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Concentrations of the key metabolites of hepatic energy metabolism, adenosine triphosphate (ATP) and inorganic phosphate (Pi), can be altered in metabolic disorders such as diabetes mellitus. 31Phosphorus (31P)‐magnetic resonance spectroscopy (MRS) is used to noninvasively measure hepatic metabolites, but measuring their absolute molar concentrations remains challenging. This study employed a 31P‐MRS method based on the phantom replacement technique for quantifying hepatic 31P‐metabolites on a 3‐T clinical scanner. Two surface coils with different size and geometry were used to check for consistency in terms of repeatability and reproducibility and absolute concentrations of metabolites. Day‐to‐day (n = 8) and intra‐day (n = 6) reproducibility was tested in healthy volunteers. In the day‐to‐day study, mean absolute concentrations of γ‐ATP and Pi were 2.32 ± 0.24 and 1.73 ± 0.26 mM (coefficient of variation [CV]: 7.3% and 8.8%) for the single loop, and 2.32 ± 0.42 and 1.73 ± 0.27 mM (CVs 6.7% and 10.6%) for the quadrature coil, respectively. The intra‐day study reproducibility using the quadrature coil yielded CVs of 4.7% and 6.8% for γ‐ATP and Pi without repositioning, and 6.3% and 7.1% with full repositioning of the volunteer. The results of the day‐to‐day data did not differ between coils and visits. Both coils robustly yielded similar results for absolute concentrations of hepatic 31P‐metabolites. The current method, applied with two different surface coils, can be readily utilized in long‐term and interventional studies. In comparison with the single loop coil, the quadrature coil also allows measurements at a greater distance between the coil and liver, which is relevant for studying people with obesity. [ABSTRACT FROM AUTHOR]

Maternal obesity and hyperglycemia are linked to an elevated risk for obesity, diabetes, and steatotic liver disease in the adult offspring. To establish and validate a noninvasive workflow for perinatal metabolic phenotyping, fixed neonates of common mouse strains were analyzed postmortem via magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) to assess liver volume and hepatic lipid (HL) content. The key advantage of nondestructive MRI/MRS analysis is the possibility of further tissue analyses, such as immunohistochemistry, RNA extraction, and even proteomics, maximizing the data that can be gained per individual and therefore facilitating comprehensive correlation analyses. This study employed an MRI and 1H‐MRS workflow to measure liver volume and HL content in 65 paraformaldehyde‐fixed murine neonates at 11.7 T. Liver volume was obtained using semiautomatic segmentation of MRI acquired by a RARE sequence with 0.5‐mm slice thickness. HL content was measured by a STEAM sequence, applied with and without water suppression. T1 and T2 relaxation times of lipids and water were measured for respective correction of signal intensity. The HL content, given as CH2/(CH2 + H2O), was calculated, and the intrasession repeatability of the method was tested. The established workflow yielded robust results with a variation of ~3% in repeated measurements for HL content determination. HL content measurements were further validated by correlation analysis with biochemically assessed triglyceride contents (R2 = 0.795) that were measured in littermates. In addition, image quality also allowed quantification of subcutaneous adipose tissue and stomach diameter. The highest HL content was measured in C57Bl/6N (4.2%) and the largest liver volume and stomach diameter in CBA (53.1 mm3 and 6.73 mm) and NMRI (51.4 mm3 and 5.96 mm) neonates, which also had the most subcutaneous adipose tissue. The observed effects were independent of sex and litter size. In conclusion, we have successfully tested and validated a robust MRI/MRS workflow that allows assessment of morphology and HL content and further enables paraformaldehyde‐fixed tissue‐compatible subsequent analyses in murine neonates. [ABSTRACT FROM AUTHOR]

Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI -0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD -0.80 (95% CI -1.09; -0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD -0.33 (95% CI -0.54; -0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats., Author(s): Esther Winters-van Eekelen [sup.1] , Inge Verkouter [sup.1] , Harry P. F. Peters [sup.2] , Marjan Alssema [sup.2] , Babette G. de Roos [sup.1] , Vera B. Schrauwen-Hinderling [sup.3] [...]

