BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions.

Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.

Linear compared to circular stapler anastomosis in laparoscopic Roux-en-Y gastric bypass leads to comparable weight loss with fewer complications: a matched pair study.

OBJECTIVE: In the course of laparoscopic Roux-en-Y gastric bypass (LRYGB), a tight gastroenterostomy (GE) may lead to higher weight loss but possibly to an increase of local complications such as strictures and ulcers. Different operative techniques for Roux-en-Y reconstruction may also influence the rate of internal hernias, a typical late complication of LRYGB. The objective of this study was to compare weight loss, rates of strictures, internal hernias, and ulcerations of linear versus circular stapler anastomosis. METHODS: Retrospective analysis of prospectively collected data in a 3:1-matched pair study. A total of 228 patients with a minimal follow-up of 2 years were matched according to BMI at baseline, age, and gender. The follow-up rate was 100 % at 1 and 2 years postoperatively; the mean follow-up time was 3.8 ± 1.63 years. In group C (circular), 57 patients were operated with a 25-mm circular stapler technique (average BMI 44.7 ± 5.18 kg/m(2), age 44.1 ± 10.8 years, 80.7 % female). In group L (linear), 171 patients were operated using a linear stapler (approximately 30 mm, average BMI 43.8 ± 5.24 kg/m(2), age 43.7 ± 12.5 years, 70.8 % female). A propensity score matching and a logrank test were used for statistical analysis. RESULTS: The average excessive BMI loss (EBMIL) after 1 year was not statistically different (70.6 ± 20.2 % in group C vs 72.5 ± 20.4 % in group L) as well as after 2 years (71.6 ± 22.5 % in group C vs 74.6 ± 19.6 % in group L). The average operation time was 155 ± 53 min in group C and 109 ± 57 min in group L (p = 0.0001). In group L, patients had significantly lower overall stricture rates at the GE compared to group C (0 [0 %] vs. 4 [7 %], p = 0.0004), a lower rate and severity of internal hernias (10 [5.8 %] vs. 7 [12.3 %] p = 0.466), and equal local ulcerations rates (3 [1.8 %] vs. 1 [1.8 %] p = 0.912). CONCLUSION: Linear stapler anastomosis in LRYGB compared to circular anastomosis leads to equal weight loss and less strictures. The lower rate of internal hernias in linear stapler anastomosis was not significantly different.

Long-term outcome after biliopancreatic diversion with duodenal switch: a single-center experience with up to 20 years follow-up.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD/DS) is the most effective standard bariatric procedure in terms of weight loss and remission of co-morbidities but carries the risk of severe long-term side effects. OBJECTIVE: The aim of this study was to analyze the long-term effects of BPD/DS in terms of morbidity, weight loss, remission of associated medical problems, deficiencies, and reoperations. SETTING: Academic teaching hospital, Switzerland. METHODS: This is a retrospective, single-center study of prospectively collected data of all patients who underwent BPD/DS from 1999 to 2011 with a minimal follow-up (FU) of 10 years. RESULTS: A total of 116 patients (83.6% female) underwent BPD/DS with a mean initial body mass index (BMI) of 47 ± 6.5 kg/m2. Of these, 68% of the procedures were performed in open technique and 32% laparoscopically. The majority (76.7%) of patients had laparoscopic adjustable gastric banding before BPD/DS. The mean FU time was 14 ± 4.4 years and the FU rate at 5, 10, and 14 years was 95.6% (n = 108), 90% (n = 98), and 75.3% (n = 70), respectively. The mean excess BMI loss at 5, 10, and 14 years was 78% ± 24.1%, 76.5% ± 26.7%, and 77.8% ± 33.8%, respectively. Complete (n = 22) or partial remission (n = 4) of type 2 diabetes was observed in 92.8% of patients. Forty reoperations were necessary in 34 patients (29.3%) because of malnutrition or refractory diarrhea (n = 13), insufficient weight loss or weight rebound (n = 7), reflux or stenosis (n = 10), and various/combined indications (n = 10). The mean time to reoperation was 7.7 ± 5 years. There were no procedure-related deaths in the short or long term. CONCLUSIONS: BPD/DS offers sustainable long-term weight loss but is associated with important side effects that may be acceptable in selected patients with a high initial BMI (>50 kg/m2) and/or for nonresponders after primary restrictive procedures. Regular FU is necessary to detect and treat malnutrition and vitamin deficiencies.

