with the clinical finding of improved whole body insulin sensitivity using the nonselective 11ß-HSD1 inhibitor carbenoxolone (18). The euglycemic, hyperinsulinemic clamp data from the present study show improvement in hepatic insulin sensitivity in both ob/ob and KKAy mice; in both models, EGP was more suppressed during insulin infusion in mice treated with BVT.2733 than in vehicle-treated control animals. Also under basal conditions EGP tended to be lower in BVT.2733-treated ob/ob and KKAy mice. The GIR was higher in ob/ob mice treated with the selective 11ß-HSD1 inhibitor compared with the vehicle-treated group, and in KKAy mice treatment with BVT.2733 tended to increase the GIR. In the latter case the GIR may have been underestimated, as the animals did not fully maintain basal glucose levels at steady-state insulin infusion conditions.
The GDR increased during insulin infusion in both vehicle- and BVT.2733-treated KKAy mice, whereas no effect of BVT.2733 administration was detected. However, a tendency toward increased GDR was seen in ob/ob mice after BVT.2733 treatment, which might be a reflection of higher levels of the target 11ß-HSD1 in adipose tissue compared with KKAy mice. Furthermore, preliminary observations of 11ß-HSD1 inhibition by BVT.2733 in adipose tissue suggest that peripheral effects are likely (data not shown). However, the primary objective of the present study was to evaluate the effect on hepatic insulin sensitivity. Therefore, mild hyperinsulinemia was employed in the clamp studies to avoid complete suppression of hepatic glucose production. A more pronounced hyperinsulinemia would have been used to reveal effects on peripheral insulin sensitivity. Such levels were employed in a pilot study where insulin was infused at 25 mU/kg·min in KKAy mice treated with BVT.2733 (400 mg/kg·d) for 3 d. In that study enhanced hepatic insulin sensitivity (EGP) as well as a trend toward increased GDR were seen (data not shown).
In ob/ob and KKAy mice BVT.2733 treatment resulted in reduced glucose levels that were accompanied by reduced or unchanged insulin levels during the OGTT. This suggests improved whole body glucose tolerance and increased insulin sensitivity. The results are in accordance with data on 11ß-HSD1 gene knockout mice exhibiting improved glucose tolerance (13) and with impaired glucose tolerance in transgenic mice having increased 11ß-HSD1 activity in white adipose tissue (22). A higher dose of BVT.2733 (400 mg/kg·d) was required for effects on glucose tolerance in the KKAy model, in which a larger effect on insulin and a lesser effect on glucose levels were observed. Thus, there are qualitative differences between the two models, which may reflect different levels of target enzyme not only in liver and adipose tissue, but also in skeletal muscle and pancreas.
In conclusion, oral administration of a selective 11ß-HSD1 inhibitor resulted in lowered circulating glucose and insulin levels in three separate mouse models of type 2 diabetes, but not in normal mice, yielding further support to the suggestion that a selective inhibitor of human 11ß-HSD1 may lower blood glucose levels in subjects with type 2 diabetes (14) without causing hyperglycemia. Decreased EGP suggests enhanced insulin sensitivity. In addition, a reduction in food intake was seen in some of the models, suggesting a beneficial reduction in weight gain over time.
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P.A. and C.N. contributed equally to the study.
Abbreviations: AUC, Area under the curve; b.i.d., bis in diem, twice a day; BVT.2733, 3-chloro-2-methyl-N-{4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1,3-thiazol-2-yl}benzenesulfonamide; EGP, endogenous glucose production; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GDR, glucose disposal rate; GIR, glucose infusion rate; G6Pase, glucose-6-phosphatase; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; OGTT, oral glucose tolerance test; PEPCK, phosphoenolpyruvate carboxykinase, p.o., per os, orally.
Received March 19, 2003.
Accepted for publication July 25, 2003.
