Till Örebro universitet

OBJECTIVE:

The menopausal transition is characterized by increased body fat accumulation, including redistribution from peripheral to central fat depots. This distribution is associated with an increased risk of type 2 diabetes and cardiovascular disease that are linked to low-grade inflammation. We determined whether postmenopausal women have higher levels of inflammatory markers, compared with premenopausal women. We also wanted to determine whether these markers are reduced by stable weight loss in obese women.

DESIGN AND METHODS:

Anthropometric data, blood samples and subcutaneous adipose tissue biopsies were collected from normal weight premenopausal and postmenopausal women and obese women before and 2 years after gastric bypass (GBP) surgery. Serum protein levels and adipose tissue gene expression of inflammatory markers were investigated.

RESULTS:

IL-8 expression in adipose tissue and circulating levels were higher in postmenopausal vs premenopausal women. IL-8 expression was associated with waist circumference, independent of menopausal status. IL-6 expression and serum levels of monocyte chemoattractant protein (MCP)-1 were higher in postmenopausal vs premenopausal women. Two years after GBP surgery, adipose expression of IL-8, tumour necrosis factor-α and MCP-1 decreased significantly. Serum insulin levels were associated with inflammation-related gene expression before GBP surgery, but these associations disappeared after surgery.

CONCLUSION:

Postmenopausal women have an increased inflammatory response in the subcutaneous fat and circulation. Inflammatory markers in adipose tissue decreased significantly after surgery-induced weight loss. This effect may be beneficial for metabolic control and reduced cardiovascular risk after weight loss.

During the last decade, digital X-ray radiometry (DXR) has been used to measure bone mineral density (BMD) in the metacarpal bones. The aim of this study was to establish Swedish reference material for bone mass in women, measured in the metacarpal bones with DXR, and compare these data with the data from the manufacturer. A sample of 1440 women aged 20-79yr living in Örebro County was randomly assigned from the population register. Microdose mammography was used (Sectra MDM L30; Sectra Imtec AB, Linköping, Sweden) to measure BMD. Cole's LMS method was used to calculate DXR. Six hundred sixty-nine (48.3%) women participated. Peak bone mass occurred at the age of 43.4yr with a BMD of 0.597g/cm(2) (standard deviation: 0.050). Our Swedish data correlated well with the manufacturer's material. Only among women aged 50-59yr did BMD differ, where the Swedish sample had lower values. The LMS method can be used to describe the DXR data and provide a more detailed picture of bone density distribution. DXR-BMD in Swedish women aged 20-79yr is equivalent to findings from other studies, showing the same distribution of BMD in most age groups except for ages 50-59yr.

OBJECTIVE: Obstructive sleep apnea has been reported to occur in 20-50% of children with Down's syndrome in case series of patients referred for evaluation of suspected sleep apnea. In this population-based controlled study, we aimed to investigate whether sleep apnea is related to Down's syndrome.

MATERIAL AND METHODS: Every child aged 2-10 years with Down's syndrome residing in the Umeå healthcare district (n = 28) was invited to participate in the study, with their siblings acting as controls. Successful overnight sleep apnea recordings and echocardiography were performed in 17/21 children with Down's syndrome and in 21 controls.

RESULTS: Obstructive sleep apnea could not be diagnosed, either in children with Down's syndrome or in the control children. The apnea-hypopnea index in the children with Down's syndrome was 1.2 +/- 1.5 and did not differ from that in controls. Snoring and hypertrophy of the tonsils were more common in children with Down's syndrome than in controls. Children with Down's syndrome slept for a shorter time (p < 0.001) and changed body position more often (p < 0.05) than the control children.

CONCLUSIONS: Snoring, restless sleep and hypertrophy of the tonsils were common among children with Down's syndrome. Obstructive sleep apnea was, however, not related to Down's syndrome in the present population-based controlled study.

Background: Gastric banding (GB) and vertical banded gastroplasty (VBG) may result in unsatisfactory weight loss or intolerable side effects. Such outcomes are potential indications for additional bariatric surgery, and Roux-en-Y gastric bypass is frequently used at such revisions (rRYGB). The present study examined long-term results of rRYGB.

Methods: In total, 175 patients who had undergone rRYGB between 1993 and 2003 at 2 university hospitals received a questionnaire regarding their current status. The questionnaire was returned by 131 patients (75% follow-up rate, 66 VBG and 65 GB patients). Blood samples were obtained and medical charts studied. The reason for conversion was mainly unsatisfactory weight loss among the VBG patients and intolerable side effects among GB patients.

Results: The 131 patients (112 women), mean age 41.8 years at rRYGB, were evaluated at mean 11.9 years (range 7-17) after rRYGB. Mean body mass index of those with prior unsatisfactory weight loss was reduced from 40.1 kg/m(2) (range 28.7-52.2) to 32.6 kg/m(2) (range 19.1-50.2) (P < .01). Only 2 patients (2%) underwent additional bariatric surgery after rRYGB. The overall result was satisfactory for 74% of the patients. Only 21% of the patients adhered to the recommendation of lifelong multivitamin supplements while 76% took vitamin B-12. Anemia was present in 18%.

