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University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Address all correspondence and requests for reprints to: Prof. Brian R. Walker, British Heart Foundation Senior Research Fellow, University of Edinburgh, Endocrinology Unit, Department of Medical Sciences, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. E-mail: B.Walker{at}ed.ac.uk.
Abstract
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 HbA1c (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 5
- and 5ß-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-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 µg 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 11ß-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11ß-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.
HYPERTENSION, OBESITY, coronary heart disease, and hyperlipidemia are extremely common in patients with glucose intolerance or type 2 diabetes mellitus (DM). These are associated with insulin resistance (1) in what is referred to as the Metabolic Syndrome, but the reasons for the associations between features of this syndrome remain obscure. A similar association of cardiovascular risk factors and insulin resistance occurs in Cushing’s syndrome, due to elevated circulating glucocorticoids. It has been proposed that subtle abnormalities in cortisol action are a missing link between these factors in patients with the Metabolic Syndrome (2, 3, 4).
The hypothalamic-pituitary-adrenal (HPA) axis controls the secretion of cortisol, with excessive secretion being inhibited by negative feedback. In addition, tissue cortisol concentrations are controlled by the relative activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD 1), which converts inactive cortisone to active cortisol, and 11ß-HSD 2, which converts cortisol to cortisone (5). Tissues may thus be exposed to a relative excess of cortisol without any increase in cortisol secretion or plasma cortisol concentrations. The potential importance of 11ß-HSD 1 in the Metabolic Syndrome has been illustrated by recent experiments in mice. 11ß-HSD 1 knockout mice are protected from insulin resistance, hyperglycemia, and dyslipidemia (6, 7), whereas mice overexpressing 11ß-HSD 1 selectively in adipose tissue under the AP2 promoter are centrally obese, hyperglycemic, and hyperlipidemic (8). Similarly, variations in glucocorticoid receptor expression can influence tissue responses independently of circulating glucocorticoid concentrations (9).
A number of cross-sectional cohort studies have found that higher 0900 h plasma cortisol and/or increased total 24 h urinary cortisol metabolite excretion is associated with insulin resistance, high blood pressure, hyperlipidemia, and hyperglycemia (4, 10, 11, 12, 13, 14, 15, 16). Negative feedback control of the HPA axis appears normal (17), however, and the activation of the HPA axis in men with the Metabolic Syndrome may reflect an increase in central drive to the hypothalamus (18, 19). Obese individuals also show subtle changes in cortisol activity with an increase in 24 h cortisol secretion despite normal (20) or enhanced (21) feedback sensitivity (as shown by suppression of plasma cortisol to 250 µg of dexamethasone). However, plasma cortisol concentrations are not elevated, perhaps because peripheral metabolic clearance of cortisol, for example by 5-reductase (22), is increased (23).
Tissue responses to glucocorticoids are also altered in patients with features of the Metabolic Syndrome. In case-control studies, individuals with essential hypertension have reduced inactivation of cortisol by 11ß-HSD 2 (24, 25, 26) and enhanced glucocorticoid-receptor-dependent tissue sensitivity to cortisol (as judged by enhanced dermal vasoconstriction following topical glucocorticoid application) (13, 17). In obesity, 11ß-HSD 2 activity and dermal glucocorticoid sensitivity are not enhanced, but there are tissue-specific changes in 11ß-HSD 1 activity, resulting in less reactivation of cortisone to cortisol in liver, but enhanced reactivation in sc abdominal adipose (20, 27, 28). Importantly, the magnitude of increase in 11ß-HSD 1 activity in adipose tissue of obese men is similar (about 3-fold) as results in dramatic obesity and hyperglycemia in transgenic mice with 11ß-HSD 1 overexpression in adipose tissue (8). This observation has reinforced the concept that inhibition of 11ß-HSD 1 would be of therapeutic benefit in patients with the Metabolic Syndrome (29).