Mid-Term Outcomes After Conversion Procedures Following Laparoscopic Sleeve Gastrectomy.

PURPOSE: In the long term, laparoscopic sleeve gastrectomy (SG) may be associated with insufficient weight loss (IWL), gastroesophageal reflux disease (GERD), and persistence or relapse of associated medical problems. This study's objective is to present mid-term results regarding weight loss (WL), evolution of associated medical problems, and reoperation rate of patients who underwent a conversion after SG. METHODS: Retrospective single-center analysis of patients with a minimal follow-up of 2 years after conversion. RESULTS: In this series of 549 SGs, 84 patients (15.3%) underwent a conversion, and 71 met inclusion criteria. They were converted to short biliopancreatic limb Roux-en-Y gastric bypass (short BPL RYGB) (n = 28, 39.4%), biliopancreatic diversion with duodenal switch (BPD/DS) (n = 19, 26.8%), long biliopancreatic limb Roux-en-Y gastric bypass (long BPL RYGB) (n = 17, 23.9%), and re-sleeve gastrectomy (RSG) (n = 7, 9.9%). Indications were GERD (n = 24, 33.8%), IWL (n = 23, 32.4%), IWL + GERD (n = 22, 31.0%), or stenosis/kinking of the sleeve (n = 2, 2.8%). The mean pre-revisional body mass index (BMI) was 38.0 ± 7.5 kg/m2. The mean follow-up time after conversion was 5.1 ± 3.1 years. The overall percentage of total weight loss (%TWL) was greatest after BPD/DS (36.6%) and long BPL RYGB (32.9%) compared to RSG (20.0%; p = 0.004; p = 0.049). In case of GERD, conversion to Roux-en-Y gastric bypass (RYGB) led to a resolution of symptoms in 79.5%. 16.9% of patients underwent an additional revisional procedure. CONCLUSION: In the event of IWL after SG, conversion to BPD/DS provides a significant and sustainable additional WL. Conversion to RYGB leads to a reliable symptom control in patients suffering from GERD after SG.

Management of gallstone disease prior to and after metabolic surgery: a single-center observational study.

BACKGROUND: Rapid weight loss after bariatric surgery is a risk factor for gallstone formation. There are different strategies regarding its management in bariatric patients, including prophylactic cholecystectomy (CCE) in all patients, concomitant CCE only in symptomatic patients, or concomitant CCE in all patients with known gallstones. We present the safety and long-term results of the last concept. METHOD: Retrospective single-center analysis of a prospective database on perioperative and long-term results of patients with laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) over a 15-year period. The minimal follow-up was 24 months. Concomitant CCE was intended for all patients with gallstones detected by preoperative sonography. SETTING: Academic teaching hospital in Switzerland. RESULTS: After exclusion of patients with a history of CCE (11.5%), a total of 1174 patients (69.6% LRYGB, 30.4% LSG) were included in the final analysis. Preoperative gallbladder pathology was detected in 21.2% of patients, of whom 98.4%, or 20.9% of the total patients, received a concomitant CCE. The additional procedure prolonged the average operation time by 38 minutes (not significant) and did not increase the complication rate compared with bariatric procedure without CCE (3.7% versus 5.7%, P = .26). No complication was directly linked to the CCE. Postoperative symptomatic gallbladder disease was observed in 9.3% of patients (LRYGB 7.0% versus LSG 2.3%, P = .15), with 19.8% of those patients initially presenting with a complication. CONCLUSION: The concept of concomitant CCE in primary bariatric patients with gallstones was feasible and safe. Nevertheless, 9.3% of primary gallstone-free patients developed postoperative symptomatic gallbladder disease and required subsequent CCE despite routine ursodeoxycholic acid prophylaxis.