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M. Berthiaume, M. Laplante, W. T. Festuccia, K. Cianflone, L. P. Turcotte, D. R. Joanisse, G. Olivecrona, R. Thieringer, and Y. Deshaies 11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1045 - E1052. [Abstract] [Full Text] [PDF]
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 E. A. Walker, A. Ahmed, G. G. Lavery, J. W. Tomlinson, S. Y. Kim, M. S. Cooper, J. P. Ride, B. A. Hughes, C. H. L. Shackleton, P. McKiernan, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function J. Biol. Chem., September 14, 2007; 282(37): 27030 - 27036. [Abstract] [Full Text] [PDF]
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M. Berthiaume, M. Laplante, W. Festuccia, Y. Gelinas, S. Poulin, J. Lalonde, D. R. Joanisse, R. Thieringer, and Y. Deshaies Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Endocrinology, May 1, 2007; 148(5): 2391 - 2397. [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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 S. Nammi, K. Dembele, and B. L. G. Nyomba Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1101 - R1109. [Abstract] [Full Text] [PDF]
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I. J Bujalska, O. M Durrani, J. Abbott, C. U Onyimba, P. Khosla, A. H Moosavi, T. T Q Reuser, P. M Stewart, J. W Tomlinson, E. A Walker, et al. Characterisation of 11{beta}-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat J. Endocrinol., February 1, 2007; 192(2): 279 - 288. [Abstract] [Full Text] [PDF]
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D. J. Wake, N. Z. M. Homer, R. Andrew, and B. R. Walker Acute In Vivo Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4682 - 4688. [Abstract] [Full Text] [PDF]
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R. Basu, D. S. Edgerton, R. J. Singh, A. Cherrington, and R. A. Rizza Splanchnic Cortisol Production in Dogs Occurs Primarily in the Liver: Evidence for Substantial Hepatic Specific 11{beta} Hydroxysteroid Dehydrogenase Type 1 Activity Diabetes, November 1, 2006; 55(11): 3013 - 3019. [Abstract] [Full Text] [PDF]
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C. U Onyimba, N. Vijapurapu, S J. Curnow, P. Khosla, P. M Stewart, P. I Murray, E. A Walker, and S. Rauz Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye. J. Endocrinol., August 1, 2006; 190(2): 483 - 493. [Abstract] [Full Text] [PDF]
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P. D. van Poelje, S. C. Potter, V. C. Chandramouli, B. R. Landau, Q. Dang, and M. D. Erion Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats Diabetes, June 1, 2006; 55(6): 1747 - 1754. [Abstract] [Full Text] [PDF]
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C. Bruley, V. Lyons, A. G. F. Worsley, M. D. Wilde, G. D. Darlington, N. M. Morton, J. R. Seckl, and K. E. Chapman A Novel Promoter for the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Gene Is Active in Lung and Is C/EBP{alpha} Independent Endocrinology, June 1, 2006; 147(6): 2879 - 2885. [Abstract] [Full Text] [PDF]
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G. G. Lavery, E. A. Walker, N. Draper, P. Jeyasuria, J. Marcos, C. H. L. Shackleton, K. L. Parker, P. C. White, and P. M. Stewart Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11beta-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation J. Biol. Chem., March 10, 2006; 281(10): 6546 - 6551. [Abstract] [Full Text] [PDF]
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S. Piccirella, I. Czegle, B. Lizak, E. Margittai, S. Senesi, E. Papp, M. Csala, R. Fulceri, P. Csermely, J. Mandl, et al. Uncoupled Redox Systems in the Lumen of the Endoplasmic Reticulum: PYRIDINE NUCLEOTIDES STAY REDUCED IN AN OXIDATIVE ENVIRONMENT J. Biol. Chem., February 24, 2006; 281(8): 4671 - 4677. [Abstract] [Full Text] [PDF]
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J. E. Ayala, D. P. Bracy, O. P. McGuinness, and D. H. Wasserman Considerations in the Design of Hyperinsulinemic-Euglycemic Clamps in the Conscious Mouse Diabetes, February 1, 2006; 55(2): 390 - 397. [Abstract] [Full Text] [PDF]
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T. Harrity, D. Farrelly, A. Tieman, C. Chu, L. Kunselman, L. Gu, R. Ponticiello, M. Cap, F. Qu, C. Shao, et al. Muraglitazar, a Novel Dual ({alpha}/{gamma}) Peroxisome Proliferator-Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves {beta}-Cell Function in db/db Mice Diabetes, January 1, 2006; 55(1): 240 - 248. [Abstract] [Full Text] [PDF]
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N. M. Morton, V. Densmore, M. Wamil, L. Ramage, K. Nichol, L. Bunger, J. R. Seckl, and C. J. Kenyon A Polygenic Model of the Metabolic Syndrome With Reduced Circulating and Intra-Adipose Glucocorticoid Action Diabetes, December 1, 2005; 54(12): 3371 - 3378. [Abstract] [Full Text] [PDF]
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M. Grino Prenatal nutritional programming of central obesity and the metabolic syndrome: role of adipose tissue glucocorticoid metabolism Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1233 - R1235. [Full Text] [PDF]
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 A. Hermanowski-Vosatka, J. M. Balkovec, K. Cheng, H. Y. Chen, M. Hernandez, G. C. Koo, C. B. Le Grand, Z. Li, J. M. Metzger, S. S. Mundt, et al. 11{beta}-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice J. Exp. Med., August 15, 2005; 202(4): 517 - 527. [Abstract] [Full Text] [PDF]