Against this background, it is important to know whether abnormalities in cortisol secretion, metabolism, or sensitivity exist in patients with type 2 diabetes or glucose intolerance, but this may be difficult to establish because these differences are confounded by contrasting effects of coexisting hypertension and obesity (30). Previous studies of cortisol in patients with DM have been conducted in heterogeneous groups with type 1 and type 2 diabetes (31, 32, 33, 34, 35, 36, 37, 38), or have been inadequately controlled for confounding factors of sex, coexisting obesity, hypertension, poor glycemic control, and diabetic complications, making interpretation difficult (39, 40, 41, 42, 43, 44). Moreover, no previous studies have examined tissue responses to glucocorticoids in patients with diabetes, or attempted to dissect tissue-specific changes in cortisol metabolism. This study set strict criteria for patient selection to examine cortisol secretion, metabolism and sensitivity in nonobese, normotensive, diet-controlled male patients with DM or impaired glucose tolerance.
Subjects and Methods
Participants
We studied 25 men with DM or impaired glucose tolerance (as defined by WHO criteria for oral glucose tolerance tests) recruited from our clinic, and 25 normal healthy controls recruited by advertisement. All patients were controlled by diet alone, without oral hypoglycemic agents or insulin, and were free of clinical or biochemical evidence of retinopathy, nephropathy, and neuropathy at last annual review. Exclusion criteria included therapy for any other medical conditions, major psychiatric disorder, weight loss more than 5 kg in the previous 3 months, blood pressure more than 160/90 mm Hg, body mass index more than 32 kg/m2, glucocorticoid therapy by any route in previous 3 months, or abnormal renal or thyroid function on biochemical screening. Control subjects were matched for weight, height, body mass index, and blood pressure. Local ethical committee approval and written informed consent were obtained.
Protocol
Participants attended on one afternoon without fasting for a medical examination, measurement of sitting blood pressure (using a Takeda UA-751 sphygmomanometer), height, and weight. Blood was obtained for full blood count, urea and electrolytes, HbA1c, liver function tests, thyroid function tests, cholesterol, and triglycerides. Beclomethasone dipropionate was then applied to the forearm and subjects returned the following morning for assessment of dermal blanching (see below). Following this visit, subjects collected a 24-h urine sample for total cortisol metabolites.
On a second occasion, participants attended at 0830 h having fasted from 2300 h the previous evening. They lay supine; an iv cannula was sited and blood was taken 30 min later for cortisol, cortisol binding globulin, glucose, and insulin.
On a third occasion, participants took 250 µg dexamethasone (Decadron, Merck, West Drayton, UK) by mouth at 2300 h and fasted until attending the following morning at 0830 h. An iv cannula was sited, and 30 min later blood was taken for cortisol estimation. Participants then took 25 mg cortisone acetate (Cortisyl, Hoechst Marion Roussel, Inc., Uxbridge, UK) by mouth and blood was taken for cortisol every 15 min for 2 h.
In vitro adipose 11ß-HSD 1 activity
Seventeen subjects (5 DM and 12 controls) consented to return for a 500 mg sc fat biopsy to be taken from the gluteal region under local anesthesia. Subcutaneous fat was frozen immediately at -70 C. After thawing, it was homogenized in Krebs buffer at pH 7.4 and 750 µg/ml protein was incubated at 37 C with nicotinamide adenine dinucleotide phosphate (2 mM) and 1,2,6,7-3H4-cortisol (100 nM) for 30 h. Samples were taken at 3, 6, 20, and 30 h for separation of cortisol and cortisone by HPLC with on-line liquid scintillation detection (20). 11ß-HSD 1 activity was measured in the dehydrogenase direction (i.e. cortisol to cortisone, rather than reductase cortisone to cortisol) because dehydrogenase activity is more stable than reductase activity in vitro, and because dehydrogenase is the preferred reaction when the enzyme is liberated from its intracellular environment (5). Under these conditions, the conversion of cortisol to cortisone is proportionate to the total protein added, and therefore reflects 11ß-HSD 1 protein concentrations in the biopsy sample.
Dermal vasoconstrictor response to glucocorticoids
This was performed as previously described (45). In brief, 50 µl beclomethasone dipropionate (Sigma, St. Louis, MO) at 0, 1, 5, 10, 100, or 1000 µg/ml in 95% ethanol were applied in random order into 6 circles of 20-mm diameter on the volar surface of the nondominant forearm. After the ethanol had evaporated, all sites were occluded with Saran wrap (Dow Corning, Midland, MI) and left for 16–18 h. At 0800 h the next day, the bandage was removed. An hour later, the intensity of the blanching was read by an observer who was blind to the order of application using a reflectance spectrophotometer (Erythemameter, Diastron Ltd., Andover, UK). This device measures the ratio of red/green light reflected from the skin surface, called the erythema index. Because red reflects oxyhemoglobin concentration and green reflects melanin concentrations, the erythema index corrects for variations in skin color between individuals. The erythema index for each test site was divided by the erythema index for the site treated with vehicle alone to produce a blanching index. The blanching index corrects for the nonspecific variations in skin color that occur in different environments in the same individuals. A lower blanching index indicates more intense blanching.
