Association of 1-deoxy-sphingolipids with steatosis but not steatohepatitis nor fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes. AIM: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis. METHODS: Sphingolipids were analysed by LC-MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD. RESULTS: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes. CONCLUSION: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis.

Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients.

AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. METHODS: Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). RESULTS: A total of 156 patients (34SG, 122RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P<0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r=0.22, P=0.007), HOMA-IR (r=0.24, P=0.005), total cholesterol (r=0.17, P=0.037) and non-HDL-C (r=0.17, P=0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. CONCLUSION: RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.

Glycaemic target attainment in people with Type 2 diabetes treated with insulin glargine/lixisenatide fixed-ratio combination: a post hoc analysis of the LixiLan-O and LixiLan-L trials.

AIMS: Both fasting (FPG) and postprandial plasma glucose (PPG) contribute to HbA1c levels. We investigated the relationship between achievement of American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommended FPG and/or PPG targets and glycaemic efficacy outcomes in two trials. METHODS: In this post hoc analysis, data from participants with Type 2 diabetes in the phase 3 LixiLan-O (NCT02058147) and LixiLan-L (NCT02058160) trials were evaluated to compare the relationship between achievement of society-recommended FPG and/or PPG targets and efficacy (HbA1c change, HbA1c goal attainment, weight change) and safety outcomes in the treatment groups. RESULTS: Across treatment arms, iGlarLixi achieved the highest proportion of participants meeting both ADA- and AACE-recommended FPG and PPG targets at study end in both trials. A higher proportion of participants in the iGlarLixi (fixed-ratio combination of insulin glargine and lixisenatide) vs. insulin glargine alone or lixisenatide alone treatment arms achieved HbA1c goals (P < 0.001 for overall comparisons), irrespective of ADA- or AACE-defined targets. Hypoglycaemia rates [any, documented symptomatic (plasma glucose ≤ 3.9 mmol/l), and clinically important (plasma glucose < 3.0 mmol/l)] were low across all groups. Participants treated with iGlarLixi tended to show weight loss or less weight gain compared with participants receiving insulin glargine alone. No differences were observed in average daily basal insulin dose at week 30 between the two treatment arms or across the different FPG and PPG target groups. CONCLUSION: Insulin glargine and lixisenatide as a fixed-ratio combination resulted in more participants reaching both FPG and PPG targets, leading to better HbA1c target attainment.

Sarcopenia in patients with non-alcoholic fatty liver disease: is it a clinically significant entity?

Sarcopenia, described as the loss of muscle mass and/or strength, is gaining importance as it can be increasingly related to many chronic diseases. It is also associated with chronic liver disease, and recently it has been more frequently linked to non-alcoholic fatty liver disease (NAFLD) in particular. Both sarcopenia and NAFLD are subject to complex and intermingled pathophysiological processes, of which some are in common. Furthermore, it is presently unclear if sarcopenia directly contributes to NAFLD or vice versa. The mechanisms that are involved may include obesity, insulin resistance, vitamin D deficiency, aging, physical inactivity and certain cytokines. Current clinical evidence is subject to an important heterogeneity in methods and definitions, with additionally also a relative overrepresentation of evidence in Asian ethnicities. Nonetheless, all studies so far point towards the same association between sarcopenia and NAFLD, including an association with NAFLD-severity and NAFLD-related fibrosis. Since the field is in its infancy, clear definitions and further research are needed to aid to improve understanding of the association between NAFLD and sarcopenia. This can eventually lead to additional potential therapeutic interventions. This review attempts to give an overview of the current published literature that links sarcopenia to NAFLD, followed by a discussion of the presumably involved pathophysiological factors, and ends by discussing current unmet needs.

Health-related costs in a sample of premenopausal non-diabetic overweight or obese females in Antwerp region: a cost-of-illness analysis.

