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Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1–18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.

Decline in cardiac high-energy phosphate metabolism [phosphocreatine-to-ATP (PCr/ATP) ratio] and whole body metabolism increase the risk of heart failure and metabolic diseases. The aim of the present study was to assess the relationship between PCr/ATP ratio and measures of body metabolic function. A total of 35 healthy women (56±14.0 years of age) underwent cardiac 31P magnetic resonance spectroscopy to assess PCr/ATP ratio – an index of cardiac high-energy phosphate metabolism. Fasting and 2-hour glucose levels were assessed using oral glucose tolerance test. Indirect calorimetry was performed to determine oxygen consumption and resting metabolic rate. There were no significant relationships between PCr/ATP ratio and resting metabolic rate (r=-0.09, p=0.62), oxygen consumption (r=-0.11, p=0.54), fasting glucose levels (r=-0.31, p=0.07), and 2-hour plasma glucose (r=-0.10, p=0.58). Adjusted analysis for covariates including age, body mass index, fat mass, and physical activity, had no significant influence on the relationship between PCr/ATP ratio and body metabolism. In conclusion, the lack of relationship between cardiac PCr/ATP ratio, glucose control and metabolic rate may suggest that overall metabolic function does not influence cardiac high-energy phosphate metabolism.

Aims/hypothesis Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. Methods A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. Results Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3–25.0%] in women vs 11.9% [7.0–23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9–1.7%] vs 4.5% [1.9–8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p−1 day−1, p = 0.01, and 0.45 [0.26–0.77] vs 0.25 [0.13–0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg−1 day−1, p = 0.34, and 0.72 [0.53–1.15] vs 0.50 [0.32–0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. Conclusions/interpretation In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes. Graphical abstract

Objective While there is an emerging role of pancreatic fat in the aetiology of type 2 diabetes mellitus (T2DM), its impact on the associated decrease in insulin secretion remains controversial. We aimed to determine whether pancreatic fat negatively affects β-cell function and insulin secretion in women with overweight or obesity but without T2DM. Methods 20 women, with normo- or dysglycaemia based on fasting plasma glucose levels, and low (< 4.5%) vs high (≥ 4.5%) magnetic resonance (MR) quantified pancreatic fat, completed a 1-hr intravenous glucose tolerance test (ivGTT) which included two consecutive 30-min square-wave steps of hyperglycaemia generated by using 25% dextrose. Plasma glucose, insulin and C-peptide were measured, and insulin secretion rate (ISR) calculated using regularisation deconvolution method from C-peptide kinetics. Repeated measures linear mixed models, adjusted for ethnicity and baseline analyte concentrations, were used to compare changes during the ivGTT between high and low percentage pancreatic fat (PPF) groups. Results No ethnic differences in anthropomorphic variables, body composition, visceral adipose tissue (MR-VAT) or PPF were measured and hence data were combined. Nine women (47%) were identified as having high PPF values. PPF was significantly associated with baseline C-peptide (p = 0.04) and ISR (p = 0.04) in all. During the 1-hr ivGTT, plasma glucose (p 0.05). Notably, the incremental areas under the curves for both first and second phase ISR were 0.04 units lower in the high than low PPF groups, but this was not significant (p > 0.05). Conclusion In women with overweight or obesity but without T2DM, PPF did not modify β-cell function as determined by ivGTT-assessed ISR. However, the salient feature in biphasic insulin secretion in those with ≥4.5% PPF may be of clinical importance, particularly in early stages of dysglycaemia may warrant further investigation.

Background Excess visceral obesity and ectopic organ fat is associated with increased risk of cardiometabolic disease. However, circulating markers for early detection of ectopic fat, particularly pancreas and liver, are lacking. Methods Lipid storage in pancreas, liver, abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 68 healthy or pre-diabetic Caucasian and Chinese women enroled in the TOFI_Asia study was assessed by magnetic resonance imaging/spectroscopy (MRI/S). Plasma metabolites were measured with untargeted liquid chromatography–mass spectroscopy (LC–MS). Multivariate partial least squares (PLS) regression identified metabolites predictive of VAT/SAT and ectopic fat; univariate linear regression adjusting for potential covariates identified individual metabolites associated with VAT/SAT and ectopic fat; linear regression adjusted for ethnicity identified clinical and anthropometric correlates for each fat depot. Results PLS identified 56, 64 and 31 metabolites which jointly predicted pancreatic fat (R2Y = 0.81, Q2 = 0.69), liver fat (RY2 = 0.8, Q2 = 0.66) and VAT/SAT ((R2Y = 0.7, Q2 = 0.62)) respectively. Among the PLS-identified metabolites, none of them remained significantly associated with pancreatic fat after adjusting for all covariates. Dihydrosphingomyelin (dhSM(d36:0)), 3 phosphatidylethanolamines, 5 diacylglycerols (DG) and 40 triacylglycerols (TG) were associated with liver fat independent of covariates. Three DGs and 12 TGs were associated with VAT/SAT independent of covariates. Notably, comparison with clinical correlates showed better predictivity of ectopic fat by these PLS-identified plasma metabolite markers. Conclusions Untargeted metabolomics identified candidate markers of visceral and ectopic fat that improved fat level prediction over clinical markers. Several plasma metabolites were associated with level of liver fat and VAT/SAT ratio independent of age, total and visceral adiposity, whereas pancreatic fat deposition was only associated with increased sulfolithocholic acid independent of adiposity-related parameters, but not age.

