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Purpose: The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. Methods: Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. Results: Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. Conclusion: Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide. [ABSTRACT FROM AUTHOR]

Purpose: The positron range effect can impair PET image quality of Gallium-68 ( 68 Ga). A positron range correction (PRC) can be applied to reduce this effect. In this study, the effect of a tissue-independent PRC for 68 Ga was investigated on patient data., Methods: PET/CT data (40 patients: [ 68 Ga]Ga-DOTATOC or [ 68 Ga]Ga-PSMA) were reconstructed using Q.Clear reconstruction algorithm. Two reconstructions were performed per patient, Q.Clear with and without PRC. SUV max and contrast-to-noise ratio (CNR) values per lesion were compared between PRC and non-PRC images. Five experienced nuclear medicine physicians reviewed the images and chose the preferred reconstruction based on the image quality, lesion detectability, and diagnostic confidence., Results: A total of 155 lesions were identified. The PRC resulted in statistically significant increase of the SUV max and CNR for soft tissue lesions (6.4%, p < 0.001; 8.6%, p < 0.001), bone lesions (14.6%, p < 0.001; 12.5%, p < 0.001), and lung lesions (3.6%, p = 0.010; 6.3%, p = 0.001). This effect was most prominent in small lesions (SUV max : 12.0%, p < 0.001, and CNR: 13.0%, p < 0.001). Similar or better image quality, lesion detectability, and diagnostic confidence was achieved in PRC images compared to the non-PRC images as those assessed by the expert readers., Conclusions: A tissue-independent PRC increased the SUV max and CNR in soft tissue, bone, and lung lesions with a larger effect for the small lesions. Visual assessment demonstrated similar or better image quality, lesion detectability, and diagnostic confidence in PRC images compared to the non-PRC images., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval for this study was granted by the medical ethics committee METC azM/UM, Maastricht, The Netherlands (Date: 09-July-2021, No: 2021–2795). Consent to participate: Written informed consent was obtained from all individual participants included in the study. Consent to publish: Informed consent was obtained from all participants to publish their anonymized data. Competing interests: Felix M. Mottaghy is medical advisor for NanoMab Technology Ltd. and Advanced Accelerator Applications (AAA) GmbH/Novartis and has recently received institutional grants from NanoMab Technology Ltd., Siemens, and GE Precision HealthCare LLC. He is also supported by the German Research Foundation (DFG) within the framework of the Research Training Group 2375 “Tumor-targeted Drug Delivery” (grant 331065168), the Clinical Research Unit CRU 5011 “Integrating emerging methods to advance translational kidney research (InteraKD)” (project 445703531). In addition, his research is funded by the German Federal Ministry of Research and Education (project 16GW0319K). Moreover, he is an editor in the European Journal of Nuclear Medicine and Molecular Imaging. Floris P. Jansen is employee of GE HealthCare. The other authors have no relevant financial or non-financial interests to disclose regarding this topic., (© 2025. The Author(s).)

