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Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pval likelihood ratio test (L RT ) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pval LRT  = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition., Competing Interests: Declaration of Interests M.Y.D. is listed as an inventor on a patent submitted by University Hospital Basel covering the use of SGLT-2 inhibitors or IL-1R antagonists for reduction of hypoglycemia after bariatric surgery (EP19151525.3). All others declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction/background: Atherosclerosis is an inflammatory disorder in which several converging immune responses modulate and induce lipid accumulation in macrophages. Activated leukocyte cell adhesion molecule (ALCAM) has been described as a structural homologue of HDL-receptor and functions as a pattern recognition receptor (PRR), while its soluble form sALCAM is involved in ALCAM-dependent and -independent immune mechanisms. The aim of this study was to investigate the effect of aggressive removal of low density lipoprotein-cholesterol (LDL-C) and lipoprotein(a) (Lp [a]) by lipoprotein-apheresis (LA) on sALCAM and blood viscosity as well as to evaluate its association with lipoproteins and serum markers of inflammation., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Assessment of the impact of type 2 diabetes (T2DM) and metformin use on vitamin B12 (VB12) associated biomarkers and their suitability to represent VB12 supply., Methods: Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction  (%AB12)=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with (DMMet+ ) and without metformin use (DMMet-) and ii) in comparison to an external non-diabetic reference group with low VB12 (<200 pmol/L)., Results: VB12 associated biomarkers were distributed equally between DMMet+  (n=29, 58%) and DMMet- (n=21, 42%). Significant differences in %AB12 in diabetic patients with low VB12 (n=19) compared to the non-diabetic reference group (n=31) were found. Higher %AB12 was associated with diabetes. Hcy levels were significantly associated with age, folic acid level, renal function and HoloTc but not with VB12., Conclusions: In T2DM patients with low VB12, %AB12 was confirmed as being higher in comparison to nondiabetic patients. The effect was not clearly attributable to metformin use. HoloTc was unaffected by the lowering of VB12 and significantly associated with the functional marker Hcy. Both findings support the use of HoloTc for the assessment of VB12 supply in diabetic patients., Competing Interests: The authors declare no conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To evaluate the occurrence of urogynecological symptoms in obese women treated in a university outpatient clinic for obesity, setting a focus on younger women., Methods: In this explorative, prospective, cross-sectional, single-center, multidisciplinary clinical trial, all consecutively recruited women received the Prolapse Quality of Life questionnaire (P-QOL) for data acquisition. The total study population (TSP) and a subgroup (SG) aged 18-49 years were evaluated descriptively regarding symptom demonstration., Results: Of the TSP (n = 166, mean age 40.2, standard deviation (SD) 12.98, mean body mass index (BMI) 45 kg/m 2 , SD 8.44) 105 (63%) and of the SG (n = 125, mean age 34.6, SD 9.29, mean BMI 44.9 kg/m 2 , SD 8.26) 72 (58%) women suffered from urinary incontinence (UI) being most impaired by stress urinary incontinence (SUI; TSP: 25%; SG: 27%) and least by urge urinary incontinence (UUI; TSP: 15%; SG: 11%). A significant correlation in the TSP between UI and age was detectable (p < 0.001, r φ  = 0.37), but not between UI and BMI (p = 0.296, r φ  = 0.08). The highest QOL impairment is detected for the domain general health perceptions [GHP; TSP & SG score >50 (score scale 0-100)]. Women with UI are significantly more affected than women with pelvic organ prolapse (GHP UI: TSP p = 0.04, SG p = 0.037; GHP POP: TSP p = 0.081, SG p = 0.659)., Conclusions: A remarkable number of young obese women mentioned urogynecological symptoms and quality-of-life impairment. The P-QOL questionnaire proved to be an easily applicable tool to scan for concerned obese women. Its use in non-urogynecological departments, as performed, enables an early introduction of symptomatic women to urogynecologists, possibly preventing future growing urogynecological health issues.

Background: The aim of this study was to investigate the effect of a lifestyle intervention in obesity on the soluble form of the activated leukocyte cell adhesion molecule (sALCAM) and its association with metabolic parameters., Methods: Twenty-nine obese subjects selected from the OPTIFAST®52 program. This program consisted into 2 crucial phases: an initial 12-week active weight reduction phase, followed by a 40-week weight maintenance phase. At baseline, after 12 weeks and at the end of the program, fasting glucose and insulin, total cholesterol, LDL-C, HDL-C, triglycerides, adiponectin, leptin, high sensitivity CRP, sALCAM, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and leptin-to-adiponectin-ratio were determined. Oral glucose tolerance test (OGTT) was performed when indicated., Results: At baseline, the serum concentration of sALCAM was increased and correlated positively with HOMA-IR and negatively with age. At the end of the program, sALCAM concentrations decreased significantly. Multivariate analysis showed that sALCAM significantly correlated with age, glucose concentration after 2 h OGTT and the HOMA-IR. A higher decrease of HOMA-IR during the study was observed in subjects with higher concentration of sALCAM at baseline., Conclusions: sALCAM might be a novel biomarker in obesity that correlates and predicts insulin sensitivity improvement and that can be affected by lifestyle intervention.

Objective: The aim of the study was to investigate the characteristics of the awakening salivary cortisol in patients with anorexia nervosa (AN) using a time series design. We included ten AN inpatients, six with a very low BMI (high symptom severity, HSS group) and four patients with less severe symptoms (low symptom severity, LSS group)., Methods: Patients collected salivary cortisol daily upon awakening. The number of collected saliva samples varied across patients between n=65 and n=229 (due to the different lengths of their inpatient stay). In addition, before retiring, the patients answered questions daily on the handheld regarding disorder-related psychosocial variables. The analysis of cortisol and diary data was conducted by using a time series approach., Results: Time series showed that the awakening cortisol of the AN patients was elevated as compared to a control group. Cortisol measurements of patients with LSS essentially fluctuated in a stationary manner around a constant mean. The series of patients with HSS were generally less stable; four HSS patients showed a non-stationary cortisol awakening series. Antipsychotic medication did not change awakening cortisol in a specific way. The lagged dependencies between cortisol and depressive feelings became significant for four patients. Here, higher cortisol values were temporally associated with higher values of depressive feelings., Conclusions: Upon awakening, the cortisol of all AN patients was in the standard range but elevated as compared to healthy controls. Patients with HSS appeared to show less stable awakening cortisol time series compared to patients with LSS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Low inhibitory control and strong hedonic response towards food are considered to contribute to overeating and obesity. Based on previous research, the present study aimed at examining the potentially crucial interplay between these two factors in terms of long-term weight loss in people with obesity., Methods: BMI, inhibitory control towards food, and food liking were assessed in obese adults prior to a weight reduction programme (OPTIFAST® 52). After the weight reduction phase (week 13) and the weight loss maintenance phase (week 52), participants' BMI was re-assessed., Results: Baseline BMI, inhibitory control and food liking alone did not predict weight loss. As hypothesised, however, inhibitory control and food liking interactively predicted weight loss from baseline to week 13 and to week 52 (albeit the latter effect was less robust). Participants with low inhibitory control and marked food liking were less successful in weight reduction., Conclusion: These findings underscore the relevance of the interplay between cognitive control and food reward valuation in the maintenance of obesity., (© 2016 The Author(s) Published by S. Karger GmbH, Freiburg.)