BACKGROUND: People with overweight or obesity are at increased risk for disease later in life which cause important health costs.The aim of this study was to estimate the health status and the corresponding costs in a sample of females with overweight or obesity which were participating in a Randomized Controlled Trial (RCT) exploring the effect of lifestyle habits changes on ectopic adipose tissue. METHODS: Sixty-two non-diabetic premenopausal females without major comorbidities of overweight and obesity were recruited among patients visiting endocrinologists at the obesity clinic of the University Hospital of Antwerp and the University of Antwerp.A RCT-embedded cost-of-illness approach with societal perspective, based on self-reported questionnaires and cost diaries (3 months recall) was applied to estimate the prevalence of different comorbidities and the related direct and indirect costs in this sample of overweight or obese females. The European Quality-of-Life-5D questionnaire was used to define the health state and the corresponding utility index of the participants. RESULTS: The average direct health costs and health utilities observed in this sample were comparable with the general Flemish female population. This may partially be explained by the strict inclusion criteria of the RCT (i.e. overweight or obesity without diabetes type 2 or cardiovascular diseases). However, 15% of the participants had five or more comorbidities resulting in higher average costs and lower average health utility as compared to the general population, only 3 participants were diagnozed with the metabolic syndrome. In this subsample productivity was low due to high average absenteeism, yielding important total costs for the society. CONCLUSION: Secondary prevention to avoid health deterioration in overweight or obese females without major comorbidies is needed to contain health care costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02831621, approval of the ethics committee of the University Hospital of Antwerp (number: 14/17/205 -ref: 7543075363).

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

BACKGROUND: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. AIM: To develop a new blood test specifically dedicated for this new diagnostic target of interest. METHODS: Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. RESULTS: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. CONCLUSION: The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.

The effect of diet or exercise on ectopic adiposity in children and adolescents with obesity: a systematic review and meta-analysis.

OBJECTIVE: Ectopic fat depostion in youth with obesity is associated with an increased cardiovascular disease risk. The aim of this meta-analysis was to summarize the evidence for the use of diet and/or exercise on ectopic adiposity in this population. METHODS: A systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Clinical trials that assessed ectopic fat deposition and included study arms with diet and/or exercise were searched in PubMed, PEDro and the Cochrane database. RESULTS: Hepatic fat content and intramyocellular lipid content were described in nine studies and three studies, respectively. Most studies included teenagers, and study duration ranged between 3 and 12 months without follow-up. Using random-effects weights, the standardized mean difference of the change in hepatic adiposity (totalling 320 subjects) was -0.54 Hedges' g (95% confidence interval: -0.69 to -0.38 with p < 0.0001). By re-expressing this effect size, it is seen that diet and/or exercise results in an absolute reduction of intrahepatic lipid with 2%, which accords with a relative reduction up to 70%. Although there were significant ameliorations of insulin sensitivity, no significant changes in intramyocellular lipid were observed. CONCLUSIONS: This meta-analysis showed that diet and/or exercise is effective to reduce hepatic adiposity in youth with obesity.

Not performing an OGTT results in significant underdiagnosis of (pre)diabetes in a high risk adult Caucasian population.

OBJECTIVE: Type 2 diabetes (T2DM) is known to be underdiagnosed. Tests for diagnosis include fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and HbA1c. HbA1c can be tested in non-fasting conditions. Therefore, general practitioners almost no longer execute OGTT's. We evaluated the performance of OGTT versus HbA1c in a population consisting of overweight and obese subjects, which can be considered a 'high risk' population. RESEARCH DESIGN AND METHODS: A total of, 1241 overweight and obese subjects without a history of diabetes (male/female: 375/866, age 44±13 years, body mass index 38.0±6.1 kg m-2) were tested for glucose tolerance status using FPG, OGTT and HbA1c. RESULTS: Exactly, 46.8% were found to have prediabetes and 11.9% were newly diagnosed with T2DM (male/female=18.9/8.9%) using ADA criteria. Testing only HbA1c would have resulted in 78 subjects being diagnosed with T2DM, but 47.3% of newly diagnosed patients would have been missed if OGTT would not have been done. Exactly 581 subjects were diagnosed with prediabetes, 1.4% subjects had impaired fasting glucose (IFG) 30.5% had impaired glucose tolerance (IGT), 5.1% subjects had a combined IFG+IGT, and 9.8% had an isolated elevated HbA1c (5.7-6.4%). Of the 581 subjects with prediabetes, 257 had an HbA1c <5.7%. Therefore, 44.2% subjects would have been missed when OGTT would not have been done. CONCLUSION: In a population with only overweight and obese adult subjects, 46.8% were diagnosed with prediabetes and 11.9% were newly diagnosed with diabetes. Exactly, 5.6 and 20.7% of total population met the diagnostic criteria of the OGTT for diabetes and prediabetes, respectively, but did not meet the diagnostic criteria of the HbA1c. These data suggest that not performing an OGTT results in significant underdiagnose of T2DM in an overweight and obese adult population.