Cold acclimation increases insulin sensitivity, and some level of muscle contraction appears to be needed for provoking this effect. Here 15 men and (postmenopausal) women with overweight or obesity, the majority of whom had impaired glucose tolerance, were intermittently exposed to cold to induce 1 h of shivering per day over 10 days. We determined the effect of cold acclimation with shivering on overnight fasted oral glucose tolerance (primary outcome) and on skeletal muscle glucose transporter 4 translocation (secondary outcome). We find that cold acclimation with shivering improves oral glucose tolerance, fasting glucose, triglycerides, non-esterified fatty acid concentrations and blood pressure. Cold acclimation with shivering may thus represent an alternative lifestyle approach for the prevention and treatment of obesity-related metabolic disorders. ClinicalTrials.gov registration: NCT04516018 ., Competing Interests: Competing interests: The authors declare no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Twenty-four hour rhythmicity in whole-body substrate metabolism, skeletal muscle clock gene expression and mitochondrial respiration is compromised upon insulin resistance. With exercise training known to ameliorate insulin resistance, our objective was to test if exercise training can reinforce diurnal variation in whole-body and skeletal muscle metabolism in men with insulin resistance. In a single-arm longitudinal design, 10 overweight and obese men with insulin resistance performed 12 weeks of high-intensity interval training recurrently in the afternoon (between 14.00 and 18.00 h) and were tested pre- and post-exercise training, while staying in a metabolic research unit for 2 days under free-living conditions with regular meals. On the second days, indirect calorimetry was performed at 08.00, 13.00, 18.00, 23.00 and 04.00 h, muscle biopsies were taken from the vastus lateralis at 08.30, 13.30 and 23.30 h, and blood was drawn at least bi-hourly over 24 h. Participants did not lose body weight over 12 weeks, but improved body composition and exercise capacity. Exercise training resulted in reduced 24-h plasma glucose levels, but did not modify free fatty acid and triacylglycerol levels. Diurnal variation of muscle clock gene expression was modified by exercise training with period genes showing an interaction (time × exercise) effect and reduced mRNA levels at 13.00 h. Exercise training increased mitochondrial respiration without inducing diurnal variation. Twenty-four-hour substrate metabolism and energy expenditure remained unchanged. Future studies should investigate alternative exercise strategies or types of interventions (e.g. diet or drugs aiming at improving insulin sensitivity) for their capacity to reinforce diurnal variation in substrate metabolism and mitochondrial respiration. KEY POINTS: Insulin resistance is associated with blunted 24-h flexibility in whole-body substrate metabolism and skeletal muscle mitochondrial respiration, and disruptions in the skeletal muscle molecular circadian clock. We hypothesized that exercise training modifies 24-h rhythmicity in whole-body substrate metabolism and diurnal variation in skeletal muscle molecular clock and mitochondrial respiration in men with insulin resistance. We found that metabolic inflexibility over 24 h persisted after exercise training, whereas mitochondrial respiration increased independent of time of day. Gene expression of Per1-3 and Rorα in skeletal muscle changed particularly close to the time of day at which exercise training was performed. These results provide the rationale to further investigate the differential metabolic impact of differently timed exercise to treat metabolic defects of insulin resistance that manifest at a particular time of day., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The liver plays a crucial role in the control of glucose homeostasis and is therefore of great interest in the investigation of the development of type 2 diabetes. Hepatic glucose uptake (HGU) can be measured through positron emission tomography (PET) imaging with the tracer [18F]-2-fluoro-2-deoxy-D-glucose (FDG). HGU is dependent on many variables (e.g. plasma glucose, insulin and glucagon concentrations), and the metabolic state for HGU assessment should be chosen with care and coherence with the study question. In addition, as HGU is influenced by many factors, protocols and measurement conditions need to be standardised for reproducible results. This review provides insights into the protocols that are available for the measurement of HGU by FDG PET and discusses the current state of knowledge of HGU and its impairment in type 2 diabetes. Overall, a scanning modality that allows for the measurement of detailed kinetic information and influx rates (dynamic imaging) may be preferable to static imaging. The combination of FDG PET and insulin stimulation is crucial to measure tissue-specific insulin sensitivity. While the hyperinsulinaemic-euglycaemic clamp allows for standardised measurements under controlled blood glucose levels, some research questions might require a more physiological approach, such as oral glucose loading, with both advantages and complexities relating to fluctuations in blood glucose and insulin levels. The available approaches to address HGU hold great potential but await more systematic exploitation to improve our understanding of the mechanisms underlying metabolic diseases. Current findings from the investigation of HGU by FDG PET highlight the complex interplay between insulin resistance, hepatic glucose metabolism, NEFA levels and intrahepatic lipid accumulation in type 2 diabetes and obesity. Further research is needed to fully understand the underlying mechanisms and potential therapeutic targets for improving HGU in these conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator-activated receptor-α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin-resistant volunteers., Methods: Ten insulin-resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double-blind crossover study. Insulin-stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18 F-fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET). Additionally, cardiac function, whole-body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24-hour blood pressure, and substrate metabolism were measured., Results: Whole-body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin-stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR-related gene expression in muscle were found., Conclusions: Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole-body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