Objective: To evaluate the effect of onsite screening with a nonmydriatic, digital fundus camera for diabetic retinopathy (DR) at a diabetes outpatient clinic., Research Design and Methods: This cross-sectional study included 502 patients, 112 with type 1 and 390 with type 2 diabetes. Patients attended screenings for microvascular complications, including diabetic nephropathy (DN), diabetic polyneuropathy (DP), and DR. Single-field retinal imaging with a digital, nonmydriatic fundus camera was used to assess DR. Prevalence and incidence of microvascular complications were analyzed and the ratio of newly diagnosed to preexisting complications for all entities was calculated in order to differentiate natural progress from missed DRs., Results: For both types of diabetes, prevalence of DR was 25.0% (n = 126) and incidence 6.4% (n = 32) (T1DM versus T2DM: prevalence: 35.7% versus 22.1%, incidence 5.4% versus 6.7%). 25.4% of all DRs were newly diagnosed. Furthermore, the ratio of newly diagnosed to preexisting DR was higher than those for DN (p = 0.12) and DP (p = 0.03) representing at least 13 patients with missed DR., Conclusions: The results indicate that implementing nonmydriatic, digital fundus imaging in a diabetes outpatient clinic can contribute to improved early diagnosis of diabetic retinopathy.

There are many known adipokines differentially secreted from the different adipose depots; however, their paracrine and autocrine effects on de novo adipocyte formation are not fully understood. By developing a coculture method of preadipocytes with primary subcutaneous and visceral adipocytes or tissue explants, we could show that the total secretome inhibited preadipocyte differentiation. Using a proteomics approach with fractionated secretome samples, we were able to identify a spectrum of factors that either positively or negatively affected adipocyte formation. Among the secreted factors, Slc27a1, Vim, Cp, and Ecm1 promoted adipocyte differentiation, whereas Got2, Cpq, interleukin-1 receptor-like 1/ST2-IL-33, Sparc, and Lgals3bp decreased adipocyte differentiation. In human subcutaneous adipocytes of lean subjects, obese subjects, and obese subjects with type 2 diabetes, Vim and Slc27a1 expression was negatively correlated with adipocyte size and BMI and positively correlated with insulin sensitivity, while Sparc and Got2 showed the opposite trend. Furthermore, we demonstrate that Slc27a1 was increased upon weight loss in morbidly obese patients, while Sparc expression was reduced. Taken together, our findings identify adipokines that regulate adipocyte differentiation through positive or negative paracrine and autocrine feedback loop mechanisms, which could potentially affect whole-body energy metabolism., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: For severely obese patients, bariatric surgery has been recommended as an effective therapy., Objectives: The Bariataric Surgery and Education (BaSE) study aimed to assess the efficacy of a videoconferencing-based psychoeducational group intervention in patients after bariatric surgery., Setting: The BaSE study is a randomized, controlled multicenter clinical trial involving 117 patients undergoing bariatric surgery (mean preoperative body mass index [BMI] 49.9 kg/m(2), SD 6.4). Patients were enrolled between May 2009 and November 2012 and were randomly assigned to receive either conventional postsurgical visits or, in addition, a videoconferencing-based 1-year group program., Methods: Primary outcome measures were weight in kilograms, health-related quality of life (HRQOL), and general self-efficacy (GSE). Secondary outcome measures were depression symptoms and eating behavior., Results: 94% of the patients completed the study. Mean weight loss for all patients was 45.9 kg (SD 16.4) 1 year after surgery (mean excess weight loss [EWL] 63%). Intention-to-treat analyses revealed no differences in weight loss, EWL, HRQOL, or self-efficacy between study groups at 1 year after surgery. However, patients with clinically significant depression symptoms (CSD) at baseline assigned to the intervention group (n = 29) had a significantly better HRQOL (P = .03), lower depression scores (P = .02), and a trend for a better EWL (.06) 1 year after surgery compared with the control group (n = 20)., Conclusion: We could not prove the efficacy of the group program for the whole study sample. However, results indicate that the intervention is effective for the important subgroup of patients with CSD., (Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Surgical management of renal secondary hyperparathyroidism (sHPT) is varying. Total parathyroidectomy with heterotopic autotransplantation (TPTX + AT) is one of the standard surgical procedures in sHPT, but there is no consensus about the optimal site for graft insertion. At the surgical department of the University Hospital of Heidelberg we prefer the autotransplantation into the tibialis anterior muscle. The aim of this study was to assess the long-term function of the auto-transplanted parathyroid tissue in this type of surgical procedure., Methods: The function of the autograft of 42 patients was assessed 8.2 ± 2.5 years after surgery, using a modified Casanova-test of the leg bearing the parathyroid tissue. Ischemic blockage was induced by tourniquet and the levels of parathyroid hormone (PTH) were assessed during the test., Results: At the point of assessment, the ischemic blockage led to a significant reduction in the concentration of PTH (≥50% of the baseline value) in 19 patients (45%) indicating well-functioning autografts. In 11 patients (26%), ischemic blockage did not cause any change in the concentration of PTH (≤20% of the baseline value), indicating functioning residual parathyroid tissue from another site. The source of PTH production was classified as unidentifiable in five patients (12%). Two patients had developed graft-dependent recurrent HPT (5%) without therapeutic consequences and three patients suffered from persistent symptomatic hypoparathyroidism (7%)., Conclusions: These results indicate that TPTX + AT into the tibialis anterior muscle is a successful surgical treatment for renal HPT and that the modified Casanova-test is a suitable diagnostic tool for autografts function.

