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Division of Medical Sciences (G.V., A.A., J.W.T., P.G.M., R.C., A.H.B., P.M.S., S.K.), University of Birmingham, Queen Elizabeth and Birmingham Heartlands Hospitals, Birmingham B15 2TH, United Kingdom; Department of Radiology (A.K.B.), Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom; Steroid Laboratory (C.H.L.S.), Children’s Hospital Oakland Research Institute, Oakland, California 94609-1809; Regional Endocrine Unit (P.J.W.), Southampton University Medical School, Southampton SO16 0XW, United Kingdom; and Regional Endocrine Laboratory (G.H.), Department of Clinical Biochemistry, University Hospital Birmingham National Health Service Trust, Birmingham B29 6JD, United Kingdom
Address all correspondence and requests for reprints to: Prof. P. M. Stewart, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: p.m.stewart{at}bham.ac.uk.
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Abstract |
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Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11ß-HSD1 activity between diabetic subjects and controls. In addition, 11ß-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5
-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11ß-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11ß-HSD1 activity could not be explained by circulating levels of adipocytokines.
Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11ß-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11ß-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.
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Introduction |
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, nonesterified fatty acids, and resistin (4, 5, 6, 7). Recent prospective studies have shown that C-reactive protein (CRP) is predictive of type 2 diabetes over 3–4 yr follow-up (8), whereas elevated adiponectin is associated with a reduced risk of diabetes (9). Subjects with central obesity share many of the metabolic and hormonal findings observed in patients with Cushing’s syndrome (10). However, circulating cortisol (F) concentrations in obesity are not elevated and are largely independent of fat distribution. F secretion rates are increased in subjects with central adiposity, but concomitant increased F metabolism ensures that normal circulating F levels are maintained (11).
Two isoenzymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) catalyze the interconversion of hormonally active F and inactive cortisone (E) (12, 13). 11ß-HSD2 inactivates F to E in the distal nephron protecting mineralocorticoid receptors from inappropriate activation by F (14). 11ß-HSD1 regenerates F from E, thereby augmenting glucocorticoid receptor activation in many tissues, including liver and adipose tissue (15, 16). Overexpression of 11ß-HSD1 in adipose tissue leads to visceral obesity and the metabolic syndrome (17, 18). However, paradoxically, impaired and not enhanced E to F conversion is seen in subjects with central obesity, suggesting a reduction in 11ß-HSD1 activity, at least in the liver (19, 20). We have argued that this may serve as a protective mechanism in obesity, reducing insulin resistance and ongoing adipogenesis.
The putative role of glucocorticoid metabolism in obesity associated with type 2 diabetes mellitus has not been established. The aim of this study was to investigate F metabolism in patients with type 2 diabetes mellitus in the context of body composition and circulating adipocytokines. Furthermore, in view of the predisposition of the Indo-Asian population to the development of the metabolic syndrome (21), we have also defined F metabolism in a small group of Indo-Asians.
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Subjects and Methods |
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The study had the approval of the East Birmingham Research and Ethics Committee, and written consent was obtained from all patients. Caucasian and Indo-Asian subjects with type 2 diabetes mellitus (World Health Organization criteria) were recruited from diabetic clinics [n = 33, 17 Indo-Asians, 18 diet controlled, 15 diet and metformin; mean body mass index (BMI) (±SD), 31.1 ± 7.5 kg/m2; mean age, 44.2 ± 13 yr]. Healthy, Caucasian and Indo-Asian subjects [n = 38, 17 Indo-Asians; mean BMI, 38.2 ± 12.8 kg/m2; mean age, 41.4 ± 14 yr] were also studied (Table 1
). Within these subjects, weight-matched diabetic and control groups were also identified (n = 23 in each group) and their results presented in Table 2. Patients with dipstick-positive proteinuria or known impairment of renal function were excluded. Liver biochemistry was normal in all subjects. In the diabetic group, two patients were taking ß-blockers, eight calcium channel antagonists, 13 angiotensin-converting enzyme inhibitors, and 12 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the control group, three were taking orlistat, three bendrofluazide, and four angiotensin-converting enzyme inhibitors.
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Weight in kilograms was measured to the nearest 0.1 kg on a beam balance in subjects without shoes and only light clothing. Height in meters was measured to the nearest 1 mm using a stadiometer, and BMI in kilograms per square meter was calculated. Waist circumference in centimeters was taken in duplicate with a 6-mm-wide flexible tape and was the maximum abdominal circumference between the costal margin and iliac crest. All measurements were taken with the subject standing and in the horizontal plane. Supine blood pressure was recorded with a mercury sphygmomanometer using the mean of three measurements.
