Search

Objectives Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men. Methods In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures. Results Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI −0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed. Conclusions In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.

Aims/hypothesis: Lifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes. Methods: This open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48–97 mmol/mol (6.5–11%), BMI >25 kg/m2, eGFR >30 ml min−1 [1.73 m]−2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev). Results: Seventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] −1.9 [−3.5, −0.3] mmol/mol [−0.18 (−0.32, −0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] −0.8 [−1.2, −0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] −4.1 [−5.9, −2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] −18 [−29, −6]%, p < 0.01) and liver fat content (by mean [95% CI] −26 [−45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets. Conclusions/interpretation: Moderate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies. Trial registration: ClinicalTrials.gov NCT03814694. Funding: The study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg. Graphical abstract: [Figure not available: see fulltext.].

AIMS: To evaluate the effect of curcumin treatment on hepatic fat content in obese individuals.MATERIALS AND METHODS: In a double-blind, parallel-group trial, 37 obese, non-diabetic individuals were randomised to placebo or curcumin treatment for six weeks. Curcumin was dosed as lecithin-formulated tablet; 200 mg twice daily. Primary endpoint was hepatic fat content as assessed by magnetic resonance spectroscopy (MRS). Other endpoints included anthropometric measurements, hepatic biomarkers including FibroScan® measurements, metabolic parameters, inflammation markers, appetite measures and ad libitum food intake.RESULTS: Baseline characteristics (mean ± SD): age 46 ±14 years; hepatic fat content 12.2 ± 8.8 percent points; body mass index 38.8 ±6.1 kg/m 2 ; waist circumference 125.8 ± 12.3 cm. After six weeks treatment with curcumin, hepatic fat content was changed by -0.86 percent points (95% CI -3.65;1.94) compared to 0.71 percent points (95% CI -2.08;3.51) with placebo, thus resulting in a non-significant estimated treatment difference of -1.57 percent points (95% CI -5.36; 2.22, P = 0.412). Compared to placebo, curcumin treatment caused small reductions in fasting plasma glucose (estimated treatment difference (ETD) -0.24 mmol/L (95% CI -0.45; -0.03)), triglycerides (ETD (percentage change) -20.22% (95% CI -33.21; -6.03)), and gamma glutamyltransferase (ETD (percentage change) -15.70 (95% CI -23.32; -7.32)), but except for gamma glutamyltransferase, none of these differences remained statistically significant after adjusting for multiple testing. Treatment was well tolerated. CONCLUSIONS: Compared to placebo, curcumin treatment for six weeks had no significant effect on MRS-assessed hepatic fat content in obese individuals with primarily mild steatosis. Curcumin was well tolerated. This article is protected by copyright. All rights reserved.

Purpose: We previously reported beneficial glucoregulatory effects of a fully provided carbohydrate-reduced, high-protein (CRHP) diet in patients with type 2 diabetes mellitus (T2DM) in a crossover 2 × 6-week trial, in which patients maintained their body weight. Here, we investigated physiological changes during an additional 6-month period on a self-selected and self-prepared CRHP diet. Methods: Twenty-eight patients with T2DM were instructed to consume a CRHP diet (30% of energy from carbohydrate and 30% from protein) for 24 weeks, after an initial 2 × 6-week trial when all food was prepared and provided to them. Patients received dietary advice every 2 weeks. At weeks 0, 6, 12 and 36, they underwent a 3-h intravenous glucose tolerance test, a 4-h mixed meal test, and a 48-h continuous glucose monitoring. Liver, muscle, pancreas, and visceral fat contents were measured by magnetic resonance imaging. Results: During the 24-week self-selected diet period (weeks 12–36), body weight, visceral fat, liver fat, and glycated haemoglobin were maintained at the same levels achieved at the end of the fully provided diet period, and were still lower than at baseline (P < 0.05). Postprandial insulinaemia and insulin secretion were significantly greater (P < 0.05). At week 36, fasting insulin and C-peptide levels increased (P < 0.01) and daily glycaemia decreased further (P < 0.05) when compared with the end of the fully provided diet period. Conclusion: Substituting dietary carbohydrate for protein and fat has metabolic benefits in patients with T2DM. These beneficial effects are maintained or augmented over the next 6 months when patients self-select and self-prepare this diet in a dietitian-supported setting. Trial registration: ClinicalTrials.gov NCT02764021.