Drug-induced obesity and its metabolic consequences: a review with a focus on mechanisms and possible therapeutic options.

Weight gain is a common side effect of many widely used drugs. Weight gain of a few kilograms to an increase of 10% or more of initial body weight has been described. Not only the weight gain as such puts a burden on the health risks of the involved patients, the accompanying increase in the incidence of the metabolic syndrome, type 2 diabetes mellitus, and cardiovascular risk factors urges the caregiver to identify and to closely monitor the patients at risk. In this review, the different classes of drugs with significant weight gaining properties and the metabolic consequences are described. Specific attention is given to pathogenetic mechanisms underlying the metabolic effects and to potential therapeutic measures to prevent them.

Do E-cigarettes induce weight changes and increase cardiometabolic risk? A signal for the future.

The prevalence of non-cigarette tobacco use in electronic cigarettes, also called vaping, is rapidly increasing, especially in adolescents and young adults, due to attractive marketing techniques promoting them as healthier alternatives to conventional tobacco cigarettes. Although smoking is associated with weight loss, it increases insulin resistance and attributes to other features of the metabolic syndrome, increasing the cardiometabolic risk profile. Whether vaping has the same deleterious effects on metabolic parameters as regular cigarette smoke has not yet been studied thoroughly in humans. However, animal model experiments attribute comparable effects of e-cigarette smoking, even without nicotine exposure, on weight and metabolic parameters as compared to smoking cigarettes. In this review paper, we want to give an overview of published data on the effects on weight and cardiometabolic parameters of e-cigarette use and formulate some mechanistic hypotheses.

The Cushing Reflex: Oliguria as a Reflection of an Elevated Intracranial Pressure.

Oliguria is one of the clinical hallmarks of renal failure. The broad differential diagnosis is well known, but a rare cause of oliguria is intracranial hypertension (ICH). The actual knowledge to explain this relationship is scarce. Almost all literature is about animals where authors describe the Cushing reflex in response to ICH. We hypothesize that the Cushing reflex is translated towards the sympathetic nervous system and renin-angiotensin-aldosterone system with a subsequent reduction in medullary blood flow and oliguria. Recently, we were confronted with a patient who had complicated pituitary surgery and displayed multiple times an oliguria while he developed ICH.

Screening for type 2 diabetes mellitus in overweight and obese subjects made easy by the FINDRISC score.

AIM: To evaluate the use of the FINDRISC score in an overweight and obese population to predict glucose status. METHODS: In 651 overweight/obese subjects (M/F: 193/458, age 43±13 y, BMI 38.2±6.1kg/m(2)) glucose status was tested using OGTT and HbA1c. Furthermore, the FINDRISC questionnaire and CT visceral fat (VAT) and subcutaneous fat (SAT) were examined. RESULTS: Exactly 50.4% were found to have prediabetes and 11.1% were newly diagnosed with type 2 diabetes (T2DM) (M/F=22.2/8.8%). Subjects without T2DM had a FINDRISC score of 11±3, those with pre-DM 13±4, and subjects with de novo T2DM 15±5. The aROC of the FINDRISC for detecting T2DM was 0.76 (95% CI 0.72-0.82), with 13 as cutoff point. The FINDRISC score correlated with VAT (r=0.34, p<0.001) and VAT/SAT ratio (r=0.39, p<0.001). The aROC of the FINDRISC to detect excess VAT was 0.79 (95%CI 0.72-0.84). CONCLUSIONS: In a large group of overweight and obese subjects, 50.4% were found to have pre-DM and 11.1% were newly diagnosed with T2DM. The FINDRISC score increased with worsening of glucose tolerance status and proved to be an independent predictor of T2DM status, as did HOMA-B, HOMA-S and VAT. The FINDRISC can also function as a good tool to predict visceral obesity.