Laboratory analyses
Plasma and urine samples were stored at -80 C and -20 C, respectively.
RIAs were used to measure plasma cortisol (46), dexamethasone (Cozart Bioscience, Abingdon, UK), and corticosteroid binding globulin (Medgenix Diagnostics, Fleurus, Belgium). Insulin was measured by enzyme immunoassay (Eurogenetics UK Ltd., Hampton, UK). Glucose was measured by an enzymatic technique (Cabas Mira Plus, Roche Molecular Biochemicals, Mannheim, Germany). Ion exchange HPLC was used to measure the HbA1c (Variant 11, Bio-Rad Laboratories, Inc., Hercules, CA).
Cortisol and its metabolites were measured in urine by electron impact gas chromatography/mass spectrometry following Sep-pak C18 extraction, hydrolysis with ß-glucuronidase, and formation of the methoxime-trimethylsilyl derivatives (47). Epi-cortisol and epi-tetrahydrocortisol were used as internal standards. Total cortisol metabolite excretion was calculated as tetrahydrocortisols (THFs) + tetrahydrocortisone (THE) + cortols + cortolones (48). Relative metabolism by 5 and 5ß-reductases were inferred from the 5ß-THF/5-THF ratio. A-ring reduction of cortisol was inferred from the ratios of THFs/cortisol (49) and 5ß-reductase activity from the ratio of THE/cortisone. Whole-body equilibrium between cortisol and cortisone, determined by the balance of tissue-specific activities of 11ß-reductase and 11ß-dehydrogenase activities, was inferred from the ratio of THFs/THE. Renal 11ß-dehydrogenase activity was inferred from the urinary free cortisol/cortisone ratio (47, 50).
Statistics
Data are expressed as means ± SE. All groups were compared by Student’s t test apart from the urine data, which were compared by Mann Whitney U test, as these data were not normally distributed. Profiles of cortisol and dermal vasoconstriction were compared by repeated measures ANOVA.
Results
Baseline characteristics
Characteristics of participants are shown in Table 1
. The groups were well matched for anthropometric, clinical, and biochemical variables except that diabetic patients had higher fasting plasma glucose, HbA1c, and triglycerides than controls. Corticosteroid binding globulin and albumin did not differ between the groups, so only total plasma cortisol was used in further analysis.
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Fasting morning plasma cortisol (Table 1
) and total urinary cortisol metabolite excretion rate (Table 2) were not different between groups. However, the morning after 250 µg oral dexamethasone, plasma cortisol was lower in diabetic patients (Table 1). This could not be attributed to differences in dexamethasone concentrations (Table 1).
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Although total cortisol metabolite excretion was not different between groups, there were changes in relative metabolite excretion (Table 2). DM patients excreted less unmetabolized cortisol (P < 0.03) and cortisone (P = 0.07) and tended to excrete more as 5ß-THF (P = 0.07). As a result, ratios reflecting 5ß-reduction of cortisol (5ß-THF/cortisol, P < 0.001) and cortisone (THE/cortisone, P < 0.005) were increased in DM patients, and there was a trend for increased 5-reduction of cortisol (5-THF/cortisol). Absolute excretion of other metabolites, and ratios reflecting 11ß-HSD2 (cortisol/cortisone) and overall 11ß-HSDs (THFs/THE), were not different.
Hepatic 11ß-HSD 1 activity, measured as conversion of orally administered cortisone to cortisol, was impaired in the DM group (Fig. 1; area under curve, 3617 ± 281 nM vs. 4475 ± 228 nM; ANOVA P < 0.005), with an increase in time taken to reach maximum plasma cortisol (111 ± 3 min vs. 100 ± 4 min, P < 0.05). By simple regression, there was no relationship between hepatic 11ß-HSD 1 and any individual urinary cortisol metabolite or ratio. Adipose in vitro 11ß-HSD 1 activity was no different between the two groups (Fig. 2; area under the curve, 119 ± 21% controls vs. 128 ± 56% DM, P = 0.8).