AIMS/HYPOTHESIS: Dietary recommendations for treating type 2 diabetes are unclear but a trend towards recommending a diet reduced in carbohydrate content is acknowledged. We compared a carbohydrate-reduced high-protein (CRHP) diet with an iso-energetic conventional diabetes (CD) diet to elucidate the effects on glycaemic control and selected cardiovascular risk markers during 6 weeks of full food provision of each diet.METHODS: The primary outcome of the study was change in HbA1c. Secondary outcomes reported in the present paper include glycaemic variables, ectopic fat content and 24 h blood pressure. Eligibility criteria were: men and women with type 2 diabetes, HbA1c 48-97 mmol/mol (6.5-11%), age >18 years, haemoglobin >6/>7 mmol/l (women/men) and eGFR >30 ml min-1 (1.73 m)-2. Participants were randomised by drawing blinded ballots to 6 + 6 weeks of an iso-energetic CRHP vs CD diet in an open label, crossover design aiming at body weight stability. The CRHP/CD diets contained carbohydrate 30/50 energy per cent (E%), protein 30/17E% and fat 40/33E%, respectively. Participants underwent a meal test at the end of each diet period and glycaemic variables, lipid profiles, 24 h blood pressure and ectopic fat including liver and pancreatic fat content were assessed at baseline and at the end of each diet period. Data were collected at Copenhagen University Hospital, Bispebjerg and Copenhagen University Hospital, Herlev.RESULTS: Twenty-eight participants completed the study. Fourteen participants carried out 6 weeks of the CRHP intervention followed by 6 weeks of the CD intervention, and 14 participants received the dietary interventions in the reverse order. Compared with a CD diet, a CRHP diet reduced the primary outcome of HbA1c (mean ± SEM: -6.2 ± 0.8 mmol/mol (-0.6 ± 0.1%) vs -0.75 ± 1.0 mmol/mol (-0.1 ± 0.1%); p CONCLUSIONS/INTERPRETATION: A moderate macronutrient shift by substituting carbohydrates with protein and fat for 6 weeks reduced HbA1c and hepatic fat content in weight stable individuals with type 2 diabetes.TRIAL REGISTRATION: ClinicalTrials.gov NCT02764021.FUNDING: The study was funded by grants from Arla Food for Health; the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; the Department of Clinical Medicine, Aarhus University; the Department of Nutrition, Exercise and Sports, University of Copenhagen; and Copenhagen University Hospital, Bispebjerg.

Aim To investigate whether the mineralocorticoid receptor antagonist eplerenone has beneficial effects on liver fat and metabolism in patients with type 2 diabetes (T2D), the mineralocorticoid receptor antagonist in type 2 diabetes (MIRAD) trial. Material and methods In this 26-week, double-blind, randomized, placebo-controlled trial, we enrolled 140 patients with T2D and high risk of cardiovascular disease. Patients were randomized 1:1 to either eplerenone with a target dose of 200 mg/day for patients with estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or more and 100 mg/day for patients with eGFR between 41 and 59 mL/min per 1.73 m2 or placebo. The primary outcome measure was change in liver fat by proton magnetic resonance spectroscopy at week 26 from baseline; secondary outcomes were changes in metabolism, and safety by incident hyperkalaemia. Results No changes in liver fat in the eplerenone group 0.91% (95% CI -0.57 to 2.39) or the placebo group -1.01% (-2.23 to 0.21) were found. The estimated absolute treatment difference was 1.92% (-3.81 to 0.01; P = 0.049). There was no beneficial impact on supporting secondary outcome variables of metabolism as fat mass distribution, lipid metabolism or insulin resistance. Despite a high dosage of eplerenone 164 versus 175 mg in patients treated with placebo (P = 0.228), the number of patients with incident hyperkalaemia (≥5.5 mmol/L) was low, with six in the eplerenone versus two in the placebo group (P = 0.276). Conclusion The addition of high doses of eplerenone to background antidiabetic and antihypertensive therapy does not show beneficial effects on liver fat and metabolism in patients with T2D.

Objective: Elevated triglyceride-rich lipoproteins (TRL), excess small dense LDL particles (LDL5) and decreased HDL2/HDL3 ratio promote atherogenesis in type 2 diabetes (T2D). Carbohydrate restriction reduced intrahepatic triglyceride (IHTG) content beyond the positive effect of weight loss in a group of T2D patients, the present study sought to determine whether parallel improvements in lipoprotein density profiles occurred in these same patients. Research Design and Methods: Seventy-two adult T2D patients with a mean BMI of 33 kg/m2 were assigned to 6 weeks of fully-provided hypocaloric dietary treatment aimed at ~6% weight loss, either with a carbohydrate-reduced high-protein (CRHP, C30E%/P30E%/F40E%) diet or a conventional diabetes (CD, C50E%/P17E%/F33E%) diet. Density profiles of lipoproteins were determined by ultracentrifugation of fluorescently labelled plasma. Magnetic resonance spectroscopy was used to assess IHTG. Results: Body weight decreased by 5.8 kg (~6%) in both groups. Compared with the CD diet, the CRHP diet reduced TRL (mean [95% CI]) by -16 [-30;1]% (p=0.07) and LDL5 by -13 [-22;-3]% (p=0.01), and increased HDL2/HDL3 by 11 [1;22]% (p=0.04). The CRHP diet also decreased IHTG more than the CD diet (-26 [-45;0]%, p=0.05), and changes in IHTG including both groups correlated significantly with changes in TRL and LDL5 (Spearman’s ρ 0.39 and 0.38, p Conclusions: Carbohydrate restriction adds to the positive effect of weight loss in T2D patients by inducing greater improvements in atherogenic lipid profile, maybe facilitated by a reduction in intrahepatic fat. Disclosure M. N. Thomsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. F. Magkos: None. H. S. Thomsen: None. R. Walzem: None. S. B. Haugaard: None. T. Krarup: None. M. J. Skytte: None. A. Samkani: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). J. Frystyk: None. E. Chabanova: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. M. Larsen: None. Funding Arla Foods; Danish Dairy Research Foundation