Brief introduction: In healthy adults, the right atrium (RA) serves as a reservoir for the systemic flow return from the superior vena cava (SVC) and inferior vena cava (IVC), preparing the two flows to be transferred to the right ventricle (RV) and pulmonary circulation. This study aims to quantify the haemodynamics of the RA and the associated SVC and IVC inflows, which have not been fully understood to date. Basic Methods Eighteen adults with structurally normal hearts underwent 4D flow magnetic resonance imaging. The cardiac cycle was resolved to 20 temporal phases with a spatial resolution of 3×3×3 mm cube. Analysis included objective visualisation of the flow structures in the RA identified by three different vortex identification criteria, kinetic energy (KE), enstrophy and dissipation. KE and helicity flux were also assessed in both caval veins. Main Results Vortex identification methods confirmed that in the majority of participants the blood flow from the caval veins filling the RA during ventricular systole is not chaotic, but rather forms an organised pattern of a single coherent forward turning vortex structure. Thirteen participants displayed a single vortex flow structure, four showed multiple vortices and one had a helical flow pattern without a clear vortex structure. A strong positive correlation exists between the flow KE and enstrophy density. Conclusions and Implications This study suggests that flow energy in the RA is mainly rotational, part of which is convected by the highly helical SVC and IVC inflows. Multiple vortices tend to be associated with higher dissipation rates in the central RA region due to turbulence. The rotational nature of the flow in the RA maintains KE better than non-rotational flow. RA flow characteristics are highly related to the helicity content in the caval veins, as well as the KE flux intensity. Lower caval helicity or IVC KE flux dominance tends to favour single vortex formation while the opposite tends to lead to multiple vortices or the rare helical flow patterns. Atria lacking single vortex flow are inclined to have a larger energy input from atrial contraction. Conflict of Interest n/a

Type 2 diabetes (T2D) in the non-obese has been regarded as etiologically distinct from that in obese people. However, clinical observation suggests that loss of fat mass above a personal fat threshold brings about remission in the same way. ReTUNE aimed to determine what proportion of T2D people with BMI In conclusion, 2/14 people with BMI Disclosure A. Al-mrabeh: None. A. C. Barnes: None. K. M. Irvine: None. T. L. Kelly: Employee; Self; Diabetes Digital Media. K. G. Hollingsworth: None. D. Romeres: None. C. Cobelli: None. R. Taylor: Speaker's Bureau; Self; Novartis AG. Funding Diabetes UK (17/0005645)

Purpose To accelerate 19 F-MR imaging of inhaled perfluoropropane using compressed sensing methods, and to optimize critical scan acquisition parameters for assessment of lung ventilation properties. Methods Simulations were performed to determine optimal acquisition parameters for maximal perfluoropropane signal-to-noise ratio (SNR) in human lungs for a spoiled gradient echo sequence. Optimized parameters were subsequently employed for 19 F-MRI of inhaled perfluoropropane in a cohort of 11 healthy participants using a 3.0 T scanner. The impact of 1.8×, 2.4×, and 3.0× undersampling ratios on 19 F-MRI acquisitions was evaluated, using both retrospective and prospective compressed sensing methods. Results 3D spoiled gradient echo 19 F-MR ventilation images were acquired at 1-cm isotropic resolution within a single breath hold. Mean SNR was 11.7 ± 4.1 for scans acquired within a single breath hold (duration = 18 s). Acquisition of 19 F-MRI scans at shorter scan durations (4.5 s) was also demonstrated as feasible. Application of both retrospective (n = 8) and prospective (n = 3) compressed sensing methods demonstrated that 1.8× acceleration had negligible impact on qualitative image appearance, with no statistically significant change in measured lung ventilated volume. Acceleration factors of 2.4× and 3.0× resulted in increasing differences between fully sampled and undersampled datasets. Conclusion This study demonstrates methods for determining optimal acquisition parameters for 19 F-MRI of inhaled perfluoropropane and shows significant reduction in scan acquisition times (and thus participant breath hold duration) by use of compressed sensing.

Objective. In this paper we elucidate the asymmetric flow pattern and the haemodynamic quantity distributions and correlations in the pulmonary artery (PA) vasculature in healthy adults having structurally normal hearts, to provide reference on the flow characteristics in the PA and the right ventricle. Approach. Velocity data are acquired non-invasively from 18 healthy volunteers by 4D flow magnetic resonance imaging, resolved to 20 phases with spatial resolution 3 × 3 × 3 mm3. Interpolation is applied to improve the accuracy in quantifying haemodynamic quantities including kinetic energy, rotational energy, helicity and energy dissipation rate. These quantities are volumetrically normalised to remove size dependency, representing densities or local intensity. Main results. Flow asymmetry in the PA is quantified in terms of all the flow dynamic quantities and their correlations. The right PA has larger diameter and higher peak stroke velocity than the left PA. It also has the highest rotational energy intensity. Counter-rotating helical streams in the main PA appear to be associated with the unidirectional helical flow noticed in the left and the right PA near the peak systole. Significance. This study provides a fundamental basis of normal flow in the PA. It implies the validity to use these flow pattern-related quantitative measures to aid with the identification of abnormal PA flow non-invasively, specifically for detecting abnormalities in the pulmonary circulation and response to therapy, where haemodynamic flow is commonly characterised by increased vortical and helical formations.