Background: Predicting an individual's success in a non-surgical weight loss approach is a demanding need since obesity is becoming an epidemic burden. A possible predictive marker is myostatin, a member of the transforming growth factor b superfamily, which has been shown to be an important regulator of muscle homeostasis., Methods: In the present study, we analyzed myostatin as a marker to predict weight loss of patients that participated in a 2 phased weight reduction program, comprising a weight loss period of 12 weeks and a weight stabilization period of 40 weeks. Therefore, 62 obese individuals with a mean BMI of 40.6 kg/m(2) were included. Plasma myostatin was measured with ELISA at the beginning (T0), after weight loss (T1) and at the end of the program (T2)., Results: Although significant weight loss of -23.9±14.9 kg was achieved, myostatin did not change significantly during the program (T0>T1: p=0.46; T1>T2: p=0.70; T0>T2: p=0.57). Myostatin at baseline did neither negatively correlate with the achieved weight loss in the weight reduction phase (T0>T1: r=0.27, p=0.16) nor with weight loss during the whole program (T0>T2: r=0.20, p=0.29). Only a minor correlation with myostatin levels after weight loss with weight regain during maintenance period was detected. (T1>T2: r=-0.37, p=0.05)., Conclusion: Plasma myostatin might be suitable in predicting weight regain after marked weight loss, but no association with weight loss was observed in patients undergoing a non-surgical weight loss program. Therefore, myostatin does not seem to be a predictor for success in non-surgical weight loss approaches., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal., Methods: We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts., Results: Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted., Conclusions: Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.

The experience of stigmatization is widespread among obese patients. The aim of the present study was to translate the English version of the weight self-stigma questionnaire (WSSQ) into German and to evaluate the psychometric properties of the German version in a sample of severely obese persons. Between March and June 2013, in the Outpatient Department of Obesity, University Hospital Heidelberg, 94 obese patients were recruited consecutively. A comprehensive questionnaire was completed by the participants. Significant correlations between WSSQ scores and mental quality of life, weight-related quality of life, depression, shame, guilt, and psychological distress all demonstrated the construct validity of the German version of the WSSQ. Patients with a BMI ≥ 50 showed a significantly higher self-stigma compared to patients with a BMI between 35 and 50.

Background/objectives: This study addressed the question whether the composition of supposedly 'healthy' or 'unhealthy' dietary regimes has a calorie-independent short-term effect on biomarkers of metabolic stress and vascular risk in healthy individuals., Subjects/methods: Healthy male volunteers (age 29.5 ± 5.9 years, n = 39) were given a standardized baseline diet for two weeks before randomization into three groups of different dietary regimes: fast food, Mediterranean and German cooking style. Importantly, the amount of calories consumed per day was identical in all three groups. Blood samples were analyzed for biomarkers of cardiovascular risk and metabolic stress after two weeks of the baseline diet and after two weeks of the assigned dietary regime., Results: No dietary intervention affected the metabolic or cardiovascular risk profile when compared in-between groups or compared to baseline. Subjects applied to the Mediterranean diet showed a statistically significant increase of uric acid compared to baseline and compared to the German diet group. Plasma concentrations of urea were significantly higher in both the fast food group and the Mediterranean group, when compared to baseline and compared to the German diet group. No significant differences were detected for the levels of vitamins, trace elements or metabolic stress markers (8-hydroxy-2-deoxyguanosine, malondialdehyde and methylglyoxal, a potent glycating agent). Established parameters of vascular risk (e.g. LDL-cholesterol, lipoprotein(a), homocysteine) were not significantly changed in-between groups or compared to baseline during the intervention period., Conclusions: The calorie-controlled dietary intervention caused neither protective nor harmful short-term effects regarding established biomarkers of vascular or metabolic risk. When avoiding the noxious effects of overfeeding, healthy individuals can possess the metabolic capacity to compensate for a potentially disadvantageous composition of a certain diet.

The aim of this study was to examine the features and changes of the cortisol awakening response (CAR) in patients with anorexia nervosa (AN) with severe and less severe symptoms over the course of inpatient treatment. Our study included n=20 AN patients who received treatment at the University Hospital, Heidelberg. N=11 patients were admitted at a psychosomatic and internal-medicine ward that specialized in the treatment of AN patients with a very low BMI (patient group with high symptom severity, HSS). The mean BMI of these patients was 13.2 kg/m(2) (SD=1.4) at the beginning of the study and 16.9 kg/m(2) (SD=1.7) at the end. N=9 patients were treated at a psychotherapeutic ward where AN patients with less severe symptoms are admitted (patient group with low symptom severity, LSS). The mean BMI of these latter patients was 16.3 kg/m(2) (SD=0.89) at the beginning of the study and 17.1 kg/m(2) (SD=0.65) at the end. Salivary cortisol was measured on two consecutive days respectively, both at the beginning and the end of the study. At the beginning of the study, patients with HSS had a significantly lower mean CAR compared to patients from the LSS group (3.4 nmol/l vs. 11.4 nmol/l). At the end of the study, the mean CAR of patients from the HSS group was still significantly lower compared to the mean CAR of patients with LSS (2.0 nmol/l vs. 9.2 nmol/l). Results indicate that AN patients with severe symptoms exhibit a lower CAR compared to AN patients with less severe symptoms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: This study assessed the effect of providing an enhanced medication plan (EMP) to patients during patient-physician conversation at hospital discharge and evaluated its immediate impact on patient knowledge on pharmacotherapy., Methods: We observed patient-physician conversations at hospital discharge in three internal medicine wards of the University Hospital Heidelberg before and after the EMP was integrated into the discharge process, and documented how and to what extent physicians provided the patients with drug information. After the conversation, the patients' knowledge was evaluated by three standardized questions about their pharmacotherapy., Results: We observed 90 conversations (50 before EMP-implementation, 40 after). In both phases, the conversation duration was 5.6-6 min (p = 0.56). However, the time spent on drug information increased significantly by 61.7% after EMP-implementation (+63 s, p = 0.02). Before implementation, physicians gave at least one drug administration recommendation for 75.1% of all drugs, compared to 84.6% after implementation (p = 0.02). The EMP provided information for almost all drugs (98.9%; p < 0.01) after implementation. Three times more patients answered all questions correctly after EMP-implementation (p < 0.01)., Conclusion: The provision of an EMP improves information transfer and therefore increases the patients' knowledge of their individual drug treatment without prolonging the overall discharge process.

Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation.

Background: It is estimated that approximately 1 million adults in Germany suffer from grade III obesity. The aim of this article is to describe the challenges faced when constructing an operative obesity center., Methods: The inflow of patients as well as personnel and infrastructure of the interdisciplinary Diabetes and Obesity Center in Heidelberg were analyzed. The distribution of continuous data was described by mean values and standard deviation and analyzed using variance analysis., Results: The interdisciplinary Diabetes and Obesity Center in Heidelberg was founded in 2006 and offers conservative therapeutic treatment and all currently available operative procedures. For every operative intervention carried out an average of 1.7 expert reports and 0.3 counter expertises were necessary. The time period from the initial presentation of patients in the department of surgery to an operation was on average 12.8 months (standard deviation SD ± 4.5 months). The 47 patients for whom remuneration for treatment was initially refused had an average body mass index (BMI) of 49.2 kg/m(2) and of these 39 had at least the necessity for treatment of a comorbidity. Of the 45 patients for whom the reason for the refusal of treatment costs was given as a lack of conservative treatment, 30 had undertaken a medically supervised attempt at losing weight over at least 6 months. Additionally, 19 of these patients could document participation in a course at a rehabilitation center, a Xenical® or Reduktil® therapy or had undertaken the Optifast® program. For the 20 patients who supposedly lacked a psychosomatic evaluation, an adequate psychosomatic evaluation was carried out in all cases., Conclusions: The establishment of an operative obesity center can last for several years. A essential prerequisite for success seems to be the constructive and targeted cooperation with the health insurance companies.

Theoretical models consider difficulties in emotion regulation (ER) as central trans-diagnostic phenomena across the spectrum of eating disorders (ED). However, there is a lack of studies directly comparing ED subtypes regarding ER problems. Furthermore, patients with anorexia nervosa-restricting type (AN-R) and patients with AN-binge/purge type (AN-BP) have usually been merged into one overall AN group in previous research on ER. In order to overcome these limitations of previous studies, the present study investigated specific ER difficulties in 120 patients with different ED subtypes, including AN-R, AN-BP, bulimia nervosa (BN), and binge-eating disorder (BED). As compared to 60 healthy normal-weight controls (NWC) and 29 healthy over-weight controls (OWC), all ED subtypes reported greater difficulties in ER. ED subtypes did not differ regarding most domains of ER except BED showing less severe ER difficulties in some domains. In addition, AN-BP but not BN reported greater impulse control difficulties than AN-R and BED. The findings underscore the relevance of ER difficulties in ED and support the trans-diagnostic view of ER difficulties being present across the whole spectrum of ED. In addition, the present results suggest that certain domains of ER may be linked more closely to certain ED subtypes than to others., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is not sufficient to avoid CAD in diabetes. Alternative views suggest that metabolic and vascular diseases share unifying cellular defects that could serve as targets for novel therapeutic strategies. Recently, a variant [single-nucleotide polymorphism (SNP); rs11212617] near the gene for ataxia telangiectasia mutated (ATM) has been associated with glycaemic response to metformin., Materials and Methods: We determined rs11212617 in 240 male patients who underwent elective coronary angiography., Results: While the variant was not associated with glucose concentrations, the A allele was significantly associated with the presence of CAD (chi-square, p = 0.003), as well as with logarithmically transformed quantitative CAD indices [severe score (SS): 0.5 (0.4-0.6) vs 0.3 (0.2-0.5); extent score (ES): 2.63 (2.4-2.9) vs 1.94 (1.4-2.4), both p < 0.05, respectively]. Multivariate analysis revealed an independent association between the A allele with ES (β = 0.17, p < 0.01)., Conclusion: Our data suggest that ATM-dependent signalling might play a role in the development of atherosclerotic vascular disease, but larger studies are necessary to substantiate such a hypothesis.

Objective: To investigate neuropsychological mechanisms of impulsivity in patients with bulimia nervosa (BN) and binge-eating disorder (BED)., Method: Nineteen BN patients and 31 age- and body-mass-index (BMI)-matched healthy controls (c-BN) as well as 54 overweight and obese BED patients and 43 age- and BMI-matched healthy controls (c-BED) were investigated using an inhibitory control task (stop signal task, SST) and a decision-making under risk task (game of dice task, GDT)., Results: Compared to c-BN, BN patients demonstrated significant greater stop signal reaction times in the SST, but no differences for the frequency of risky decisions in the GDT. BED patients did not differ from c-BED in the SST or the GDT., Discussion: BN but not BED patients differed from their respective control groups concerning the "stopping" component of impulsivity. These differences in motor inhibition may contribute to the behavioral distinctions in binge-eating behavior between BN and BED., (Copyright © 2013 Wiley Periodicals, Inc.)

Aims: We aimed to develop a generic knowledge base with drug administration recommendations which allows the generation of a dynamic and comprehensive medication plan and to evaluate its comprehensibility and potential benefit in a qualitative pilot study with patients and physicians., Methods: Based on a literature search and previously published medication plans, a prototype was developed and iteratively refined through qualitative evaluation (interviews with patients and focus group discussions with physicians). To develop the recommendations for safe administration of specific drugs we screened the summary of product characteristics (SmPC) of different exemplary brands, allocated the generated advice to groups with brands potentially requiring the same advice, and reviewed these allocations regarding applicability and appropriateness of the recommendations., Results: For the recommendations, 411 SmPCs of 140 different active ingredients including all available galenic formulations, routes of administrations except infusions, and administration devices were screened. Finally, 515 distinct administration recommendations were included in the database. In 926 different generic groups, 29,879 allocations of brands to general advice, food advice, indications, step-by-step instructions, or combinations thereof were made. Thereby, 27,216 of the preselected allocations (91.1%) were confirmed as appropriate. In total, one third of the German drug market was labelled with information., Conclusions: Generic grouping of brands according to their active ingredient and other drug characteristics and allocation of standardized administration recommendations is feasible for a large drug market and can be integrated in a medication plan., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Aims/introduction: Glyoxalase 1 catalyses the detoxification of methylglyoxal, a major precursor of advanced glycation end products associated with aging, neurodegenerative diseases, and microvascular complications of diabetes. Here, we examine a possible association of a single nucleotide polymorphism of glyoxalase 1 gene (Glo1 A332C, rs4746 or rs2736654) with the prevalence of microvascular diabetic complications in patients with type 1 and type 2 diabetes., Materials and Methods: Genotyping was performed in 209 patients with type 1 and 524 patients with type 2 diabetes using polymerase chain reaction and subsequent cleavage by restriction endonuclease Bsa I., Results: Frequencies of the glyoxalase 1 genotypes were different with respect to diabetes type with a significantly higher prevalence of A332A-genotype in type 1 diabetes (35.9% vs. 27.3%; p=0.03). In type 1 diabetes, there was no correlation of any genotype with diabetic retinopathy, nephropathy or neuropathy. In contrast, type 2 diabetic patients homozygous for the C332C allele showed a significantly increased prevalence of diabetic neuropathy (p=0.03; OR=1.49 [95%-CI: 1.04; 2.11]), while no association with diabetic nephropathy or retinopathy was found. However, the significance of this association was lost after correction for multiple testing., Conclusions: Our data suggest a possible association of C332C-genotype of the glyoxalase 1 gene with diabetic neuropathy in type 2 diabetes, supporting the hypothesis that methylglyoxal might be an important mediator of diabetic neuropathy in type 2 diabetes., (© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.)