Background: We hypothesized that dietary carbohydrate reduction will add to the effect of a diet-induced 6% body-weight loss on glycemic control and hepatic fat content in patients with type 2 diabetes (T2D). Methods: Forty-four persons of mean HbA1c 56.4 mmol/mol and 9 years of T2D were randomized 1:1 for 6-weeks full food provision, a hypo-caloric carbohydrate-reduced high-protein (CRHP) or a conventional diabetes (CD) diet (carbohydrate 30E%/50E%, protein 30E%/17E% and fat 40E%/33E%). Body-weight loss was aimed at 6% and reinforced bi-weekly by adjustment of hypo-caloric diets. Hepatic fat content was estimated by Magnetic Resonance (MR) spectroscopy and analyzed by a MR research technician, blinded to the protocol. Results: Six weeks of a hypo-caloric CRHP diet compared with a CD diet improved HbA1c (mean±SD) by further 2 mmol/mol (-8.7±4.6 mmol/mol vs. -6.7±3.9 mmol/mol, p=0.04) with comparable weight losses, 5.5±1.7 kg (5.6 %) and 5.6±2.2 kg (5.9 %) of body-weight, respectively. Hepatic fat content (median (IQR) was reduced significantly while consuming the CRHP diet (5.2% (1.3-6.9)) and CD diet (2.6% (1.6-6.5)), but with no difference between diets (p=0.40). Conclusion: Reducing carbohydrate and increasing protein and fat adds clinical relevance to the positive effects of body-weight loss on glucose control in T2D patients. Disclosure M.N. Thomsen: None. M.J. Skytte: None. A. Samkani: None. M.H. Carl: None. P. Weber: None. A. Astrup: Advisory Panel; Self; Gelesis, Novo Nordisk A/S, Saniona, Weight Watchers International, Inc. Research Support; Self; Arla Food for Health, Gelesis, Novo Nordisk A/S. Speaker’s Bureau; Self; Arla Food for Health. Stock/Shareholder; Self; Gelesis. T.M. Larsen: Advisory Panel; Self; Advisor for Sense diet programme. J. Frystyk: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. B. Hartmann: None. H. Thomsen: None. E. Chabanova: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.B. Haugaard: None. T. Krarup: None.

AIMS To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P

Women with polycystic ovary syndrome (PCOS) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT), and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled, randomized clinical trial 72 women with PCOS and BMI >25 kg/m(2) and/or insulin resistance were treated with liraglutide or placebo 1.8 mg/day (2:1) for 26 weeks. Liver fat content was assessed by (1) HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD with two-thirds (all p

Rationale and Objectives The purpose of the present study was to obtain a cutoff value of liver fat content for the diagnosis of hepatic steatosis by comparing magnetic resonance (MR) spectroscopy results in children and adolescents with normal and excess weight. Materials and Methods The study included 420 children and adolescents (91 normal-weight, 99 overweight, and 230 obese) 8–18 years of age. Proton magnetic resonance spectroscopy was performed with a 3T MR system using point resolved spectroscopy sequence with series echo times. Results The mean absolute mass concentration of liver fat was obtained: 0.5 ± 0.04% in normal-weight boys; 0.5 ± 0.03% in normal-weight girls; 0.9 ± 0.16% in boys with overweight; 1.1 ± 0.24% in girls with overweight; 1.7 ± 0.24% in boys with obesity; and 1.4 ± 0.21% in girls with obesity. The cutoff value of absolute mass concentration of liver fat for hepatic steatosis was found to be 1.5%. Based on this cutoff value, hepatic steatosis was diagnosed in 16% of boys with overweight, 11% of girls with overweight, 32% of boys with obesity, and 27% of girls with obesity. Conclusions Proton magnetic resonance spectroscopy was successfully applied to obtain the cutoff value of absolute mass concentration of liver fat for the diagnosis of hepatic steatosis in children and adolescents. Children and adolescents with obesity have higher risk of hepatic steatosis than their peers with overweight.