Nut-based products may aid low-glycaemic dietary strategies that are important for diabetes prevention in populations at increased risk of dysglycaemia, such as Asian Chinese. This randomised cross-over trial assessed the postprandial glycaemic response (0–120 min) of a higher-protein nut-based (HP-NB) snack formulation, in bar format (1009 kJ, Nutrient Profiling Score, NPS, −2), when compared with an iso-energetic higher-carbohydrate (CHO) cereal-based bar (HC-CB, 985 kJ, NPS +3). It also assessed the ability to suppress glucose response to a typical CHO-rich food (white bread, WB), when co-ingested. Ten overweight prediabetic Chinese adults (mean, sd: age 47⋅9, 15⋅7 years; BMI 25⋅5, 1⋅6 kg/m2), with total body fat plus ectopic pancreas and liver fat quantified using dual-energy X-ray absorptiometry and magnetic resonance imaging and spectroscopy, received the five meal treatments in random order: HP-NB, HC-CB, HP-NB + WB (50 g available CHO), HC-CB + WB and WB only. Compared with HC-CB, HP-NB induced a significantly lower 30–120 min glucose response (P < 0⋅05), with an approximately 10-fold lower incremental area under the glucose curve (iAUC0–120; P < 0⋅001). HP-NB also attenuated glucose response by approximately 25 % when co-ingested with WB (P < 0⋅05). Half of the cohort had elevated pancreas and/or liver fat, with 13–21 % greater suppression of iAUC0–120 glucose in the low v. high organ fat subgroups across all five treatments. A nut-based snack product may be a healthier alternative to an energy equivalent cereal-based product with evidence of both a lower postprandial glycaemic response and modulation of CHO-induced hyperglycaemia even in high-risk, overweight, pre-diabetic adults.

Background:\ud The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission.\ud \ud Methods:\ud For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA1c

Men are more susceptible to type 2 diabetes and NAFLD than women, possibly secondary to differences in hepatic lipoprotein metabolism. The Tyneside cohort of Diabetes Remission Clinical Trial (34M/30F, 52.3±8.0 years, BMI 35.1±4.5kg/m2) were studied at baseline and to 24 months after weight loss. 3-point Dixon MRI was used for intra-organ fat. Hepatic VLDL-TG production was measured using a competitive blocking method. In the nondiabetic group, both liver and pancreas fat differed markedly in men and women (5.4± 1.1 vs. 3.4±0.1%, p=0.005, and 7.6±0.5 vs. 4.7±0.4%, p=0.0006, respectively). In diabetes, both liver and pancreas fat were similar in men and women at baseline (15.4±1.9 vs. 16.9±1.9%, p=0.57; and 8.5±0.4 vs. 8.4±0.5%, p=0.66, respectively). They decreased similarly after weight loss in both men and women (liver fat: 2.6±0.6% and 3.6±0.7%; pancreas fat: 7.6 ±0.4% and 7.5±0.5%, p Disclosure A. Al-Mrabeh: None. S. Melhem: None. S.V. Zhyzhneuskaya: None. C. Peters: Speaker’s Bureau; Self; Sanofi-Aventis. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M.E. Lean: None. R. Taylor: Speaker’s Bureau; Self; Novo Nordisk Foundation. Funding Diabetes UK

Introduction There has been little work on the relationship between sarcopenia, a progressive skeletal muscle disorder, and age-related neurodegenerative diseases such as Parkinson's disease (PD). Objectives We aimed to determine: 1) the feasibility of characterizing skeletal muscle across a range of cognitive function in PD; 2) if muscle mitochondrial respiratory chain (MRC) function and content are preserved in older adults with PD. Methods Sarcopenia was defined using handgrip strength, chair rise and bioimpedance analysis. MRC function was assessed using phosphorous magnetic resonance spectroscopy (MRS) by estimating τ1/2 PCr (s) (phosphocreatine half-time recovery) in the calf muscles following a bout of aerobic exercise. Biopsy of the vastus lateralis muscle was performed, and MRC content assessed by fluorescent immunohistochemistry for porin and components of MRC Complexes I and IV. Results Nine participants (78% male; mean age 79.9; PD duration 3.3 years) were recruited. Four had cognitive impairment. Six participants had probable sarcopenia. Eight participants completed MRS and had mean (SD) τ1/2 PCr of 37.8 (7.6) seconds, suggesting preserved mitochondrial function. Muscle biopsies were obtained in all and the procedure was well tolerated. Porin Z-score, a proxy for mitochondrial mass, was lower than expected compared to controls (0–89% of fibres with low porin). There was a small amount of Complex I (0.16–4.59%) and Complex IV (0–3.79%) deficiency. Conclusions Detailed phenotyping, muscle biopsy and imaging was feasible and acceptable across a spectrum of cognitive function in PD. Sarcopenia was relatively common and may be associated with lower mitochondrial mass and low levels of MRC deficiency.

Objective: In healthy adults, the right atrium (RA) serves as a reservoir for the systemic flow return from the superior vena cava (SVC) and inferior vena cava (IVC), preparing the two flows to be transferred to the right ventricle (RV) and pulmonary circulation. This study aims to quantify the haemodynamics of the RA and the associated SVC and IVC inflows, which have not been fully understood to date. Approach: Eighteen adults with structurally normal hearts underwent 4D flow magnetic resonance imaging. The cardiac cycle was resolved to 20 temporal phases with a spatial resolution of 3x3x3mm3. Analysis included objective visualisation of the flow structures in the RA identified by three different vortex identification criteria, kinetic energy (KE), enstrophy and dissipation. KE and helicity flux were also assessed in both caval veins. Main results: Vortex identification methods confirmed that in the majority of subjects the blood flow from the caval veins filling the RA during ventricular systole is not chaotic, but rather forms an organised pattern of a single coherent forward turning vortex structure. Thirteen subjects displayed a single vortex flow structure, four showed multiple vortices and one had a helical flow pattern without a clear vortex structure. A strong positive correlation exists between the flow KE and enstrophy density. Significance: This suggests that flow energy in the RA is mainly rotational, part of which is convected by the highly helical SVC and IVC inflows. Multiple vortices tend to be associated with higher dissipation rates in the central RA region due to turbulence. The rotational nature of the flow in the RA maintains KE better than non-rotational flow. RA flow characteristics are highly related to the helicity content in the caval veins, as well as the KE flux intensity. Lower caval helicity or IVC KE flux dominance tends to favour single vortex formation while the opposite tends to lead to multiple vortices or the rare helical flow patterns. Atria lacking single vortex flow are inclined to have a larger energy input from atrial contraction.

