BackgroundMuscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).Methods and FindingsWe measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with 31P/1H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%–99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%–42%; older: 11%, 95% CI 2%–25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.ConclusionsPatients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.

DW imaging based on readout-segmented echo-planar imaging provided significantly higher image quality and lesion conspicuity than single-shot echo-planar imaging by reducing geometric distortions, image blurring, and artifact level with a clinical high-field-strength MR imager. Thereby, readout-segmented echo-planar imaging reached a higher diagnostic accuracy for the differentiation of benign and malignant breast lesions.

Phosphorus ( 31 P) T 1 and T 2 relaxation times in the resting human calf muscle were assessed by interleaved, surface coil localized inversion recovery and frequency-selective spin-echo at 3 and 7 T. The obtained T 1 (mean ؎ SD) decreased significantly (P < 0.05) from 3 to 7 T for phosphomonoesters (PME) (8.1 ؎ 1.7 s to 3.1 ؎ 0.9 s), phosphodiesters (PDE) (8.6 ؎ 1.2 s to 6.0 ؎ 1.1 s), phosphocreatine (PCr) (6.7 ؎ 0.4 s to 4.0 ؎ 0.2 s), ␥-NTP (nucleotide triphosphate) (5.5 ؎ 0.4 s to 3.3 ؎ 0.2 s), ␣-NTP (3.4 ؎ 0.3 s to 1.8 ؎ 0.1 s), and ␤-NTP (3.9 ؎ 0.4 s to 1.8 ؎ 0.1 s), but not for inorganic phosphate (Pi) (6.9 ؎ 0.6 s to 6.3 ؎ 1.0 s). The decrease in T 2 was significant for Pi (153 ؎ 9 ms to 109 ؎ 17 ms), PDE (414 ؎ 128 ms to 314 ؎ 35 ms), PCr (354 ؎ 16 ms to 217 ؎ 14 ms), and ␥-NTP (61.9 ؎ 8.6 ms to 29.0 ؎ 3.3 ms). This decrease in T 1 with increasing field strength of up to 62% can be explained by the increasing influence of chemical shift anisotropy on relaxation mechanisms and may allow shorter measurements at higher field strengths or up to 62% additional signal-to-noise ratio (SNR) per unit time. The fully relaxed SNR increased by ؉96%, while the linewidth increased from 6.5 ؎ 1.2 Hz to 11.2 ؎ 1.9 Hz or ؉72%. Key words: phosphor; spectroscopy; human muscle; relaxation times; 7 Tesla; high field; chemical shift anistrophy Phosphorus ( 31 P) MR spectroscopy (MRS) is a powerful tool for the noninvasive investigation of human muscle metabolism under various physiological and pathological conditions (1). High-field MR systems, i.e., 7 T, offer advantages to 31 P-MRS in terms of sensitivity and spectral resolution, which has recently been shown in the brain (2).To optimize the measurement parameters of clinical spectroscopy protocols, such as echo time (TE) and repetition time (TR), an accurate knowledge of T 1 and T 2 relaxation times is essential. With TR chosen on the order of T 1 , severe saturation effects must be taken into account, in addition to T 2 decay. For absolute quantification of metabolites, it is therefore essential to accurately determine relaxation times to allow subsequent corrections for T 1 and T 2 decay (3,4).Relaxation times vary not only between different metabolites, but also with B 0 . The T 1 and T 2 of 31 P metabolites in the human leg were previously determined only at lower field strengths, i.e., at 1.5 T (5-13), 2.0 T (14), 2.35 T (15), and 3 T (16), while in vivo data at higher fields have been obtained only from animal studies (17,18).Relaxation in 1 H-MRS is dominated by magnetic dipoledipole interactions according to the Bloembergen-Purcell-Pound (BPP) theory (19). Therefore, 1 H-MRS T 1 relaxation times are increasing with B 0 (20). However, for 31 P-MRS, both dipolar relaxation and chemical shift anisotropy (CSA) are the two major, competing relaxation mechanisms (17,(21)(22)(23). In contrast to dipolar interaction, the contributions of CSA to 1/T 1 and 1/T 2 relaxation rates are proportional to the gyromagnetic ratio (␥), B 0 2 , the asymmetry of the magnetic shielding (...