The current Meat Standards Australia (MSA) and AUS-MEAT grading system assumes that marbling through the M. longissmus thoracis et lumborum (loin) is represented by the score of the grading site. However, studies have indicated marbling varies within the beef loin, but commercially individual portion steaks are not graded for marbling. Cube rolls from a wide phenotypic marbling range (n = 102) were collected and sliced into 15 mm portion steaks, which were imaged with a Marel vision scanner to obtain objective marbling scores. Additionally, three locations (grading site, middle, cranial) across each cube roll were tested for intramuscular fat percentage (IMF%). The effect of steak location demonstrated marked variation across the length of the cube roll for both vision scanner marbling scores and IMF%. This variation in vision scanner marbling scores, expressed in units of MSA marbling score, equated to 316 MSA units. This work suggests an opportunity for individual portion marbling measurements and segregation of individual portion cut steaks based upon their marbling levels., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cardiac energy status, measured as phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio with 31P-Magnetic Resonance Spectroscopy (31P-MRS) in vivo, is a prognostic factor in heart failure and is lowered in cardiometabolic disease. It has been suggested that, as oxidative phosphorylation is the major contributor to ATP synthesis, PCr/ATP ratio might be a reflection of cardiac mitochondrial function. The objective of the study was to investigate whether PCr/ATP ratios can be used as in vivo marker for cardiac mitochondrial function. We enrolled thirty-eight patients scheduled for open-heart surgery in this study. Cardiac 31P-MRS was performed before surgery. Tissue from the right atrial appendage was obtained during surgery for high-resolution respirometry for the assessment of mitochondrial function. There was no correlation between the PCr/ATP ratio and ADP-stimulated respiration rates (octanoylcarnitine R 2  < 0.005, p = 0.74; pyruvate R 2  < 0.025, p = 0.41) nor with maximally uncoupled respiration (octanoylcarnitine R 2  = 0.005, p = 0.71; pyruvate R 2  = 0.040, p = 0.26). PCr/ATP ratio did correlate with indexed LV end systolic mass. As no direct correlation between cardiac energy status (PCr/ATP) and mitochondrial function in the heart was found, the study suggests that mitochondrial function might not the only determinant of cardiac energy status. Interpretation should be done in the right context in cardiac metabolic studies., (© 2023. The Author(s).)

This study describes the performance of a Marel conveyer vision scanner, across beef carcases (n = 102) from a wide visual marbling score range, in its ability to predict chemical intramuscular fat (IMF%), Meat Standards Australia (MSA) and AUS-MEAT marbling scores of portion steaks. Vision scanner marbling scores were acquired on fresh-cut steaks, with its predictions tested using a leave-one-out cross validation method, which demonstrated precise and accurate predictions of IMF% (R 2  = 0.87; RMSEP = 1.16; slope = 0.09; bias = 0.22), MSA (R 2  = 0.82; RMSEP = 70.11; slope = 0.09; bias = 17.08) and AUS-MEAT marbling (R 2  = 0.79; RMSEP = 0.75; slope = 0.16; bias = 0.08). Care must be taken when calibrating devices on non-fresh-cut steak, as fresh-cut steaks produced different vision scanner marbling values suggesting different prediction equations are warranted. The Marel vision scanner prediction of visual grader scores was relatively less precise and accurate than its prediction of IMF%, however in this case it may have been due to error in the grader scores., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m²/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (ΔRd:13.2 ± 1.8 vs. 9.6 ± 1.8 µmol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D., (© 2022. The Author(s).)

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.

Creatine availability in adipose tissue has been shown to have profound effects on thermogenesis and energy balance in mice. However, whether dietary creatine supplementation affects brown adipose tissue (BAT) activation in humans is unclear. In the present study, we report the results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) in which 14 young, healthy, vegetarian adults, who are characterized by low creatine levels, received 20 g of creatine monohydrate per day or placebo. Participants were eligible if they met the following criteria: male or female, white, aged 18-30 years, consuming a vegetarian diet (≥6 months) and body mass index 20-25 kg m -2 . BAT activation after acute cold exposure was determined by calculating standard uptake values (SUVs) acquired by [ 18 F]fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. BAT volume (-31.32 (19.32) SUV (95% confidence interval (CI) -73.06, 10.42; P = 0.129)), SUV mean (-0.34 (0.29) SUV (95% CI -0.97, 0.28; P = 0.254)) and SUV max (-2.49 (2.64) SUV (95% CI -8.20, 3.21; P = 0.362)) following acute cold exposure were similar between placebo and creatine supplementation. No side effects of creatine supplementation were reported; one participant experienced bowel complaints during placebo, which resolved without intervention. Our data show that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure.