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open‐label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600–1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV‐immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF‐21), growth and differentiation factor 15 (GDF‐15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long‐term sequelae., There are currently no treatments for mitochondrial disorders. Bezafibrate has been shown to induce mitochondrial biogenesis and improve mitochondrial function in pre‐clinical models, but has not been systematically studied in patients.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by absence of dystrophin protein. Dystrophin is expressed in muscle, but also in the brain. Difficulties with attention/inhibition, working memory and information processing are well described in DMD patients but their origin is poorly understood. The default mode network (DMN) is one of the networks involved in these processes. Therefore we aimed to assess DMN connectivity in DMD patients compared to matched controls, to better understand the cognitive profile in DMD. T1-weighted and resting state functional MRI scans were acquired from 33 DMD and 24 male age-matched controls at two clinical sites. Scans were analysed using FMRIB Software Library (FSL). Differences in the DMN were assessed using FSL RANDOMISE, with age as covariate and threshold-free cluster enhancement including multiple comparison correction. Post-hoc analyses were performed on the visual network, executive control network and fronto-parietal network with the same methods. In DMD patients, the level of connectivity was higher in areas within the control DMN (hyperconnectivity) and significant connectivity was found in areas outside the control DMN. No hypoconnectivity was found and no differences in the visual network, executive control network and fronto-parietal network. We showed differences both within and in areas outside the DMN in DMD. The specificity of our findings to the DMN can help provide a better understanding of the attention/inhibition, working memory and information processing difficulties in DMD. Supplementary Information The online version contains supplementary material available at 10.1007/s11682-020-00422-3.

Background: \ud Type 2 diabetes is a chronic disorder that requires lifelong treatment. We aimed to assess whether intensive weight management within routine primary care would achieve remission of type 2 diabetes.\ud \ud Methods: \ud We did this open-label, cluster-randomised trial (DiRECT) at 49 primary care practices in Scotland and the Tyneside region of England. Practices were randomly assigned (1:1), via a computer-generated list, to provide either a weight management programme (intervention) or best-practice care by guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700). Participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician. We recruited individuals aged 20–65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27–45 kg/m2, and were not receiving insulin. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825–853 kcal/day formula diet for 3–5 months), stepped food reintroduction (2–8 weeks), and structured support for long-term weight loss maintenance. Co-primary outcomes were weight loss of 15 kg or more, and remission of diabetes, defined as glycated haemoglobin (HbA1c) of less than 6·5% (

Objective Diminished cardiac high-energy phosphate metabolism (phosphocreatine-to-ATP (PCr:ATP) ratio) and cardiac power with age may play an important roles in development of cardiac dysfunction and heart failure. The study defines the impact of age on PCr:ATP ratio and cardiac power and their relationship. Methods Thirty-five healthy women (young≤50 years, n=20; and old≥60 years, n=15) underwent cardiac MRI with 31P spectroscopy to assess PCr:ATP ratio and performed maximal graded cardiopulmonary exercise testing with simultaneous gas-exchange and central haemodynamic measurements. Peak cardiac power output, as the best measure of pumping capability and performance of the heart, was calculated as the product of peak exercise cardiac output and mean arterial blood pressure. Results PCr:ATP ratio was significantly lower in old compared with young age group (1.92±0.48 vs 2.29±0.55, p=0.03), as were peak cardiac power output (3.35±0.73 vs 4.14±0.81W, p=0.01), diastolic function (ie, early-to-late diastolic filling ratio, 1.33±0.54 vs 3.07±1.84, p

Background Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease of childhood, is characterised by synovitis. Clinical assessments of synovitis are imperfect, relying on composite and indirect measures of disease activity including clinician-reported measures, patient-reported measures and blood markers. Contrast-enhanced MRI is a more sensitive synovitis assessment technique but clinical utility is currently limited by availability and inter-observer variation. Improved quantitative MRI techniques may enable future development of more stringent MRI-defined remission criteria. The objective of this study was to determine the utility and feasibility of quantitative MRI measurement of synovial volume and vascularity in JIA before and twelve weeks after intra-articular glucocorticoid injection (IAGI) of the knee and to assess the acceptability of MRI to participating families. Methods Children and young people with JIA and a new episode of knee synovitis requiring IAGI were recruited from the Great North Children’s Hospital in Newcastle upon Tyne. Quantitative contrast-enhanced MRI was performed prior to and twelve weeks after IAGI, in addition to standard clinical assessment tools, including the three-variable clinical juvenile arthritis disease activity score (cJADAS) and active joint count. Results Eleven young people (5 male, median age 13 years, range 7–16) with JIA knee flare were recruited and 10 completed follow-up assessment. Following IAGI, the median (interquartile range) cJADAS improved from 8.5 (2.7) to 1.6 (3.9), whilst the median synovial volume improved from 38.5cm3 (82.1cm3) to 0.0cm3 (0.2cm3). Six patients presented with frank synovitis outside normal limits on routine MRI reporting. A further three had baseline MRI reports within normal limits but the quantitative measurements identified measurable synovial uptake. Post-IAGI quantitative measurements highlighted significant improvements in 9 patients. Conclusions IAGI led to a marked reduction in synovial volume, with quantitative MRI identifying more patients with an improved synovial volume than routine qualitative clinical reporting. Improvements in cJADAS scores were more variable with the patient/parent global assessment component contributing most to the scores. Further work is indicated, exploring the utility of quantitative MRI in the assessment of less accessible joints and comparing the impact of different treatment modalities.