Background: Water T1 of the liver has been shown to be promising in discriminating the progressive forms of fatty liver diseases, inflammation, and fibrosis, yet proper correction for iron and lipid is required. Purpose: To examine the feasibility of an empirical approach for iron and lipid correction when measuring imaging‐based T1 and to validate this approach by spectroscopy on in vivo data. Study Type: Retrospective. Population: Next to mixed lipid‐iron phantoms, individuals with different hepatic lipid content were investigated, including people with type 1 diabetes (N = 15, %female = 15.6, age = 43.5 ± 14.0), or type 2 diabetes mellitus (N = 21, %female = 28.9, age = 59.8 ± 9.7) and healthy volunteers (N = 9, %female = 11.1, age = 58.0 ± 8.1). Field Strength/Sequences: 3 T, balanced steady‐state free precession MOdified Look‐Locker Inversion recovery (MOLLI), multi‐ and dual‐echo gradient echo Dixon, gradient echo magnetic resonance elastography (MRE). Assessment: T1 values were measured in phantoms to determine the respective correction factors. The correction was tested in vivo and validated by proton magnetic resonance spectroscopy (1H‐MRS). The quantification of liver T1 based on automatic segmentation was compared to the T1 values based on manual segmentation. The association of T1 with MRE‐derived liver stiffness was evaluated. Statistical Tests: Bland–Altman plots and intraclass correlation coefficients (ICCs) were used for MOLLI vs. 1H‐MRS agreement and to compare liver T1 values from automatic vs. manual segmentation. Pearson's r correlation coefficients for T1 with hepatic lipids and liver stiffness were determined. A P‐value of 0.05 was considered statistically significant. Results: MOLLI T1 values after correction were found in better agreement with the 1H‐MRS‐derived water T1 (ICC = 0.60 [0.37; 0.76]) in comparison with the uncorrected T1 values (ICC = 0.18 [−0.09; 0.44]). Automatic quantification yielded similar liver T1 values (ICC = 0.9995 [0.9991; 0.9997]) as with manual segmentation. A significant correlation of T1 with liver stiffness (r = 0.43 [0.11; 0.67]) was found. A marked and significant reduction in the correlation strength of T1 with liver stiffness (r = 0.05 [−0.28; 0.38], P = 0.77) was found after correction for hepatic lipid content. Data Conclusion: Imaging‐based correction factors enable accurate estimation of water T1 in vivo. Level of Evidence: 1 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but it changes over time, and relationships with comorbidities remain unclear. We examined IMCL during the initial course of diabetes and its associations with complications. Participants of the German Diabetes Study (GDS) with recent-onset type 1 (n = 132) or type 2 diabetes (n = 139) and glucose-tolerant control subjects (n = 128) underwent 1H-MRS to measure IMCL and muscle volume, whole-body insulin sensitivity (hyperinsulinemic-euglycemic clamps; M-value), and cycling spiroergometry (VO2max). Subgroups underwent the same measurements after 5 years. At baseline, IMCL was ∼30% higher in type 2 diabetes than in other groups independently of age, sex, BMI, and muscle volume. In type 2 diabetes, the M-value was ∼36% and ∼62% lower compared with type 1 diabetes and control subjects, respectively. After 5 years, the M-value decreased by ∼29% in type 1 and ∼13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation between IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, the Framingham risk score for cardiovascular disease, and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror the progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications. Article Highlights: Intramyocellular lipid content (IMCL) can be elevated in insulin-resistant humans, but its dynamics and association with comorbidities remain unclear. Independently of age, sex, body mass, and skeletal muscle volume, IMCL is higher in recent-onset type 2, but not type 1 diabetes, and remains unchanged within 5 years, despite worsening insulin resistance. A degree of physical fitness modulates the association between IMCL and insulin sensitivity in type 2 diabetes. Whereas higher IMCL associates with lower insulin sensitivity in people with lower physical fitness, there is no association between IMCL and insulin sensitivity in those with higher degree of physical fitness. IMCL associates with progression of microalbuminuria, cardiovascular disease risk, and cardiac autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Objective: This study (1) investigated the effect of weight loss on whole‐body and tissue‐specific insulin sensitivity and on intrahepatic lipid (IHL) content and composition and (2) investigated the association between weight‐loss‐induced changes in insulin sensitivity and IHL content in individuals with overweight or obesity. Methods: In this secondary analysis of the European SWEET project, 50 adults (age 18–65 years) with overweight or obesity (BMI ≥ 25 kg/m2) followed a low‐energy diet (LED) for 2 months. At baseline and after the LED, body composition (dual‐energy x‐ray absorptiometry), IHL content and composition (proton magnetic resonance spectroscopy), whole‐body insulin sensitivity (Matsuda index), muscle insulin sensitivity index (MISI), and hepatic insulin resistance index (HIRI) were determined (7‐point oral glucose tolerance test). Results: The LED reduced body weight (p < 0.001). This was accompanied by increased Matsuda index and reduced HIRI (both p < 0.001) but no change in MISI (p = 0.260). Weight loss decreased IHL content (mean [SEM], 3.9% [0.7%] vs. 1.6% [0.5%], p < 0.001) and the hepatic saturated fatty acid fraction (41.0% [1.5%] vs. 36.6% [1.9%], p = 0.039). The reduced IHL content was associated with an improvement in HIRI (r = 0.402, p = 0.025). Conclusions: Weight loss decreased IHL content and the hepatic saturated fatty acid fraction. The decrease in IHL content was associated with weight‐loss‐induced improvement in hepatic insulin sensitivity in individuals with overweight or obesity. [ABSTRACT FROM AUTHOR]