Magnetic resonance imaging (MRI) to assess intraabdominal fat
Forty male subjects out of the total population, 20 diabetic (nine Caucasians, 11 Indo-Asians), and 20 controls (12 Caucasians, eight Indo-Asians) consented to have an MRI scan. Fat measurements were carried out with the subjects lying in a supine position with arms extended above the head in a Phillips NT-1 MR scanner (Philips Medical Systems, Best, The Netherlands). T1 weighted axial images were obtained through the abdomen using a body coil (time to repetition, 575 ms; time to echo, 12 ms; field of view, 37.5 mm; rectangular field of view, 80%; number of signal averages, 5). Measurements of regional body fat were obtained at the level of the umbilicus and the 4th lumbar vertebra. The data from the scans were transferred onto a Phillips Easyvision (Philips Medical Systems) workstation release 2.1. A segmentation program was used to obtain the threshold value for fat at a particular level (L4) for each individual patient. The visceral, sc, and total MRI adipose tissue were calculated in square centimeters at this level (L4).
Biochemistry
Patients were studied after an overnight fast and had blood drawn at 0900 h for serum F and E, plasma ACTH, glucose, and lipids. Serum F was measured with an automated competitive chemiluminescent assay on the ACS 180 (Chiron Diagnostics, Halstead, UK), with interassay coefficients of variation (CVs) of less than 10% over the concentration range of 53–944 nmol/liter. The 0900-h reference range is quoted at 180–550 nmol/liter. Serum E was analyzed by RIA using antiserum N-137 and 21-acetyl-cortisone-3CMO-histamine[125I] tracer as reported (22). ACTH was measured using an immunoradiometric assay (Nichols Institute Diagnostics Ltd., Saffron Walden, UK) with the interassay CVs of less than 15% from 8.4–1333 ng/liter. The 0900-h reference range is 9–52 ng/liter (2–11 pmol/liter; Systeme International conversion factor, 0.2202). Serum fasting glucose, glycosylated hemoglobin, triglycerides, and total high-density lipoprotein and low-density lipoprotein cholesterols were measured using standard laboratory methods. Fasting insulin levels were determined using a Medgenix immunoenzymetric assay (Biosource-Europe S.A., B-1400 Nivelles, Belgium). Insulin sensitivity was derived from fasting glucose and insulin data, using the homeostasis model assessment (HOMA) mathematical model (23).
All subjects collected a 24-h urine sample for determination of urinary free F (UFF) (measured by a dichloromethane extraction RIA, with interassay CVs of less than 16% over the range of 153–798 nmol/liter). In addition, a urinary steroid metabolite profile was analyzed using gas chromatography/mass spectrometry as previously reported (24, 25). Results are presented for total F metabolites [sum of tetrahydrocortisol (THF), 5-THF, tetrahydrocortisone (THE), cortols and cortolones, free F metabolites]. The urinary THF+allo-THF:THE ratio is regarded as an index of global 11ß-HSD activity, but if the UFF:urinary free E(UFE) ratio is unaltered [reflecting specifically the activity of renal 11ß-HSD2 (25)], any changes in this ratio result from alterations in 11ß-HSD1 activity. Thus, a reduction in the urinary THF+allo-THF:THE ratio correlates well with impaired generation of serum F from orally administered E indicative of reduced 11ß-HSD1 activity (19).
Fasting serum leptin and adiponectin concentrations were determined using RIAs (Linco Research Inc., St. Charles, MO). Human adiponectin sensitivity was 1 ng/ml when using a 100-µl sample size, and assay range is 1–200 ng/ml. Interassay CV was 9.25% at concentration of 1.5 ng/ml and intraassay CV was 3.59%, respectively. Fasting serum TNF- was measured using commercially available ELISA kits (R&D Systems, Oxon, UK). CRP was measured with a highly sensitive in-house ELISA (Roche, Indianapolis, IN). Fasting serum resistin concentrations were determined using an enzyme immunoassay (ELISA) (Phoenix, Belmont, CA) with sensitivity of 4 ng/ml and interassay and intraassay CVs of less than 14% and less than 5%, respectively. Linear range of the assay is 4–75.3 ng/ml, with range of 0–500 ng/ml.
