Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

Increased GH/IGF-I Axis Activity Relates to Lower Hepatic Lipids and Phosphor Metabolism.

CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is a leading causes of liver-related morbidity and mortality. While data on acromegaly, a state of chronic growth hormone (GH)/insulin-like growth factor I (IGF-I) excess, suggest an inverse relationship with intrahepatic lipid (IHL) content, less is known about the impact of the GH/IGF-I axis on IHL, lipid composition, and phosphor metabolites in individuals without disorders of GH secretion. OBJECTIVE: The aim was to investigate the relation between activity of the GH/IGF-I axis and IHL content and phosphor metabolism. METHODS: We performed a cross-sectional study in 59 otherwise metabolically healthy individuals (30 females), of which 16 met the criteria of NAFLD with IHL of ≥5.6%. The GH/IGF-I axis was evaluated in a fasting state and during an oral glucose tolerance test (OGTT). Insulin sensitivity was estimated by validated indices. IHL, lipid composition (unsaturation index), and phosphate metabolites were analyzed by using 1H/31P magnetic resonance spectroscopy. RESULTS: In the overall cohort (40.6 ± 15 years; body mass index: 24.5 ± 3 kg/m2; IGF-I: 68.0 ± 17% upper limit of normal), fasting GH (R = -0.31; P = .02), GH during oral glucose tolerance test (R = -0.51; P < .01), and IGF-I (R = -0.28; P = .03) inversely correlated with IHL. GH levels during OGTT were significantly lower in NAFLD than in controls (47.7 [22; 143] ng/mL/min vs 16.8 [7; 32] ng/mL/min; P = .003). GH/IGF-I axis activity correlated with lipid composition and with phosphor metabolites. In multiple regression analysis, the GH/IGF-I axis activity was a strong predictor for IHL and lipid composition independent from insulin sensitivity. CONCLUSION: GH/IGF-I axis activity impacts hepatic lipid and phosphate metabolism in individuals without disorders in GH secretion. Lower GH axis activity is associated with higher IHL and an unfavorable lipid composition, probably mediated by changes in hepatic energy metabolism.

Potential role of skeletal muscle glycerophosphocholine in response to altered fluid balance in humans: an in vivo nuclear magnetic resonance study.

Many cells adapt to hyperosmolal conditions by upregulation of organic osmolytes to maintain cell function and integrity. Glycerophosphocholine (GPC), a recognized osmolyte in renal medullary cells, is the major phosphodiester (PDE) in human skeletal muscle, wherefore we hypothesized muscular GPC to be associated with surrogate parameters of fluid status and osmolality in healthy humans. The objective of this study was to investigate the relationship of muscular GPC with surrogate parameters of body fluid status and osmolality. We analyzed data of 30 healthy volunteers who underwent noninvasive 31P-magnetic resonance spectroscopy of either calf (n = 17) or thigh (n = 13) muscle. Therefore, we conducted correlation analyses between phosphor metabolites, and blood values depicting body fluid status and osmolality. Relevant parameters were further implemented in a multivariable regression model to evaluate if GPC concentrations can depict variations in fluid and electrolyte balance. Uric acid (0.437, P = 0.018) and urea (0.387, P = 0.035) were significantly correlated with GPC, which in case of uric acid was independent of sex. Considering sex, following multivariable regression reported GPC as suitable parameter to predict uric acid (R2 = 0.462, adjusted R2 = 0.421; P < 0.001). Our data indicate a connection between muscular GPC concentrations and uric acid, which is a marker of body fluid status, in healthy human subjects, suggesting that skeletal muscle might regulate GPC content in adaptation to changes in fluid status.NEW & NOTEWORTHY Using in vivo magnetic resonance spectroscopy, our study is the first one indicating fluid balance-dependent properties of glycerophosphocholine concentrations in human skeletal muscle. In vivo examination of GPC as organic osmolyte in human skeletal muscle marks a novel approach, which might give further insight on how water and electrolyte balance affect muscle tissue. Beside this main finding, glycerophosphocholine of both calf and thigh muscle correlated remarkably with blood laboratory parameters of lipid metabolism in our study population.

Leptin increases hepatic triglyceride export via a vagal mechanism in humans.

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n = 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n = 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n = 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

Concentration of Gallbladder Phosphatidylcholine in Cholangiopathies: A Phosphorus-31 Magnetic Resonance Spectroscopy Pilot Study.