Long-term Effects of Laparoscopic Sleeve Gastrectomy: What Are the Results Beyond 10 Years?

PURPOSE: Laparoscopic sleeve gastrectomy (LSG) has become the most commonly performed bariatric procedure worldwide. Newer studies providing long-term follow-up show a high incidence of weight regain and a high incidence of reflux. The study's objective was to present 5 to 15-year follow-up results regarding weight loss, comorbidities, reoperation rate, and a potential learning curve. METHODS: This is a retrospective analysis of prospectively collected data. Patients who underwent LSG between August 2004 and December 2014 were included. RESULTS: A total of 307 patients underwent LSG either as a primary bariatric procedure (n = 262) or as a redo operation after failed laparoscopic gastric banding (n = 45). Mean body mass index at the time of primary LSG was 46.4 ± 8.0 kg/m2, and mean age at operation was 43.7 ± 12.4 years with 68% females. Follow-up was 84% and 70% at 5 and 10 years, respectively. The mean percentage excess body mass index loss (%EBMIL) for primary LSG was 62.8 ± 23.1% after 5 years, 53.6 ± 24.6% after 10 years, and 51.2 ± 20.3% after 13 years. Comorbidities improved considerably (e.g., type 2 diabetes mellitus 61%), while the incidence of new-onset reflux was 32.4%. Reoperation after LSG was necessary in almost every fifth LSG-patient: 24 patients (7.8%) were reoperated due to insufficient weight loss, 12 patients (3.9%) due to reflux, 23 due to both (7.5%). CONCLUSIONS: LSG provides a long-term %EBMIL from 51 to 54% beyond 10 years and a significant improvement of comorbidities. On the other hand, a high incidence of insufficient weight loss and de novo reflux was observed, leading to reoperation and conversion to a different anatomy in 19.2%.

Preoperative Cardiac Diagnostics in Bariatric Patients with Diabetes and Perioperative Morbidity: Results of a Cohort of 258 Patients.

PURPOSE: The combination of obesity and diabetes mellitus are well-known risk factors for cardiovascular complications and perioperative morbidity in metabolic surgery. The aim of this study was to evaluate effectivity and reliability of the cardiac assessment in patients with diabetes prior to bariatric surgery. SETTING: Private, university-affiliated teaching hospital, Switzerland MATERIAL AND METHODS: Retrospective analysis of prospectively collected data on results and consequences of cardiac assessments in 258 patients with obesity and diabetes scheduled for primary bariatric surgery at our institution between January 2010 and December 2018. RESULTS: Out of 258 patients, 246 (95.3%) received cardiac diagnostics: 173 (67.1%) underwent stress-rest myocardial perfusion scintigraphy (MPS), 15 (5.8%) patients had other cardiac imaging including cardiac catheterization, 58 (22.5%) patients had echocardiography and/or stress electrocardiography, and 12 (4.7%) patients received no cardiac evaluation. Subsequently, cardiac catheterization was performed in 28 patients (10.9%), and coronary heart disease was detected and treated in 15 subjects (5.8%). Of these 15 individuals, 5 (33.3%) patients had diffuse vascular sclerosis, 8 (53.3%) patients underwent coronary angioplasty and stenting, and 2 (13.3%) patients coronary artery bypass surgery. Bariatric surgery was performed without perioperative cardiovascular events in all 258 patients. CONCLUSION: Our data suggest that a detailed cardiac assessment is mandatory in bariatric patients with diabetes to identify those with yet unknown cardiovascular disease before performing bariatric surgery. We recommend carrying out myocardial perfusion scintigraphy as a reliable diagnostic tool in this vulnerable population. If not viable, stress echocardiography should be performed as a minimum.

Outcome of revisional bariatric surgery for insufficient weight loss after laparoscopic Roux-en-Y gastric bypass: an observational study.