Conclusions: rRYGB results in sustained weight loss and satisfied patients when VBG or GB have failed. Subsequent bariatric surgery was rare but micronutrient deficiencies were frequent.

Background: Roux-en-Y gastric bypass surgery (RYGB) as treatment of morbid obesity results in substantial weight loss. Most published long-term studies have included few patients at the last follow-up point. The aim of the present study was to explore long-term results in a large cohort of patients 7-17 years after gastric bypass.

Methods: All 539 patients who had undergone primary RYGB from 1993 to 2003 at Uppsala and Orebro University Hospitals received a questionnaire regarding their postoperative status. Blood samples were obtained and the medical charts studied.

Results: Of the 539 patients, 384 responded (71.2% response rate, mean age 37.9 yr, body mass index 44.5 kg/m(2) at surgery, 317 women, and 67 men). At a mean follow-up of 11.4 years (range 7-17), the body mass index had decreased to 32.5 kg/m(2), corresponding to an excess body mass index loss of 63.3%. Similar weight loss was observed, regardless of the length of follow-up. Orally treated diabetes resolved in 72% and sleep apnea and hyperlipidemia were improved. Revisional bariatric surgery had been performed in 2.1% and abdominoplasty in 40.2%. The gastrointestinal symptoms were considered tolerable. The overall result was satisfactory for 79% of the patients and 92% would recommend Roux-en-Y gastric bypass to a friend. Attendance to the annual checkups was 37%. Vitamin B-12 supplements were taken by 72% and multivitamins by 24%.

Conclusion: At 11 years, substantial weight loss was maintained and revisional surgery was rare. Surprisingly few patients were compliant with the recommendation of lifelong supplements and yearly evaluations; however, patient satisfaction was high.

The adipocyte-derived hormone leptin is associated with insulin resistance and reduced fibrinolytic status--or dysfibrinolysis--in humans. As leptin associates differentially to the development of cardiovascular disease and diabetes in men and women, we hypothesized that leptin and insulin sensitivity are related to dysfibrinolysis in a sex-dependent manner. Thirty-two men and 40 women were recruited from the Monitoring of trends and determinants in Cardiovascular disease (MONICA) population sample, representing the highest and lowest quartiles of fasting insulin levels. Lipids, fibrinolytic status [plasminogen activator inhibitor 1 (PAI-1) activity, tissue plasminogen activator (tPA) mass and activity, and tPA-PAI complex], leptin, testosterone and sex-hormone-binding globulin were measured. Insulin sensitivity was estimated using the euglycaemic clamp technique. Body composition was determined by bioimpedance. Determinants for circulating levels of fibrinolytic factors were explored in a multivariate linear regression analysis. Levels of fibrinolytic variables and estimated insulin sensitivity did not differ between men and women. Leptin was independently associated with reduced fibrinolytic status (high PAI-1 activity, low tPA activity, high tPA mass, and high tPA-PAI complex) in men (P < 0.001-0.002). In women, fat mass and/or insulin sensitivity were related to these factors (P < 0.001-0.03), and leptin only to reduced tPA activity (P = 0.002). Hyperleptinemia, dysfibrinolysis, insulin sensitivity and androgenicity associate differentially in men and women.

BACKGROUND: Symptomatic postbariatric hypoglycemia (PBH) is a known complication that can occur a few years after Roux-en-Y gastric bypass (RYGB). There is currently no established rating scale for PBH-associated symptoms developed for use in Swedish populations. The aim of the study was to translate an already existing questionnaire into Swedish and to test its reliability.

METHODS: The study included forward and backward translations of the original Dumping Severity Scale (DSS) questionnaire with 8 items regarding symptoms of early dumping and 6 items regarding hypoglycemia, with each item graded on a 4-point Likert scale. The reliability of the Swedish translated questionnaire (DSS-Swe) was estimated using internal consistency and test-retest methods.

RESULTS: A total of 200 patients were included in the study. Good internal consistency was demonstrated regarding the items related to early dumping symptoms, with a Cronbach's alpha coefficient of 0.82, and very good agreement in terms of test-retest reliability, with an overall intraclass correlation coefficient (ICC) of 0.91 (95% CI 0.88-0.93). The items related to hypoglycemia yielded a good Cronbach's alpha coefficient of 0.76 and an ICC of 0.89 (95% CI 0.85-0.91).

CONCLUSION: The DSS-Swe questionnaire shows good reliability regarding both internal consistency and test-retest performance for use in Swedish populations.

Bariatric surgery has gained wide acceptance as treatment for severe obesity and is associated with decreased overall mortality. The aims of this study were to evaluate the prevalence of anemia long term after Roux-en-Y gastric bypass (RYGB) and to search for factors predicting anemia.

All 745 patients who underwent RYGB between 1993 and 2003 at either A-rebro or Uppsala University Hospital and who were living in Sweden were invited to participate by providing a fasting blood sample and completing a questionnaire about their health status. Full blood count, serum iron, transferrin, vitamin B-12, and folic acid were determined.

