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Brian R Walker

Publications and source records attributed to Brian R Walker.

52 records · Page 3Linked to original sources
PubMed2003

Obese Zucker rats have reduced mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type 1 expression in hippocampus-implications for dysregulation of the hypothalamic-pituitary-adrenal axis in obesity.

Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11betaHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37-47%, P < 0.05), whereas 11betaHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37-49%, P < 0.05 for CA1-2 and P < 0.01 for dentate gyrus) and in frontal cortex (by 16%, P < 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11betaHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P < 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups. We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11betaHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Ten years on: Safety of short synacthen tests in assessing adrenocorticotropin deficiency in clinical practice.

Since 1988, when a retrospective study of patients attending this unit was published, we have advocated the use of the short synacthen test (SST) as the primary screening investigation to detect ACTH deficiency. However, others have published comparisons of SST and insulin tolerance tests that suggest a significant false negative rate with SST, leading to concern that some patients who pass the SST are in danger from the clinical consequences of ACTH deficiency. To address this, we audited biochemical results and clinical outcome in 63 patients who did not have ACTH deficiency detected (i.e. who passed the test) by SST after pituitary surgery. Twelve of the 63 patients who passed a SST after pituitary surgery became ACTH-deficient later as diagnosed by SST: 4 within the first year, 2 of whom had received postoperative radiotherapy (3 had symptoms of tiredness and 1 was admitted to the hospital with a viral infection); 8 in yr 3-5, 7 of whom had received postoperative radiotherapy (all had either no symptoms or symptoms of tiredness alone). Thus, the predictive value of the SST in excluding ACTH deficiency is approximately 97% (2 of 63 patients who initially passed the SST were found to be ACTH-deficient within 12 months without having received postoperative radiotherapy). Only 1 patient was ill enough to require hospital admission. Setting the risk of false negatives with SST against the morbidity and manpower implications associated with insulin tolerance tests, SST remains the primary screening test for ACTH deficiency in our practice. However, a high index of clinical suspicion to detect false negative results must be maintained.

Acromegaly↗
PubMed2003

Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes.

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) regenerates cortisol from inactive cortisone in liver and adipose tissue. Inhibition of 11 beta-HSD1 offers a novel potential therapy to lower intracellular cortisol concentrations and thereby enhance insulin sensitivity and hepatic lipid catabolism in type 2 diabetes, obesity, and hyperlipidemia. We evaluated this approach using the nonselective 11 beta-HSD inhibitor, carbenoxolone, in healthy men and lean male patients with type 2 diabetes. Six diet-controlled nonobese diabetic patients with hemoglobin A(1c) less than 8%, and six matched controls participated in a double-blind, cross-over comparison of carbenoxolone (100 mg every 8 h, orally, for 7 d) and placebo. They were admitted overnight for infusions of insulin (as required to maintain arterialized plasma glucose of 5.0 mM) and [13C6]glucose. Glucose kinetics were measured in the fasted state from 0700-0730 h, during a 3-h euglycemic hyperinsulinemic clamp (including somatostatin infusion and replacement of physiological GH and glucagon levels), and during a 2-h euglycemic hyperinsulinemic clamp with a 4-fold increase in glucagon levels. Data are the mean +/- SEM. Carbenoxolone had the expected effects of raising blood pressure and lowering plasma potassium. Carbenoxolone reduced total cholesterol in healthy subjects (5.25 +/- 0.34 vs. 4.78 +/- 0.40 mM; P < 0.01), but had no effect on other serum lipids or on cholesterol in diabetic patients. Carbenoxolone did not affect the rate of glucose disposal or the suppression of free fatty acids during hyperinsulinemia. However, carbenoxolone reduced the glucose production rate during hyperglucagonemia in diabetic patients (1.90 +/- 0.2 vs. 1.53 +/- 0.3 mg/kg x min; P < 0.05). This was attributable to reduced glycogenolysis (1.31 +/- 0.2 vs. 1.01 +/- 0.2 mg/kg x min; P < 0.005) rather than altered gluconeogenesis. These observations reinforce the potential metabolic benefits of inhibiting 11 beta-HSD1 in the liver of patients with type 2 diabetes. Further studies in obesity and hyperlipidemia are now warranted. However, clinically useful therapeutic effects will probably require selective 11 beta-HSD1 inhibitors that lower intraadipose cortisol levels and enhance peripheral glucose uptake.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2003

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians.