Background:19F-MRI of inhaled perfluoropropane (PFP) typically involves breath-hold manoeuvres, which may be difficult for patients with respiratory disease. Aim: We assessed the utility of compressed sensing (CS) to reduce 19F-MRI scan time and breath-hold duration compared to fully-sampled acquisitions in a group of healthy volunteers. Methods: 11 participants (3M, 8F; aged 24-63) provided written informed consent and were screened for eligibility. Participants underwent a single MRI scan session on a 3T scanner, involving periodic inhalation of a 79% PFP/21% oxygen gas mixture. Inhalation sessions comprised three deep breaths of gas followed by a breath-hold. All participants underwent fully-sampled image acquisitions (breath-hold=18s). Retrospective CS (1.8x acceleration) was performed in 8 participants. Prospective CS was performed in 3 participants (breath-hold=10s). The percentage ventilated lung volume (%VV) was calculated for all acquisitions. Results: CS acquisitions demonstrated comparable image quality to fully-sampled acquisitions (Figure 1). %VV values (mean±SD) were similar across fully-sampled (98.5±0.9%), retrospective (98.0±0.9%) and prospective (98.1±0.8%) datasets, respectively. Conclusions: Application of CS to 19F-MRI of inhaled PFP can shorten scan times with negligible impact on image quality or content, offering scope to substantially reduce the duration of breath-hold imaging in future patient studies.

Aims: Observational studies have suggested that beta cell functional mass inevitably decreases over time. We assessed this after 2 years in a geographically defined subgroup of DiRECT who achieved initial remission after diet-induced weight loss. Methods: A Stepped Insulin Secretion Test with Arginine (SISTA) was used to quantify functional beta cell mass (maximum insulin secretory response during hyperglycemia). Insulin secretion rates were estimated by de-convolution; 40 subjects initially achieved remission (HbA1c Results: In the responder group, median (IQ range) maximum rate of insulin secretion increased from 0.58 (0.48 to 0.81) at baseline to 0.74 (0.54 to 1.00) at 5 months, 0.94 (0.57 to 1.24) (p=0.017 from baseline) at 12 months, and 0.94(0.64 to 1.44) (p=0.030 from baseline) nmol/min/m2 at 24 months. This was comparable to NDC (1.02(0.86 to 1.51) nmol/min/m2) by 12 (p=0.064) and 24 months (p=0.244). Median first phase insulin response increased in responders from 0.042 (0.004 to 0.0637) at baseline to 0.108 (0.058 to 0.163) nmol/min/m2 (p Those who failed to maintain remission were characterized by more weight regain 5-24 months (11. 3±1.9 vs. 6.6±1.0 kg, p=0.036). In responders mean HBA1C was 6.0±0.0% at 24 months. Conclusion: Provided weight regain is minimized, remission of type 2 diabetes is durable over 2 years, with a gradual increase to normal beta cell functional mass. Disclosure S.V. Zhyzhneuskaya: None. A. Al-Mrabeh: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. H. Pilkington: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. M.E. Lean: Consultant; Self; Counterweight Ltd., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. R. Taylor: Advisory Panel; Self; Wilmington Healthcare. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG. Funding Diabetes UK

The Diabetes Remission Clinical Trial (DiRECT) demonstrated initial remission of type 2 diabetes in about half of a large primary care population, and this was associated with decrease in intrapancreatic fat content and return of beta cell function. We have carried out detailed metabolic studies on a subgroup at 2 years, comparing those who remained in remission (HbA1c Disclosure A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. A.C. Barnes: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Consultant; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Amgen Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Roche Diagnostics France, Sanofi. M.E. Lean: Consultant; Self; Counterweight Ltd., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. R. Taylor: Advisory Panel; Self; Wilmington Healthcare. Speaker's Bureau; Self; Lilly Diabetes, Novartis AG. Funding Diabetes UK

Background Adolescents with DMD treated with chronic high dose GC therapy typically have profound pubertal delay. Testosterone, the main circulating androgen in men, promotes virilisation and growth with associated accrual of fat-free muscle mass and bone mineral content. Testosterone therapy is routinely used to mimic the normal stages of pubertal development in patients with hypogonadotrophic hypogonadism, androgen deficiency secondary to testicular disease and in constitutional delay of growth and puberty (CDGP). Improved life expectancy in DMD has meant that more adolescents are eligible for testosterone supplementation but there is little objective data regarding the impact of this treatment on muscle structure and function, bone integrity and overall well-being. Methods This is a single centre observational clinical trial (NCT02571205) that aims to follow the progress of 15 adolescents with Duchenne muscular dystrophy and delayed puberty as they are managed with incremental testosterone therapy to induce puberty. Subjects will all be treated with a steadily increasing dose of testosterone administered by injection every 4 weeks and data will be collected to help us determine the effectiveness and tolerability of the described treatment regimen. We will use the data to explore the effects of testosterone on pubertal development, growth, muscle strength and function, bone mineral density, body composition with a detailed record of any adverse events. We will also carry out interviews to explore the boys’ views on the tolerability of the regimen. The study will last for 27 months in total for each participant. Discussion Our experience has indicated that testosterone treatment in adolescents with DMD is liked and well tolerated but we have not collected objective data on a specific treatment regimen and there is no current consensus. Testosterone supplementation is not part of the standard of care of pubertal delay in DMD but inclusion in future protocols may be appropriate depending on the results of this trial. Trial registration EudraCT Number: 2015–003195-68. Research Registry & References: Clinical trials.gov- NCT02571205 (registered 8/10/15). Electronic supplementary material The online version of this article (10.1186/s12887-019-1503-x) contains supplementary material, which is available to authorized users.