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Dermal vasoconstriction to topical beclomethasone dipropionate was more intense in the DM group than in the control group (Fig. 3).
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This study demonstrates that nonobese normotensive men with hyperglycemia exhibit abnormalities in cortisol activity. The differences in cortisol metabolism and tissue sensitivity were more striking than any differences in HPA axis function. Specifically, these patients with DM or impaired glucose tolerance show: 1) normal cortisol secretion and circulating levels in the face of enhanced negative feedback sensitivity (as measured with dexamethasone); 2) enhanced in vivo peripheral tissue sensitivity to glucocorticoids (as measured by dermal blanching); 3) impaired hepatic 11ß-HSD 1 activity but normal adipose 11ß-HSD 1 activity, suggesting tissue-specific alterations in 11ß-HSD 1 activity; and 4) increased relative excretion of A-ring reduced metabolites of cortisol. These findings suggest that isolated hyperglycemia is associated with some, but not all, of the changes in cortisol metabolism and action that have been observed in subjects with hypertension or obesity and the Metabolic Syndrome. This has implications for understanding underlying mechanisms predisposing to hyperglycemia, determinants of altered glucocorticoid signaling, and therapeutic opportunities to manipulate cortisol action to improve metabolic control in DM.
Previous studies of cortisol in patients with diabetes have focused on individuals with type 1 diabetes. These showed increased plasma and urinary free cortisol levels among patients with poor glycemic control and/or diabetic complications (40, 41, 42, 51, 52, 53), but these abnormalities were less marked in well controlled uncomplicated patients (40, 54). A number of older studies looking at patients with both type 1 and type 2 diabetes found less consistent abnormalities (34, 35, 36, 37, 55) but again showed higher plasma cortisol concentrations in patients with complications (32, 37). Few studies have included only patients with type 2 diabetes and these did not show altered secretion (44, 57) or circulating levels (58) of cortisol. However, obesity (22), gender and blood pressure (13) affect cortisol secretion and metabolism; these factors were not controlled for in previous studies of patients with diabetes. Against this background, the strength of the current study is the careful matching of controls and patients with type 2 diabetes or impaired glucose tolerance, the focus on men only, and the exclusion of patients with obesity, hypertension, and diabetes complications. The aim was to isolate the influence of abnormal insulin action and hyperglycemia from these confounding effects. This was achieved in so far as the only detected differences in baseline characteristics between patients and controls were in fasting plasma glucose, HbA1C, and triglyceride levels. Fasting insulin levels were not different between groups, consistent with relative insulin deficiency in the hyperglycemic patients. To achieve this close matching with healthy controls, however, necessitated selection of a group of patients with extremely good metabolic control of their hyperglycemia. As a result, the current study may underestimate effects of hyperglycemia per se, but nonetheless will detect differences that are intrinsic to patients who have pancreatic ß-cell dysfunction.
Other studies have used conventional techniques to assess cortisol secretion, i.e. plasma cortisol concentrations and urinary free cortisol, which are relatively insensitive. Urinary free cortisol is a small fraction (<5%) of total cortisol metabolite excretion, determined principally by free plasma cortisol clearance. The sum of the urinary metabolites of cortisol in 24 h urine, as used in this study, provides a better assessment of 24 h secretion of cortisol (48). Using this method, the current study showed that cortisol secretion over 24 h is normal in lean patients with type 2 diabetes or impaired glucose tolerance.
The rate of cortisol secretion is controlled by central drive to the HPA axis and by negative feedback suppression by glucocorticoids. Dexamethasone suppression of plasma cortisol is the conventional test to examine negative feedback. Previous studies in patients with diabetes have used 1 mg of dexamethasone (34, 35, 38), as is used in clinical practice to detect Cushing’s syndrome, and found that in most cases suppression was normal. Interpretation of this test is qualitative rather than quantitative, because the vast majority of controls and patients suppress to below the detection limit for plasma cortisol. As previously described (16, 17) we have selected 250 µg of dexamethasone as an approximate ED50 dose to quantify more subtle variations in suppression within the non-Cushing’s range. Using this very low dose test, we have shown that patients with type 2 diabetes have greater sensitivity of the HPA axis to negative feedback. This could not be accounted for by differences in dexamethasone concentrations achieved. Although recent data suggest differences in the feedback response to synthetic and endogenous glucocorticoids in man (59), the finding of normal 24 h secretion in the face of this enhanced feedback sensitivity suggests that another factor is driving cortisol secretion.