Relationship of body mass index with efficacy of exenatide twice daily added to insulin glargine in patients with type 2 diabetes.

This post hoc analysis assessed the evidence behind common reimbursement practices by evaluating the relationship of body mass index (BMI) ranges (<30, 30-35 and >35 kg/m(2) ) with treatment effects of exenatide twice daily among patients with type 2 diabetes. Patients received exenatide twice daily added to insulin glargine in two 30-week studies (exenatide twice daily vs insulin lispro, n = 627; exenatide twice daily vs placebo, n = 259). No association of baseline BMI with changes in efficacy variables was observed. Glycated haemoglobin (HbA1c) reductions were significant (p < 0.0001) and similar across BMI range groups in the lispro-comparator study and greater for exenatide versus placebo in the placebo-controlled study. Significant weight loss occurred with exenatide across BMI range groups (p < 0.0001), while weight increased with both comparators. Achievement of HbA1c <7.0% (<53 mmol/mol) without weight gain was greater for exenatide versus comparators. Systolic blood pressure decreased across BMI range groups with exenatide in the lispro-comparator study (p < 0.0001); changes in lipids were not clinically meaningful. Minor hypoglycaemia was less frequent for exenatide versus insulin lispro. These findings suggest that BMI alone should not limit clinical decision-making or patient access to medication.

LEADER 5: prevalence and cardiometabolic impact of obesity in cardiovascular high-risk patients with type 2 diabetes mellitus: baseline global data from the LEADER trial.

BACKGROUND: Epidemiological data on obesity are needed, particularly in patients with type 2 diabetes mellitus (T2DM) and high cardiovascular (CV) risk. We used the baseline data of liraglutide effect and action in diabetes: evaluation of CV outcome results-A long term Evaluation (LEADER) (a clinical trial to assess the CV safety of liraglutide) to investigate: (i) prevalence of overweight and obesity; (ii) relationship of the major cardiometabolic risk factors with anthropometric measures of adiposity [body mass index (BMI) and waist circumference (WC)]; and (iii) cardiometabolic treatment intensity in relation to BMI and WC. METHODS: LEADER enrolled two distinct populations of high-risk patients with T2DM in 32 countries: (1) aged ≥50 years with prior CV disease; (2) aged ≥60 years with one or more CV risk factors. Associations of metabolic variables, demographic variables and treatment intensity with anthropometric measurements (BMI and WC) were explored using regression models (ClinicalTrials.gov identifier: NCT01179048). RESULTS: Mean BMI was 32.5 ± 6.3 kg/m(2) and only 9.1 % had BMI <25 kg/m(2). The prevalence of healthy WC was also extremely low (6.4 % according to International Joint Interim Statement for the Harmonization of the Metabolic Syndrome criteria). Obesity was associated with being younger, female, previous smoker, Caucasian, American, with shorter diabetes duration, uncontrolled blood pressure (BP), antihypertensive agents, insulin plus oral antihyperglycaemic treatment, higher levels of triglycerides and lower levels of high-density lipoprotein cholesterol. CONCLUSIONS: Overweight and obesity are prevalent in high CV risk patients with T2DM. BMI and WC are related to the major cardiometabolic risk factors. Furthermore, treatment intensity, such as insulin, statins or oral antihypertensive drugs, is higher in those who are overweight or obese; while BP and lipid control in these patients are remarkably suboptimal. LEADER confers a unique opportunity to explore the longitudinal effect of weight on CV risk factors and hard endpoints.

Pivotal Role for the Visceral Fat Compartment in the Release of Persistent Organic Pollutants During Weight Loss.