Follow-up was completed in 431 patients (58 %) with mean age 51.3 +/- 10 years. Of all patients, 27 % had anemia postoperatively and related deficiencies; iron, folic acid, and vitamin B-12 were seen in 20, 12, and 2 %, respectively. There was no correlation between anemia and sex, follow-up time, 25-OH vitamin D level, and preoperative or postoperative BMI. An inverse correlation was found between anemia and regular medical checkups concerning gastric bypass surgery.

Twenty-seven percent of patients had anemia more than 10 years after RYGB. Anemia does not seem to progress with time and was less common in patients with regular medical checkups. Thus, improved long-term follow-up is needed.

The primary aim of this study was to evaluate the prevalence of vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass. Secondly, we have tried to assess predictors for vitamin D deficiency. Five hundred thirty-seven patients who underwent primary Roux-en-Y gastric bypass surgery between 1993 and 2003 at the A-rebro University Hospital and Uppsala University Hospital were eligible for the study. Patients were asked to provide a blood sample between November 2009 and June 2010 and to complete a questionnaire about their postoperative health status. Serum values of 25-OH vitamin D, parathyroid hormone (PTH), alkaline phosphatase (ALP) and calcium were determined. Follow-up was completed in 293 patients, of which 83 % were female, with an age of 49 +/- 9.9 years after a median time of 11 +/- 2.8 years. Vitamin D, PTH and albumin-corrected calcium values were 42 +/- 20.4 nmol/L, 89.1 +/- 52.7 ng/L and 2.3 +/- 0.1 mmol/L, respectively. Of all patients, 65 % were vitamin D deficient, i.e. 25-OH vitamin D < 50 nmol/L, and 69 % had PTH above the upper normal reference range, i.e. > 73 ng/L. Vitamin D was inversely correlated with PTH levels (p < 0.001) and positively correlated with calcium (p = 0.016). Vitamin D did not correlate with ALP. The only factor found to predict vitamin D deficiency was high preoperative body mass index (BMI) (p = 0.008), whereas gender, age, time after surgery and BMI at follow-up did not. Vitamin D deficiency and secondary hyperparathyroidism after Roux-en-Y gastric bypass (RYGB) were confirmed in our study because 65 % of patients had vitamin D deficiency, and 69 % had increased PTH levels more than 10 years after surgery. These data are alarming and highlight the need for improved long-term follow-up. Vitamin D deficiency does not seem to progress with time after surgery, possibly due to weight loss. Only preoperative BMI, cutoff point 43 kg/m(2), was a predictor of vitamin D deficiency at follow-up. Improved long-term follow-up of patients that undergo RYGB is needed.

Background: The discovery of an epimeric form of 25(OH)D3 may complicate the interpretation of vitamin Dstatus. The aim of this study was to examine the prevalence and determinants of 25-hydroxy-3-epi-vitamin D3 (3- epi-25(OH)D3) in a mid-Swedish region and to investigate how the measurement of 3-epi-25(OH)D3 would affect the assessment of vitamin D status using current thresholds.

Methods: We conducted a cross-sectional study of 8286 in- and outpatients in primary as well as secondary care settings. Plasma 25(OH)D, 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3 were measured using High Pressure Liquid Chromatography – Tandem Mass Spectrometry (HPLC – MS/MS). The relative 3-epi-25(OH)D3 contribution was calculated as a percentage of the total 25(OH)D3. Blood samples were collected between March 2014 and July 2015 providing a seasonal aspect to the results.

Results: 3-epi-25(OH)D3was detected in 635 cases (7.7% of all subjects), and the mean concentration was8.4 ± 3.5 nmol/L. 3-epi-25(OH)D3correlated significantly with 25(OH)D3(r =0.38, p < 0.001).A multivariateanalysis among the detected showed that male gender and winter season were independently associatedwith higher 3-epi-25(OH)D3/25(OH)D3percentage ratio (R2=0.044). Infants and children had a significantlyhigher detection rate compared to the reference age category (18–45 years) as well as those who were testedduring the summer season.

Conclusions: We report findings from the first epidemiologic study of 3-epi-25(OH)D3 conducted in Sweden, based on a large population sample. 3-epi-25(OH)D3 was detected in 7.7% of the study population and the mean concentration was 8.4 nmol/L. The quantification of 3-epi-25(OH)D3 would not significantly influence the clinical interpretation of vitamin D levels. Additional studies are needed to understand the metabolic pathway and the possible physiological functions of this metabolite.

Purpose: Several observational studies have shown an association between vitamin D deficiency and non-skeletal major health issues including impaired cardiorespiratory fitness and adiposity. Only a few studies have examined the impact of vitamin D supplementation on these conditions and the results are ambiguous. The aim of this study was to examine the effect of vitamin D supplementation on body composition and cardiorespiratory fitness in overweight/obese men with vitamin D deficiency.

Methods: This study was a prospective, placebo controlled, double blinded, randomized trial with a study period of 6 months. Forty overweight/obese men (BMI > 25 kg/m²) with vitamin D deficiency (25(OH)D ≤ 55 nmol/L) were randomized to receive either 2000 IU Cholecalciferol drops or the equivalent amount of drops of placebo. At baseline and follow up body composition and cardiorespiratory fitness were measured and blood samples were obtained. Body composition was measured using bioelectrical impedance analysis (BIA) and cardiorespiratory fitness using cardiopulmonary exercise test (CPET). The primary outcomes were changes in percentage body fat and in maximum oxygen uptake (VO_2max).