BACKGROUND: Insufficient weight loss or secondary weight regain with or without recurrence of comorbidity can occur years after laparoscopic Roux en Y gastric bypass (LRYGB). In selected patients, increasing restriction or adding malabsorption may be a surgical option after conservative measures failed. OBJECTIVES: Evaluation of short and long term results of revisional surgery for insufficient weight loss or weight regain after LRYGB. SETTING: Tertiary hospital. METHODS: Retrospective analysis of prospectively collected data from a cohort of 1150 LRYGB patients. Included were patients, who underwent revisional bariatric surgery after LRYGB for insufficient weight loss with a follow-up of minimal 1 year. RESULTS: Fifty-four patients were included in the analysis. After an interdisciplinary evaluation, patients with insufficient weight loss, signs of dumping syndrome, and lacking restriction were offered a nonadjustable band around the pouch (banded group, n = 34) and patients with sufficient restriction, excellent compliance, and adherence were offered a revision to laparoscopic biliopancreatic diversion (BPD group, n = 20). The revisional procedure was performed 3.3 ± 2.3 years after LRYGB in the banded-group and after 6.4 ± 4.3 years in the BPD group (P = .001). Mean body mass index at the time of the primary bariatric procedure was 41.7 ± 6.2 kg/m2 in the banded group and 45.2 ± 8.2 kg/m2 in the BPD group (P = .08); minimal body mass index between both operations was 29.1 ± 4.7 kg/m2 in the banded group and 36.5 ± 9.4 kg/m2 in the BPD group, and, at the time of revisional surgery, 31.4 ± 5.5 kg/m2 in the banded group and 40.8 ± 6.7 kg/m2 in the BPD group (P = .0001). The mean body mass index difference 1 year after revisional surgery was 1.3 ± 3.0 kg/m2 in the banded group and 6.7 ± 4.5 kg/m2 in the BPD group (P = .01). In the banded group, 11 patients (32.4%) needed removal of the band, 4 patients (11.8%) needed an adjustment, and 4 patients (11.8%) were later converted to BPD. In the BPD group, 2 (10.0%) patients needed revision for severe protein malabsorption. CONCLUSIONS: Insufficient weight loss or secondary weight regain after LRYGB is a rare indication for revisional surgery. Banded bypass has modest results for additional weight loss but can help patients suffering from dumping. In very carefully selected cases, BPD can achieve additional weight loss with acceptable complication rate but higher risk for reoperation. Future "adjuvant medical treatments," such as glucagon-like peptide 1 analogues and other pharmacologic treatment options could be an alternative for achieving additional weight loss and better metabolic response.

Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine.

BACKGROUND: Dosage of T(4) in central hypothyroidism is primarily guided by the free serum T(4) level (fT4). However, the optimum fT4 range is ill defined, and subtle hypothyroidism might be missed using this approach. OBJECTIVES: Our aim was to investigate the effects of a body weight (bw)-adapted T(4) treatment, alone or in combination with T(3), on metabolism, well-being, and cognitive function in comparison to a regimen leading to normal fT4. DESIGN: This was a placebo-controlled trial (double-blind, crossover). PATIENTS: A total of 29 patients (age 52 +/- 2 yr; females/males, 8/21) with hypopituitarism, including TSH deficiency, participated in the study. INTERVENTIONS: Three regimens were compared (5 wk each): "EMPIRICAL-T4," empirical T(4) dosage (1 +/- 0.05 microg/kg bw) leading to normal fT4; BW-ADAPTED-T4 (1.6 microg/kg bw T(4)); and "BW-ADAPTED-T3T4," bw-adapted combination of T(3) and T(4) (ratio of 1:10). RESULTS: BW-ADAPTED-T4 administration increased mean fT4 concentrations to the upper limit of the normal range (peak levels). Compared with EMPIRICAL-T4, BW-ADAPTED-T4 treatment resulted in a lower body mass index (BMI) (29.0 +/- 0.7 vs. 29.5 +/- 0.7 kg/m(2); P < 0.03), lower total cholesterol (198 +/- 9 vs. 226 +/- 7 mg/dl; P < 0.01), and lower low-density lipoprotein (LDL) cholesterol (116 +/- 5 vs. 135 +/- 7 mg/dl; P < 0.01). BW-ADAPTED-T3T4 treatment was associated with additional beneficial effects on ankle reflex time and working memory but resulted in supraphysiological free serum T(3) (fT(3)) levels. LIMITATIONS: Long-term side effects may have been missed. CONCLUSIONS: Using a dose of 1.6 microg/kg bw improved markers commonly associated with central hypothyroidism. This suggests that T(4) dosage based on bw and aiming at fT4 in the upper reference range is superior to titration of T(4) aiming at middle normal fT4 concentrations in those patients.