Background Elevated plasma concentrations of liver enzymes are routinely used as markers of liver injury in adults and children. Currently, the age- and sex-specific effects of adiposity on pediatric liver enzyme concentrations are unclear. Methods We included participants from 2 cohorts of Danish children and adolescents: 1858 from a population-based cohort and 2155 with overweight or obesity, aged from 6 to 18 years. Age- and sex-specific percentile curves were calculated for fasting plasma concentrations of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase (ALP) in both cohorts. Hepatic fat content was assessed by proton magnetic resonance spectroscopy in 458 participants. Results Concentrations of ALT, AST, LDH, and ALP decreased with age in both girls and boys, while GGT and bilirubin were comparable across age groups in girls and increased slightly with age in boys. Children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups. Concentrations of ALT, and to a lesser degree GGT, increased with age in boys with overweight or obesity. Optimal ALT cut-points for diagnosing hepatic steatosis (liver fat content > 5%) was 24.5 U/L for girls (sensitivity: 55.6%, specificity: 84.0%), and 34.5 U/L for boys (sensitivity: 83.7%, specificity: 68.2%). Conclusions Pediatric normal values of liver enzymes vary with both age and sex. Overweight and obesity is associated with elevated biochemical markers of liver damage. These findings emphasize the need for prevention and treatment of overweight and obesity in children and adolescents. (J Clin Endocrinol Metab XX: 0-0, 2019)

OBJECTIVE Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes. A growing body of evidence points at a beneficial effect of MR antagonists (MRAs) on adipocyte function via the inhibition of adipocyte differentiation, downregulation of rho-kinase activity, pro-inflammatory proteins and increase of adiponectin expression in visceral fat. Therefore, intervention with MRAs may improve dysfunctional adipose tissue metabolism and reverse NAFLD. The primary hypothesis of the MIRAD trial was that treatment with high dose of the selective MRA eplerenone as an add-on to standard therapy, would improve liver fat content, lipid and glucose metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this investigator-initiated, double-blinded clinical trial, 140 patients with type 2 diabetes and high cardiovascular disease risk were randomized 1:1 to eplerenone 100 - 200 mg or placebo for 26 weeks. The primary outcome was change in liver fat assessed by proton magnetic resonance spectroscopy. Secondary outcomes were changes in fat distribution assessed by DXA scan, measures of lipid and glucose metabolism by 4 point OGTT with measurements of glucose and insulin, and safety as evaluated by incident hyperkalaemia and increase in serum creatinine. RESULTS The mean ± SD age was 63.4 ± 9 years, BMI 30.7 ± 4.2 kg/m2, HbA1c 7.6 ± 3.5% (59.6 ± 14.5 mmol/mol) and duration of diabetes was 11.7 ± 7.2 years. At baseline, more than 80% of the patients were on ACE-inhibitor or ARB. The prevalence of NAFLD, defined as liver fat content ≥5.6%, was 48%. Liver fat content did not change after 26 weeks of treatment with eplerenone (1.1% [0.68; 1.66], P = 0.776) or with a placebo (-0.8% [-1.4; 0.5], P = 0.500), while a minor difference between groups was observed (P=0.026). Furthermore, there was no beneficial impact on supporting secondary outcome measures of lipid and glucose metabolism as abdominal fat distribution, lipids, circulating free fatty acids, plasma adiponectin or IR. Despite a high dosage of eplerenone (164 vs 175 mg) in patients treated with placebo (P = 0.228), the incidence of hyperkalaemia during the 26 weeks was low (p-potassium ≥5.5 mmol/L; 10 vs 2) for eplerenone vs placebo (P = 0.038). Only four patients had an increase ≥ 30% in s-creatinine during titration, with no difference between groups. At baseline, no differences between groups in liver fibrosis score NFS was observed, while at week 26, the NFS score decreased in the eplerenone group compared to placebo (P = 0.021). CONCLUSIONS We report no metabolic beneficial effect from eplerenone on liver fat or parameters of glucose and lipid metabolism in patients with type 2 diabetes, although a potential beneficial effect on liver fibrosis was found.

Background The metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between Mets and ectopic fat may offer clinical relevance. Objectives To investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these. Methods Two-hundred-and-sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry, and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy. Results We observed an odds ratio in girls with overweight/obesity of 12.2 (95% CI: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses. Conclusion Hepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity. Trial registration ClinicalTrials.gov registration number: NCT00928473, the Danish Childhood Obesity Biobank. Registered June 25, 2009.