The serotonergic pathway plays a major role in the development of obesity. Its activity can be modulated by the 5-HT transporter-linked polymorphic region in the SLC6A4 gene and the upstream variable number of tandem repeats polymorphism in the MAOA gene. We studied whether these genetic modulations have an influence on weight reduction and weight maintenance in a one-year weight reduction program (OPTIFAST ® 52). The polymorphisms were genotyped by PCR in a sample of 135 female and 67 male subjects with severe obesity (44 ± 13 years, 122.3 ± 22.2 kg, BMI: 41.7 ± 6.7 kg/m 2 ). The program leads to a total weight loss of 19.9 ± 9.8 kg (16.9 ± 8.3 %) in women and 27.4 ± 13.6 kg (20.4 ± 9.9 %) in men. Anthropometric measurements and blood levels were determined at the start of the program (T0), after the weight reduction phase (T1) and after the subsequent weight maintenance phase at the end of the program (T2). Each polymorphism alone did not significantly influence weight loss or weight maintenance neither in men nor in women. However, women carrying both risk genotypes (SS and 3/3) displayed a lower total weight loss during the program (p = 0.05). This effect derived mainly from difficulties in the weight maintenance phase (p = 0.11), while the weight reduction phase was not affected (p = 0.61). No influence was found in men (p = 0.93). Modulation of the serotonergic pathway by carrying both risk alleles seems to influence success of weight loss programs in women with severe obesity due to problems in stabilizing body weight after weight reduction.

Background: Type 2 diabetes mellitus (T2DM) is a disease with high prevalence, associated with severe co-morbidities as well as being a huge burden on public health. It is known that glycemic control decreases long-term morbidity and mortality. The current standard therapy for T2DM is medical treatment. Several randomized controlled trials (RCTs) performed in obese patients showed remission of T2DM after bariatric surgery. Recent RCTs have shown bariatric procedures to produce a similar effect in non-morbidly and non-severely obese, insulin-dependent T2DM patients suggesting procedures currently used in bariatric surgery as new therapeutical approach in patients with T2DM. This study aims at investigating whether Roux-en-Y gastric bypass (RYGB) is an efficient treatment for non-severely obese T2DM patients in terms of preventing long-term complications and mortality., Methods: The DiaSurg 2 trial is a multicenter, open randomized controlled trial comparing RYGB including standardized medical treatment if needed to exclusive standardized medical treatment of T2DM (control group). The primary endpoint is a composite time-to-event endpoint (cardiovascular death, myocardial infarction, coronary bypass, percutaneous coronary intervention, non-fatal stroke, amputation, surgery for peripheral atherosclerotic artery disease), with a follow-up period of 8 years. Insulin-dependent T2DM patients aged between 30 and 65 years will be included and randomly assigned to one of the two groups. The experimental group will receive RYGB and, if needed, standardized medical care, whereas the control group will receive exclusive standardized medical care, both according to the national treatment guidelines for T2DM. Statistical analysis is based on Cox proportional hazards regression for the intention-to-treat population. Assuming a loss to follow-up rate of 20%, 200 patients will be randomly allocated to the comparison groups. A total sample size of n=400 is sufficient to ensure 80% power in a two-tailed significance test at alpha=5%., Discussion: The DiaSurg2 trial will yield long-term data (8 years) on diabetes-associated morbidity and mortality in patients with insulin-dependent T2DM receiving either RYGB or standardized medical care., Trial Registration: The trial protocol has been registered in the German Clinical Trials Register DRKS00004550.

Since end of 2012 a new therapeutical approach for the treatment of type 2 diabetes is available in Germany. It relies on the modulation of glucose re-absorption in the kidney by inhibition of so called Sodium Glucose Linked Transporters (SGLT) thereby leading to therapeutical glucosuria. Putting the kidney in the centre of therapeutical approach of glucose regulation is unfamiliar for physicians. Therefore, it is helpful to elucidate the underlying renal mechanisms and to present the advantages and disadvantages of this new therapeutic class., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lipid mobilization (lipolysis) in white adipose tissue (WAT) critically controls lipid turnover and adiposity in humans. While the acute regulation of lipolysis has been studied in detail, the transcriptional determinants of WAT lipolytic activity remain still largely unexplored. Here we show that the genetic inactivation of transcriptional cofactor transducin beta-like-related 1(TBLR1) blunts the lipolytic response of white adipocytes through the impairment of cAMP-dependent signal transduction. Indeed, mice lacking TBLR1 in adipocytes are defective in fasting-induced lipid mobilization and, when placed on a high-fat-diet, show aggravated adiposity, glucose intolerance, and insulin resistance. TBLR1 levels are found to increase under lipolytic conditions in WAT of both human patients and mice, correlating with serum free fatty acids (FFAs). As a critical regulator of WAT cAMP signaling and lipid mobilization, proper activity of TBLR1 in adipocytes might thus represent a critical molecular checkpoint for the prevention of metabolic dysfunction in subjects with obesity-related disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Altered adipose tissue formation is a well-known effectors of obesity and T2D. Here, we describe the role of Lrh1 and its co-repressor Shp in the control of adipocyte formation. Expression of Lrh1 in the pre-adipocyte containing SVF is induced in obese mice models and humans while Shp expression is reduced. We demonstrate, that Lrh1 is an inhibitor of adipogenesis while Shp acts functions as an activator through repression of Lrh1 activity. This regulation is at least in part modulated by estradiol conversion through the regulation of Cyp19a1 gene expression. In vivo, loss of Lrh1 leads to induced adipogenesis, while loss of Shp causes uncontrolled activation of Lrh1 and reduced adipogenesis. As Shp expression has been linked to the development of obesity and metabolic disorders, it is possible that alterations of the Shp/Lrh1 network lead to changes in adipocyte formation, which might contribute to the development of obesity associated T2D.