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver.

In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease.

11beta-hydroxysteroid dehydrogenase Type 1 (11HSD1) catalyses regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues. Inhibition of 11HSD1 has been proposed as a novel strategy to lower intracellular glucocorticoid concentrations, without affecting circulating glucocorticoid levels and their responsiveness to stress. Increased 11HSD1 activity may be pathogenic, for example, in adipose tissue in obesity. Experiments in transgenic mice and using prototype inhibitors in humans show benefits of 11HSD1 inhibition in liver, adipose and brain tissue in treating features of the metabolic syndrome and cognitive dysfunction with ageing. The clinical development of potent selective 11HSD1 inhibitors is now a high priority.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2003

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

OBJECTIVE: Glucocorticoids may contribute to the association between retarded growth in utero and insulin resistance in adulthood. Administration of dexamethasone (dex) to pregnant rats results in low birth weight offspring, which develop glucose intolerance, hyperinsulinaemia and hypercorticosteronaemia. This may be explained by tIssue-specific differences in expression of glucocorticoid receptors (GR) in adult offspring: GR is increased in visceral fat and liver, and decreased in hippocampus and soleus muscle. However, cause and effect between altered GR expression, hypercorticosteronaemia, and hyperinsulinaemia remains to be established. DESIGN AND METHODS: Rats were treated with dex (100 microg/kg per day) or saline during the third week of pregnancy. In 5-8-Month-old male offspring, GR expression in insulin target tIssues was quantified by RNase protection assay in rats that were adrenalectomised (ADX group), sham operated (SHAM group), or adrenalectomised with supra-physiological corticosterone replacement (CORT group) (n=7-8 per group), and in rats treated orally with vehicle, metformin (43 mg/kg per day) or rosiglitazone (1 mg/kg per day), after 3 weeks. RESULTS: Manipulation of corticosterone concentration did not affect GR mRNA in skeletal muscle or adipose. In liver, sham-operated animals showed lower GR mRNA, but there was no difference between adrenalectomised and hypercorticosteronaemic animals (SHAM 0.11+/-0.01 ratio to beta-actin, vs ADX 0.22+/-0.02, CORT 0.23+/-0.02, (values expressed as means+/-s.e.m.), P<0.001). Rosiglitazone reduced GR mRNA by approximately 30% in liver of dex- and saline-treated offspring (P<0.05), but had no effect on GR in adipose and skeletal muscle. Metformin abolished the 38% up-regulation of liver GR mRNA induced by antenatal dex and also reduced GR mRNA preferentially in muscle of dex-treated animals (0.14+/-0.01 vs 0.10+/-0.01; P=0.03). CONCLUSIONS: We conclude that neither hypercorticosteronaemia nor hyperinsulinaemia are sufficient to cause the changes in GR expression in dex-programmed rats, implying that these changes may be primary in determining the programmed insulin resistant phenotype. Normalisation of GR expression by metformin may be important in the mode of action of this anti-diabetic agent and may be especially useful to reverse-programmed up-regulation of GR.

Animals↗
PubMed2002

Effect of glycyrrhetinic acid on 11 beta-hydroxysteroid dehydrogenase activity in normotensive and hypertensive subjects.