Long-term outcome of laparoscopic adjustable gastric banding (LAGB): results of a Swiss single-center study of 405 patients with up to 18 years' follow-up.

BACKGROUND: In the past, laparoscopic adjustable gastric banding (LAGB) seemed to be a promising bariatric procedure. However, many studies showed high rates of reoperation due to complications or insufficient weight loss. There is a lack of long-term studies with follow-up beyond 15 years. OBJECTIVE: To conduct long-term follow-up of patients after LAGB and analyze their weight loss as a primary endpoint. SETTING: Tertiary referral center for bariatric surgery, St. Claraspital, Switzerland. METHODS: A retrospective analysis of prospectively collected clinical data in a cohort of 405 patients having undergone LAGB was performed. RESULTS: A total of 405 patients (age 41±10 years, body mass index [BMI] 44.3±6 kg/m2) were treated with LAGB between 1996 and 2010. Mean follow-up was 13±3 years, with a follow-up rate of 85% (range 8-18 years), corresponding to 343 patients. One hundred patients exceeded 15-year follow-up. In 216 patients (63%), sleeve gastrectomy, gastric bypass, or biliopancreatic diversion with duodenal switch was performed as revisional surgery. Twenty-seven patients (8%) refused revisional surgery after band removal. Finally, 100 patients (29%) still have the band in place, with a mean BMI of 35±7 kg/m2, corresponding to an excess BMI loss of 48±27%. Among these, the failure rate was 25%, according to the Bariatric Analysis and Reporting Outcome System (BAROS); 50% had a good to excellent outcome. CONCLUSION: More than 10 years after LAGB, 71% of patients lost their bands and only 15% of the 343 followed patients with the band in place have a good to excellent result, according to BAROS.

Lipotoxicity, overnutrition and energy metabolism in aging.

The safest place to store lipids is the white adipose tissue, but its storage capacity may become saturated resulting in excess of fat "overspilled" to non-adipose tissues. This overspill of fat occurs in apparently opposite pathological states such as lipodistrophy or obesity. When the excess of energy is redirected towards peripheral organs, their initial response is to facilitate the storage of the surplus in the form of triacylglycerol, but the limited triacylglycerol buffer capacity becomes saturated soon. Under these conditions excess of lipids enter alternative non-oxidative pathways that result in production of toxic reactive lipid species that induce organ-specific toxic responses leading to apoptosis. Reactive lipids can accumulate in non-adipose tissues of metabolically relevant organs such as pancreatic beta-cells, liver, heart and skeletal muscle leading to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. The effects of this lipotoxic insult can be minimised by several strategies: (a) decreased incorporation of energy, (b) a less orthodox approach such as increased adipose tissue expandability and/or (c) increased oxidation of fat in peripheral organs. Aging should be considered as physiological degenerative process potentially accelerated by concomitant lipotoxic insults. Conversely, the process of aging can sensitise cells to effects of lipid toxicity.

Gonadectomy in mice of the inbred strain CE/J induces proliferation of sub-capsular adrenal cells expressing gonadal marker genes.

