Reliability of the DSS-Swe Questionnaire.

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.

A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls.

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® (100 µg/m2) 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.

Delayed puberty in boys in central Sweden: an observational study on diagnosing and management in clinical practice.

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.

Bone Mineral Density, Parathyroid Hormone, and Vitamin D After Gastric Bypass Surgery: a 10-Year Longitudinal Follow-Up.

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: Twenty-three women, mean age 43.4 ± 8.7 years and mean body mass index (BMI) 44.6 ± 5.17 kg/m2 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.

The Effect of Laparoscopic Gastric Bypass Surgery on Insulin Resistance and Glycosylated Hemoglobin A1c: a 2-Year Follow-up Study.

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 Örebro 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.

[Hypoglycemia following gastric bypass surgery - a case, causes and coping]. / Hypoglykemi ­ problematisk komplikation av överviktskirurgi.

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.

Effect of Vitamin D supplementation on body composition and cardiorespiratory fitness in overweight men-a randomized controlled trial.

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 (VO2max). RESULTS: No statistically significant difference between the placebo and the intervention group regarding changes in percentage body fat (p = 0.54) and VO2max (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.

Effect of Gastric Bypass on Bone Mineral Density, Parathyroid Hormone and Vitamin D: 5 Years Follow-up.

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.

Health-Related Quality-of-Life (HRQoL) on an Average of 12 Years After Gastric Bypass Surgery.

BACKGROUND: 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. MATERIAL AND METHODS: 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 Örebro 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. RESULTS: 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. CONCLUSION: 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.

Prevalence of anemia and related deficiencies 10 years after gastric bypass--a retrospective study.

BACKGROUND: 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. METHODS: All 745 patients who underwent RYGB between 1993 and 2003 at either Örebro 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 B12, and folic acid were determined. RESULTS: 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 B12 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. CONCLUSION: 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.

Twelve-year results for revisional gastric bypass after failed restrictive surgery in 131 patients.

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 B12. 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.

Vitamin D status 10 years after primary gastric bypass: gravely high prevalence of hypovitaminosis D and raised PTH levels.

BACKGROUND: 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. METHODS: Five hundred thirty-seven patients who underwent primary Roux-en-Y gastric bypass surgery between 1993 and 2003 at the Örebro 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. RESULTS: 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. CONCLUSIONS: 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.

Reference data for bone mineral density in Swedish women using digital x-ray radiometry.

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.

Long-term results 11 years after primary gastric bypass in 384 patients.

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 Örebro 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 B12 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.

Adipose tissue IL-8 is increased in normal weight women after menopause and reduced after gastric bypass surgery in obese women.

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.

Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue.

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.

Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling.

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).

Sex-related differences in the associations between hyperleptinemia, insulin resistance and dysfibrinolysis.

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.

Gender-specific links between hepatic 11beta reduction of cortisone and adipokines.

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.