CONTEXT: Polychlorinated biphenyls (PCBs), are implicated as potential endocrine disruptors and obesogens. These lipophilic substances are preferentially stored in the fat compartment and released into the circulation during weight loss. OBJECTIVE: The aim of this study was to examine the contribution of abdominal adiposity, and visceral adiposity in particular, to the increase of serum PCB levels during weight loss. MATERIALS AND METHODS: Fourty-five obese women were prospectively recruited. Twenty individuals received dietary counseling and 25 underwent bariatric surgery. Anthropometric data were collected and intra-abdominal adiposity was assessed by measurement computed tomography scanning of the abdominal fat compartment, delineating the visceral and subcutaneous compartment. Serum levels of 27 PCBs were determined and the sum of all PCBs (ΣPCBs) calculated. Follow-up measurements of anthropometric data, computed tomography scanning, and PCB levels were performed after 6 months in all patients. RESULTS: In patients who lost weight, serum ΣPCB levels displayed an increase after 6 months of approximately 50%. Both correlation and regression analysis, focusing on the relative contribution of the visceral vs the subcutaneous fat compartment, suggested that the increase in ΣPCB serum levels after 6 months of weight loss was more pronounced in patients losing relatively more visceral adipose tissue. This trend could be established in the diet-treated, but not the surgery-treated subgroup. CONCLUSION: Our study suggests that the contribution of PCBs released from the visceral fat compartment might be more pronounced compared with the subcutaneous fat compartment during weight loss. These findings are present in the entire study group whereas subanalysis of the diet vs surgery groups suggested the same effect in the diet group but failed to reach statistical significance in the surgery group. This suggests a possible weight-loss method-specific effect.

Visceral, subcutaneous abdominal adiposity and liver fat content distribution in normal glucose tolerance, impaired fasting glucose and/or impaired glucose tolerance.

OBJECTIVES: To examine the specific distribution of liver fat content, visceral and subcutaneous adiposity in normal glucose tolerance (NGT/NGT), isolated impaired fasting glucose (iIFG), isolated impaired glucose tolerance (iIGT) and combined conditions (IFG+IGT), as well as with newly diagnosed type 2 diabetes (nT2D). DESIGN: Multicenter, international observational study: cross-sectional analysis. SUBJECTS: Two thousand five hundred and fifteen patients (50.0% women, 54.5% non-Caucasian) without previously known diabetes were recruited from 29 countries. Abdominal fat distribution was measured by computed tomography (CT). Liver fat was estimated using the CT-liver mean attenuation. RESULTS: Compared with NGT/NGT patients, increased visceral adiposity was found in iIFG, iIGT, IFG+IGT and nT2D; estimated liver fat progressively increased across these conditions. A one-s.d. increase in visceral adiposity was associated with an increased risk of having iIFG (men: odds ratio (OR) 1.41 (95% confidence interval (CI) 1.15-1.74), women: OR 1.62 (1.29-2.04)), iIGT (men: OR 1.59 (1.15-2.01), women: OR 1.30 (0.96-1.76)), IFG+IGT (men: OR 1.64 (1.27-2.13), women: OR 1.83 (1.36-2.48)) and nT2D (men: OR 1.80 (1.35-2.42), women: OR 1.73 (1.25-2.41)). A one-s.d. increase in estimated liver fat was associated with iIGT (men: OR 1.46 (1.12-1.90), women: OR 1.81 (1.41-2.35)), IFG+IGT (men: OR 1.42 (1.14-1.77), women: OR 1.74 (1.35-2.26)) and nT2D (men: OR 1.77 (1.40-2.27), women: OR 2.38 (1.81-3.18)). Subcutaneous abdominal adipose tissue showed an inverse relationship with nT2D in women (OR 0.63 (0.45-0.88)). CONCLUSIONS: Liver fat was associated with iIGT but not with iIFG, whereas visceral adiposity was associated with both. Liver fat and visceral adiposity were associated with nT2D, whereas subcutaneous adiposity showed an inverse relationship with nT2D in women.

Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial.

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. SUBJECTS/METHODS: 9804 males and females, aged ⩾55 years, with a body mass index of 27-45 kg m(-)(2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9±7.7 beats per minute (bpm) with weight increase; 1.4±7.3 bpm, 0-5 kg weight loss; 0.6±7.4 bpm, ⩾5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management.

Sleep-disordered breathing and pulmonary function in obese children and adolescents.