Ocular fundus photography allows detection of both ocular and systemic diseases. This study investigated the efficacy of a broad screening in a department of internal medicine using nonmydriatic digital fundus photography. For 8 weeks a medical technician was trained in using the camera as well as interpreting the photographs. The medical technician and an ophthalmologist evaluated the fundus photographs separately by using a self-developed questionnaire. The fundus camera was user-friendly and after several weeks of adjustment and practical application the medical technician was able to detect the majority of pathological fundus photographs. Out of 218 patients examined 148 (68%) were identified as pathological by the medical technician and 163 (75%) by the ophthalmologist (p = 0.0003). The medical technician missed 15 (7%) patients. Furthermore the diagnoses made by the medical technician were faulty. In summary an ophthalmological screening by a medical technician is feasible but the diagnosis still remains the responsibility of ophthalmologists. Such a compromise could facilitate the examination of a large number of patients and disclose previously unrecognized diseases.

Aims: To compare effectiveness of a 1-year weight loss program in moderately and severely obese patients., Methods: The study sample included 311 obese patients participating in a weight loss program, which comprised a 12-week weight reduction phase (low-calorie formula diet) and a 40-week weight maintenance phase. Body weight and glucose and lipid values were determined at the beginning of the program as well as after the weight reduction and the weight maintenance phase. Participants were analyzed according to their BMI class at baseline (30-34.9 kg/m²; 35-39.9 kg/m²; 40-44.9 kg/m²; 45-49.9 kg/m²; ≥50 kg/m²). Furthermore, moderately obese patients (BMI < 40 kg/m²) were compared to severely obese participants (BMI ≥ 40 kg/m²)., Results: Out of 311 participants, 217 individuals completed the program. Their mean baseline BMI was 41.8 ± 0.5 kg/m². Average weight loss was 17.9 ± 0.6%, resulting in a BMI of 34.3 ± 0.4 kg/m² after 1 year (p < 0.001). Overall weight loss was not significantly different in moderately and severely obese participants. Yet, severely obese participants achieved greater weight loss during the weight maintenance phase than moderately obese participants (-3.1 ± 0.7% vs. -1.2 ± 0.6%; p = 0.04). Improvements in lipid profiles and glucose metabolism were found throughout all BMI classes., Conclusion: 1-year weight loss intervention improves body weight as well as lipid and glucose metabolism not only in moderately, but also in severely obese individuals., (© 2013 S. Karger GmbH, Freiburg.)

Background: Hypothyroidism can usually be treated effectively by oral levothyroxine supplementation. There are, however, some rare circumstances, when oral levothyroxine application is not sufficient, for example malabsorption, interactions with food or other medications, or various gastrointestinal diseases., Case Report: We present a 42 year old woman with refractory and severe symptomatic hypothyroidism after subtotal thyroidectomy in spite of high dose oral levothyroxine supplementation. By stepwise increasing oral levothyroxine dosage up to 2200 micrograms plus 80 micrograms of thyronine, no sufficient substitution could be achieved. After suspicion of enteral malabsorption due to a pathological D-Xylose-test, subcutaneous levothyroxine supplementation was started. Finally, a sustained euthyroid state could be achieved., Conclusions: For selected patients who do not respond to oral treatment subcutaneous application of levothyroxine can be a suitable and effective therapy.

Objective: The A-allele of the fat mass and obesity-associated (FTO) gene variant rs9939609 has been associated with increased body weight, whereas no effect on weight loss during weight reduction programs has been observed. We questioned whether the AA-genotype interferes with weight stabilization after weight loss., Design: We conducted a monocentric, longitudinal study involving obese individuals. The FTO gene variant rs9939609 was genotyped in participants attending a weight reduction program that was divided into two phases: a weight reduction period with formula diet (12 weeks) and a weight maintenance phase (40 weeks). Body weight, body mass index (BMI), blood pressure and concentrations of blood glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides were determined in week 0 (T(0)), after 12 weeks (T(1)) and at the end in week 52 (T(2))., Subjects: A total of 193 obese subjects aged between 18 and 72 years (129 female, 64 male; initial body weight: 122.4±22.3 kg, initial BMI: 41.8±6.7 kg m(-2)) were included., Results: Genotyping revealed 32.1% TT-, 39.4% AT- and 28.5% AA-genotype carriers. At T (0), carriers of the AA-genotype had significantly higher body weight (P=0.04) and BMI (P=0.005) than carriers of the TT-genotype. Of the 193 participants, 68 discontinued and 125 completed the program. Dropout rate was not influenced by genotype (P=0.33). Completers with AA-genotype showed significantly lower additional weight loss during the weight maintenance phase than TT-genotype carriers (P=0.02). Furthermore, among participants facing weight regain during weight maintenance (n=52), more subjects were carrying the AA-genotype (P=0.006). No influence of genotype on weight reduction under formula diet was observed (P=0.32)., Conclusion: In this program, the AA-genotype of rs9939609 was associated with a higher initial body weight and did influence success of weight stabilization. Thus, emphasizing the maintenance phase during a weight reduction program might result in better success for AA-genotype carriers.