Mouse models of adrenal tumorigenesis have the potential to give insights in the dysregulation of adrenal growth and differentiation. The inbred mouse strain CE/J has been reported to develop adrenal tumors upon gonadectomy (GDX) similar to mice with targeted deletions of the inhibin alpha subunit (Inh-/-). We performed a detailed morphological and molecular characterization of adrenal glands from CE/J mice 8-50 weeks of age to define the cellular origin of these tumors as well as the spatial and temporal expression of marker genes associated with tumor growth. In contrast to the induction of x-zone growth upon GDX in Inh-/- mice, GDX in CE/J mice induced the appearance of sub-capsular nests of densely packed cells that progress into adrenal tumors. Staining for proliferative cell nuclear antigen confirms a substantial increased in cellular proliferation within this sub-capsular compartment and lack of apoptosis upon GDX. Induction of adrenal tumor growth was accompanied by transcriptional changes that otherwise define gonadal endocrine cells. These regulated genes included transcription factors such as GATA-4, WT-1, FOG-1, and steroidogenic factor-1 (SF-1), peptide hormones such as Mullerian-inhibiting substance (MIS), hormone receptors including luteinizing hormone and MIS receptor, and steroidogenic enzymes such as P450c17 and P450 aromatase. The functional significance of steroid enzyme expression was demonstrated by a gradual increase of adrenal androgens after GDX. Taken together these data suggest that adrenal tumors in gonad-ectomized CE/J mice are direct derivatives from cells of the proposed sub-capsular stem cell zone. The distinct expression pattern of this cell population is consistent with a defect in the differentiation of these cells into a cell population with functional properties that otherwise define a gonadal endocrine phenotype.

Laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass lead to equal changes in body composition and energy metabolism 17 months postoperatively: a prospective randomized trial.

BACKGROUND: Weight loss is the sum of fat and lean mass loss. The aim of this study was to examine whether there are differences between 2 surgical procedures, laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB), in terms of their effect on body composition and energy metabolism. In addition, the predictive value of preoperative body composition and energy metabolism on postoperative outcome was evaluated. SETTING: All procedures were performed by the same surgeon (RP) at the St. Claraspital Basel in Switzerland. Calorimetry and DEXA were carried out at the same institution (Interdisciplinary Center of Nutritional and Metabolic Diseases, St. Claraspital Basel). METHODS: Forty-two morbidly obese, mainly female (85%), nondiabetic and diabetic (50%) patients (body mass index [BMI]: 43.9 kg/m(2)±1.3) before and 17±5.6 months after LSG (n = 23) and LRYGB (n = 19) were examined. Body composition was analyzed by dual-energy X-ray absorptiometry (DEXA) and resting energy expenditure (REE); fat and carbohydrate oxidation was determined by indirect calorimetry. RESULTS: Follow-up was 100%. Excessive BMI loss (EBMIL) was 64.4% in the LSG group and 76.4% in the LRYGB group (P<.046). In both groups total fat and muscle mass decreased significantly compared with baseline (P<.001) and the percentage of muscle mass per kilogram of weight increased postoperatively (results not significant). REE decreased (P<.001) and REE per kilogram of weight increased significantly (P<.003) compared with baseline. Carbohydrate oxidation remained stable in both groups, and fat oxidation decreased significantly (P<.001) compared with baseline. In diabetic patients compared with nondiabetic patients there were no statistically significant differences in REE, substrate oxidation, or reduction in truncal fat. Postoperatively, lean mass was higher in diabetic patients (P = .037). Preoperative indirect calorimetry and DEXA results were of no predictive value for outcome. CONCLUSION: Changes in REE and body composition were equal after both procedures in a bariatric population mainly consisting of women. No predictors for amount of weight loss could be found.

Genetic influence of an ACTH receptor promoter polymorphism on adrenal androgen secretion.

OBJECTIVE: Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating secretion of adrenal androgens (AA). Yet, genetic and environmental factors are assumed to play a determining role in the regulation of their biosynthesis and thus might explain the high variability of AA levels. Here we investigate the influence of an ACTH receptor promoter polymorphism affecting ACTH receptor gene transcription on ACTH-dependent dehydroepiandrosterone (DHEA) secretion. DESIGN: We recently reported a polymorphism within the transcription initiation site of the ACTH receptor gene promoter that alters the consensus sequence from CTC to CCC at -2 bp. This results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. We now studied 14 normal, lean volunteers aged 20-35 years (eight CTC/CTC and six CCC/CCC carriers) in a 6-h ACTH stimulation test. METHODS: After overnight dexamethasone suppression, ACTH1-24 was administered continuously in each subject with hourly increasing doses (120-3840 ng/m2 body surface area/h) within a 6-h period. On a separate day, baseline DHEA samples were collected. RESULTS: In the 6-h ACTH stimulation test, CTC/CTC carriers showed a significantly higher DHEA response than CCC/CCC carriers (area under the curve: 19 367 +/- 2919 vs 11 098 +/- 1241 nmol/l per min; P < 0.04, Mann-Whitney U-test). In contrast, baseline DHEA concentrations did not differ between groups. CONCLUSION: These data demonstrate that genetic variations within the ACTH receptor promoter result in decreased DHEA secretion. Thus, we might have identified one of the genetic factors responsible for variation in ACTH-dependent DHEA secretion.