Aim Natriuretic peptides (NPs) have emerged as important regulators of lipid metabolism. Reduced levels of NPs are reported in obesity and in patients with type 2 diabetes (T2D). This NP deficiency may affect their ectopic fat distribution and lead to high risk of non-alcoholic fatty liver disease (NAFLD). Methods In this cross-sectional study, the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and liver fat content was quantified using 1H-magnetic resonance spectroscopy in 120 patients with T2D. Results NAFLD (defined as liver fat content ≥ 5.6%) was found in 57 (48%) of the T2D patients, who also had significantly lower NT-proBNP (P = 0.002) levels compared with patients without NAFLD, but did not differ as regards the presence of cardiovascular disease (CVD) or in kidney function. After adjusting for potential confounders (age, gender, HbA1c, BMI, HOMA2-IR, CVD, eGFR), the odds ratio for the presence of NAFLD was increased by 2.9 (P = 0.048) for NT-proBNP levels Conclusion Reduced plasma NT-proBNP levels are independently associated with high liver fat content in patients with T2D. The present study suggests that NP deficiency may play a role in the development of NAFLD in T2D.

We aimed to compare the effect of aerobic interval training (AIT) versus a low energy diet (LED) on physical fitness, body composition, cardiovascular risk factors and symptoms in overweight individuals with coronary artery disease (CAD).Seventy non-diabetic participants with CAD, a BMI28 kg/m(2) and aged 45 to 75 years were randomised to 12 weeks' AIT at 90% peak heart rate three times a week or LED (800-1000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet.Twenty-six (74%) AIT and 29 (83%) LED participants completed intervention per protocol. VO2peak (mL/kg fat free mass(0.67)/min) increased by 10.4% (p = 0.002) following AIT, whereas no change was observed after LED (-3.0%, p = 0.095). The LED group lost 10.6% body weight and 26.6% body fat mass (p 0.001) compared to 1.6% (p = 0.002) and 5.5% (p 0.001) following AIT. Waist circumference and visceral abdominal fat were reduced by both interventions but were most pronounced following LED (between-group, p 0.001). Total cholesterol, non-HDL-C and triglycerides decreased significantly in both groups whereas HDL-C and blood pressure were unchanged. Six participants had their antihypertensive treatment reduced following LED (between-group, p = 0.032). Canadian Cardiovascular Society (CCS), New York Heart Association (NYHA) and anxiety scores were improved, while depressive symptoms remained unchanged. Intention-to-treat analyses including 65 participants (93%) were similar to per protocol analysis.Both interventions were feasible and effective in achieving the desired effects. LED was superior in improving body composition and blood pressure, whereas effects on lipids and symptoms were similar in the two groups. Thus, both AIT and LED improve the cardiovascular risk profile in overweight individuals with contemporarily treated CAD.

In recent years, proton magnetic resonance spectroscopy (MRS) has emerged as a non-invasive technique for measurement of fat content in the liver. The technique is often applied for overweight and obese patients. However, excessively obese patients cannot be examined in most conventional magnetic resonance systems due to limited space. The purpose of this study was to examine the ability of open 1T system to monitor liver fat with proton MRS and to compare hepatic fat fractions (HFFs) obtained using an open 1T system with assessment with 3T proton MRS.The study included 23 children and adolescents up to 20 years of age with a body mass index above the 97th percentile according to age and gender. Proton MRS for each patient was performed in both 1T and 3T using point resolved spectroscopy sequence in a single volume positioned in the right liver lobe.Average T2 relaxation times obtained for an open 1T system (55 ± 7 ms for water and 85 ± 11 ms for fat) were higher than average T2 relaxation times obtained for a 3T system (31 ± 4 ms for water and 66 ± 10 ms for fat). HFFs measured using an open 1T system showed strong correlation with HFFs measured using a 3T system (r = 0.99, P0.0001).Proton MRS measurements of HFF with an open 1T system are feasible. Open 1T system may reliably replace 3T magnetic resonance system for the assessment of liver fat.

Objective The objective was to investigate T 2 relaxation values and to optimize hepatic fat quantification using proton MR spectroscopy ( 1 H MRS) at 3 T in overweight and obese children and adolescents. Subjects The study included 123 consecutive children and adolescents with a body mass index above the 97th percentile according to age and sex. 1 H MR spectroscopy was performed at 3.0 T using point resolved spectroscopy sequence with series TE. T 2 relaxation values and hepatic fat content corrected for the T 2 relaxation effects were calculated. Results T 2 values for water ranged from 22 ms to 42 ms (mean value 28 ms) and T 2 values for fat ranged from 36 ms to 99 ms (mean value 64 ms). Poor correlation was observed: (1) between T 2 relaxation times of fat and T 2 relaxation times of water (correlation coefficient r = 0.038, P = 0.79); (2) between T 2 relaxation times of fat and fat content ( r = 0.057, P = 0.69); (3) between T 2 relaxation times of water and fat content ( r = 0.160, P = 0.26). Correlation between fat peak content and the T 2 corrected fat content decreased with increasing echo time TE: r = 0.97 for TE = 45, r = 0.93 for TE = 75, r = 0.89 for TE = 105, P Conclusion 1 H MRS at 3 T is an effective technique for measuring hepatic fat content in overweight and obese children and adolescents. It is necessary to measure T 2 relaxation values and to correct the spectra for the T 2 relaxation effects in order to obtain an accurate estimate of the hepatic fat content.