Results: No statistically significant difference between the placebo and the intervention group regarding changes in percentage body fat (p = 0.54) and VO_2max (p = 0.90) was observed. Moreover, there was no statistically significant difference between the groups concerning changes in BMI (p = 0.26), maximum load (p = 0.89) and oxygen uptake at anaerobic threshold (AT) (p = 0.14).

Conclusions: We conclude that treatment with 2000 IU/d vitamin D for 6 months does not impact body composition or maximum oxygen uptake in overweight/obese men with vitamin D deficiency.

OBJECTIVE: Reduction of cortisone to cortisol is mediated by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), a putative key enzyme in obesity-related complications. Experimental studies suggest that adipokines, notably leptin and tumor necrosis factor-alpha (TNF-alpha), are of importance for 11betaHSD1 activity. We hypothesized that the regulation of hepatic preceptor glucocorticoid metabolism is gender-specific and associated with circulating levels of leptin and TNF-alpha receptors and/or sex hormones.

RESEARCH METHODS AND PROCEDURES: A total of 34 males and 38 women (14 premenopausal and 22 postmenopausal) underwent physical examination and fasting blood sampling. Insulin sensitivity was tested by euglycemic hyperinsulinemic clamps, and hepatic 11betaHSD1 enzyme activity was estimated by the conversion of orally-ingested cortisone to cortisol.

RESULTS: Hepatic 11betaHSD1 activity was negatively associated with leptin and soluble TNF (sTNF) r1 and sTNFr2 in males. These correlations remained significant after adjustment for age and insulin sensitivity, and for sTNF-alpha receptors also after adjustment of BMI and waist circumference. In contrast, 11beta reduction of cortisone was positively associated to leptin in females after adjustment for BMI and waist circumference.

DISCUSSION: Hepatic 11beta reduction shows different links to circulating adipocyte-derived hormones in males and females. This emphasizes the need for further studies on tissue-specific regulation of 11betaHSD1 in both genders.

It is evident that morbidly obese patients have a low health-related quality-of-life (HRQoL), and this low HRQoL has become a common reason for them to seek bariatric surgery. Several HRQoL studies demonstrate a dramatic postoperative improvement, but most of these have had a short follow-up period.

An observational, cross-sectional study for HRQoL was conducted to study 486 patients (average age of 50.7 +/- 10.0 years, with 84 % of them being female) operated with gastric bypass (GBP) in the period 1993 to 2003 at the University Hospitals of A-rebro and Uppsala. Mean follow-up after gastric bypass was 11.5 +/- 2.7 years (range 7-17). Two HRQoL instruments were used, SF-36 and the Obesity-related Problems scale (OP). The study group was compared with two control groups, both matched for age and gender, one from the general population and one containing morbidly obese patients evaluated and awaiting bariatric surgery.

The study group scored better in the SF-36 domains (all four physical domains and the vitality subscore) and OP scale compared to obese controls, but their HRQoL scores were lower than those of the general population. HRQoL was better among younger patients and in the following subgroups: men, patients with satisfactory weight loss, satisfied with the procedure, free from co-morbidities and gastrointestinal symptoms, employment, good oral status and those not hospitalised or regularly followed up for non-bariatric reasons.

Long-term follow-up after GBP for morbid obesity showed better scores in most aspects of HRQoL compared to obese controls but did not achieve the levels of the general population. Patients with better medical outcome after gastric bypass operation had better HRQoL.

BACKGROUND: The aim of the present study was to study longitudinal changes in bone mineral density (BMD), vitamin D, and parathyroid hormone (PTH) levels in females over a 10-year period after laparoscopic Roux-en-Y gastric bypass (LRYGB).

METHODS: at baseline, were included. BMD, BMI, S-calcium, S-25(OH)-vitamin D, and fP-PTH were measured preoperatively and 2, 5, and 10 years postoperatively.

RESULTS: Ten years after surgery, BMD of the spine and femoral neck decreased by 20% and 25%, respectively. Changes in serum levels of vitamin D, PTH, and calcium over the same period were small.

CONCLUSION: After LRYGB with subsequent massive weight loss, a large decrease in BMD of the spine and femoral neck was seen over a 10-year postoperative period. The fall in BMD largely occurred over the first 5 years after surgery.

Background: The aim of the present study was to see if there are longitudinal changes in bone mineral density (BMD), vitamin D or parathyroid hormone (PTH) in females 5 years after Laparoscopic Roux-en-Y Gastric Bypass (LRYGB).

Methods: Thirty-two women with mean age 41.6 ± 9.3 years and mean body mass index (BMI) 44.5 ± 4.6 kg/m(2) were included. Preoperatively, 2 and 5 years postoperatively, BMD, weight, height, S-calcium, S-albumin, S-creatinine, S-25(OH)-vitamin D and fP-PTH were measured.

