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Background Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD). Objectives The aim of this study was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue. Methods Ten healthy subjects (age: 28 ± 19 y; BMI: 22.2 ± 0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4 ± 3.95 y; BMI: 28.4 ± 1.25) were characterized as “positive controls.” Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T. Results High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured [Δhepatocellular lipid (HCL)_healthy_baseline: −15.9 ± 10.7 compared with ± ΔHCL_healthy_follow-up: −6.9 ± 4.6; P = 0.17] and hepatic glycogen (Δglycogen_baseline: 64.4 ± 14.1 compared with Δglycogen_follow-up: 51.1 ± 9.8; P = 0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD. Conclusions Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.

Background Hepatic disorders are often associated with changes in the concentration of phosphorus‐31 ( 31 P) metabolites. Absolute quantification offers a way to assess those metabolites directly but introduces obstacles, especially at higher field strengths (B 0 ≥ 7T). Purpose To introduce a feasible method for in vivo absolute quantification of hepatic 31 P metabolites and assess its clinical value by probing differences related to volunteers' age and body mass index (BMI). Study Type Prospective cohort. Subjects/Phantoms Four healthy volunteers included in the reproducibility study and 19 healthy subjects arranged into three subgroups according to BMI and age. Phantoms containing 31 P solution for correction and validation. Field Strength/Sequence Phase‐encoded 3D pulse‐acquire chemical shift imaging for 31 P and single‐volume 1 H spectroscopy to assess the hepatocellular lipid content at 7T. Assessment A phantom replacement method was used. Spectra located in the liver with sufficient signal‐to‐noise ratio and no contamination from muscle tissue, were used to calculate following metabolite concentrations: adenosine triphosphates (γ‐ and α‐ATP); glycerophosphocholine (GPC); glycerophosphoethanolamine (GPE); inorganic phosphate (P i ); phosphocholine (PC); phosphoethanolamine (PE); uridine diphosphate‐glucose (UDPG); nicotinamide adenine dinucleotide‐phosphate (NADH); and phosphatidylcholine (PtdC). Correction for hepatic lipid volume fraction (HLVF) was performed. Statistical Tests Differences assessed by analysis of variance with Bonferroni correction for multiple comparison and with a Student's t ‐test when appropriate. Results The concentrations for the young lean group corrected for HLVF were 2.56 ± 0.10 mM for γ‐ATP (mean ± standard deviation), α‐ATP: 2.42 ± 0.15 mM, GPC: 3.31 ± 0.27 mM, GPE: 3.38 ± 0.87 mM, P i : 1.42 ± 0.20 mM, PC: 1.47 ± 0.24 mM, PE: 1.61 ± 0.20 mM, UDPG: 0.74 ± 0.17 mM, NADH: 1.21 ± 0.38 mM, and PtdC: 0.43 ± 0.10 mM. Differences found in ATP levels between lean and overweight volunteers vanished after HLVF correction. Data Conclusion Exploiting the excellent spectral resolution at 7T and using the phantom replacement method, we were able to quantify up to 10 31 P‐containing hepatic metabolites. The combination of 31 P magnetic resonance spectroscopy imaging data acquisition and HLVF correction was not able to show a possible dependence of 31 P metabolite concentrations on BMI or age, in the small hea...

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OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90–180 min (MR1), and 300–390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg−1 min−1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg−1 min−1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (−3.28 ± 0.49 vs. −2.53 ± 0.56 μmol kg−1 min−1; P = n.s.) or T2DM-P and T2DM-D (−0.74 ± 0.23 vs. −1.21 ± 0.33 μmol kg−1 min−1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg−1 min−1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.