What is already known about this subject • Investigations of non-alcoholic fatty liver disease (NAFLD) by non-invasive imaging procedures have limited evidence. • Thirty percent of obese children are estimated to have NAFLD and implications for future morbidity are uncertain. What this study adds • Many obese children and youths exhibit a high liver fat content as examined by magnetic resonance spectroscopy. • Associations between liver fat content, anthropometry, abdominal adipose tissue distribution and liver enzymes are illustrated. Summary The study aims to investigate the degree of hepatic steatosis and associations with the amount of abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), anthropometric data and biochemical measures of liver enzymes in children and youths included in obesity treatment. The study included 164 patients, aged 6–20 years, with a body mass index (BMI) above the 90th percentile for sex and age. Liver fat content was measured by magnetic resonance spectroscopy (MRS). SAT and VAT were measured by magnetic resonance imaging. Hepatic steatosis was defined as liver fat content >5% (steatosis-5%) and 9% (steatosis-9%), respectively. Data on waist circumference (WC) and blood samples were available in 124 patients. Steatosis-5% and steatosis-9% were identified in 45% and 27% of the patients, respectively. These patients had increased SAT, VAT, BMI standard deviation score, WC/height ratio, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels. GGT, ALT and VAT were found to be independent risk factors of hepatic steatosis. In this study, a substantial proportion of obese children and youths have hepatic steatosis. Therefore, it is important to examine these subjects for the degree of fat in their liver. Future studies focusing on hepatic steatosis should consider the use of MRS in addition to blood samples.

Background Ectopic fat deposition in liver and skeletal muscle tissue is related to cardiovascular disease risk and is a common metabolic complication in obese children. We evaluated the hypotheses of ectopic fat in these organs could be diminished following 1 year of multidisciplinary care specialized in childhood obesity, and whether this reduction would associate with changes in other markers of metabolic function. Methods This observational longitudinal study evaluated 40 overweight children and adolescents enrolled in a multidisciplinary treatment protocol at the Children’s Obesity Clinic, Holbæk, Denmark. The participants were assessed by anthropometry, fasting blood samples (HbA1c, glucose, insulin, lipids, and biochemical variables of liver function), and liver and muscle fat content assessed by magnetic resonance spectroscopy at enrollment and following an average of 12.2 months of care. Univariate linear regression models adjusted for age, sex, treatment duration, baseline degree of obesity, and pubertal developmental stage were used for investigating possible associations. Results The standard deviation score (SDS) of baseline median body mass index (BMI) was 2.80 (range: 1.49–3.85) and the median age was 14 years (10–17). At the end of the observational period, the 40 children and adolescents (21 girls) significantly decreased their BMI SDS, liver fat, muscle fat, and visceral adipose tissue volume. The prevalence of hepatic steatosis changed from 28 to 20 % (p = 0.26) and the prevalence of muscular steatosis decreased from 75 to 45 % (p = 0.007). Changes in liver and muscle fat were independent of changes in BMI SDS, baseline degree of obesity, duration of treatment, age, sex, and pubertal developmental stage. Conclusions A 1-year multidisciplinary intervention program in the setting of a childhood obesity outpatient clinic confers a biologically important reduction in liver and muscle fat; metabolic improvements that are independent of the magnitude of concurrent weight loss. Trial registration ClinicalTrials.gov registration number: NCT00928473, the Danish Childhood Obesity Biobank. Registered June 25, 2009. Electronic supplementary material The online version of this article (doi:10.1186/s12887-015-0513-6) contains supplementary material, which is available to authorized users.

Objectives This cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children. Methods Fasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8–18 years. Results In 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed. Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol. Conclusion Hepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk.

Background : Proton MR Spectroscopy ( 1 H MRS) can be used to measure hepatic fat fractions (HFF) in liver cells for assessment of non-alcoholic fatty liver disease (NAFLD). The measurement is typically performed in a single volume. For correct diagnosis it is important to know variability of HFF within liver. The purpose of this study was to investigate regional differences in HFF in a large group of overweight and obese children and adolescents using 1H MRS at 3T. Methods: The study included 175 consecutive children and adolescents from 7 to 18 years old with a body mass index above the 97th percentile according to age and gender. 1 H MRS was performed at 3.0T using a point resolved spectroscopy sequence in two 11mmx11mmx11mm volumes positioned in different parts of the right liver lobe. Results: Up to 12% difference in HFF between the two volumes was observed: the regional differences in HFF are below 1% for patients with HFF under 3%; patients with HFF between 3% and 20% have regional differences in HFF up to 5%; patients with HFF over 20% have regional differences in HFF up to 12%. Conclusions: 1H MRS diagnosis and severity assessment of NAFLD in overweight and obese children and adolescents should take up to 12% regional differences in hepatic fat fractions into account.