Results: The mean decrease in BMI between baseline and 5 years after surgery was 29.4 %. BMD of the spine and femur measured as z- and t-scores, showed a linear, statistically significant declining trend over the years. The fall in BMD of the spine and femoral neck between baseline and 5 years after surgery was 19 and 25 %, respectively. The mean fP-PTH showed a significant increase over the study period (20.2 μg/L increase, 95 % CI:-31.99 to -8.41). S-calcium, both free and corrected for albumin, showed a decrease between baseline and 5 years after surgery. Eight patients developed osteopenia and one osteoporosis after a 5-year follow-up.

Conclusion: LRYGB is an efficient method for sustained long-term body weight loss. There is, however, a concomitant decrease in BMD and S-calcium, and an increase in fP-PTH.

In one of two cases of systemic effects of high-dose inhaled corticosteroid treatment with fluticasone propionate, adrenal suppression was demonstrated in a young man, and in the other retarded growth and severe general effects were observed in connection with infection in a child. These cases illustrate the risk of systemic effects of inhaled corticosteroids, and the importance of using the lowest possible maintenance dose.

Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local pre-receptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1). In obese Zucker rats 11 beta -HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin sensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from le participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r=0.47, p<0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r=0.43, p<0.02), and converted less cortisone to cortisol after oral administration (r=-0.49, p<0.01), suggesting impaired hepatic 11<beta>-HSD1 activity. By contrast, in vitro 11 beta -HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r=0.66, p<0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11<beta>-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11 beta -HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P = .018) and lower OGIS (397 21 v 463 12 mL/min/m(2); P = .005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 51 v 774 91 nmol/min/m(2), p = .001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P < .001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P = .035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P < .001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P = .055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P = .036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response. (C) 2004 Elsevier Inc. All rights reserved.

OBJECTIVE:

To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake.

RESEARCH DESIGN AND METHODS:

From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured.

RESULTS:

Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insulin-resistant tertile compared with the most insulin-sensitive tertile. During the first hour, the AUC of GLP-1 correlated significantly with insulin sensitivity (r = 0.47, P < 0.01). Multiple linear regression analysis showed that insulin resistance, but not obesity, was an independent predictor of these decreased incretin responses.

CONCLUSIONS:

In insulin resistance, the GIP and GLP-1 responses to a mixed meal are impaired and are related to the degree of insulin resistance. Decreased incretin responsiveness may be of importance for the development of impaired glucose tolerance.

Bariatric surgery is a well-documented and good alternative for treatment of obesity with and without type 2-diabetes. One of the documented complications is postprandial hypoglycemia, with possibly serious consequences. We present such a case, what is known of underlying mechanisms, and treatment options. © 2019, Swedish Medical Association. All rights reserved.

OBJECTIVE:

To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake.

RESEARCH DESIGN AND METHODS:

From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured.

RESULTS:

Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insulin-resistant tertile compared with the most insulin-sensitive tertile. During the first hour, the AUC of GLP-1 correlated significantly with insulin sensitivity (r = 0.47, P < 0.01). Multiple linear regression analysis showed that insulin resistance, but not obesity, was an independent predictor of these decreased incretin responses.

CONCLUSIONS:

In insulin resistance, the GIP and GLP-1 responses to a mixed meal are impaired and are related to the degree of insulin resistance. Decreased incretin responsiveness may be of importance for the development of impaired glucose tolerance.

Objective Increased glucocorticoid metabolite excretion and enhanced expression and activity of 11-hydroxysteroid dehydrogenase type 1 in adipose tissue are closely correlated with obesity and its detrimental consequences. Weight loss ameliorates the latter. The aim of this study was to explore whether increased glucocorticoid exposure in obesity is improved with substantial weight loss and thus is a consequence rather than a cause of obesity.

Design and patients A prospective cohort study in 31 women.

Measurements 11-HSD type 1 expression and activity, urinary glucocorticoid metabolite excretion, body composition including regional adipose tissue depots and insulin resistance by HOMA-IR before and 2years after gastric bypass surgery.

Results After weight loss, excretion of cortisol and cortisone metabolites decreased. Both cortisol and cortisone metabolite excretion correlated with central obesity, where the intraabdominal fat depot showed the strongest association. Cortisol metabolites correlated with 11-HSD type 1 activity in abdominal subcutaneous adipose tissue. The ratio of cortisol to cortisone metabolites [(5-tetrahydrocortisol (5THF)+tetrahydrocortisol (THF)+-cortol)/(tetrahydrocortisone (THE)+-cortolone)] and the ratio of 5-THF/THF both decreased after stable weight loss, reflecting a downregulation of the net activities of 11-HSD type 1 and 5-reductase.

Conclusion Long-term weight loss in women is not only followed by reduced glucocorticoid production, but also favourably decreases the global and tissue-specific activity of the cortisol-activating enzyme 11 -HSD type 1, possibly contributing to the health benefits of bariatric surgery.

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.

Introduction: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels.

Methods: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH (R)(100 mu g/m(2)) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels.

Results: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 +/- 257.1 vs. 247.6 +/- 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041).