Summary Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation. For complete details on the use and execution of this protocol, please refer to (Taylor et al., 2018) and (Al-Mrabeh et al., 2020b)., Graphical Abstract, Highlights • Step-by-step description of intraorgan fat quantification in liver and pancreas • Description of in vivo measurement of hepatic lipoprotein triglyceride export • Application of novel magnetic resonance and lipoprotein turnover methods • Easy to reproduce methods without use of isotopes or ionization radiation, Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation.

AIMS: To compare directly the impact of glucagon-like peptide-1 secretion on glucose metabolism in individuals with Type 2 diabetes listed for Roux-en-Y gastric bypass surgery, randomized to be studied before and 7 days after undergoing Roux-en-Y gastric bypass or after following a very-low-calorie diet. METHODS: A semi-solid meal test was used to investigate glucose, insulin and glucagon-like peptide-1 response. Insulin secretion in response to intravenous glucose and arginine stimulus was measured. Hepatic and pancreatic fat content was quantified using magnetic resonance imaging. RESULTS: The decrease in fat mass was almost identical in the Roux-en-Y gastric bypass and the very-low-calorie diet groups (3.0±0.3 and 3.0±0.7kg). The early rise in plasma glucose level and in acute insulin secretion were greater after Roux-en-Y gastric bypass than after a very-low-calorie diet; however, the early rise in glucagon-like peptide-1 was disproportionately greater (sevenfold) after Roux-en-Y gastric bypass than after a very-low-calorie diet. This did not translate into a greater improvement in fasting glucose level or area under the curve for glucose. The reduction in liver fat was greater after Roux-en-Y gastric bypass (29.8±3.7 vs 18.6±4.0%) and the relationships between weight loss and reduction in liver fat differed between the Roux-en-Y gastric bypass group and the very-low-calorie diet group. CONCLUSIONS: This study shows that gastroenterostomy increases the rate of nutrient absorption, bringing about a commensurately rapid rise in insulin level; however, there was no association with the large post-meal rise in glucagon-like peptide-1, and post-meal glucose homeostasis was similar in the Roux-en-Y gastric bypass and very-low-calorie diet groups. (Clinical trials registry number: ISRCTN11969319.).

Aims/hypothesis This study was designed to establish whether the low volume and irregular border of the pancreas in type 2 diabetes would be normalised after reversal of diabetes. Methods A total of 29 individuals with type 2 diabetes undertook a very low energy (very low calorie) diet for 8 weeks followed by weight maintenance for 6 months. Methods were established to quantify the pancreas volume and degree of irregularity of the pancreas border. Three-dimensional volume-rendering and fractal dimension (FD) analysis of the MRI-acquired images were employed, as was three-point Dixon imaging to quantify the fat content. Results There was no change in pancreas volume 6 months after reversal of diabetes compared with baseline (52.0 ± 4.9 cm3 and 51.4 ± 4.5 cm3, respectively; p = 0.69), nor was any volumetric change observed in the non-responders. There was an inverse relationship between the volume and fat content of the pancreas in the total study population (r =−0.50, p = 0.006). Reversal of diabetes was associated with an increase in irregularity of the pancreas borders between baseline and 8 weeks (FD 1.143 ± 0.013 and 1.169 ± 0.006, respectively; p = 0.05), followed by a decrease at 6 months (1.130 ± 0.012, p = 0.006). On the other hand, no changes in FD were seen in the non-reversed group. Conclusions/interpretation Restoration of normal insulin secretion did not increase the subnormal pancreas volume over 6 months in the study population. A significant change in irregularity of the pancreas borders occurred after acute weight loss only after reversal of diabetes. Pancreas morphology in type 2 diabetes may be prognostically important, and its relationship to change in beta cell function requires further study. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-3984-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

To determine the limits of agreement of hepatic fat fraction and R2* relaxation rate quantified with accelerated magnetic resonance (MR) imaging reconstructed with combined compressed sensing and parallel imaging compared with conventional fully sampled acquisitions.Eleven subjects with type 2 diabetes and a healthy control subject were recruited with the approval of the Newcastle and North Tyneside 2 ethics committee and written consent. Undersampled data at ratios of 2.6×, 2.9×, 3.8×, and 4.8× were prospectively acquired in addition to fully sampled data by using five gradient echoes per repetition time at 3.0 T. Fat fraction maps were calculated by using combined compressed sensing and parallel imaging (CS-PI) reconstruction and Bland-Altman analysis performed to assess bias and 95% limits of agreement. Inter- and intrarater analysis was performed for quantitative fat fraction and R2* relaxation rate, and image quality was assessed with a four-point scale by two independent observers.The fat fractions from the accelerated acquisitions had 95% limits of agreement of 1.2%, 1.2%, 1.1%, and 1.5%, respectively, with no bias. When compared with the intra- and interrater 95% limits of agreement (0.7% and 0.8%), acceleration of up to 3.8× did not greatly degrade the fat fraction measurements. No or minimal artifact was detected at 2.6× and 2.9× accelerations, moderate artifact was detected at 3.8× acceleration, and substantial artifact was detected at 4.8× acceleration.Prospective undersampling and CS-PI reconstruction of liver fat fractions can be used to accelerate liver fat fraction measurements. The fat fractions and image quality produced were acceptable up to a factor of 3.8×, thereby shortening the required breath-hold duration from 17.7 seconds to 4.7 seconds.

