Growth differentiation factor 15 is not modified after weight loss induced by liraglutide in South Asians and Europids with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor (GLP-1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP-1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26 weeks of treatment with daily liraglutide (n = 44) or placebo (n = 50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26 weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. HIGHLIGHTS: What is the central question of this study? Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP-1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)? What is the main finding and its importance? Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26 weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite-suppressing effect of liraglutide is likely exerted via pathways other than GDF15.

Thyrotrophin and thyroxine support immune homeostasis in humans.

The endocrine and the immune systems interact by sharing receptors for hormones and cytokines, cross-control and feedback mechanisms. To date, no comprehensive study has assessed the impact of thyroid hormones on immune homeostasis. By studying immune phenotype (cell populations, antibody concentrations, circulating cytokines, adipokines and acute-phase proteins, monocyte-platelet interactions and cytokine production capacity) in two large independent cohorts of healthy volunteers of Western European descent from the Human Functional Genomics Project (500FG and 300BCG cohorts), we identified a crucial role of the thyroid hormone thyroxin (T4) and thyroid-stimulating hormone (TSH) on the homeostasis of lymphocyte populations. TSH concentrations were strongly associated with multiple populations of both effector and regulatory T cells, whereas B-cell populations were significantly associated with free T4 (fT4). In contrast, fT4 and TSH had little impact on myeloid cell populations and cytokine production capacity. Mendelian randomization further supported the role of fT4 for lymphocyte homeostasis. Subsequently, using a genomics approach, we identified genetic variants that influence both fT4 and TSH concentrations and immune responses, and gene set enrichment pathway analysis showed enrichment of fT4-affected gene expression in B-cell function pathways, including the CD40 pathway, further supporting the importance of fT4 in the regulation of B-cell function. In conclusion, we show that thyroid function controls the homeostasis of the lymphoid cell compartment. These findings improve our understanding of the immune responses and open the door for exploring and understanding the role of thyroid hormones in the lymphocyte function during disease.

The associations of leptin and adiponectin with the metabolic syndrome in an Indonesian and a Dutch population.

BACKGROUND AND AIMS: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. METHODS AND RESULTS: We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1.2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively. CONCLUSIONS: Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI.

Effect of Liraglutide on Cardiovascular Function and Myocardial Tissue Characteristics in Type 2 Diabetes Patients of South Asian Descent Living in the Netherlands: A Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide may be beneficial in the regression of diabetic cardiomyopathy. South Asian ethnic groups in particular are at risk of developing type 2 diabetes. PURPOSE: To assess the effects of liraglutide on left ventricular (LV) diastolic and systolic function in South Asian type 2 diabetes patients. STUDY TYPE: Prospective, double-blind, randomized, placebo-controlled trial. POPULATION: Forty-seven type 2 diabetes patients of South Asian ancestry living in the Netherlands, with or without ischemic heart disease, who were randomly assigned to 26-week treatment with liraglutide (1.8 mg/day) or placebo. FIELD STRENGTH/SEQUENCE: 3T (balanced steady-state free precession cine MRI, 2D and 4D velocity-encoded MRI, 1 H-MRS, T1 mapping). ASSESSMENT: Primary endpoints were changes in LV diastolic function (early deceleration peak [Edec], ratio of early and late peak filling rate [E/A], estimated LV filling pressure [E/Ea]) and LV systolic function (ejection fraction). Secondary endpoints were changes in aortic stiffness (aortic pulse wave velocity [PWV]), myocardial steatosis (myocardial triglyceride content), and diffuse fibrosis (extracellular volume [ECV]). STATISTICAL TESTS: Data were analyzed according to intention-to-treat. Between-group differences were reported as mean (95% confidence interval [CI]) and were assessed using analysis of covariance (ANCOVA). RESULTS: Liraglutide (n = 22) compared with placebo (n = 25) did not change Edec (+0.2 mL/s2 × 10-3 (-0.3;0.6)), E/A (-0.09 (-0.23;0.05)), E/Ea (+0.1 (-1.2;1.3)) and ejection fraction (0% (-3;2)), but decreased stroke volume (-9 mL (-14;-5)) and increased heart rate (+10 bpm (4;15)). Aortic PWV (+0.5 m/s (-0.6;1.6)), myocardial triglyceride content (+0.21% (-0.09;0.51)), and ECV (-0.2% (-1.4;1.0)) were unaltered. DATA CONCLUSION: Liraglutide did not affect LV diastolic and systolic function, aortic stiffness, myocardial triglyceride content, or extracellular volume in Dutch South Asian type 2 diabetes patients with or without coronary artery disease. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1679-1688.

Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes.

BACKGROUND AND AIMS: Several studies have shown that glucagon-like peptide-1 (GLP-1) analogues can affect resting energy expenditure, and preclinical studies suggest that they may activate brown adipose tissue (BAT). The aim of the present study was to investigate the effect of treatment with liraglutide on energy metabolism and BAT fat fraction in patients with type 2 diabetes. METHODS AND RESULTS: In a 26-week double-blind, placebo-controlled trial, 50 patients with type 2 diabetes were randomized to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after treatment for 4, 12 and 26 weeks, we assessed resting energy expenditure (REE) by indirect calorimetry. Furthermore, at baseline and after 26 weeks, we determined the fat fraction in the supraclavicular BAT depot using chemical-shift water-fat MRI at 3T. Liraglutide reduced REE after 4 weeks, which persisted after 12 weeks and tended to be present after 26 weeks (week 26 vs baseline: liraglutide -52 ± 128 kcal/day; P = 0.071, placebo +44 ± 144 kcal/day; P = 0.153, between group P = 0.057). Treatment with liraglutide for 26 weeks did not decrease the fat fraction in supraclavicular BAT (-0.4 ± 1.7%; P = 0.447) compared to placebo (-0.4 ± 1.4%; P = 0.420; between group P = 0.911). CONCLUSION: Treatment with liraglutide decreases REE in the first 12 weeks and tends to decrease this after 26 weeks without affecting the fat fraction in the supraclavicular BAT depot. These findings suggest reduction in energy intake rather than an increase in REE to contribute to the liraglutide-induced weight loss. TRIAL REGISTRY NUMBER: NCT01761318.

The Effect of Helminths on Granulocyte Activation: A Cluster-Randomized Placebo-Controlled Trial in Indonesia.

BACKGROUND: Eosinophils are a prominent cell type in the host response to helminths, and some evidence suggests that neutrophils might also play a role. However, little is known about the activation status of these granulocytes during helminth infection. METHODS: We analyzed the expression of eosinophil and neutrophil activation markers in peripheral blood by flow cytometry and measured serum levels of eosinophil granule proteins in 300 subjects residing in an area endemic for soil-transmitted helminths (STH). The data generated are on samples before and after 1 year of 3-monthly albendazole treatment. RESULTS: Anthelmintic treatment significantly reduced the prevalence of STH. While eosinophil numbers were significantly higher in STH-infected compared to uninfected subjects and significantly decreased following albendazole treatment, there was no effect exerted by the helminths on either eosinophil nor neutrophil activation. Although at baseline eosinophil granule protein levels were not different between STH-infected and uninfected subjects, treatment significantly reduced the levels of eosinophil-derived neurotoxin (EDN) in those infected at baseline. CONCLUSIONS: These results show that besides decreasing eosinophil numbers, anthelmintic treatment does not significantly change the activation status of eosinophils, nor of neutrophils, and the only effect seen was a reduction in circulating levels of EDN. CLINICAL TRIALS REGISTRATION: http://www.isrctn.com/ISRCTN75636394.

Phenotyping diabetic cardiomyopathy in Europeans and South Asians.

BACKGROUND: The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans. METHODS: T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model. RESULTS: A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group. CONCLUSIONS: Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.

A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients.