Conclusion: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels. (C) 2022 The Author(s). Published by S. Karger AG, Basel

Introduction: Ghrelin is a growth hormone-releasing acylated peptide stimulating the appetite, mainly produced in the stomach, and with an important role in pubertal development (1). Two ghrelin forms have been described, acylated (AG) and desacylated (DAG), but it is debated whether DAG is an active hormone or a degradation product of AG (2). Our aim was to evaluate the effects of adding the protease inhibitor 4-(2-aminoethyl) benzenesufonyl fluoride hydrochloride (AEBSF) to sampling tubes and acidification of plasma on levels of AG and DAG in girls with suspected central precocious puberty (CPP).

Methods: 13 girls aged 6.6 to 10.1 years with suspected CPP undergoing a gonadotropin-releasing hormone stimulation test during 2015-2017 at the Departments of Paediatrics, at Örebro or Uppsala University Hospital were included. Blood samples were collected at 0 min in precooled EDTA tubes with or without AEBSF at a final concentration of 2mg/ml. After cold centrifugation, HCl at a final concentration of 50 μmol/l, was added to 50% of the plasma tubes containing AEBSF. The AG and DAG concentrations were measured by ELISA kits. Comparison was performed using one-way ANOVA for repeated measurements.

Results: The mean plasma AG levels were significantly higher after the addition of AEBSF only (650.9 +/- 257.1 pg/ml) or AEBSF+HCl (681.2 +/- 299 pg/ml) compared to the concentrations without additives (247.6 +/- 123.4 pg/ml, p<0.01 for both comparisons). There was no significant difference between the AG levels after AEBSF and AEBSF+HCl addition. The plasma levels of DAG were significantly lower after the addition of AEBSF+HCl (69.3 +/- 30.6 pg/ml) and even further lowered after the addition of AEBSF only (56.3+/- 30.9 pg/ml) compared to the concentrations of DAG in tubes without any additives (149.9 +/- 73.7 pg/ml, p < 0.01 for both comparisons).

Discussion: Due to the unstable nature of AG, special procedures are required for accurate measurement of its plasma levels in children, including the use of a protease inhibitor like AEBSF. However, DAG was still measurable indicating that it may not only be a degradation product of AG. 1. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522.2. Blatnik M, Soderstrom CI, Dysinger M, Fraser SA. Prandial ghrelin attenuation provides evidence that des-acyl ghrelin may be an artifact of sample handling in human plasma. Bio-analysis. 2012;4(20):2447-55.

OBJECTIVES: To compare the usefulness of the classical definition of delayed puberty (DP) in boys with puberty nomograms and to describe the management of DP in boys in a hospital-based setting.

STUDY DESIGN: Observational retrospective multicentre study with a short-term follow-up.

SETTING AND PARTICIPANTS: Boys diagnosed with DP during 2013-2015 at paediatric departments in four counties in central Sweden. The medical records of 165 boys were reviewed.

PRIMARY AND SECONDARY OUTCOME MEASURES: Number of boys with DP after re-evaluation of the diagnosis according to the classical definition in comparison with puberty nomograms. Description of investigations performed and treatment provided to boys with DP.

RESULTS: In total, 45 and 58 boys were found to have DP according to the classical definition and the nomograms, respectively. Biochemical and/or radiological testing was performed in 91% of the 58 boys, but an underlying disease was only found in 9% of them. Approximately 79% of the boys received testosterone treatment, either as injections of testosterone enanthate or as testosterone undecanoate.

CONCLUSIONS: Puberty nomograms may be helpful instruments when diagnosing pubertal disorders in boys as they are not limited to an age close to 14 years and also identify boys with pubertal arrest. The majority of boys with DP undergo biochemical or radiological examinations, but underlying diseases are unusual emphasising the need for structural clinical practice guidelines for this patient group.

Introduction: Delayed puberty is defined as the absence of physical signs of puberty by the age of 14 years in boys and 13 years in girls. According to this definition, the prevalence of delayed puberty would be 2%, if the ages of pubertal onset were normally distributed in the population. However, the prevalence or incidence of delayed puberty has not been described before, as far as we know. Our aim was to study the incidence of delayed puberty in central Sweden.

Methods: In this population-based retrospective study all adolescents given the ICD-10 diagnosis “delayed puberty” in Örebro county during the period 2013-2015 were identified. Adolescents with other diagnoses potentially related to delayed puberty (e.g. short stature) were also identified to ensure that there were no additional cases. The medical records of these patients, except those not willing to participate, were systematically reviewed to ensure that the diagnosis was correct. The cases were then categorized into four groups depending on how accurate we found the diagnosis (certain, possible, wrong diagnosis, or unclear cases). Data on the total numbers of adolescents in Örebro county were obtained from the authority of statistics in Sweden.

Results: One hundred and twenty-eight of 180 eligible medical records were reviewed (response rate: 71 %). Nine boys and one girl were diagnosed with delayed puberty during the study time period and fulfilled our strict criteria for a certain diagnosis and 4 boys were classified as possible new cases. The total population in Örebro county for boys aged 14-18 years was on average 6,546 each year during the time period. The minimal annual incidence for boys was 46 per 100,000 (95% confidence interval (CI) 15-142 per 100,000). When possible cases were included, the annual incidence for boys increased to 66 (CI 26-170) per 100,000. Due to the low number of girls with delayed puberty no incidence for girls was calculated.