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S. Arampatzis, B. Kadereit, D. Schuster, Z. Balazs, R. A S Schweizer, F. J Frey, T. Langer, and A. Odermatt Comparative enzymology of 11{beta}-hydroxysteroid dehydrogenase type 1 from six species J. Mol. Endocrinol., August 1, 2005; 35(1): 89 - 101. [Abstract] [Full Text] [PDF]
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I. J Bujalska, N. Draper, Z. Michailidou, J. W Tomlinson, P. C White, K. E Chapman, E. A Walker, and P. M Stewart Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11{beta}-hydroxysteroid dehydrogenase type 1 J. Mol. Endocrinol., June 1, 2005; 34(3): 675 - 684. [Abstract] [Full Text] [PDF]
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K. N. Hewitt, E. A. Walker, and P. M. Stewart Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity Endocrinology, June 1, 2005; 146(6): 2539 - 2543. [Abstract] [Full Text] [PDF]
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R. Andrew, J. Westerbacka, J. Wahren, H. Yki-Jarvinen, and B. R. Walker The Contribution of Visceral Adipose Tissue to Splanchnic Cortisol Production in Healthy Humans Diabetes, May 1, 2005; 54(5): 1364 - 1370. [Abstract] [Full Text] [PDF]
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G. Apostolova, R. A. S. Schweizer, Z. Balazs, R. M. Kostadinova, and A. Odermatt Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E957 - E964. [Abstract] [Full Text] [PDF]
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E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, and J. S. Flier Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity Diabetes, April 1, 2005; 54(4): 1023 - 1031. [Abstract] [Full Text] [PDF]
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T. C. Sandeep, R. Andrew, N. Z.M. Homer, R. C. Andrews, K. Smith, and B. R. Walker Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone Diabetes, March 1, 2005; 54(3): 872 - 879. [Abstract] [Full Text] [PDF]
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D. J. Hosfield, Y. Wu, R. J. Skene, M. Hilgers, A. Jennings, G. P. Snell, and K. Aertgeerts Conformational Flexibility in Crystal Structures of Human 11{beta}-Hydroxysteroid Dehydrogenase Type I Provide Insights into Glucocorticoid Interconversion and Enzyme Regulation J. Biol. Chem., February 11, 2005; 280(6): 4639 - 4648. [Abstract] [Full Text] [PDF]
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A. J. Drake, D. E. W. Livingstone, R. Andrew, J. R. Seckl, N. M. Morton, and B. R. Walker Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats Endocrinology, February 1, 2005; 146(2): 913 - 919. [Abstract] [Full Text] [PDF]
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S. Boullu-Ciocca, A. Dutour, V. Guillaume, V. Achard, C. Oliver, and M. Grino Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood: Its Relationship With the Metabolic Syndrome Diabetes, January 1, 2005; 54(1): 197 - 203. [Abstract] [Full Text] [PDF]
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 J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]
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K. Kannisto, K. H. Pietilainen, E. Ehrenborg, A. Rissanen, J. Kaprio, A. Hamsten, and H. Yki-Jarvinen Overexpression of 11{beta}-Hydroxysteroid Dehydrogenase-1 in Adipose Tissue Is Associated with Acquired Obesity and Features of Insulin Resistance: Studies in Young Adult Monozygotic Twins J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4414 - 4421. [Abstract] [Full Text] [PDF]
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G. Valsamakis, A. Anwar, J. W. Tomlinson, C. H. L. Shackleton, P. G. McTernan, R. Chetty, P. J. Wood, A. K. Banerjee, G. Holder, A. H. Barnett, et al. 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity in Lean and Obese Males with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4755 - 4761. [Abstract] [Full Text] [PDF]
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C. Frick, A. G. Atanasov, P. Arnold, J. Ozols, and A. Odermatt Appropriate Function of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in the Endoplasmic Reticulum Lumen Is Dependent on Its N-terminal Region Sharing Similar Topological Determinants with 50-kDa Esterase J. Biol. Chem., July 23, 2004; 279(30): 31131 - 31138. [Abstract] [Full Text] [PDF]
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G. Banhegyi, A. Benedetti, R. Fulceri, and S. Senesi Cooperativity between 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-phosphate Dehydrogenase in the Lumen of the Endoplasmic Reticulum J. Biol. Chem., June 25, 2004; 279(26): 27017 - 27021. [Abstract] [Full Text] [PDF]
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R. A. S. Schweizer, M. Zurcher, Z. Balazs, B. Dick, and A. Odermatt Rapid Hepatic Metabolism of 7-Ketocholesterol by 11{beta}-Hydroxysteroid Dehydrogenase Type 1: SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME J. Biol. Chem., April 30, 2004; 279(18): 18415 - 18424. [Abstract] [Full Text] [PDF]
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 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
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