Objective: The A1 allele of the TaqIA polymorphism in the dopamine D2 receptor gene (rs1800497) has been associated with obesity. However, the effect of the polymorphism on the success in weight loss and/or weight maintenance during weight-loss programs has not been evaluated thus far., Methods: The rs1800497 was genotyped in 202 (135 female, 67 male) severely obese individuals with an initial body mass index of 41.7 ± 0.5 kg/m² who participated in a weight-loss program consisting of a weight-loss phase with a formula diet (12 wk) and a weight-maintenance phase (40 wk). Measurements were collected at baseline, after the weight-loss phase, and at the end of the weight-maintenance phase at 1 y., Results: Genotyping revealed 4 A1A1, 67 A1A2, and 131 A2A2 genotype carriers. Of the 202 subjects in the program, 66.8% completed the program and 33.2% terminated prematurely. Neither the attrition rate (P = 0.44) nor the overall weight loss was influenced by the different genotypes (P = 0.96). However, younger A1⁺ participants (A1A1 and A1A2) had a higher body mass index at all time points (baseline, P = 0.04; after weight loss, P = 0.05; after weight maintenance, P = 0.02). They also showed less overall weight loss (P = 0.05), which derived mainly from a greater weight regain during the maintenance phase (P = 0.02)., Conclusion: In this program, younger A1⁺ participants exhibited problems in maintaining weight loss during a weight-loss program., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Lowering LDL-cholesterol by statins has been proven to be associated with reduction of proinflammatory regulators e.g. activation of the transcription factor NF-κB. To our knowledge, anti-inflammatory potential of newer cholesterol lowering agents such as ezetimibe is less intensively studied. Therefore we analyzed the effects of equipotent LDL-lowering therapy with simvastatin alone compared to a combination with ezetimibe on NF-κB activation in peripheral blood mononuclear cells (PBMCs) of patients with type 2 diabetes., Methods: Thirty-one patients with type 2 diabetes were included in a double-blind, randomized trial receiving either 80 mg simvastatin (sim80; n = 10) or a combination of 10 mg simvastatin and 10 mg ezetimibe (sim10eze10; n = 11) or placebo (n = 9) for eight weeks. NF-κB binding activity and inflammatory markers (IL-6, hsCRP) were analyzed at baseline and after eight weeks of treatment. NF-κB binding activity was analyzed by electrophoretic mobility shift assay. IL-6 and hsCRP were measured by ELISA., Results: After eight weeks of treatment LDL-cholesterol was lowered to the same extent in both treatment groups (p = 0.40) but not in placebo. However, patients taking sim80 showed a significant reduction of mononuclear NF-κB binding activity compared to baseline (p = 0.009) while no effect was observed in the sim10eze10 group (p = 0.79). Similar differences in anti-inflammatory effects were also observed when analyzing hsCRP (sim80: p = 0.03; sim10eze10: p = 0.40) and IL-6 levels (sim80: p = 0.15; sim10eze10: p = 0.95)., Conclusion: High dose simvastatin therapy reduces proinflammatory transcription factor NF-κB binding activity and hsCRP levels, while combination of low dose simvastatin with ezetimibe resulting in a similar LDL-reduction does not affect these inflammatory markers., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Chronic renal failure is a well-known complication of long-standing diabetes. Moreover, audiological abnormalities are a common feature of patients with end-stage renal disease. Severe deafness, however, is not a typical symptom in most patients with chronic renal failure and likewise in patients with diabetes mellitus. In this case report, we describe a young patient with insulin-dependant diabetes mellitus, severe deafness requiring hearing aid and chronic renal failure outlining typical clinical features of the maternally inherited diabetes with deafness syndrome. Genetic testing confirmed the presence of the m.3243A>G mutation.

The aim of this article is to describe the methods and effectiveness of the Public Engagement in Genetic Variation and Haplotype Mapping Issues (PEGV) Project, which engaged a community in policy discussion about genetic variation research. The project implemented a 6-stage community engagement model in New Rochelle, New York. First, researchers recruited community partners. Second, the project team created community oversight. Third, focus groups discussed concerns generated by genetic variation research. Fourth, community dialogue sessions addressed focus group findings and developed policy recommendations. Fifth, a conference was held to present these policy recommendations and to provide a forum for HapMap (haplotype mapping) researchers to dialogue directly with residents. Finally, findings were disseminated via presentations and papers to the participants and to the wider community beyond. The project generated a list of proposed guidelines for genetic variation research that addressed the concerns of New Rochelle residents. Project team members expressed satisfaction with the engagement model overall but expressed concerns about how well community groups were utilized and what segment of the community actually engaged in the project. The PEGV Project represents a model for researchers to engage the general public in policy development about genetic research. There are benefits of such a process beyond the desired genetic research., (© Mary Ann Liebert, Inc.)

Increased nutrient intake leads to excessive adipose tissue accumulation, obesity, and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analog liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC, and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Because GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling.

Background: Hypercalcemia is a common problem in clinical practice and can be related to endocrine disorders or malignant disease, especially in elderly patients. Although rare, other causes can also be responsible., Case Report: Granulomatous inflammation of the skin and lymph nodes induced by intravenous or injectable silicone is a rare condition of hypercalcemia that is usually not within the scope of differential diagnosis. Here, we report a 72-year-old woman with symptomatic hypercalcemia related to cosmetic treatment of the neck. Topical applied liquid silicone by means of a focal ultrasound device induced extensive granulomatous inflammation of the skin and local lymph nodes, being the underlying cause for hypercalcemia in this case., Conclusions: In rare cases, symptomatic hypercalcemia can be caused by silicone due to a severe granulomatous tissue reaction. This is the first time that a transdermal silicone treatment has been reported to cause severe granulomatous tissue inflammation.

Obesity is a well-known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid-related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorγ-deficient mice is enhanced and obese Rorγ(-/-) mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ(-/-) mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify RORγ as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance., (Copyright © 2011 EMBO Molecular Medicine.)

Background: Postoperative hyperthyroidism occurs in approximately one third of patients following parathyroidectomy due to primary hyperparathyroidism (PHP), but has only rarely been described in secondary hyperparathyroidism (SHP). The frequency, course, and laboratory markers of postoperative hyperthyroidism in SHP remain unknown. Our purpose was to evaluate the frequency and the clinical course of postoperative hyperthyroidism following surgery of SHP and to determine the diagnostic value of thyroglobulin in this setting., Material and Methods: A total of 40 patients undergoing parathyroidectomy because of SHP were included in this study. Thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and thyroglobulin (Tg) were determined one day before and on day 1, 3, 5, 10, and 40 after surgery. At each of these visits patients were clinically evaluated for signs or symptoms of hyperthyroidism., Results: Biochemical evidence of hyperthyroidism was evident in 77% of patients postoperatively despite of preoperatively normal serum levels. TSH dropped from 1.18 ± 0.06mU/L to 0.15 ± 0.07mU/L (p = 0.0015). Free triiodothyronine (fT3) and fT4 levels increased from 2.86 ± 0.02ng/L and 10.32 ± 0.13ng/L, respectively, to their maximum of 4.83 ± 0.17ng/L and 19.35 ± 0.58ng/L, respectively. Thyroglobulin levels rose from 3.8 ± 0.8ng/mL to 111.8 ± 45.3ng/mL (p<0.001). At day 40 all thyroid related laboratory values were within normal range. Correlation analysis of postoperative values revealed significant correlations for lowest TSH (r = -0.32; p = 0.038), and highest fT3 (r = 0.55; p<0.001) and fT4 levels (r = 0.67; p<0.001) with Tg., Conclusion: Transient hyperthyroidism is frequent after parathyroidectomy for SHP with Tg being a suitable marker. Awareness of this self-limiting disorder is important to avoid inappropriate and potentially harmful treatment.