BACKGROUND: South Asians have a high risk to develop type 2 diabetes, which may be related to substantial ectopic fat deposition. Since glucagon-like peptide-1 analogues can reduce ectopic fat accumulation, the aim of the present study was to assess the effect of treatment with liraglutide for 26 weeks on ectopic fat deposition and HbA1c in South Asian patients with type 2 diabetes. METHODS: In a placebo-controlled trial, 47 South Asian patients with type 2 diabetes were randomly assigned to treatment with liraglutide (1.8 mg/day) or placebo added to standard care. At baseline and after 26 weeks of treatment we assessed abdominal subcutaneous, visceral, epicardial and paracardial adipose tissue volume using MRI. Furthermore, myocardial and hepatic triglyceride content were examined with proton magnetic resonance spectroscopy. RESULTS: In the intention-to-treat analysis, liraglutide decreased body weight compared to placebo (- 3.9 ± 3.6 kg vs - 0.6 ± 2.2 kg; mean change from baseline (liraglutide vs placebo): - 3.5 kg; 95% CI [- 5.3, - 1.8]) without significant effects on the different adipose tissue compartments. HbA1c was decreased in both groups without between group differences. In the per-protocol analysis, liraglutide did decrease visceral adipose tissue volume compared to placebo (- 23 ± 27 cm2 vs - 2 ± 17 cm2; mean change from baseline (liraglutide vs placebo): - 17 cm2; 95% CI [- 32, - 3]). Furthermore, HbA1c was decreased by liraglutide compared to placebo (- 1.0 ± 0.8% (- 10.5 ± 9.1 mmol/mol)) vs (- 0.6 ± 0.8% (- 6.1 ± 8.8 mmol/mol)), with a between group difference (mean change from baseline (liraglutide vs placebo): - 0.6% (- 6.5 mmol/mol); 95% CI [- 1.1, - 0.1 (- 11.5, - 1.5)]). Interestingly, the decrease of visceral adipose tissue volume was associated with the reduction of HbA1c (ß: 0.165 mmol/mol (0.015%) per 1 cm2 decrease of visceral adipose tissue volume; 95% CI [0.062, 0.267 (0.006, 0.024%)]). CONCLUSIONS: While the intention-to-treat analysis did not show effects of liraglutide on ectopic fat and HbA1c, per-protocol analysis showed that liraglutide decreases visceral adipose tissue volume, which was associated with improved glycaemic control in South Asians. Trial registration NCT02660047 (clinicaltrials.gov). Registered 21 January 2016.

Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism.

IMPORTANCE: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism. OBJECTIVE: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older. DESIGN, SETTING, AND PARTICIPANTS: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018. EXPOSURES: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial). MAIN OUTCOMES AND MEASURES: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9). RESULTS: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants). CONCLUSIONS AND RELEVANCE: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

Effect of Anthelmintic Treatment on Insulin Resistance: A Cluster-Randomized, Placebo-Controlled Trial in Indonesia.

Background: Emerging evidence suggests that helminth infections are associated with lower insulin resistance (IR). Current deworming programs might remove this helminth-associated protective effect. Therefore, we evaluated the anthelmintic treatment effect on changes in IR. Methods: We conducted a double-blind, household-cluster-randomized, placebo-controlled clinical trial on Flores island, Indonesia, an area endemic for soil-transmitted helminths (STHs). All subjects received 4 rounds of albendazole or matching placebo with 3-month intervals, for 3 consecutive days. The primary outcome was the change in homeostatic model assessment of IR in those aged >16 years. An intention-to-treat analysis was performed involving all subjects and ad hoc in the helminth-infected subjects. Results: We examined 797 (in 329 households) and 872 (in 353 households) subjects, who were assigned randomly into the albendazole and placebo arms, respectively. Albendazole was associated with a significant reduction in STH prevalence, total immunoglobulin E (IgE), and eosinophil count. Whereas albendazole had no effect on IR (estimated treatment effect, 0.006 [95% confidence interval, -.010 to .021]; P = .48) at the community level, it was associated with a significant increase in IR (estimated treatment effect, 0.031 [95% confidence interval, .004 to .059]; P = .04) (P value for interaction = .01) among helminth-infected subjects as detected by microscopy. Pathway analysis suggested that this might in part be due to an increased body mass index or a reduced eosinophil count. Conclusions: Anthelmintic treatment reduces STH prevalence, total IgE, and eosinophil count but has no effect on IR at the community level. In helminth-infected subjects, treatment significantly increases IR, highlighting the need for metabolic health monitoring with ongoing deworming programs. Clinical Trials Registration: ISRCTN 75636394.

Is Hepatic Triglyceride Content Associated with Aortic Pulse Wave Velocity and Carotid Intima-Media Thickness? The Netherlands Epidemiology of Obesity Study.