Background: Intake of industrially produced trans fatty acids (TFAs) is, according to observational studies, associated with an increased risk of cardiovascular disease, but the causal mechanisms have not been fully elucidated. Besides inducing dyslipidemia, TFA intake is suspected to promote abdominal and liver fat deposition. Objective: We examined the effect of a high intake of TFA as part of an isocaloric diet on whole-body, abdominal and hepatic fat deposition, and blood lipids in postmenopausal women. Methods: In a 16-week double-blind parallel intervention study, 52 healthy overweight postmenopausal women were randomized to receive either partially hydrogenated soybean oil providing 15.7 g day−1 of TFA or a control oil with mainly oleic and palmitic acid. Before and after the intervention, body composition was assessed by dual-energy X-ray absorptiometry, abdominal fat by magnetic resonance (MR) imaging, and liver fat by 1H MR spectroscopy. Results: Compared with the control fat, TFA intake decreased plasma high-density lipoprotein (HDL)-cholesterol by 10%, increased low-density lipoprotein (LDL)-cholesterol by 18% and resulted in an increased LDL/HDL-cholesterol ratio (baseline adjusted mean (95% CI) difference between diet groups 0.41 (0.22; 0.60); P

Background: The consumption of sucrose-sweetened soft drinks (SSSDs) has been associated with obesity, the metabolic syndrome, and cardiovascular disorders in observational and short-term intervention studies. Too few long-term intervention studies in humans have examined the effects of soft drinks. Objective: We compared the effects of SSSDs with those of isocaloric milk and a noncaloric soft drink on changes in total fat mass and ectopic fat deposition (in liver and muscle tissue). Design: Overweight subjects (n = 47) were randomly assigned to 4 different test drinks (1 L/d for 6 mo): SSSD (regular cola), isocaloric semiskim milk, aspartame-sweetened diet cola, and water. The amount of intrahepatic fat and intramyocellular fat was measured with 1 H-magnetic resonance spectroscopy. Other endpoints were fat mass, fat distribution (dual-energy X-ray absorptiometry and magnetic resonance imaging), and metabolic risk factors. Results: The relative changes between baseline and the end of 6-mo intervention were significantly higher in the regular cola group than in the 3 other groups for liver fat (132‐143%, sex-adjusted mean;P , 0.01), skeletal muscle fat (117‐221%; P , 0.05), visceral fat (24‐31%; P , 0.05), blood triglycerides (32%; P , 0.01), and total cholesterol (11%; P , 0.01). Total fat mass was not significantly different between the 4 beverage groups. Milk and diet cola reduced systolic blood pressure by 10‐15% compared with regular cola (P , 0.05). Otherwise, diet cola had effects similar to those of water. Conclusion: Daily intake of SSSDs for 6 mo increases ectopic fat accumulation and lipids compared with milk, diet cola, and water. Thus, daily intake of SSSDs is likely to enhance the risk of cardiovascular and metabolic diseases. This trial is registered at clinicaltrials.gov as NCT00777647. Am J Clin Nutr doi: 10.3945/ajcn. 111.022533.

The degree of fat deposition in muscle and its implications for obesity-related complications in youth are not well understood. One hundred and fifty-nine patients (mean age: 13.3 years; range: 6-20) with a body mass index (BMI) >90th percentile for age and sex were included. Muscle fat content (MFC) was measured in the psoas muscle by proton magnetic resonance spectroscopy. The patients were assigned to two groups: MFC

Intake of industrially produced trans-fatty acids (TFA) has been linked to increased risk of type 2 diabetes mellitus in observational studies. We investigated the causality of this association by examining if a high intake of TFA impairs measures of glucose homeostasis and induces intramuscular lipid deposition in abdominally obese women. In a double-blind, parallel dietary intervention study, 52 healthy but overweight postmenopausal women were randomized to receive either partially hydrogenated soybean oil (15 g/d TFA) or a control oil (mainly oleic and palmitic acid) for 16 weeks. Three markers of glucose homeostasis and 4 markers of lipolysis were derived from glucose, insulin, C-peptide, nonesterified fatty acid, and glycerol concentrations during a 3-hour frequent sampling oral glucose tolerance test. Intramuscular lipids were assessed by magnetic resonance spectroscopy. Forty-nine women completed the study. Insulin sensitivity (assessed by ISI(composite)), β-cell function (the disposition index), and the metabolic clearance rate of insulin were not significantly affected by the dietary intervention. Neither was the ability of insulin to suppress plasma nonesterified fatty acid and glycerol during oral glucose ingestion nor the intramuscular lipid deposition. In conclusion, high TFA intake did not affect glucose metabolism over 16 weeks in postmenopausal overweight women. A study population with a stronger predisposition to insulin resistance and/or a longer duration of exposure may be required for insulin sensitivity to be affected by intake of industrial TFA.