BACKGROUND: Biliary phosphatidylcholine (PtdC) concentration plays a role in the pathogenesis of bile duct diseases. In vivo phosphorus-31 magnetic resonance spectroscopy (31 P-MRS) at 7 T offers the possibility to assess this concentration noninvasively with high spectral resolution and signal intensity. PURPOSE: Comparison of PtdC levels of cholangiopathic patient groups to a control group using a measured T1 relaxation time of PtdC in healthy subjects. STUDY TYPE: Case control. SUBJECTS: Two patient groups with primary sclerosing cholangitis (PSC, 2f/3 m; age: 43 ± 7 years) and primary biliary cholangitis (PBC, 4f/2 m; age: 57 ± 6 years), and a healthy control group (CON, 2f/3 m; age: 38 ± 7 years). Ten healthy subjects for the assessment of the T1 relaxation time of PtdC. FIELD STRENGTH/SEQUENCE: A 3D phase-encoded pulse-acquire 31 P-MRSI sequence for PtdC quantification and a 1D image-selected in vivo 31 P spectroscopy for T1 estimation at 7 T, and a T2-weighted half-Fourier single-shot turbo spin echo MRI sequence for volumetry at 3 T. ASSESSMENT: Calculation of gallbladder volumes and PtdC concentration in groups using hepatic gamma-adenosine triphosphate signal as an internal reference and correction for insufficient relaxation of PtdC with a T1 value assessed in healthy subjects. STATISTICAL TESTS: Group comparison of PtdC content and gallbladder volumes of the PSC/PBC and CON group using Student's t-tests with a significance level of 5%. RESULTS: PtdC T1 value of 357 ± 85 msec in the gallbladder. Significant lower PtdC content for the PSC group, and for the female subgroup of the PBC group compared to the CON group (PSC/CON: 5.74 ± 0.73 mM vs. 9.64 ± 0.97 mM, PBC(f)/CON: 5.77 ± 1.44 mM vs. 9.64 ± 0.97 mM). Significant higher gallbladder volumes of the patient groups compared to the CON group (PSC/CON: 66.3 ± 15.8 mL vs. 20.9 ± 2.2 mL, PBC/CON: 49.8 ± 18.2 mL vs. 20.9 ± 2.2 mL). DATA CONCLUSION: This study demonstrated the application of a 31 P-MRSI protocol for the quantification of PtdC in the human gallbladder at 7 T. Observed differences in PtdC concentration suggest that this metabolite could serve as a biomarker for specific hepatobiliary disorders. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Feasibility of Hepatic Fat Quantification Using Proton Density Fat Fraction by Multi-Echo Chemical-Shift-Encoded MRI at 7T.

Fat fraction quantification and assessment of its distribution in the hepatic tissue become more important with the growing epidemic of obesity, and the increasing prevalence of diabetes mellitus type 2 and non-alcoholic fatty liver disease. At 3Tesla, the multi-echo, chemical-shift-encoded magnetic resonance imaging (CSE-MRI)-based acquisition allows the measurement of proton density fat-fraction (PDFF) even in clinical protocols. Further improvements in SNR can be achieved by the use of phased array coils and increased static magnetic field. The purpose of the study is to evaluate the feasibility of PDFF imaging using a multi-echo CSE-MRI technique at ultra-high magnetic field (7Tesla). Thirteen volunteers (M/F) with a broad range of age, body mass index, and hepatic PDFF were measured at 3 and 7T by multi-gradient-echo MRI and single-voxel spectroscopy MRS. All measurements were performed in breath-hold (exhalation); the MRI protocols were optimized for a short measurement time, thus minimizing motion-related problems. 7T data were processed off-line using Matlab® (MRI:multi-gradient-echo) and jMRUI (MRS), respectively. For quantitative validation of the PDFF results, a similar protocol was performed at 3T, including on-line data processing provided by the system manufacturer, and correlation analyses between 7 and 3T data were performed off-line. The multi-echo CSE-MRI measurements at 7T with a phased-array coil configuration and an optimal post-processing yielded liver volume coverage ranging from 30 to 90% for high- and low-BMI subjects, respectively. PDFFs ranged between 1 and 20%. We found significant correlations between 7T MRI and -MRS measurements (R2 ≅ 0.97; p < 0.005), and between MRI-PDFF at 7T and 3T fields (R2 ≅ 0.94; p < 0.005) in the evaluated volumes. Based on the measurements and analyses performed, the multi-echo CSE-MRI method using a 32-channel coil at 7T showed its aptitude for MRI-based quantitation of PDFF in the investigated volumes. The results are the first step toward qMRI of the whole liver at 7T with further improvements in hardware.

In Vivo 1 H MR Spectroscopy of Biliary Components of Human Gallbladder at 7T.

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 T2 relaxation of water in the gallbladder and in the liver. Concentrations of biliary components were calculated using water signal. All data were corrected for T2 relaxation times measured in healthy subjects. STATISTICAL TESTS: The range of T2 relaxation time and concentration per bile component, and the resulting mean and standard deviation, were calculated. RESULTS: The concentrations of gallbladder components in healthy subjects were: NHCBA: 93 ± 66 mM, OLC: 154 ± 124 mM, CCPL: 42 ± 17 mM, TCBA: 48 ± 35 mM, GCBA: 67 ± 32 mM, ML: 740 ± 391 mM, BALC1.0: 175 ± 92 mM, BALC0.9: 260 ± 138 mM, and TBAC: 153 ± 90 mM. Mean concentrations of all bile components were found to be lower in patients. DATA CONCLUSION: This work provides a protocol for designing future MRS investigations of the bile system in vivo. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1.