Purpose To test the hypothesis that hepatic triglyceride content is associated with subclinical vascular impairment and is not confounded by various cardiometabolic risk factors. Materials and Methods This study was approved by the institutional review board, and all participants gave written informed consent. In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, a population-based cohort study, 1899 participants (52% men; mean age, 55 years ± 6 [standard deviation]) underwent magnetic resonance (MR) spectroscopy and MR imaging to assess hepatic triglyceride content, aortic pulse wave velocity (PWV), and visceral fat. Carotid intima-media thickness (IMT) was acquired and measured by trained research nurses according to standard procedures. Multivariate regression analyses were used to study associations of hepatic triglyceride content with total and regional aortic PWV and carotid IMT while adjusting for several possible confounding factors, including the metabolic syndrome. Results Total aortic PWV (mean difference, 0.5 m/sec; 95% confidence interval [CI]: 0.3, 0.7) and carotid IMT (mean difference, 37 µm; 95% CI: 25, 49) were higher in participants with hepatic steatosis. After adjusting for various covariates, a 10-fold increase in hepatic triglyceride content was associated with an increased mean aortic PWV of 0.19 m/sec (95% CI: 0.03, 0.36) in total and an increased mean aortic PWV of 0.42 m/sec (95% CI: 0.03, 0.81) in the abdominal segment. A 10-fold increase in hepatic triglyceride content was also associated with an increased mean carotid IMT of 15 µm (95% CI: 0, 29) but not after additional adjustments for visceral and total body fat. Conclusion In this relatively large population-based cohort study, hepatic triglyceride content was associated with aortic pulse wave velocity and carotid IMT. These associations were only partly explained by the metabolic syndrome and visceral adiposity, suggesting a possible specific contribution of hepatic steatosis to subclinical vascular impairment. © RSNA, 2017 Online supplemental material is available for this article.

Association between Hepatic Triglyceride Content and Left Ventricular Diastolic Function in a Population-based Cohort: The Netherlands Epidemiology of Obesity Study.

PURPOSE: To investigate the association between hepatic triglyceride content and left ventricular (LV) diastolic function while taking potential confounding factors into account, including the components of the metabolic syndrome. MATERIALS AND METHODS: The study was approved by the institutional review board, and all participants gave informed consent. In this cross-sectional analysis of baseline data from the Netherlands Epidemiology of Obesity study, a population-based, prospective cohort study, participants (45% men; mean age ± standard deviation, 55.3 years ± 6.2) underwent magnetic resonance (MR) spectroscopy and MR imaging to assess hepatic triglyceride content and LV diastolic heart function (ratio of peak filling rates of the early filling phase and atrial contraction [E/A ratio]). Multivariate linear regression analysis was performed while adjusting for confounding factors, and results were additionally stratified according to body mass index. RESULTS: Adjustment for age, sex, heart rate, alcohol consumption, pack-years of smoking, all components of the metabolic syndrome, and visceral adiposity attenuated crude observed associations. A 10-fold increase in hepatic triglyceride content was associated with a change in mean E/A ratio of -0.004 (95% confidence interval [CI]: -0.134, 0.125) in the total study population, -0.194 (95% CI: -0.430, 0.042) in the normal-weight subgroup, 0.079 (95% CI: -0.090, 0.248) in the overweight subgroup, and -0.109 (95% CI: -0.186, -0.032) in the obese subgroup. CONCLUSION: Fatty liver itself could, at least in obesity, pose a risk of myocardial dysfunction above and beyond known cardiovascular risk factors that are clustered within the metabolic syndrome. The association in the obese subgroup was small, and future studies with larger samples sizes are required to investigate to what extent the association exists and differs in normal-weight, overweight, and obese persons to unravel its clinical relevance.

Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.

UNLABELLED: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration. CONCLUSIONS: Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.

Middle-aged overweight South Asian men exhibit a different metabolic adaptation to short-term energy restriction compared with Europeans.

AIMS/HYPOTHESIS: South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers. METHODS: Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic-euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy. RESULTS: South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy restriction. CONCLUSIONS/INTERPRETATION: We conclude that South Asian men exhibit a different metabolic adaptation to short-term energy restriction than European men. TRIAL REGISTRATION: Dutch trial registry ( www.trialregister.nl ), trial number NTR 2473.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.

BACKGROUND: Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS: Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). INTERPRETATION: Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Helminth infections and type 2 diabetes: a cluster-randomized placebo controlled SUGARSPIN trial in Nangapanda, Flores, Indonesia.