Contains fulltext : 53230.pdf (Publisher’s version ) (Closed access) Recently, a new oral liver-specific manganese-based MR agent (CMC-001) has been introduced. This contrast medium is delivered to the liver in high concentrations in the portal vein and very low doses in the hepatic artery, as only small amounts of manganese enter the general circulation. It is taken up by the hepatocytes and excreted in the bile. Our initial experience with the new MR contrast medium in a variety of patients is reported. A total of 20 patients (11 males and 9 females) were studied with MR imaging 2 h after oral ingestion of the contrast agent. Sixteen patients were referred for evaluation of focal liver lesion(s), whereas in the remaining four patients, evaluation of the biliary tract was requested. In the 17 patients without biliary obstruction, there was an increased signal intensity of the liver parenchyma, whereas in the three patients with biliary obstruction, the uptake was delayed. There was excellent visualization of the biliary system on the T1-weighted images in the 16 patients without biliary obstruction referred for evaluation of a focal liver lesion. In seven patients, the uptake was patchy. In patients with focal liver lesions or biliary tract diseases, it is possible to increase the signal intensity of the liver parenchyma after the oral intake of CMC-001. In patients without biliary tract obstruction, the biliary system is easily visualized. Oral manganese seems to be useful in hepatobiliary MRI. Further research is strongly warranted.

Prostate cancer is one of the most common malignancies leading to cancer-related mortality in elderly men. Despite recent improvements in detection and treatment, more accurate disease characteriza...

Background Coronary artery disease (CAD) is accountable for more than 7 million deaths each year according to the World Health Organization (WHO). In a European population 80% of patients diagnosed with CAD are overweight and 31% are obese. Physical inactivity and overweight are major risk factors in CAD, thus central strategies in secondary prevention are increased physical activity and weight loss. Methods/Design In a randomized controlled trial 70 participants with stable CAD, age 45–75, body mass index 28–40 kg/m2 and no diabetes are randomized (1:1) to 12 weeks of intensive exercise or weight loss both succeeded by a 40-week follow-up. The exercise protocol consist of supervised aerobic interval training (AIT) at 85-90% of VO2peak 3 times weekly for 12 weeks followed by supervised AIT twice weekly for 40 weeks. In the weight loss arm dieticians instruct the participants in a low energy diet (800–1000 kcal/day) for 12 weeks, followed by 40 weeks of weight maintenance combined with supervised AIT twice weekly. The primary endpoint of the study is change in coronary flow reserve after the first 12 weeks’ intervention. Secondary endpoints include cardiovascular, metabolic, inflammatory and anthropometric measures. Discussion The study will compare the short and long-term effects of a protocol consisting of AIT alone or a rapid weight loss followed by AIT. Additionally, it will provide new insight in mechanisms behind the benefits of exercise and weight loss. We wish to contribute to the creation of effective secondary prevention and sustainable rehabilitation strategies in the large population of overweight and obese patients diagnosed with CAD. © 2013 Pedersen et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Background Coronary artery disease (CAD) has a negative impact on exercise capacity. The aim of this study was to determine how coronary microvascular function, glucose metabolism and body composition contribute to exercise capacity in overweight patients with CAD and without diabetes. Methods Sixty-five non-diabetic, overweight patients with stable CAD, BMI 28–40 kg/m2 and left ventricular ejection fraction (LVEF) above 35 % were recruited. A 3-hour oral glucose tolerance test was used to evaluate glucose metabolism. Peak aerobic exercise capacity (VO2peak) was assessed by a cardiopulmonary exercise test. Body composition was determined by whole body dual-energy X-ray absorptiometry scan and magnetic resonance imaging. Coronary flow reserve (CFR) assessed by transthoracic Doppler echocardiography was used as a measure of microvascular function. Results Median BMI was 31.3 and 72 % had impaired glucose tolerance or impaired fasting glucose. VO2peak adjusted for fat free mass was correlated with CFR (r = 0.41, p = 0.0007), LVEF (r = 0.33, p = 0.008) and left ventricular end-diastolic volume (EDV) (r = 0.32, p = 0.01) while it was only weakly linked to measures of glucose metabolism and body composition. CFR, EDV and LVEF remained independent predictors of VO2peak in multivariable regression analysis. Conclusion The study established CFR, EDV and LVEF as independent predictors of VO2peak in overweight CAD patients with no or only mild functional symptoms and a LVEF > 35 %. Glucose metabolism and body composition had minor impact on VO2peak. The findings suggest that central hemodynamic factors are important in limiting exercise capacity in overweight non-diabetic CAD patients.