Importance Thyroid hormones play a key role in modulating myocardial contractility. Subclinical hypothyroidism in patients with acute myocardial infarction is associated with poor prognosis. Objective To evaluate the effect of levothyroxine treatment on left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism. Design, Setting, and Participants A double-blind, randomized clinical trial conducted in 6 hospitals in the United Kingdom. Patients with acute myocardial infarction including ST-segment elevation and non–ST-segment elevation were recruited between February 2015 and December 2016, with the last participant being followed up in December 2017. Interventions Levothyroxine treatment (n = 46) commencing at 25 µg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L or identical placebo (n = 49), both provided in capsule form, once daily for 52 weeks. Main Outcomes and Measures The primary outcome measure was left ventricular ejection fraction at 52 weeks, assessed by magnetic resonance imaging, adjusted for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary measures were left ventricular volumes, infarct size (assessed in a subgroup [n = 60]), adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression. Results Among the 95 participants randomized, the mean (SD) age was 63.5 (9.5) years, 72 (76.6%) were men, and 65 (69.1%) had ST-segment elevation myocardial infarction. The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean (SD) free thyroxine level was 1.14 (0.16) ng/dL. The primary outcome measurements at 52 weeks were available in 85 patients (89.5%). The mean left ventricular ejection fraction at baseline and at 52 weeks was 51.3% and 53.8%, respectively, in the levothyroxine group compared with 54.0% and 56.1%, respectively, in the placebo group (adjusted difference in groups, 0.76% [95% CI, −0.93% to 2.46%];P = .37). None of the 6 secondary outcomes showed a significant difference between the levothyroxine and placebo treatment groups. There were 15 (33.3%) and 18 (36.7%) cardiovascular adverse events in the levothyroxine and placebo groups, respectively. Conclusions and Relevance In this preliminary study involving patients with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks. These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction. Trial Registration isrctn.org Identifier:http://www.isrctn.com/ISRCTN52505169

The role of hepatic lipoprotein metabolism in diet-induced remission of type 2 diabetes is currently unclear. Here, we determined the contributions of hepatic VLDL1-triglyceride production rate and VLDL1-palmitic acid content to changes in intra-pancreatic fat and return of first phase insulin response in a subgroup of the Diabetes Remission Clinical Trial. Liver fat, VLDL1-triglyceride production, and intra-pancreatic fat decreased after weight loss and remained normalized after 24 months of remission. First-phase insulin response remained increased only in those maintaining diabetes remission. Compared with those in remission at 24 months, individuals who relapsed after initial remission had a greater rise in the content of VLDL1-triglyceride and VLDL1-palmitic acid, re-accumulated intra-pancreatic fat, and lost first-phase response by 24 months. Thus, we observed temporal relationships between VLDL1-triglyceride production, hepatic palmitic acid flux, intra-pancreatic fat, and β-cell function. Weight-related disordered fat metabolism appears to drive development and reversal of type 2 diabetes.

Purpose To accelerate 19F‐MR imaging of inhaled perfluoropropane using compressed sensing methods, and to optimize critical scan acquisition parameters for assessment of lung ventilation properties. Methods Simulations were performed to determine optimal acquisition parameters for maximal perfluoropropane signal‐to‐noise ratio (SNR) in human lungs for a spoiled gradient echo sequence. Optimized parameters were subsequently employed for 19F‐MRI of inhaled perfluoropropane in a cohort of 11 healthy participants using a 3.0 T scanner. The impact of 1.8×, 2.4×, and 3.0× undersampling ratios on 19F‐MRI acquisitions was evaluated, using both retrospective and prospective compressed sensing methods. Results 3D spoiled gradient echo 19F‐MR ventilation images were acquired at 1‐cm isotropic resolution within a single breath hold. Mean SNR was 11.7 ± 4.1 for scans acquired within a single breath hold (duration = 18 s). Acquisition of 19F‐MRI scans at shorter scan durations (4.5 s) was also demonstrated as feasible. Application of both retrospective (n = 8) and prospective (n = 3) compressed sensing methods demonstrated that 1.8× acceleration had negligible impact on qualitative image appearance, with no statistically significant change in measured lung ventilated volume. Acceleration factors of 2.4× and 3.0× resulted in increasing differences between fully sampled and undersampled datasets. Conclusion This study demonstrates methods for determining optimal acquisition parameters for 19F‐MRI of inhaled perfluoropropane and shows significant reduction in scan acquisition times (and thus participant breath hold duration) by use of compressed sensing.

We have evaluated changes in liver function tests and liver fat following 12-month weight change in the Tyneside participants of the prospective, randomised Diabetes Remission Clinical Trial (DiRECT). Complete data were available on 45 of the Intervention group participants. The group was typical of early type 2 diabetes: 53.7±1.2 years; 56% male; weight 99.6±2.6 kg; BMI 34.6±0.7 kg/m2, diabetes duration 3.3±0.2 years. Fasting liver fat content was measured by 3-point Dixon MRI. Baseline fasting plasma glucose was 157±7 mg/dl, with liver fat grossly elevated at 16.2±1.5% (mean±SEM; upper level of normal 5.5%). Mean weight loss was 11.5±1.1 kg (0-37kg) and liver fat was normalised at 4.7±0.9% (p10kg, 5-10kg, Following weight loss in type 2 diabetes, changes in ALT and GGT reflect change in liver fat even within the normal range. Early type 2 diabetes is associated with severe nonalcoholic fatty liver disease, and monitoring change by a simple inexpensive blood test is important in clinical practice. Disclosure S.V. Zhyzhneuskaya: None. A. Al-Mrabeh: None. C. Peters: None. A.C. Barnes: None. K.G. Hollingsworth: None. H. Pilkington: None. P. Welsh: Research Support; Self; Boehringer Ingelheim GmbH, Theracos, Inc. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced. R. Taylor: None.