BACKGROUND: Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus. Chronic helminth infections might protect against insulin resistance via a caloric restriction state and indirectly via T-helper-2 polarization of the immune system. Therefore the elimination of helminths might remove this beneficial effect on insulin resistance. METHODS/DESIGN: To determine whether soil-transmitted helminth infections are associated with a better whole-body insulin sensitivity and whether this protection is reversible by anthelmintic treatment, a household-based cluster-randomized, double blind, placebo-controlled trial was conducted in the area of Nangapanda on Flores Island, Indonesia, an area endemic for soil-transmitted helminth infections. The trial incorporates three monthly treatment with albendazole or matching placebo for one year, whereby each treatment round consists of three consecutive days of supervised drug intake. The presence of soil-transmitted helminths will be evaluated in faeces using microscopy and/or PCR. The primary outcome of the study will be changes in insulin resistance as assessed by HOMA-IR, while the secondary outcomes will be changes in body mass index, waist circumference, fasting blood glucose, 2 h-glucose levels after oral glucose tolerance test, HbA1c, serum lipid levels, immunological parameters, and efficacy of anthelmintic treatment. DISCUSSION: The study will provide data on the effect of helminth infections on insulin resistance. It will assess the relationship between helminth infection status and immune responses as well as metabolic parameters, allowing the establishment of a link between inflammation and whole-body metabolic homeostasis. In addition, it will give information on anthelmintic treatment efficacy and effectiveness. TRIAL REGISTRATION: This study has been approved by the ethical committee of Faculty of Medicine Universitas Indonesia (ref: 549/H2.F1/ETIK/2013), and has been filed by the ethics committee of Leiden University Medical Center, clinical trial number: ISRCTN75636394. The study is reported in accordance with the CONSORT guidelines for cluster-randomised trials.

Effects of bariatric surgery on pericardial ectopic fat depositions and cardiovascular function.

OBJECTIVE: Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride (TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en-Y gastric bypass (RYGB) surgery. PATIENTS: Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53·7 ± 8·9 years (mean ± SD)] scheduled to undergo RYGB surgery were included. MEASUREMENTS: Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance (MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery. RESULTS: Body mass index decreased from 41·3 ± 4·3 at baseline to 34·1 ± 2·8 kg/m(2) (P < 0·001) after 16 weeks. Glycemic control improved as well [HbA1c: 7·8 ± 1·1 to 6·8 ± 1·3% (62 ± 12 to 51 ± 14 mm) (P < 0·05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (-35·5 ± 9·6%) as compared to subcutaneous fat volume (-25·0 ± 6·3%) and in paracardial (-17·3 ±17·2%) as compared to epicardial fat volume (-6·4 ± 6·0%). CONCLUSIONS: This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change.

Short-term effects of a standardized glucose load on region-specific aortic pulse wave velocity assessed by MRI.

PURPOSE: To assess the short-term effects of a standardized oral glucose load on regional aortic pulse wave velocity (PWV) using two-directional in-plane velocity encoded MRI. MATERIALS AND METHODS: A randomized, controlled intervention was performed in 16 male subjects (mean ± standard deviation: age: 59±7 years, body mass index: 28±3 kg/m2) with impaired fasting glucose. The intervention consisted of an oral glucose load (75 grams of carbohydrates in 300 mL water) at 1 study day and water (300 mL) at the other study day. PWV was measured using multislice two-directional in-plane velocity-encoded MRI. RESULTS: PWV in the proximal aorta at 1 h post-glucose load decreased compared with PWV 1-h post-water (delta PWV: -1.0±2.6 m/s versus 0.6±2.0 m/s, P=0.02). Eight responding subjects showed a significant decrease in PWV of the proximal aorta after the glucose load and had a decreased waist circumference (P=0.037) compared with nonresponders, being one of the major criteria of the metabolic syndrome. There was no significant change in PWV of the distal aorta at 1 h post-load comparing both intervention groups. CONCLUSION: A standardized oral glucose load induces a decrease of the proximal, but not of the distal, aortic PWV. Regional response of aortic PWV may be associated with features of the metabolic syndrome.

Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.

OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.

Towards Personalized TSH Reference Ranges: A Genetic and Population-Based Approach in Three Independent Cohorts.

Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions. Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically determined TSH reference ranges in a thyroid disease-free cohort (n = 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132). Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other nongenetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7 × 10-8). Conclusions: Individual genetic profiles have the potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.