A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males.

A novel delivery system has been developed for testosterone replacement. This formulation, COL-1621 (Striant), a testosterone-containing buccal mucoadhesive system, has been shown in preliminary studies to replace testosterone at physiological levels when used twice daily. Therefore, the current study compared the steady-state pharmacokinetics and tolerability of the buccal system with a testosterone-containing skin patch (Andropatch or Androderm) in an international multicenter study of a group of hypogonadal men. Sixty-six patients were randomized into two groups; one applied the buccal system twice daily, whereas the other applied the transdermal patch daily, in each case for 7 d. Serum total testosterone and dihydrotestosterone concentrations were measured at d 1, 3 or 4, and 6, and serially over the last 24 h of the study. Pharmacokinetic parameters for each formulation were calculated, and the two groups were compared. The tolerability of both formulations was also evaluated. Thirty-three patients were treated with the buccal preparation, and 34 were treated with the transdermal patch. The average serum testosterone concentration over 24 h showed a mean of 18.74 nmol/liter (SD =; 5.90) in the buccal system group and 12.15 nmol/liter (SD =; 5.55) in the transdermal patch group (P < 0.01). Of the patients treated with the buccal system, 97% had average steady-state testosterone concentrations within the physiological range (10.41-36.44 nmol/liter), whereas only 56% of the transdermal patch patients achieved physiological total testosterone concentrations (P < 0.001 between groups). Testosterone concentrations were within the physiological range in the buccal system group for a significantly greater portion of the 24-h treatment period than in the transdermal patch group (mean, 84.9% vs. 54.9%; P < 0.001). Testosterone/dihydrotestosterone ratios were physiological and similar in both groups. Few patients experienced major adverse effects from either treatment. No significant local tolerability problems were noted with the buccal system, other than a single patient withdrawal. We conclude that this buccal system is superior to the transdermal patch in achieving testosterone concentrations within the normal range. It may, therefore, be a valuable addition to the range of choices for testosterone replacement therapy.

Characterization of an adrenocorticotropin (ACTH) receptor promoter polymorphism leading to decreased adrenal responsiveness to ACTH.

The ACTH receptor has a pivotal role in the regulation of adrenal cortisol secretion. Here, we describe a polymorphism within the transcription initiation site of the ACTH receptor promoter altering the consensus sequence from CTC to CCC. The prevalence of the polymorphism in 1266 unrelated healthy men was 80.2% for CTC/CTC, 19.0% for CTC/CCC, and 0.8% for CCC/CCC, respectively. In vitro studies using luciferase assays demonstrated a lower basal (CCC, 73 +/- 4%; CTC, 100 +/- 5%; P = 0.02) and forskolin-stimulated (CCC, 143 +/- 13%; CTC, 194 +/- 15%; P = 0.0008) promoter activity in the CCC construct compared with CTC. The clinical significance of the in vitro findings was investigated by a 6-h ACTH stimulation test with increasing ACTH(1-24) doses in normal subjects, demonstrating a blunted cortisol response in CCC/CCC subjects compared with CTC/CTC individuals (area under the curve, 12176 +/- 966; 16334 +/- 1051 nmol/liter.min; P < 0.03). Accordingly, after CRH stimulation, subjects with CCC/CCC showed a higher ACTH/cortisol ratio (P < 0.05) suggesting a decreased adrenal responsiveness to endogenous ACTH. In conclusion, we describe an ACTH receptor promoter polymorphism that results in a lower promoter activity in vitro and is associated with a lower cortisol secretion to prolonged ACTH stimulation in vivo. This polymorphism might influence cortisol homeostasis under stress conditions.