Background: Previous in vivo proton MR spectroscopy (MRS) studies have demonstrated the possibility of quantifying amide groups of conjugated bile acids (NHCBA), olefinic lipids and cholesterol (OLC), choline-containing phospholipids (CCPLs), taurine and glycine conjugated bile acids (TCBA, GCBA), methylene group of lipids (ML), and methyl groups of bile acids, lipids, and cholesterol (BALC1.0, BALC0.9, and TBAC) in the gallbladder, which may be useful for the study of cholestatic diseases and cholangiopathies. However, these studies were performed at 1.5T and 3T, and higher magnetic fields may offer improved spectral resolution and signal intensity. Purpose: To develop a method for gallbladder MRS at 7T. Study Type: Retrospective, technical development. Population: Ten healthy subjects (five males and five females), two patients with primary biliary cholangitis (PBC) (one male and one female), and one patient with primary sclerosing cholangitis (PSC) (female). Field Strength/Sequence: Free-breathing single-voxel MRS with a modified stimulated echo acquisition mode (STEAM) sequence at 7T. Assessment: Postprocessing was based on the T 2 relaxation of water in the gallbladder and in the liver. Concentrations of biliary components were calculated using water signal. All data were corrected for T 2 relaxation times measured in healthy subjects. Statistical Tests: The range of T 2 relaxation time and concentration per bile component, and the resulting mean and standard deviation, were calculated.

Background Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, primary adrenal insufficiency (AI) is associated with an increased mortality, mainly due to cardiovascular disease. The role of MC replacement is not known. Therefore, we assessed whether renin concentrations during routine GC and MC substitution therapy are associated with heart function and morphology. Methods Thirty two patients with primary AI were included in a cross-sectional case–control study. In total, 17 patients and 34 healthy controls (age: 48 ± 12 vs. 46 ± 18 years; BMI: 23 ± 3 vs. 24 ± 3 kg/m 2 ) underwent magnetic resonance spectroscopy and imaging measurements to assess cardiac function, morphology, ectopic lipids, and visceral/subcutaneous fat mass. Patients were divided according to their actual plasma renin concentration at the study visit (Actual-Renin low vs. Actual-Renin high ) and their median plasma renin concentration of previous visits (Median-Renin low vs. Median-Renin high ). Results Ejection fraction was higher (67 ± 5 vs. 55 ± 3%; p = 0.001) and left ventricular mass was lower (60 ± 9 vs. 73 ± 10 g/m 2 ; p = 0.025) in Actual-Renin high . Median-Renin high was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m 2 ; p = 0.029). Blood pressure, glucose, and lipid metabolism, as well as ectopic lipid content, pericardial fat mass, and visceral/subcutaneous fat were not different between the groups. Compared with controls, ejection fraction was significantly lower in patients with AI (56 ± 4 vs. 63 ± 8%; p = 0.019). No differences were found in patients with ≤20 mg compared with >20 mg of hydrocortisone per day. Conclusions Higher renin concentrations are associated with more favorable cardiac function and morphology in patients with primary AI.

The prevalence of obesity and metabolic syndrome increases in patients with type 1 diabetes mellitus (T1DM). In the general population this is linked with ectopic lipid accumulation in liver (HCL) and skeletal muscle (IMCL), representing hallmarks in the development of insulin resistance. Moreover, hepatic mitochondrial activity is lower in newly diagnosed patients with T1DM. If this precedes later development of diabetes related fatty liver disease is currently not known. This study aims to investigate energy metabolism in liver ( k ATP ) and skeletal muscle ( k CK ) and its impact on HCL, IMCL, cardiac fat depots and heart function in 10 patients with long standing T1DM compared to 11 well-matched controls by 31 P/ 1 H magnetic resonance spectroscopy. HCL was almost 70% lower in T1DM compared to controls (6.9 ± 5% vs 2.1 ± 1.3%; p = 0.030). Also k ATP was significantly reduced (0.33 ± 0.1 s −1 vs 0.17 ± 0.1 s −1 ; p = 0.018). In T1DM, dose of basal insulin strongly correlated with BMI (r = 0.676, p = 0.032) and HCL (r = 0.643, p = 0.045), but not with k ATP . In the whole cohort, HCL was significantly associated with BMI (r = 0.615, p = 0.005). In skeletal muscle k CK was lower in patients with T1DM (0.25 ± 0.05 s −1 vs 0.31 ± 0–04 s −1 ; p = 0.039). No significant differences were found in IMCL. Cardiac fat depots as well as heart function were not different. Our results in patients with long standing T1DM show that HCL is lower compared to matched controls, despite reduced energy metabolism in liver and skeletal muscle.