The 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) isoenzymes catalyse the interconversion of cortisol and cortisone. Type 1 11 beta-HSD mainly converts cortisone into active cortisol. Type 2 11 beta-HSD inactivates cortisol in mineralocorticoid target tissues, and its activity can be inhibited by glycyrrhetinic acid (GA). Inactivation of cortisol to cortisone is impaired in a subgroup of patients with primary hypertension. To study where this defect is located, we measured cortisol and cortisone concentrations in arterial plasma, in saliva and across the forearm at baseline and after administration of GA in normotensive and hypertensive subjects. GA (500 mg) or placebo was administered orally to 20 normotensive subjects in a placebo-controlled double-blind fashion. Further, we compared the effect of GA in 20 patients with primary hypertension with that in 20 normotensive subjects. Cortisol and cortisone were measured in plasma from the brachial artery and vein and in saliva. Samples were obtained at 0, 90 and 150 min. Forearm blood flow (FBF) was measured simultaneously. Forearm production of corticosteroid hormones was assessed by multiplying the arteriovenous difference in corticosteroid concentration by FBF. The cortisol/cortisone ratio in arterial plasma remained at baseline levels after placebo (4.9 +/- 1.2; mean +/- S.D.), while after GA the ratio increased similarly in normotensive subjects (12.3 +/- 3.4) and in hypertensive patients (12.2 +/- 3.7). A similar effect of GA on the salivary cortisol/cortisone ratio was found. In both normotensive subjects and hypertensive patients no forearm production of cortisol or cortisone could be demonstrated, either at baseline or after administration of GA. Thus, both before and after GA administration, we did not find any difference in systemic and salivary 11 beta-HSD type 2 activity between subjects with primary hypertension and normotensive controls. Further, both at baseline and after GA administration we were not able to demonstrate net inactivation or re-activation of cortisol and cortisone by the 11 beta-HSD isoenzymes in the forearm in either normotensive or primary hypertensive subjects.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2002

Contrasting effects of intrauterine growth retardation and premature delivery on adult cortisol secretion and metabolism in man.

OBJECTIVE: Among babies born at term, intrauterine growth retardation (IUGR) predicts adult hypertension and hyperglycaemia. This might be due to elevated circulating glucocorticoids in adulthood, as described in animal models and in several cohorts of men who were low birthweight at term. Recently, we found that premature low birthweight babies also have adult cardiovascular risk factors, irrespective of IUGR. We have now investigated cortisol secretion in this group. DESIGN PATIENTS AND MEASUREMENTS: We studied 29 women and 23 men aged 22-25 years who had been recruited at birth as either normal term (mean birthweight 3.1 kg, gestation 39 weeks), premature appropriate for gestational age (AGA; 1.7 kg, 32 weeks), or premature IUGR (1.7 kg, 35 weeks) babies. Body composition was measured by dual-energy X-ray absorptiometry (DEXA); plasma was obtained at 0900 h after overnight fast; and cortisol metabolites were measured in a 24-h urine sample by gas chromatography/mass spectrometry (GCMS). RESULTS: Cortisol metabolites were different in men and women, so results were analysed separately. Among women, adult body composition did not differ between groups. Plasma cortisol was not different, but total urinary cortisol metabolite excretion was lower in AGA (3.29 +/- 1.91 mg/day, n = 7, P < 0.02) than in either normals (6.77 +/- 4.10, n = 14) or IUGR (9.47 +/- 8.84, n = 8). Relative excretion of cortisol and cortisone metabolites was not different. Statistically significant differences in cortisol parameters between groups were not seen in men. CONCLUSIONS: Premature AGA baby girls have lower cortisol secretion in adulthood but normal plasma cortisol, suggesting impaired metabolic clearance of cortisol. By contrast, premature IUGR babies maintain normal cortisol secretion as adults, suggesting that IUGR, rather than premature delivery, is responsible for programmed activation of the hypothalamic-pituitary-adrenal (HPA) axis. The ability to detect such dramatic differences in a small study suggests that programming has a potent influence on adult cortisol secretion.

Adult↗
PubMed2002

Acute intrarenal administration of cortisol has no effect on renal blood flow in hypertensive individuals.