Diagnosis of primary aldosteronism: value of different screening parameters and influence of antihypertensive medication.

OBJECTIVE: The aim of this study was to investigate the utility of different screening techniques for primary aldosteronism (PA), including serum aldosterone (SA), plasma renin activity (PRA) and the SA/PRA ratio in hypertensive patients of a tertiary-care centre. Furthermore, the influence of antihypertensive medication on SA and the SA/PRA ratio were studied. DESIGN: Clinical records of 425 hypertensive patients who had SA and PRA measurements over a 27-month period were analysed retrospectively. Eighty patients were excluded from further analysis because of incomplete data. The remaining 345 patients were classified into the following groups: patients with essential hypertension (EH) (n=260, 75.4%), patients with PA (n=49, 14.2%) and patients with secondary hypertension other than PA (n=36, 10.4%). Diagnosis of PA was made in accordance with established laboratory criteria (including measurements of SA, PRA, urinary excretion of aldosterone and metabolites, imaging techniques and response to treatment). RESULTS: Although mean serum potassium values were significantly lower (P<0.001) in the PA group compared with the EH group, 61% of PA subjects were normokalaemic (3.4-5.2 mmol/l). The SA/PRA ratio alone identified 94% of the patients with PA, but was false positive in 30% of the patients with EH. The SA/PRA ratio together with SA>150 g/ml increased the diagnostic accuracy, led to the correct identification of 84% of the patients with PA, and decreased the false-positive rate to 3%. A multivariate binary logistic regression analysis based on SA and PRA was performed, which identified PA with 90% sensitivity and 91% accuracy. The SA(2)/PRA or the SA(3)/PRA ratio was found useful for simplification of the regression analysis. Antihypertensive medication influenced SA, PRA and the SA/PRA ratio only in EH patients. In EH patients taking beta-adrenoceptor antagonists PRA tended to be lower, leading to a significantly higher SA/PRA ratio and therefore increasing the false-negative rate. CONCLUSION: To reduce false-positive results in screening for PA, and thereby avoid unnecessary and cost-intensive diagnostic procedures, SA should be taken into account in addition to the SA/PRA ratio as a second screening criterion. Alternatively, the SA(2)/PRA or the SA(3)/PRA ratio is more accurate screening tests than the SA/PRA ratio. Beta-blockers should be avoided whilst screening for PA.

Five-year results of laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is gaining popularity, but studies reporting long-term results are still rare. The objective of this study was to present the 5-year outcome concerning weight loss, modification of co-morbidities, and late complications. METHODS: This is a retrospective analysis of a prospective cohort with a minimal follow-up of 5 years. A total of 68 patients underwent LSG either as primary bariatric procedure (n = 41) or as redo operation after failed laparoscopic gastric banding (n = 27) between August 2004 and December 2007. At the time of LSG, the mean body mass index (BMI) was 43.0 ± 8.0 kg/m(2), the mean age 43.1 ± 10.1 years, and 78% were female. The follow-up rate was 100% at 1 year postoperatively, 97% after 2 years, and 91% after 5 years; the mean follow-up time was 5.9 ± 0.8 years. RESULTS: The average excessive BMI loss was 61.5% ± 23.4% after 1 year, 61.1% ± 23.4% after 2 years, and 57.4% ± 24.7% after 5 years. Co-morbidities improved considerably; a remission of type 2 diabetes could be reached at 85%. The following complications were observed: 1 leak (1.5%), 2 incisional hernias (2.9%), and new-onset gastroesophageal reflux in 11 patients (16.2%). Reoperation due to insufficient weight loss was necessary in 8 patients (11.8%). CONCLUSIONS: LSG was effective 5.9 years postoperatively with an excessive BMI loss of almost 60% and a considerable improvement or even remission of co-morbidities.

Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature.

CONTEXT: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. OBJECTIVE: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. MAIN OUTCOME MEASURES: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. RESULTS: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. CONCLUSIONS: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.