DiRECT is a prospective, randomised study of type 2 diabetes of 48mmol/mol (n=16; non-responders). At baseline, the two groups were similar (age 53.3±1.2 vs. 53.6±2.2 years, weight 100.3±2.8 vs. 98.2 ±3.9kg, BMI 34.9±0.7 vs. 34.9±1.2kg/m2) but not duration of diabetes (2.7±0.3 vs. 3.8±0.4 years, p=0.04) nor HbA1c 57.1±1.8 vs. 62.5±2.3 mmol/mol; p Disclosure R. Taylor: None. A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. C. Peters: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced.

Type 2 diabetes is characterized by excess hepatic and intrapancreatic fat deposition. Liver-derived Very Low Density Lipoprotein-Triglyceride (VLDL1-TG) delivers fat to all peripheral tissues. Relative changes in VLDL1-TG production and intrapancreatic fat were investigated in a sub-group of the prospective, randomized Diabetes Remission Clinical Trial (DiRECT). Individuals with complete datasets at 12 months (n=45) were included. Detailed metabolic tests were carried out at baseline, 4 months, and 12 months after low calorie diet (825-853 kcal/day). Intra-organ fat was quantified using 3-point Dixon MRI, VLDL1-TG production was quantified using a competitive blocking non-isotopic method, and insulin secretion was measured by the Stepped Insulin Secretion Test with Arginine (SISTA). Weight loss induced major changes in liver and intrapancreatic fat with 69% remission of diabetes (responders, defined as HbA1c Disclosure A. Al-Mrabeh: None. S.V. Zhyzhneuskaya: None. C. Peters: None. A.C. Barnes: None. B. Aribisala: None. K.G. Hollingsworth: None. N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. M.E. Lean: Advisory Panel; Self; Novo Nordisk Inc., Orexigen Therapeutics, Inc.. Research Support; Self; Cambridge Weight Plan. Consultant; Self; Counterweight Ltd. Stock/Shareholder; Self; Eat Balanced. R. Taylor: None.

Cardiovascular disease is the principle cause of death in patients with elevated liver fat unrelated to alcohol consumption, more so than liver-related morbidity and mortality. The aim of this study was to evaluate the relationship between liver fat and cardiac and autonomic function, as well as to assess how impairment in cardiac and autonomic function is influenced by metabolic risk factors.Cardiovascular and autonomic function were assessed in 96 sedentary individuals: i) non-alcoholic fatty liver disease (NAFLD) (n = 46, hepatic steatosis5% by magnetic resonance spectroscopy), ii) Hepatic steatosis and alcohol (dual aetiology fatty liver disease [DAFLD]) (n = 16, hepatic steatosis5%, consuming20 g/day of alcohol) and iii) CONTROL (n = 34, no cardiac, liver or metabolic disorders,20 g/day of alcohol).Patients with NAFLD and DAFLD had significantly impaired cardiac and autonomic function when compared with controls. Diastolic variability and systolic variability (LF/HF-sBP [n/1]; 2.3 (1.7) and 2.3 (1.5) vs. 3.4 (1.5), p0.01) were impaired in patients with NAFLD and DAFLD when compared to controls, with DAFLD individuals showing a decrease in diastolic variability relative to NAFLD patients. Hepatic steatosis and fasting glucose were negatively correlated with stroke volume index. Fibrosis stage was significantly negatively associated with mean blood pressure (r = -0.47, p = 0.02), diastolic variability (r = -0.58, p ≤0.01) and systolic variability (r = -0.42, p = 0.04). Hepatic steatosis was independently associated with cardiac function (p ≤0.01); TNF-α (p ≤0.05) and CK-18 (p ≤0.05) were independently associated with autonomic function.Cardiac and autonomic impairments appear to be dependent on level of liver fat, metabolic dysfunction, inflammation and fibrosis staging, and to a lesser extent alcohol intake. Interventions should be sought to moderate the excess cardiovascular risk in patients with NAFLD or DAFLD.Increased levels of fat in the liver impair the ability of the cardiovascular system to work properly. The amount of fat in the liver, metabolic control, inflammation and alcohol are all linked to the degree that the cardiovascular system is affected.

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31 P-magnetic resonance spectroscopy ( 31 P-MRS) and laboratory muscle biopsy analysis. 31 P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

An error has been identified in the formula used to calculate VLDL1 production rate in the article cited above. This error does not affect the conclusions of the study …

The Diabetes Remission Clinical Trial reported return and persistence of non-diabetic blood glucose control in 46% of people with type 2 diabetes of up to 6 years duration. Detailed metabolic studies were performed on a subgroup (intervention, n = 64; control, n = 26). In the intervention group, liver fat content decreased (16.0% ± 1.3% to 3.1% ± 0.5%, p 0.0001) immediately after weight loss. Similarly, plasma triglyceride and pancreas fat content decreased whether or not glucose control normalized. Recovery of first-phase insulin response (0.04[-0.05-0.32] to 0.11[0.0005-0.51] nmol/min/m

Aims/hypothesis:\ud \ud Substantial weight loss in type 2 diabetes can achieve a return to non-diabetic biochemical status, without the need for medication. The Diabetes Remission Clinical Trial (DiRECT), a cluster-randomised controlled trial, is testing a structured intervention designed to achieve and sustain this over 2 years in a primary care setting to determine practicability for routine clinical practice. This paper reports the characteristics of the baseline cohort.\ud Methods:\ud \ud People with type 2 diabetes for