Discussion: This is, to our knowledge, the first study describing the incidence of delayed puberty in boys. We evaluated the accuracy of the diagnosis using strict criteria. The presented incidence should be regarded as the minimum incidence since some adolescents with delayed puberty may not seek medical advice or may be unrecognized by the health services in schools. Because of our small study population, larger studies are needed to confirm our findings and for calculation of the incidence in girls, where our data implies a much lower incidence.

Introduction: Kisspeptin stimulates the gonadotropin releasing hormone (GnRH) neurons in hypothalamus initiating puberty. However, it is not known whether GnRH inhibits kisspeptin secretion by negative feedback and whether there are any associations between circulating levels of kisspeptin and other hormones, like ghrelin, important for the onset of puberty.

Methods: Thirteen girls with suspected central precocious puberty performed an adjusted GnRH stimulation test twice, placebo-controlled in a randomized order, at Örebro or Uppsala University Hospital, Sweden. Blood was sampled 0, 30, 60, 90, 120 and 150 min after the iv injection of either Relefact LHRH® or saline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes to a final concentration of 2 mg/ml. An ELISA kit from LifeSpan BioSciences, Inc. (No LS-F8231) was used for the analyses of Kisspeptin-1 levels. The levels of acylated ghrelin were analyzed with Millipore® Human Ghrelin (Active) ELISA kit (#EZGRA-88K). Serum ultrasensitive estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin and glucose levels were analyzed using the usual clinical methods.

Results: The median Kisspeptin-1 level at baseline was 39 pg/ml (min–max: 0.1–221.3 pg/ml). The area-under-the curve for Kisspeptin-1 levels was not significantly lower after the GnRH injection as compared to the placebo injection. We did not find any significant correlations between the levels of kisspeptin-1 and acylated ghrelin, estradiol, LH, FSH, or insulin. However, we could see a positive correlation between kisspeptin-1 and glucose levels at baseline (Spearman’s rank test, rho = 0.63, p=0.021).

Discussion: We did not find evidence of a negative feedback mechanism between GnRH and kisspeptin in girls with suspected central precocious puberty since the circulating levels of kisspeptin-1 were unaffected by an intravenous injection of a GnRH analogue. However, paracrine actions in the hypothalamus cannot be ruled out by this study. The positive correlation found between kisspeptin-1 and glucose levels is in accordance with previous findings in both adults and children, suggesting a possible role for kisspeptin signaling in glucose metabolism.

BACKGROUND AND AIMS: The role of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in the pathogenesis of obesity has been elucidated in humans and in various rodent models. Obesity is accompanied by disturbances in glucocorticoid metabolism, circulating adipokine levels, and fatty acid (FA) reesterification. This study was undertaken to evaluate glucocorticoid metabolism in sc fat before and after weight loss and to explore putative associations between 11beta-HSD1 and leptin, adiponectin, and FA recycling.

SUBJECTS AND METHODS: Twenty-seven obese (mean body mass index 44.4 + or - 4.4 kg/m(2)) women underwent gastric bypass surgery. Subcutaneous fat biopsies were collected before and 2 yr after surgery. The expression of 11beta-HSD1, leptin, adiponectin, and phosphoenolpyruvate carboxykinase (PEPCK) mRNA was evaluated with real-time PCR. Serum leptin and adiponectin protein levels were estimated by ELISA.

RESULTS: Two years after gastric bypass surgery, significant reductions were observed in the mean body mass index (from 44.4 to 30.8 kg/m(2)) and mean waist circumference (from 121.9 to 90.6 cm). After weight loss, 11beta-HSD1 mRNA expression decreased 4-fold (P < 0.001). Both leptin and adiponectin mRNA expression decreased, with concomitantly decreased circulating leptin and increased circulating adiponectin levels. PEPCK mRNA expression did not change.

CONCLUSION: Weight loss after gastric bypass surgery was followed by metabolically favorable changes in insulin sensitivity, circulating leptin and adiponectin, and peripheral glucocorticoid metabolism. A significant reduction in 11beta-HSD1 expression was observed in sc adipose tissue after weight loss. This suggests that up-regulation of 11beta-HSD1 is a consequence, rather than a cause, of obesity.