OBJECTIVE: Obese children have an increased risk of developing obstructive sleep apnea syndrome (OSAS) compared to normal-weight children. In obese children, OSAS is more frequently associated with oxygen desaturations, which might be caused by pulmonary function abnormalities. Our goal was to investigate the association between OSAS and pulmonary function in obese children and adolescents. METHODS: There were 185 children included and distributed in groups based on their obstructive apnea-hypopnea index (151 controls, 20 mild OSAS, and 14 moderate-to-severe OSAS). All subjects underwent polysomnography and pulmonary function testing. RESULTS: Several differences in pulmonary function were observed between groups. Vital capacity (VC) and forced expired volume in 1s (FEV1) were significantly decreased in patients with moderate-to-severe OSAS, as were expiratory reserve volume (ERV), total lung capacity, and functional residual capacity (FRC). Correlations between FEV1, FRC, and ERV with OSAS severity remained significant independent of the degree of adiposity. Correlations between FEV1/VC and sleep-related respiratory parameters did not persist after correction for adiposity. CONCLUSION: An association between awake pulmonary function and sleep-related respiratory parameters could be observed in our population of obese children. These results suggest that OSAS severity is correlated with a diminished lung function. However, the level of obesity remains an important confounding factor in both OSAS severity and pulmonary function.

Common genetic variation in sFRP5 is associated with fat distribution in men.

Considering the role of sFRP5 in Wnt signalling, an important group of pathways regulating adipogenesis and inflammation, we performed a genetic association study on sFRP5 polymorphisms in a population of obese and lean individuals. Using information from the HapMap, two tagSNPs were identified in the sFRP5 gene region and genotyped on a population of 1,014 obese, non-diabetic individuals and 606 lean controls. We performed logistic and linear regression analysis including a wide variety of obesity parameters (BMI, waist circumference, height, WHR, fat mass, fat mass percentage and visceral, subcutaneous and total abdominal fat), in addition to OGTT and HOMA-IR values. We were able to show a significant association of sFRP5 with both total abdominal and subcutaneous fat. The association signal was only seen in obese males, and in this population, the minor allele of rs7072751 explains 1.8 % of variance in total abdominal fat. In addition, we saw a trend towards an association of rs10748709 with glucose metabolism. Although further research is necessary, we can conclude that sFRP5 is a significant regulator of fat development and distribution in obese males. We postulate that altered transcription factor binding on the rs7072751 surrounding sequence might play a role in the associations we found with both total abdominal and subcutaneous fat. In addition, although no conclusive evidence was found, our results indicate that sFRP5 genetic variation may affect glucose metabolism and it would be interesting to investigate this further.

Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity.

BACKGROUND: The transcription factor SIM1 (Single-minded 1) is involved in the control of food intake and in the pathogenesis of obesity. In mice, Sim1 is involved in the development of the paraventricular nucleus, and Sim1 deficiency leads to severe obesity and hyperphagia. In humans, chromosomal abnormalities in the SIM1 gene region have been reported in obese individuals. Furthermore, recent data also suggest that loss-of-function point mutations in SIM1 are responsible for SIM1 haplo-insufficiency that is involved in causing human obesity. In this study, we therefore wanted to expand the evidence regarding the involvement of SIM1 mutations in the pathogenesis of severe early-onset obesity. METHODS: We screened 561 severely overweight and obese children and adolescents and 453 lean adults for mutations in the coding region of the SIM1 gene. Mutation screening in all patients and lean individuals was performed by high-resolution melting curve analysis combined with direct sequencing. To evaluate the effect of the mutations on SIM1 transcriptional activity, luciferase reporter assays were performed. RESULTS: Mutation analysis identified four novel nonsynonymous coding variants in SIM1 in four unrelated obese individuals: p.L242V, p.T481K, p.A517V and p.D590E. Five synonymous variants, p.P57P, p.F93F, p.I183I, p.V208V and p.T653T, were also identified. Screening of the lean control population revealed the occurrence of four other rare SIM1 variants: p.G408R, p.R471P, p.S492P and p.S622F. For variants p.T481K and p.A517V, which were found in obese individuals, a decrease in SIM1 transcriptional activity was observed, whereas the transcriptional activity of all variants found in lean individuals resembled wild type. CONCLUSIONS: In this study, we have demonstrated the presence of rare SIM1 variants in both an obese pediatric population and a population of lean adult controls. Further, we have shown that functional in vitro analysis of SIM1 variants may help in distinguishing benign variants of no pathogenic significance from variants which contribute to the obesity phenotype.