Statistical analysis
Results are expressed as mean ± SD in the case of normally distributed data or median (interquartile range) in the case of non-Gaussian distribution. Statistical analyses comparing groups of subjects were undertaken using Student’s t test using loge-transformed values where appropriate and Mann-Whitney U test in the case of non-Gaussian distribution of the variables. To test the association between different variables, Spearman correlation analyses were performed. Stepwise forwards and backwards regression analyses were undertaken to define predictive variables. A P-value < 0.05 was considered to be significant. The SPSS statistical software was used for statistical analysis (SPSS, Inc., Chicago, IL).
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Results |
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and 2, respectively. Within the diabetic group, there were no differences between those patients treated with drugs or diet alone. In comparison with weight-matched controls, patients with diabetes had higher plasma glucose, insulin, triglycerides, resistin, and CRP concentrations (Table 2). F metabolism in controls and diabetic subjects
The 0900-h F concentrations were higher in diabetic subjects compared with controls (348 ± 114 vs. 291 ± 113 nmol/liter, P < 0.01). In addition, 0900-h F:E ratios were also significantly higher (6.4 ± 1.8 vs. 5.3 ± 1.5, diabetics vs. control, P < 0.01) (Table 1). When controlled for BMI, these observations remained significant (Table 2). However, there were no differences between diabetics and controls in total F metabolite excretion, THF+allo-THF:THE, or UFF:UFE ratios (Tables 1 and 2)
When divided according to BMI (<25, 25–30, >30 kg/m2), THF+allo-THF:THE and UFF:UFE ratios were similar in diabetics and controls (Fig. 1, A and B). However, with increasing BMI in control subjects only, THF+allo-THF:THE ratio decreased significantly (1.29 ± 0.4 vs. 0.96 ± 0.2, BMI < 25 vs. >30 kg/m2, P < 0.05) (Fig. 1A) with no change in the UFF:UFE ratio (Fig. 1B). Furthermore, we observed an inverse correlation between THF+allo-THF:THE ratio and BMI in control subjects (r = –0.32, P = 0.04) but not in diabetics (r = –0.11, P > 0.05). This appeared to be related to visceral fat mass. In the 40 subjects in whom visceral fat was quantified by MRI scanning, an inverse correlation between 11ß-HSD1 activity and visceral fat was observed in the control patients (n = 20, r = –0.49, P < 0.05) but not in diabetics (n = 20, r = 0.02, P > 0.05) (Fig. 2).
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There were no differences in F metabolism between Caucasians and Indo-Asians after matching for age and BMI [e.g. THF+allo-THF:THE ratio, 1.02 ± 0.07 vs. 1.02 ± 0.09; Caucasian (n = 13) vs. Indo-Asian (n = 10)].
Relationship between F metabolism with anthropometric and biochemical parameters
The urinary THF+allo-THF:THE ratio increased with serum adiponectin (r = 0.36, P = 0.04) in the control group only and correlated inversely with serum resistin (r = –0.38, P = 0.03) in the diabetic group. However, the observed changes in F metabolism as a function of BMI between controls and diabetics could not be accounted for by differences in adipocytokines. Serum resistin was significantly higher in the diabetic group compared with controls (Tables 1 and 2) but was unaltered with increasing BMI (17.5 ± 5.9 vs. 16.2 ± 4.4 ng/ml; BMI < 25 vs. >30 kg/m2, P = not significant). Adiponectin levels were not different between diabetic and controls and did not change with BMI.
In the diabetic group, but not controls, circulating F:E ratio correlated with HOMA-S (r = 0.34, P = 0.03) and serum cholesterol (r = 0.34, P = 0.03).
Stepwise forward multiple regression in all 71 subjects revealed serum triglycerides (P = 0.002, ß = –0.31) (Fig. 3A) and serum resistin (P = 0.001, ß = –0.32) (Fig. 3B) as the best predictors of 11ß-HSD1 activity among ethnicity, diabetes, MRI-assessed visceral fat mass, cholesterol, age, BMI, adiponectin, HOMA-S, CRP, TNF-, and systolic blood pressure.