Muscle glycogen use and glucose uptake during cold exposure increases with shivering intensity. We hypothesized that cold exposure, with shivering, would subsequently increase glucose tolerance. Fifteen healthy men (age = 26 ± 5 yr, body mass index = 23.9 ± 2.5 kg·m -2  ) completed two experimental trials after an overnight fast. Cold exposure (10°C) was applied during the first trial, via a water-perfused suit, to induce at least 1 h of shivering in each participant. For comparison, a thermoneutral (32°C) condition was applied during the second trial, under identical conditions, for the same duration as determined during the cold exposure. After the thermal exposures, participants rested under a duvet for 90 min, which was followed by a 3-h oral glucose tolerance test. Skin temperature (means ± SE) decreased at the end of the cold exposure compared with that before (26.9 ± 0.3 vs. 33.7 ± 0.1°C, P < 0.001). Total energy expenditure during the 1 h of shivering was greater than that during the time-matched thermoneutral condition (619 ± 23 vs. 309 ± 7 kJ, P < 0.001). Cold exposure increased the areas under the glucose and insulin curves by 4.8% ( P = 0.066) and 24% ( P = 0.112), respectively. The Matsuda and insulin-glucose indices changed after cold exposure by -21% ( P = 0.125) and 30% ( P = 0.100), respectively. Cold exposure did not subsequently increase glucose tolerance. Instead, the Matsuda and insulin-glucose indices suggest insulin resistance post shivering. NEW & NOTEWORTHY This is the first study to examine the effect of cold-induced shivering on subsequent glucose tolerance determined under thermoneutral conditions. Plasma glucose and insulin concentrations increased during the oral glucose tolerance test post shivering. Additionally, insulin sensitivity indices suggest insulin resistance following cold exposure. These results provide evidence for an acute post-shivering response, whereby glucose metabolism has deteriorated, contrary to the results from earlier studies on cold acclimation.

Background: Pericardial fat (PF) has been suggested to directly act on cardiomyocytes, leading to diastolic dysfunction. The aim of this study was to investigate whether a higher PF volume is associated with a lower diastolic function in healthy subjects., Methods: 254 adults (40-70 years, BMI 18-35 kg/m 2 , normal left ventricular ejection fraction), with (a)typical chest pain (otherwise healthy) from the cardiology outpatient clinic were retrospectively included in this study. All patients underwent a coronary computed tomographic angiography for the measurement of pericardial fat volume, as well as a transthoracic echocardiography for the assessment of diastolic function parameters. To assess the independent association of PF and diastolic function parameters, multivariable linear regression analysis was performed. To maximize differences in PF volume, the group was divided in low (lowest quartile of both sexes) and high (highest quartile of both sexes) PF volume. Multivariable binary logistic analysis was used to study the associations within the groups between PF and diastolic function, adjusted for age, BMI, and sex., Results: Significant associations for all four diastolic parameters with the PF volume were found after adjusting for BMI, age, and sex. In addition, subjects with high pericardial fat had a reduced left atrial volume index (p = 0.02), lower E/e (p < 0.01) and E/A (p = 0.01), reduced e' lateral (p < 0.01), reduced e' septal p = 0.03), compared to subjects with low pericardial fat., Conclusion: These findings confirm that pericardial fat volume, even in healthy subjects with normal cardiac function, is associated with diastolic function. Our results suggest that the mechanical effects of PF may limit the distensibility of the heart and thereby directly contribute to diastolic dysfunction. Trial registration NCT01671930.

Background: Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation., Objectives: We aimed to investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers., Methods: A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism., Results: Markers of increased NAD+ synthesis-nicotinic acid adenine dinucleotide and methyl nicotinamide-were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism., Conclusions: NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed.This trial was registered at clinicaltrials.gov as NCT02835664., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Aims/hypothesis: Physical inactivity, low mitochondrial function, increased intramyocellular lipid (IMCL) deposition and reduced insulin sensitivity are common denominators of chronic metabolic disorders, like obesity and type 2 diabetes. Yet, whether low mitochondrial function predisposes to insulin resistance in humans is still unknown., Methods: Here we investigated, in an intervention study, whether muscle with low mitochondrial oxidative capacity, induced by one-legged physical inactivity, would feature stronger signs of lipid-induced insulin resistance. To this end, ten male participants (age 22.4 ± 4.2 years, BMI 21.3 ± 2.0 kg/m 2 ) underwent a 12 day unilateral lower-limb suspension with the contralateral leg serving as an active internal control., Results: In vivo, mitochondrial oxidative capacity, assessed by phosphocreatine (PCr)-recovery half-time, was lower in the inactive vs active leg. Ex vivo, palmitate oxidation to 14 CO 2 was lower in the suspended leg vs the active leg; however, this did not result in significantly higher [ 14 C]palmitate incorporation into triacylglycerol. The reduced mitochondrial function in the suspended leg was, however, paralleled by augmented IMCL content in both musculus tibialis anterior and musculus vastus lateralis, and by increased membrane bound protein kinase C (PKC) θ. Finally, upon lipid infusion, insulin signalling was lower in the suspended vs active leg., Conclusions/interpretation: Together, these results demonstrate, in a unique human in vivo model, that a low mitochondrial oxidative capacity due to physical inactivity directly impacts IMCL accumulation and PKCθ translocation, resulting in impaired insulin signalling upon lipid infusion. This demonstrates the importance of mitochondrial oxidative capacity and muscle fat accumulation in the development of insulin resistance in humans., Trial Registration: ClinicalTrial.gov NCT01576250., Funding: PS was supported by a 'VICI' Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618).