Aims/hypothesis: Extracellular matrix reorganisation is a crucial step of adipocyte differentiation and is controlled by the matrix metalloproteinase-tissue inhibitor of matrix metalloproteinase (TIMP) enzyme system. We therefore sought to define the role of TIMP1 in adipogenesis and to elucidate whether upregulation of TIMP1 in obesity has direct effects on adipocyte formation., Methods: TIMP1 protein levels and mRNA were measured in lean and obese mice with a focus on levels in adipose tissue. We also analysed the effect of recombinant murine TIMP1 on adipogenesis, adipocyte size and metabolic control in vitro and in vivo., Results: TIMP1 levels were increased in the serum and adipose tissue of obese mouse models. Recombinant murine TIMP1 inhibited adipocyte differentiation in 3T3-L1 as well as in subcutaneous primary pre-adipocytes. Conversely, neutralising TIMP1 with a specific antibody enhanced adipocyte differentiation. In vivo, injection of recombinant TIMP1 in mice challenged with a high-fat diet led to enlarged adipocytes. TIMP1-treated mice developed an impaired metabolic profile with increased circulating NEFA levels, hepatic triacylglycerol accumulation and accelerated insulin resistance. Altered glucose clearance in TIMP1-injected mice was due to changes in adipose tissue glucose uptake, whereas muscle glucose clearance remained unaffected., Conclusions/interpretation: TIMP1 is a negative regulator of adipogenesis. In vivo, TIMP1 leads to enlarged adipocytes in the state of overnutrition. This might contribute to the detrimental metabolic consequences seen in TIMP1-injected mice, such as systemic fatty acid overload, hepatic lipid accumulation and insulin resistance.

Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved survival in sepsis). The consequences of enhanced coagulation activation, as observed in FVL carriers, on microvascular diabetic complications remain unknown. We therefore investigated the role of FVL in diabetic nephropathy. In heterozygous or homozygous diabetic FVL mice, albuminuria and indices of diabetic nephropathy were reduced compared with diabetic wild-type mice. This was associated with reduced glomerular apoptosis and preservation of podocytes in diabetic FVL-positive mice. In vitro, low-dose thrombin (50pM) prevented, whereas high-dose thrombin (20nM) aggravated, glucose-induced apoptosis in podocytes. In diabetic patients, the FVL mutation, but not the plasminogen activator inhibitor-1 4G/5G polymorphism, is associated with reduced albuminuria, which is consistent with a nephroprotective role of low but sustained thrombin generation. Consistently, anticoagulation of diabetic FVL-positive mice with hirudin abolished the nephroprotective effect. These results identify a nephroprotective function of low but sustained thrombin levels in FVL carriers, supporting a dual, context-dependent function of thrombin in chronic diseases.

This prospective study was performed in order to establish whether improvement of endothelial function after weight reduction can be explained by a decrease of elevated asymmetric dimethyl arginine (ADMA), an inhibitor of endogenous NO-synthase (eNOS). Therefore, 21 obese subjects (BMI: 41.1±6.4 kg/m(2)) were studied at baseline and after 12 weeks of weight reduction with a very low calorie diet. Biochemical and clinical parameters of endothelial function were assessed before and after weight loss. Biochemical parameters were determined by measurement of ADMA and soluble intercellular adhesion molecule (sICAM). Clinical parameters were assessed by pulse wave analysis (PWA). Weight intervention resulted in a 21.4±6.8 kg reduction of body weight from 119.7±12.8 kg at study start to 98.3±11.6 kg at study end (p<0.001). Accordingly, biochemical markers improved under weight reduction (ADMA from 0.47±0.07 mmol/l to 0.42±0.08 mmol/l; p=0.002; ICAM from 276±42 ng/ml to 236±29 ng/ml; p<0.001). Further, clinical parameters of functional endothelial function improved with an increase of deltaRI after salbutamol inhalation from -1% before to -9% after weight reduction (p=0.02). Interestingly, improvement of endothelial function correlated with improved HOMA index only (r=-0.60, p=0.04) but not with reduced ADMA levels, improved hypertension or reduced body weight. In conclusion, weight reduction with a very low calorie diet improves endothelial function measured by pulse wave velocity. The missing correlation with ADMA suggests possible further mechanisms underlying this observed effect, for example, improvement of insulin resistance., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Kyphoplasty immediately improves pain and mobility in patients with painful osteoporotic vertebral fractures, but long-term clinical outcomes are still unclear. This controlled trial evaluates pain, mobility and fracture incidence 3 years after kyphoplasty., Materials and Methods: Kyphoplasty was performed in 40 patients with painful osteoporotic vertebral fractures; 20 patients who were selected for kyphoplasty but chose not to undergo the procedure served as controls. All patients received pharmacologic antiosteoporosis treatment, pain medication, and physiotherapy. Pain (visual analog scale of 0-100), mobility (European Vertebral Osteoporosis Study questionnaire score of 0-100), and incident vertebral fractures were assessed at baseline, postprocedurally, and after 12 and 36 months., Results: Pain score improved after kyphoplasty from 73.8 to 55.9 (immediately after kyphoplasty), 55.6 (12 months), and 54.0 (36 months; P < .001). Pain score in the control group changed from 66.4 to 65.7 at 12 months and 64.0 at 36 months (P = .521). The pain score of the kyphoplasty group was significantly improved versus controls after 36 months (P = .023). Mobility score improved after kyphoplasty from 43.8 to 54.2 (immediately after kyphoplasty), 54.5 (12 months), and 54.8 (36 months; P = .0008) and remained increased (P = .308) compared with controls (39.8 immediately after kyphoplasty, 44.3 at 12 months, and 43.6 at 36 months). The incidence of new vertebral fractures after kyphoplasty was significantly reduced versus controls after 3 years (P = .0341)., Conclusions: Kyphoplasty reduces pain and improves mobility as long as 3 years after the procedure. The long-term risk of new vertebral fractures after kyphoplasty of chronically painful vertebral fractures is reduced versus controls.