Obese individuals also show increased cortisol secretion in spite of normal or increased feedback sensitivity (21). Here, increased metabolic clearance of cortisol (23), principally by 5-reductase (14, 22) but with increased 5ß-reduced metabolites also (20), may be a driving force for the increase in cortisol secretion. In this study, we found increased relative excretion of 5- and, most strikingly, 5ß-reduced cortisol metabolites in the absence of obesity in the hyperglycemic group. Notably, it has been shown that insulin therapy reduces excretion of 5-reduced cortisol metabolites (44). This suggests that peripheral clearance of cortisol is enhanced by mechanisms directly associated with relative insulin deficiency and hyperglycemia. An alternative explanation is that inappropriate central drive to the HPA, rather than enhanced cortisol clearance, is maintaining cortisol secretion in the face of enhanced feedback in these individuals. This is consistent, for example, with the observation that habituation of cortisol in response to repeated sampling is impaired in hyperglycemic men (19).
The finding of normal cortisol secretion and circulating cortisol levels in hyperglycemic patients suggests that if cortisol is to play a role in the pathogenesis of type 2 diabetes, it will be determined by variations in peripheral tissue sensitivity to cortisol. One important determinant of tissue response to cortisol is the extent of metabolism of cortisol within the target tissues by 11ß-hydroxysteroid dehydrogenases (11ß-HSDs). Two enzymes exist: 11ß-HSD 1, which reactivates cortisone to cortisol and serves to maintain adequate exposure of glucocorticoid receptors to cortisol (5); and 11ß-HSD 2, which converts cortisol to cortisone and prevents cortisol from gaining inappropriate access to mineralocorticoid receptors. Overall activities of these enzymes can be inferred from the balance of cortisol and cortisone metabolites in urine. These have been measured in previous studies in patients with type 1 diabetes (41), in whom the ratio of cortisol/cortisone metabolites was lower than in controls, and type 2 diabetes (44), in which there was no difference between relatively obese patients and controls. However, these urinary ratios are insensitive to tissue-specific changes in 11ß-HSD 1 activity (30). In obese rats (60) and humans, 11ß-HSD 1 is decreased in liver (61) but increased in adipose tissue (20, 27, 28). Here, in nonobese hyperglycemic men, hepatic first pass conversion of cortisone to cortisol was impaired, albeit to a lesser extent than in obese subjects (20, 61). However, there was no change in adipose 11ß-HSD 1 activity, albeit that here we biopsied sc fat from the gluteal region where previously we have biopsied from the periumbilical region (20) and that relatively few subjects (n = 17 of the original 50) returned for a biopsy. Nonetheless, there is no trend to suggest that anything approaching the approximately 3-fold differences observed in obesity occur in lean hyperglycemic subjects. The mechanism for tissue-specific dysregulation of 11ß-HSD 1 in obesity is unknown (62, 63), but these data hint that hepatic dysregulation is related to insulin action, whereas adipose dysregulation is determined by some other factor associated with obesity, or indeed may be a primary mechanism in obesity (8, 64). We tested whether variations in A-ring reductase activities might explain variation in hepatic 11ß-HSD 1 but did not find any correlations. It is intriguing to speculate that down-regulation of 11ß-HSD 1 is a compensatory mechanism to protect the liver from glucocorticoid excess in obesity and hyperglycemia; it may be that the lack of simultaneous increase in adipose 11ß-HSD 1 explains why the group of patients studied here are members of the unusual cohort with impaired glucose tolerance without obesity. Importantly, inhibition of 11ß-HSD 1 has been proposed as a therapy to improve metabolic control in diabetes and obesity (29, 64); these data suggest that sufficient 11ß-HSD 1 activity exists in patients with type 2 diabetes to make this strategy worthwhile, although it remains to be seen whether inhibition in liver and/or adipose tissue will be most influential.