The etiology of metabolic disease in humans is far from understood, and even though potential pathways are identified in animal models and cell studies, it is often difficult to determine their relevance in humans, as the possibilities of tissue sampling are limited. The application of non-invasive imaging techniques can provide essential metabolic information and this mini review focuses on the opportunities of Magnetic Resonance Spectroscopy (MRS) to add to our understanding of the metabolic processes during health and disease. MRS is a volatile technique that can give us information about the concentrations of endogenous metabolites in a completely non-invasive way. In this mini review we discuss the opportunities that MRS is giving us by describing how the investigation of ectopic fat depots has gained a lot of attention and has really taken off after 1 H-MRS for quantification of lipid content became widely available. We furthermore discuss how other MRS techniques, such as 31 P-MRS and 13 C-MRS can add valuable information and especially highlight the strength of MRS to be applied dynamically and therefore monitor metabolic changes during physiological challenges such as exercise or meal tests., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Glioblastoma is the most aggressive adult primary brain tumor which is incurable despite intensive multimodal treatment. Inter- and intratumoral heterogeneity poses one of the biggest barriers in the diagnosis and treatment of glioblastoma, causing differences in treatment response and outcome. Noninvasive prognostic and predictive tests are highly needed to complement the current armamentarium. Noninvasive testing of glioblastoma uses multiple techniques that can capture the heterogeneity of glioblastoma. This set of diagnostic approaches comprises advanced MRI techniques, nuclear imaging, liquid biopsy, and new integrated approaches including radiogenomics and radiomics. New treatment options such as agents targeted at driver oncogenes and immunotherapy are currently being developed, but benefit for glioblastoma patients still has to be demonstrated. Understanding and unraveling tumor heterogeneity and microenvironment can help to create a treatment regime that is patient-tailored to these specific tumor characteristics. Improved noninvasive tests are crucial to this success. This review discusses multiple diagnostic approaches and their effect on predicting and monitoring treatment response in glioblastoma.

In this review, current imaging techniques and their future perspectives in the field of cardiac metabolic imaging in humans are discussed. This includes a range of noninvasive imaging techniques, allowing a detailed investigation of cardiac metabolism in health and disease. The main imaging modalities discussed are magnetic resonance spectroscopy techniques for determination of metabolite content (triglycerides, glucose, ATP, phosphocreatine, and so on), MRI for myocardial perfusion, and single-photon emission computed tomography and positron emission tomography for quantitation of perfusion and substrate uptake.

Objective: To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care., Research Design and Methods: Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique., Results: Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction., Conclusions: Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes., (© 2016 by the American Diabetes Association.)

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). We investigated muscle lipid turnover in T2D versus BMI-matched control subjects (controls) and examined whether putative in vivo differences would be preserved in the myotubes. Male obese T2D individuals (n = 6) and BMI-matched controls (n = 6) underwent a hyperinsulinemic-euglycemic clamp, VO2max test, dual-energy X-ray absorptiometry scan, underwater weighing, and muscle biopsy of the vastus lateralis. (14)C-palmitate and (14)C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue as well as in primary myotubes. Palmitate oxidation (controls: 0.99 ± 0.17 nmol/mg protein; T2D: 0.53 ± 0.07 nmol/mg protein; P = 0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (controls: 0.45 ± 0.13 nmol/mg protein; T2D: 0.11 ± 0.02 nmol/mg protein; P = 0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P = 0.38); however, incorporation of FAs into TAG was lower in T2D (P = 0.03 for oleate and P = 0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r = 0.848, P = 0.008). The data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D.