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Discussion |
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On this background, the analysis of 11ß-HSD1 activity in patients with type 2 diabetes mellitus might be particularly revealing. Here we have confirmed inhibition of 11ß-HSD1 with increasing BMI in simple obesity but have extended this to delineate the association with visceral fat mass. In keeping with earlier studies where DEXA scanning was used to determine trunk and gluteal fat mass (19), an inverse correlation was seen specifically with MRI-assessed visceral fat mass. These data are also supported by CT-assessed intraabdominal fat studies (38), observations that collectively strengthen a link between visceral fat mass and inhibition of 11ß-HSD1 activity. The underlying basis for this association, however, remains unclear. It is attractive to speculate that circulating factors released from visceral adipose tissue might inhibit hepatic 11ß-HSD1 activity. Although correlations were observed between the urinary THF+allo-THF:THE ratio and resistin in the group as a whole and diabetics, this was not marked in the control group (resistin and adiponectin seem unlikely to be implicated in hepatic 11ß-HSD1 inhibition in obesity). Similarly, although insulin has been variably reported to inhibit 11ß-HSD1 activity (39), and visceral obesity is associated with hyperinsulinemia, no relationship between the urinary THF+allo-THF:THE ratio and insulin levels was observed in this study.
The most striking abnormality was a lack of inhibition of 11ß-HSD1 with increasing BMI in the diabetic cohort, such that there was no relationship between the urinary THF+allo-THF:THE ratio and either BMI or visceral fat. This ongoing E to F conversion in the face of increasing BMI in the diabetic cohort might have contributed to the increased circulating F:E ratio seen in the diabetic group, although it should be noted that no changes were observed between the groups in terms of total F metabolite excretion. Other studies have also examined cortisol metabolism in cohorts of type 2 diabetic patients. They too have failed to show differences in total cortisol metabolite excretion or THF+allo-THF:THE ratios between diabetic patients and controls (40, 41). In a single study, decreased hepatic 11ß-HSD1 activity (as measured by cortisol generation form oral cortisone) has been described (41).
All our subjects had normal liver biochemistry; however, we did not obtain information with respect to hepatic triglyceride content. Recent data have suggested that increased hepatic triglyceride content is associated with decreased 11ß-HSD1 activity (42). Although not measured, we would anticipate that hepatic triglyceride content may be higher in our diabetic subjects. This would lower 11ß-HSD1 activity and therefore seems unlikely to explain the lack of 11ß-HSD1 down-regulation with BMI in patients with diabetes.
In our study, it was of interest that the circulating F:E ratio did correlate with some markers of the metabolic syndrome in the diabetic group, notably serum cholesterol and HOMA-S, and it is possible that this may be linked to the ongoing hyperinsulinemia and hyperresistinemia of diabetes. However, we need to exert a note of caution. The 0900-h F:E ratio provides information as to the relative amounts of inactive and active glucocorticoid at a single time point. Its relationship to total glucocorticoid exposure and 11ß-HSD1 activity is not clear. Further studies determining F:E ratios over a 24-h period are clearly warranted. Although Indo-Asians are more prone to develop diabetes mellitus for a given BMI (21), no ethnic differences were observed in cortisol secretion or metabolism.
Collectively, these data support our hypothesis that a reduction in 11ß-HSD1 might act as an autocrine protective mechanism to prevent increasing adiposity and increased hepatic glucose output with advancing obesity. This adaptive mechanism of reduced 11ß-HSD1 activity, and therefore reduced cortisol regeneration, does not occur in obesity-associated type 2 diabetes mellitus; and this might contribute to the underlying pathogenesis of the disease. Its true role will only be determined in well-designed prospective clinical studies.
Recent data in hyperglycemic and hyperinsulinemic mice indicate that selective 11ß-HSD1 inhibitors are effective in lowering blood glucose concentrations (36, 43). Carbenoxolone (a nonselective inhibitor of 11ß-HSDs) improves insulin sensitivity in healthy controls (44) and in diabetic patients decreases hepatic glucose output by decreasing glycogenolysis (45). Our data would suggest that 11ß-HSD1 inhibition might be of particular benefit in patients with type 2 diabetes mellitus and visceral obesity.
In conclusion, the impaired 11ß-HSD1 activity with increasing BMI in patients with obesity is closely associated with visceral adipose mass, but the causative factors underpinning this relationship remain unknown. In patients with type 2 diabetes mellitus, no such adaptive mechanism occurs. Failure to increase cortisol clearance at an endocrine level and switch-off the autocrine generation of cortisol in liver and fat might contribute to the hyperglycemia and ongoing obesity observed in this group. Further studies are needed to establish the mechanisms underlying dysregulation of cortisol metabolism in type 2 diabetes mellitus, but inhibition of 11ß-HSD1 in this group might be an effective way of controlling features of the metabolic syndrome.
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Footnotes |
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Received December 31, 2003.
Accepted May 20, 2004.
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and TNF receptors in obesity and insulin resistance. J Intern Med 245:621–625[CrossRef][Medline]
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