BACKGROUND: Cortisol is known to increase blood pressure. One possible mechanism is the reported increase in renal vascular resistance (RVR). It is unknown whether this is due to a direct effect of cortisol on the kidneys. OBJECTIVE: To study the effect of infusion of cortisol directly into the renal artery on renal blood flow (RBF) and on renal 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-mediated conversion of cortisol to cortisone in patients with primary hypertension. DESIGN AND METHODS: Twenty-seven patients with primary hypertension participated in this study. Fifteen received placebo and 12 received glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625, 1.25 and 2.5 microg/kg per min), for 10 min each dose. At the end of each infusion step, RBF was measured using the xenon-133 washout technique. Plasma samples from the femoral artery and renal vein were taken for measurement of cortisol and cortisone. Urine was collected for measurement of steroid concentrations for 6 h on the day before the infusion and for 6 h after the infusion. RESULTS: After placebo or GRA, cortisol infusion did not change RVR, RBF or blood pressure. RVR values were 0.72 (0.45-0.89) mmHg/ml per min per 100 ml tissue [median (first and third quartiles)] and 0.71 (0.64-0.91) mmHg/ml per min per 100 ml tissue during infusion of 5% glucose and infusion of the highest dose of cortisol, respectively ( P= NS). Cortisol infusion increased the venous-arterial difference in plasma cortisone concentration across the kidney from 76 (40-115) nmol/l to 138 (100-186) nmol/l (P< 0.05) and increased the cortisol : cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with placebo, administration of GRA increased the cortisol : cortisone ratios in peripheral and renal veins and in the urine. CONCLUSION: Acute infusion of cortisol in high doses directly into the renal artery in patients with primary hypertension did not affect RBF or RVR. Infusion of cortisol resulted in increased cortisol-cortisone conversion by renal 11beta-HSD2, but the concurrent increase in renal and urinary cortisol : cortisone ratio suggests a relative insufficiency of renal 11beta-HSD2 activity as a result of enzyme saturation. This may enhance mineralocorticoid receptor stimulation by cortisol.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2002

Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance.

Recent evidence suggests that increased cortisol secretion, altered cortisol metabolism, and/or increased tissue sensitivity to cortisol may link insulin resistance, hypertension, and obesity. Whether these changes are important in type 2 diabetes mellitus (DM) is unknown. We performed an integrated assessment of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose intolerance by World Health Organization criteria) and 25 healthy men, carefully matched for body mass index, age, and blood pressure. Data are mean +/- SE. Patients with hyperglycemia (DM) had higher HbA(1c) (6.9 +/- 0.2% vs. 6.0 +/- 0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites. However, the proportion of cortisol excreted as 5alpha- and 5beta-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) was impaired in DM patients (area under the curve, 3617 +/- 281 nM.2 h vs. 4475 +/- 228; P < 0.005). In contrast, in sc gluteal fat biopsies from 17 subjects (5 DM and 12 controls) in vitro 11beta-HSD 1 activity was not different (area under the curve, 128 +/- 56% conversion.30 h DM vs. 119 +/- 21, P = 0.86). Sensitivity to glucocorticoids was increased in DM patients both centrally (0900 h plasma cortisol after overnight 250 micro g oral dexamethasone 172 +/- 16 nM vs. 238 +/- 20 nM, P < 0.01) and peripherally (more intense forearm dermal blanching following overnight topical beclomethasone; 0.56 +/- 0.92 ratio to vehicle vs. 0.82 +/- 0.69, P < 0.05). In summary, in patients with glucose intolerance, cortisol secretion, although normal, is inappropriately high given enhanced central and peripheral sensitivity to glucocorticoids. Normal 11beta-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11beta-HSD 1 activity in hyperglycemia differ from those in primary obesity but may still be susceptible to pharmacological inhibition of the enzyme to reduce intracellular cortisol concentrations. Thus, altered cortisol action occurs not only in obesity and hypertension but also in glucose intolerance, and could therefore contribute to the link between these multiple cardiovascular risk factors.

Administration, Topical↗
PubMed2002

Distinguishing the activities of 11beta-hydroxysteroid dehydrogenases in vivo using isotopically labeled cortisol.

The isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSDs) catalyze the interconversion of cortisol and cortisone. The type 2 dehydrogenase inactivates cortisol to cortisone, whereas the type 1 catalyzes predominantly the reverse reductive reaction. These reactions take place in different tissues, where they are subject to distinct regulation, and may be important in common pathologies. Current methods to determine the activities of these enzymes in vivo rely only on the balance between cortisol and cortisone, do not measure turnover, and cannot distinguish between the two reactions. We have investigated the use of [9,11,12,12-2H4]cortisol (d4F) to distinguish the dehydrogenase and reductase activities. On metabolism by dehydrogenation, d4F loses 11alpha- deuterium, forming trideuterated cortisone (d3E) and is regenerated by reduction to trideuterated cortisol (d3F). Healthy men (n = 6) participated in a randomized, double blind, cross-over study comparing oral placebo and the 11betaHSD inhibitor, carbenoxolone (100 mg every 8 h for 7 d). d4F and its metabolites were measured in plasma and urine during a steady state infusion. Inhibition of 11betaHSDs by carbenoxolone was measured by increased steady state concentrations of d4F (41 +/- 5.1 vs. 48 +/- 7.7 nM; P < 0.05) and a fall in the rate of appearance of d3F (P < 0.05). 11betaHSD1 reductase activity could be measured specifically as conversion of d3E to d3F (28 +/- 4.2 vs. 17 +/- 3.1 nM; P < 0.05), whereas 11betaHSD2 could be measured by initial rates of appearance of d3E or from urinary ratios of d4F/(d3E + d3F) (0.73 +/- 0.06 vs. 1.02 +/- 0.03; P < 0.05). This technique offers a significant advance in the methods available to measure turnover in 11betaHSDs and isozymes of 11betaHSDs in vivo in human studies, and this study confirms that carbenoxolone inhibits both isozymes of 11betaHSD.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2002

Peripheral vascular structure and function in men with contrasting GH levels.

Both GH deficiency and excess are associated with cardiovascular disease. The mechanisms are unclear, but direct effects of GH in the vessel wall may be important. Previous reports suggest that GH enhances endothelium-dependent vasodilatation and alters large artery structure. Here we report a detailed assessment of large artery and microvascular structure and function in patients with contrasting GH levels. We studied six age-matched healthy control men, five men with acromegaly, and seven men with adult-onset GH deficiency before and at the end of 16 wk of GH replacement therapy. We measured arterial wall thickness by ultrasound of the common carotid artery; arterial stiffness by pulse wave analysis at the radial artery; microvascular structure by measurement of flow during maximal dilatation in the forearm and dermal circulation and counting dermal capillaries using video microscopy; and endothelial function in the forearm during brachial artery infusion of vasodilators (acetylcholine and sodium nitroprusside). Cardiac output was measured by Doppler ultrasound in GH-deficient patients and controls. GH-deficient patients tended to have increased arterial wall thickness and arterial stiffness, compared with controls. GH replacement reduced arterial stiffness (radial augmentation index 0.28 +/- 0.07 to 0.20 +/- 0.12, P = 0.02) and increased the number of dermal capillaries perfused (28.6 +/- 5.0 to 30.9 +/- 6.5 cm(-2), P = 0.03), but a reduction in arterial wall thickness was not statistically significant. With respect to maximum flow in forearm and dermis and endothelial function, GH-deficient patients were not different from controls, and GH therapy had no effect. Moreover, acromegalic patients were not different from controls in any vascular parameters studied. We conclude that the direct vascular effects of GH excess and deficiency in man are of modest magnitude and should not therefore be given the highest priority in considering the risks of cardiovascular events in patients with pituitary disease.

Acromegaly↗
PubMed2002

Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.

Cushing's syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-HSD1 activity in women with moderate obesity and insulin resistance. Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11beta-HSD type 1 activity in vitro. Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5alpha- and, to a lesser extent, 5beta-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11beta-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 +/- 28,528, 115,903 +/- 26,032, and 90,460 +/- 18,590 nmol/liter.min; P < 0.001). However, 11beta-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05). In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