Aims/hypothesis: In our current society sedentary behaviour predominates in most people and is associated with the risk of developing type 2 diabetes. It has been suggested that replacing sitting time by standing and walking could be beneficial for individuals with type 2 diabetes but the underlying mechanisms are unknown and direct comparisons with exercise are lacking. Our objective was to directly compare metabolic responses of either sitting less or exercising, relative to being sedentary. Methods: We performed a randomised, crossover intervention study in 12 overweight women who performed three well-controlled 4 day activity regimens: (1) sitting regimen (sitting 14 h/day); (2) exercise regimen (sitting 13 h/day, exercise 1 h/day); and (3) sitting less regimen (sitting 9 h/day, standing 4 h/day and walking 3 h/day). The primary outcome was insulin sensitivity measured by a two-step hyperinsulinaemic–euglycaemic clamp. We additionally performed metabolomics on muscle biopsies taken before the clamp to identify changes at the molecular level. Results: Replacing sitting time by standing and walking over 4 days resulted in improved peripheral insulin sensitivity, comparable with the improvement achieved by moderate-to-vigorous exercise. Specifically, we report a significant improvement in peripheral insulin sensitivity in the sitting less (~13%) and the exercise regimen (~20%), compared with the sitting regimen. Furthermore, sitting less shifted the underlying muscle metabolome towards that seen with moderate-to-vigorous exercise, compared with the sitting regimen. Conclusions/interpretations: Replacing sitting time by standing and walking is an attractive alternative to moderate-to-vigorous exercise for improving metabolic health. Trial registration: ClinicalTrials.gov NCT03912922. Graphical

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.

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 ¹⁸F‐fluorodeoxyglucose‐positron emission tomography (¹⁸F‐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.

Objectives The objective of the study was to validate PCr/ATP ratios as an in vivo marker for cardiac mitochondrial function.Background Cardiac energy status, measured as PCr/ATP ratio with ³¹P-MRS in vivo, was shown to be a prognostic factor in heart failure and is lowered in cardiometabolic disease. As mitochondrial function is also hampered in these diseases and oxidative phosphorylation is the major contributor to ATP synthesis, the PCr/ATP ratio might be a reflection of cardiac mitochondrial function.Methods Thirty-eight patients scheduled for open heart surgery were enrolled in this study. Before surgery, cardiac ³¹P-MRS was performed. During surgery, tissue specimens from the right atrial appendage were obtained for the ex vivo assessment of mitochondrial function using high-resolution respirometry.Results The patient population included was heterogenous resulting in wide ranges of PCr/ATP ratios and ADP-stimulated respiration rates (PCr/ATP ranging from 0.533 to 1.717; ADP-stimulated respiration rates ranging from 28.5 to 94.6 pmol/mg/s). Correlation analysis however showed no relationship between PCr/ATP and ADP-stimulated respiration rates fueled by various substrates (octanoylcarnitine R² < 0.005, p = 0.74; pyruvate R² < 0.025, p = 0.41). Also, no correlations between PCr/ATP and maximally uncoupled respiration were found (octanoylcarnitine R² = 0.005, p = 0.71; pyruvate R² = 0.040, p = 0.26).Conclusions Our results do not support the use of cardiac energy status (PCr/ATP) as a surrogate marker of mitochondrial function in the heart. The dissociation of the two parameters in the present study suggests that mitochondrial function is not the only determinant of cardiac energy status.Condensed abstractThis study does not support the use of in vivo cardiac energy status (PCr/ATP ratio) as a surrogate marker of ex vivo mitochondrial function (maximal oxidative respiration). Although both PCr/ATP and mitochondrial function are reduced in cardiovascular disease, the dissociation of the two parameters in the present study shows that PCr/ATP is determined by more factors than only mitochondrial function. Hence, PCr/ATP is not a good marker for mitochondrial function, but it can be a valuable marker for cardiometabolic health in cardiometabolic studies.Trial registration: https://clinicaltrials.gov (NCT03049228).

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/m², 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