Mitochondria are organelles that fuel cellular energy requirements by ATP formation via aerobic metabolism. Given the wide variety of methods to assess skeletal muscle mitochondrial capacity, we tested how well different invasive and noninvasive markers of skeletal muscle mitochondrial capacity reflect mitochondrial respiration in permeabilized muscle fibers. Nineteen young men (mean age: 24 ± 4 years) were recruited, and a muscle biopsy was collected to determine mitochondrial respiration from permeabilized muscle fibers and to quantify markers of mitochondrial capacity, content such as citrate synthase (CS) activity, mitochondrial DNA copy number, TOMM20, VDAC, and protein content for complex I–V of the oxidative phosphorylation (OXPHOS) system. Additionally, all participants underwent noninvasive assessments of mitochondrial capacity: PCr recovery postexercise (by 31P‐MRS), maximal aerobic capacity, and gross exercise efficiency by cycling exercise. From the invasive markers, Complex V protein content and CS activity showed the strongest concordance (Rc = 0.50 to 0.72) with ADP‐stimulated coupled mitochondrial respiration, fueled by various substrates. Complex V protein content showed the strongest concordance (Rc = 0.72) with maximally uncoupled mitochondrial respiration. From the noninvasive markers, gross exercise efficiency, VO2max, and PCr recovery exhibited concordance values between 0.50 and 0.77 with ADP‐stimulated coupled mitochondrial respiration. Gross exercise efficiency showed the strongest concordance with maximally uncoupled mitochondrial respiration (Rc = 0.67). From the invasive markers, Complex V protein content and CS activity are surrogates that best reflect skeletal muscle mitochondrial respiratory capacity. From the noninvasive markers, exercise efficiency and PCr recovery postexercise most closely reflect skeletal muscle mitochondrial respiratory capacity. [ABSTRACT FROM AUTHOR]

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (¹H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE ¹H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS ([sup.31]P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with ¹H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity., Introduction The use of proton magnetic resonance spectroscopy ('H-MRS) in human skeletal muscle has been instrumental in establishing the importance of ectopic fat accumulation in the development of type 2 [...]