Another factor that is important in determining the tissue response to cortisol is the expression and activity of glucocorticoid receptors, which is difficult to measure in vivo in man. Studies comparing sensitivity to synthetic glucocorticoid receptor agonists in different sites suggest that there can be tissue-specific differences. For example, although sensitivity in skin correlates with that in lung (65), it may not correlate with that in leukocytes (66) or in the HPA axis (67). In this study, we show that dermal vascular sensitivity to beclomethasone dipropionate is increased in patients with glucose intolerance. Similar findings have been described in hypertensive and insulin resistant men (13, 17). This provides circumstantial evidence that glucocorticoid receptors are more readily activated in dermal vessels, although there may be confounding factors influencing the dermal blanching response. Up-regulation of glucocorticoid receptor expression has been implicated in the pathophysiology of insulin resistance in animal models (68). Moreover, glucocorticoid receptor mRNA levels in skeletal muscle are elevated in men with insulin resistance (69, 70). These observations suggest that therapeutic strategies to alter glucocorticoid action in key insulin-sensitive target tissues are likely to be especially beneficial in hyperglycemic patients.
In summary, we have demonstrated that patients with type 2 diabetes or glucose intolerance exhibit abnormalities in cortisol action in the absence of hypertension or obesity. These findings add further weight to the hypothesis that abnormalities in cortisol action may be a factor that links insulin resistance, hypertension, glucose intolerance, and obesity.
Acknowledgments
We are grateful to Jill Campbell and Susan Walker for technical assistance and Dr. T. Sandeep for help with obtaining clinical material.
Footnotes
This study was supported by Diabetes UK and the British Heart Foundation.
Present address for R.C.A.: Lecturer in Medicine, University of Bristol, University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.
Abbreviations: DM, Type 2 diabetes mellitus or impaired glucose tolerance; HPA, hypothalamic-pituitary-adrenal; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; THE, tetrahydrocortisone; THF, tetrahydrocortisol.
Received January 16, 2002.
Accepted August 21, 2002.
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R. Basu, R. J. Singh, A. Basu, E. G. Chittilapilly, C. M. Johnson, G. Toffolo, C. Cobelli, and R. A. Rizza Splanchnic Cortisol Production Occurs in Humans: Evidence for Conversion of Cortisone to Cortisol Via the 11-{beta} Hydroxysteroid Dehydrogenase (11{beta}-HSD) Type 1 Pathway Diabetes, August 1, 2004; 53(8): 2051 - 2059. [Abstract] [Full Text] [PDF]
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J. W. Tomlinson, J. S. Moore, P. M. S. Clark, G. Holder, L. Shakespeare, and P. M. Stewart Weight Loss Increases 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Human Adipose Tissue J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2711 - 2716. [Abstract] [Full Text] [PDF]
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C. M. Alexander The Metabolic Syndrome: The Emperor Needs Some Consistent Clothes: Response to Vinicor and Bowman Diabetes Care, May 1, 2004; 27(5): 1244 - 1244. [Full Text] [PDF]
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 T. C. Sandeep, J. L. W. Yau, A. M. J. MacLullich, J. Noble, I. J. Deary, B. R. Walker, and J. R. Seckl From The Cover: 11{beta}-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics PNAS, April 27, 2004; 101(17): 6734 - 6739. [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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J. Westerbacka, H. Yki-Jarvinen, S. Vehkavaara, A.-M. Hakkinen, R. Andrew, D. J. Wake, J. R. Seckl, and B. R. Walker Body Fat Distribution and Cortisol Metabolism in Healthy Men: Enhanced 5{beta}-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men with Fatty Liver J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4924 - 4931. [Abstract] [Full Text] [PDF]
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R. S. Lindsay, D. J. Wake, S. Nair, J. Bunt, D. E. W. Livingstone, P. A. Permana, P. A. Tataranni, and B. R. Walker 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 J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2738 - 2744. [Abstract] [Full Text] [PDF]
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M. N. Kerstens and R. P. F. Dullaart Cortisol Metabolism and Glucose Intolerance J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2951 - 2951. [Full Text] [PDF]
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B. R. Walker and R. Andrew Cortisol Metabolism in Type 2 Diabetes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2951 - 2952. [Full Text] [PDF]
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