The glucocorticoid activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is of major interest in obesity-related morbidity. Alterations in tissue-specific cortisol levels may influence lipogenetic and gluco/glyceroneogenetic pathways in fat and liver. We analyzed the expression and activity of 11betaHSD1 as well as the expression of phosphoenolpyruvate carboxykinase (PEPCK), sterol regulatory element binding protein (SREBP), and fatty acid synthase (FAS) in adipose and liver and investigated putative associations between 11betaHSD1 and energy metabolism genes. A total of 33 obese women (mean BMI 44.6) undergoing gastric bypass surgery were enrolled. Subcutaneous adipose tissue (SAT), omental fat (omental adipose tissue (OmAT)), and liver biopsies were collected during the surgery. 11betaHSD1 gene expression was higher in SAT vs. OmAT (P = 0.013), whereas the activity was higher in OmAT (P = 0.009). The SAT 11betaHSD1 correlated with waist circumference (P = 0.045) and was an independent predictor for the OmAT area in a linear regression model. Energy metabolism genes had AT depot-specific expression; higher leptin and SREBP in SAT than OmAT, but higher PEPCK in OmAT than SAT. The expression of 11betaHSD1 correlated with PEPCK in both AT depots (P = 0.05 for SAT and P = 0.0001 for OmAT). Hepatic 11betaHSD1 activity correlated negatively with abdominal adipose area (P = 0.002) and expression positively with PEPCK (P = 0.003). In human obesity, glucocorticoid regeneration in the SAT is associated with central fat accumulation indicating that the importance of this specific fat depot is underestimated. Central fat accumulation is negatively associated with hepatic 11betaHSD1 activity. A disturbance in peripheral glucocorticoid metabolism is associated with changes in genes involved in fatty acid (FA) recycling in adipose tissue (AT).

Background: Bariatric surgery improves insulin sensitivity and secretion in patients with type 2 diabetes, but the effect on patients with prediabetes or even normal glucose tolerance deserves further consideration.

Methods: Cohort study including patients operated with laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) between November 2012 and June 2017 at the orebro University Hospital (n = 813) with follow-up of 742 patients 2 years after surgery. Fasting insulin, glucose, glycosylated hemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) were analyzed at baseline and 2 years after surgery for patients with overt type 2 diabetes, prediabetes, or non-diabetes.

Results: Fasting insulin levels improved for all groups (diabetics baseline 25.5 mIU/L, IQR 17.5-38.0, 2 years 7.6 mIU/L, IQR 5.4-11.1, p < 0.001; prediabetics baseline 25.0 mIU/L, IQR 17.5-35.0, 2 years 6.7mIU/L, IQR 5.3-8.8, p < 0.001; non-diabetics baseline 20.0 mIU/L, IQR 14.0-30.0, 2 years 6.4 mIU/L, IQR 5.0-8.5, p < 0.001). HbA1c improved in all groups (diabetics baseline 56 mmol/mol, IQR 49-74 [7.3%, IQP 6.6-8.9], 2 years 38 mmol/mol, IQR 36-47 [5.6%, IQR 5.4-6.4], p < 0.001; prediabetics baseline 40 mmol/mol, IQR 39-42 [5.8%, IQR5.7-6.0], 2 years 36 mmol/mol, IQR 34-38 [5.5%, IQR 5.3-5.6], p < 0.001; non-diabetics baseline 35 mmol/mol, IQR 33-37 [5.4%, IQR 5.2-5.5]; 2 years 34 mmol/mol, IQR 31-36 [5.3%, IQR 5.0-5.4], p < 0.001). HOMA-IR improved in all groups (diabetics baseline 9.3 mmol/mol, IQR 5.4-12.9, 2 years 1.9 mmol/mol, IQR 1.4-2.7, p < 0.001; prediabetics baseline 7.0 mmol/mol, IQR 4.3-9.9, 2 years 1.6 mmol/mol, IQR 1.2-2.1, p < 0.001; non-diabetics 4.9 mmol/mol, IQR 3.4-7.3, 2 years 1.4 mmol/mol, IQR 1.1-1.9, p < 0.001).

Conclusion: Insulin homeostasis and glucometabolic control improve in all patients after LRYGB, not only in diabetics but also in prediabetics and non-diabetic obese patients, and this improvement is sustained 2 years after surgery.

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.

OBJECTIVE: Causes of visceral fat accumulation include glucocorticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra-adipose cortisol-generating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue.

DESIGN: A cross-sectional study.

PATIENTS: Forty-five healthy men and women with body mass index (BMI) 21-36 kg/m(2).

MEASUREMENTS: In subcutaneous adipose biopsies we measured mRNAs for enzymes metabolizing local oestrogens (aromatase) and androgens [5alpha-reductase type 1; AKR1C2 (3alpha-HSD3); AKR1C3 (17beta-HSD5, 3alpha-HSD2)] and for sex steroid receptors [oestrogen receptor (ER)-alpha and androgen receptor (AR)]. We related these to body fat mass and distribution.

RESULTS: Generalized obesity (BMI) was associated with increased aromatase mRNA (r = 0.35, P < 0.05). Central obesity (waist : hip ratio) was associated with mRNA for AKR1C2 (r = 0.28, P < 0.05) and AKR1C3 (r = 0.38, P < 0.01) but not aromatase (r = 0.06). 5alpha-Reductase type 1, ER and AR mRNA levels did not predict fat amount or its distribution.

CONCLUSION: These data on transcript levels suggest that, in idiopathic obesity, increased intra-adipose oestrogen generation by aromatase predicts peripheral fat distribution, while androgen metabolism by AKR1C isoforms predicts central fat distribution, supporting the hypothesis that intra-adipose sex steroid metabolism is a determinant of gynoid vs. android patterns of body fat.