Introduction: Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects., Methods: 49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects., Results: Fasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R(2) = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R(2) = 0.29, p<0.001) and metabolic flexibility (R(2) = 0.40, p<0.001)., Conclusions: These results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.

MRI has been proven to be an accurate method for noninvasive assessment of cardiac function. One of the current limitations of cardiac MRI is that it is time consuming. Therefore, various geometrical models are used, which can reduce scan and postprocessing time. It is unclear how appropriate their use is in rodents. Left ventricular (LV) volumes and ejection fraction (EF) were quantified based on 7.0 Tesla cine-MRI in 12 wild-type (WT) mice, 12 adipose triglyceride lipase knockout (ATGL(-/-)) mice (model of impaired cardiac function), and 11 rats in which we induced cardiac ischemia. The LV volumes and function were either assessed with parallel short-axis slices covering the full volume of the left ventricle (FV, gold standard) or with various geometrical models [modified Simpson rule (SR), biplane ellipsoid (BP), hemisphere cylinder (HC), single-plane ellipsoid (SP), and modified Teichholz Formula (TF)]. Reproducibility of the different models was tested and results were correlated with the gold standard (FV). All models and the FV data set provided reproducible results for the LV volumes and EF, with interclass correlation coefficients ≥0.87. All models significantly over- or underestimated EF, except for SR. Good correlation was found for all volumes and EF for the SR model compared with the FV data set (R(2) ranged between 0.59-0.95 for all parameters). The HC model and BP model also predicted EF well (R(2) ≥ 0.85), although proved to be less useful for quantitative analysis. The SP and TF models correlated poorly with the FV data set (R(2) ≥ 0.45 for EF and R(2) ≥ 0.29 for EF, respectively). For the reduction in acquisition and postprocessing time, only the SR model proved to be a valuable method for calculating LV volumes, stroke volume, and EF.

Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.

Background: Increased cardiac lipid content has been associated with diabetic cardiomyopathy. We recently showed that cardiac lipid content is reduced after 12 weeks of physical activity training in healthy overweight subjects. The beneficial effect of exercise training on cardiovascular risk is well established and the decrease in cardiac lipid content with exercise training in healthy overweight subjects was accompanied by improved ejection fraction. It is yet unclear whether diabetic patients respond similarly to physical activity training and whether a lowered lipid content in the heart is necessary for improvements in cardiac function. Here, we investigated whether exercise training is able to lower cardiac lipid content and improve cardiac function in type 2 diabetic patients., Methods: Eleven overweight-to-obese male patients with type 2 diabetes mellitus (age: 58.4 ± 0.9 years, BMI: 29.9 ± 0.01 kg/m2) followed a 12-week training program (combination endurance/strength training, three sessions/week). Before and after training, maximal whole body oxygen uptake (VO2max) and insulin sensitivity (by hyperinsulinemic, euglycemic clamp) was determined. Systolic function was determined under resting conditions by CINE-MRI and cardiac lipid content in the septum of the heart by Proton Magnetic Resonance Spectroscopy., Results: VO2max increased (from 27.1 ± 1.5 to 30.1 ± 1.6 ml/min/kg, p = 0.001) and insulin sensitivity improved upon training (insulin stimulated glucose disposal (delta Rd of glucose) improved from 5.8 ± 1.9 to 10.3 ± 2.0 μmol/kg/min, p = 0.02. Left-ventricular ejection fraction improved after training (from 50.5 ± 2.0 to 55.6 ± 1.5%, p = 0.01) as well as cardiac index and cardiac output. Unexpectedly, cardiac lipid content in the septum remained unchanged (from 0.80 ± 0.22% to 0.95 ± 0.21%, p = 0.15)., Conclusions: Twelve weeks of progressive endurance/strength training was effective in improving VO2max, insulin sensitivity and cardiac function in patients with type 2 diabetes mellitus. However, cardiac lipid content remained unchanged. These data suggest that a decrease in cardiac lipid content in type 2 diabetic patients is not a prerequisite for improvements in cardiac function., Trial Registration: ISRCTN: ISRCTN43780395.

Objective: Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes., Research Design and Methods: Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and VO2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training., Results: Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (-64%; P < 0.01 in control subjects and -52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers., Conclusions: Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near-significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.