Gluconeogenesis, But Not Glycogenolysis, Contributes to the Increase in Endogenous Glucose Production by SGLT-2 Inhibition.

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.

Effects of Thyroid Function on Phosphodiester Concentrations in Skeletal Muscle and Liver: An In Vivo NMRS Study.

CONTEXT: Thyroid function is clinically evaluated by determination of circulating concentrations of thyrotropin (thyroid-stimulating hormone; TSH) and free thyroxine (fT4). However, a tissue-specific effector substrate of thyroid function is lacking. Energy-rich phosphorus-containing metabolites (PM) and phospholipids (PL) might be affected by thyroid hormone action and can be noninvasively measured by 31P nuclear magnetic resonance spectroscopy (NMRS). OBJECTIVES: To measure the actions of peripheral thyroid hormones on PM and PL tissue concentrations. DESIGN AND SETTING: A longitudinal, prospective pilot study was performed. PARTICIPANTS: Nine patients with hyperthyroidism (HYPER) and 4 patients with hypothyroidism (HYPO) were studied at baseline and 3 months after treatment. MAIN OUTCOME MEASURES: High-field 1H/31P NMRS was used to assess profiles of PM, PL, and flux through oxidative phosphorylase in liver and skeletal muscle, as well as ectopic tissue lipid content. RESULTS: The concentrations of total skeletal muscle (m-) and hepatic (h-) phosphodiesters (PDE) and one of the PDE constituents, glycerophosphocholine (GPC), were lower in HYPER compared with HYPO (m-PDE: 1.4 ±â€…0.4 mM vs 7.4 ±â€…3.5 mM, P = 0.003; m-GPC: 0.9 ±â€…0.3 mM vs 6.7 ±â€…3.5 mM, P = 0.003; h-PDE: 4.4 ±â€…1.4 mM vs 9.9 ±â€…3.9 mM, P = 0.012; h-GPC: 2.2 ±â€…1.0 mM vs 5.1 ±â€…2.4 mM, P = 0.024). Both h-GPC (rho = -0.692, P = 0.018) and h-GPE (rho = -0.633, P = 0.036) correlated negatively with fT4. In muscle tissue, a strong negative association between m-GPC and fT4 (rho = -0.754, P = 0.003) was observed. CONCLUSIONS: Thyroxine is closely negatively associated with the PDE concentrations in liver and skeletal muscle. Normalization of thyroid dysfunction resulted in a decline of PDE in hypothyroidism and an increase in hyperthyroidism. Thus, PDE might be a sensitive tool to estimate tissue-specific peripheral thyroid hormone action.

Increased ATP synthesis might counteract hepatic lipid accumulation in acromegaly.

Patients with active acromegaly (ACRO) exhibit low hepatocellular lipids (HCL), despite pronounced insulin resistance (IR). This contrasts the strong association of IR with nonalcoholic fatty liver disease in the general population. Since low HCL levels in ACRO might be caused by changes in oxidative substrate metabolism, we investigated mitochondrial activity and plasma metabolomics/lipidomics in active ACRO. Fifteen subjects with ACRO and seventeen healthy controls, matched for age, BMI, sex, and body composition, underwent 31P/1H-7-T MR spectroscopy of the liver and skeletal muscle as well as plasma metabolomic profiling and an oral glucose tolerance test. Subjects with ACRO showed significantly lower HCL levels, but the ATP synthesis rate was significantly increased compared with that in controls. Furthermore, a decreased ratio of unsaturated-to-saturated intrahepatocellular fatty acids was found in subjects with ACRO. Within assessed plasma lipids, lipidomics, and metabolomics, decreased carnitine species also indicated increased mitochondrial activity. We therefore concluded that excess of growth hormone (GH) in humans counteracts HCL accumulation by increased hepatic ATP synthesis. This was accompanied by a decreased ratio of unsaturated-to-saturated lipids in hepatocytes and by a metabolomic profile, reflecting the increase in mitochondrial activity. Thus, these findings help to better understanding of GH-regulated antisteatotic pathways and provide a better insight into potentially novel therapeutic targets for treating NAFLD.

Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects.

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.

Plasma renin levels are associated with cardiac function in primary adrenal insufficiency.

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/m2) 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-Reninlow vs. Actual-Reninhigh) and their median plasma renin concentration of previous visits (Median-Reninlow vs. Median-Reninhigh). 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/m2; p = 0.025) in Actual-Reninhigh. Median-Reninhigh was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m2; 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.

Reduced hepatocellular lipid accumulation and energy metabolism in patients with long standing type 1 diabetes mellitus.

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 (kATP) and skeletal muscle (kCK) 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 31P/1H 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 kATP 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 kATP. In the whole cohort, HCL was significantly associated with BMI (r = 0.615, p = 0.005). In skeletal muscle kCK 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.

Absolute Quantification of Phosphor-Containing Metabolites in the Liver Using 31 P MRSI and Hepatic Lipid Volume Correction at 7T Suggests No Dependence on Body Mass Index or Age.

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 (B0 ≥ 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 (Pi ); 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, Pi : 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 healthy population used in this study. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:597-607.