Increased hepatocellular lipids relate to insulin resistance and are typical for individuals with type 2 diabetes mellitus (T2DM). Steatosis and T2DM have been further associated with impaired muscular adenosine triphosphate (ATP) turnover indicating reduced mitochondrial fitness. Thus, we tested the hypothesis that hepatic energy metabolism could be impaired even in metabolically well-controlled T2DM. We measured hepatic lipid volume fraction (HLVF) and absolute concentrations of ␥ATP, inorganic phosphate (Pi), phosphomonoesters and phosphodiesters using noninvasive 1 H/ 31 P magnetic resonance spectroscopy in individuals with T2DM (58 ؎ 6 years, 27 ؎ 3 kg/m 2 ), and age-matched and body mass index-matched (mCON; 61 ؎ 4 years, 26 ؎ 4 kg/m 2 ) and young lean humans (yCON; 25 ؎ 3 years, 22 ؎ 2 kg/m 2 , P < 0.005, P < 0.05 versus T2DM and mCON). Insulin-mediated whole-body glucose disposal (M) and endogenous glucose production (iEGP) were assessed during euglycemic-hyperinsulinemic clamps. Individuals with T2DM had 26% and 23% lower ␥ATP (1.68 ؎ 0.11; 2.26 ؎ 0.20; 2.20 ؎ 0.09 mmol/L; P < 0.05) than mCON and yCON individuals, respectively. Further, they had 28% and 31% lower Pi than did individuals from the mCON and yCON groups (0.96 ؎ 0.06; 1.33 ؎ 0.13; 1.41 ؎ 0.07 mmol/L; P < 0.05). Phosphomonoesters, phosphodiesters, and liver aminotransferases did not differ between groups. HLVF was not different between those from the T2DM and mCON groups, but higher (P ‫؍‬ 0.002) than in those from the yCON group. T2DM had 13-fold higher iEGP than mCON (P < 0.05). Even after adjustment for HLVF, hepatic ATP and Pi related negatively to hepatic insulin sensitivity (iEGP) (r ‫؍‬ ؊0.665, P ‫؍‬ 0.010, r ‫؍‬ ؊0.680, P ‫؍‬ 0.007) but not to whole-body insulin sensitivity. Conclusion: These data suggest that impaired hepatic energy metabolism and insulin resistance could precede the development of steatosis in individuals with T2DM. (HEPATOLOGY

This work describes a new approach for high-spatial-resolution (1)H MRSI of the human brain at 7 T. (1)H MRSI at 7 T using conventional approaches, such as point-resolved spectroscopy and stimulated echo acquisition mode with volume head coils, is limited by technical difficulties, including chemical shift displacement errors, B(0)/B(1) inhomogeneities, a high specific absorption rate and decreased T(2) relaxation times. The method presented here is based on free induction decay acquisition with an ultrashort acquisition delay (TE*) of 1.3 ms. This allows full signal detection with negligible T(2) decay or J-modulation. Chemical shift displacement errors were reduced to below 5% per part per million in the in-slice direction and were eliminated in-plane. The B(1) sensitivity was reduced significantly and further corrected using flip angle maps. Specific absorption rate requirements were well below the limit (~20 % = 0.7 W/kg). The suppression of subcutaneous lipid signals was achieved by substantially improving the point-spread function. High-quality metabolic mapping of five important brain metabolites was achieved with high in-plane resolution (64 × 64 matrix with a 3.4 × 3.4 × 12 mm(3) nominal voxel size) in four healthy subjects. The ultrashort TE* increased the signal-to-noise ratio of J-coupled resonances, such as glutamate and myo-inositol, several-fold to enable the mapping of even these metabolites with high resolution. Four measurement repetitions in one healthy volunteer provided proof of the good reproducibility of this method. The high spatial resolution allowed the visualization of several anatomical structures on metabolic maps. Free induction decay MRSI is insensitive to T(2) decay, J-modulation, B(1) inhomogeneities and chemical shift displacement errors, and overcomes specific absorption rate restrictions at ultrahigh magnetic fields. This makes it a promising method for high-resolution (1)H MRSI at 7 T and above.

OBJECTIVESteatosis associates with insulin resistance and may even predict type 2 diabetes and cardiovascular complications. Because muscular insulin resistance relates to myocellular fat deposition and disturbed energy metabolism, we hypothesized that reduced hepatic ATP turnover (fATP) underlies insulin resistance and elevated hepatocellular lipid (HCL) contents.RESEARCH DESIGN AND METHODSWe measured hepatic fATP using 31P magnetic resonance spectroscopy in patients with type 2 diabetes and age- and body mass–matched controls. Peripheral (M and M/I) and hepatic (suppression of endogenous glucose production) insulin sensitivity were assessed with euglycemic-hyperinsulinemic clamps.RESULTSDiabetic individuals had 29% and 28% lower peripheral and hepatic insulin sensitivity as well as 42% reduced fATP than controls. After adjusting for HCL, fATP correlated positively with peripheral and hepatic insulin sensitivity but negatively with waist circumference, BMI, and fasting plasma glucose. Multiple regression analysis identified waist circumference as an independent predictor of fATP and inorganic phosphate (PI) concentrations, explaining 65% (P = 0.001) and 56% (P = 0.003) of the variations. Hepatocellular PI primarily determined the alterations in fATP.CONCLUSIONSIn patients with type 2 diabetes, insulin resistance relates to perturbed hepatic energy metabolism, which is at least partly accounted for by fat depots.

In addition to direct assessment of high energy phosphorus containing metabolite content within tissues, phosphorus magnetic resonance spectroscopy (31P-MRS) provides options to measure phospholipid metabolites and cellular pH, as well as the kinetics of chemical reactions of energy metabolism in vivo. Even though the great potential of 31P-MR was recognized over 30 years ago, modern MR systems, as well as new, dedicated hardware and measurement techniques provide further opportunities for research of human biochemistry. This paper presents a methodological overview of the 31P-MR techniques that can be used for basic, physiological, or clinical research of human skeletal muscle and liver in vivo. Practical issues of 31P-MRS experiments and examples of potential applications are also provided. As signal localization is essential for liver 31P-MRS and is important for dynamic muscle examinations as well, typical localization strategies for 31P-MR are also described.

Liver dysfunction correlates with alterations of intracellular concentrations of 31 P metabolites. Localization and absolute quantification should help to trace regional hepatic metabolism. An improved protocol for the absolute quantification of 31 P metabolites in vivo in human liver was developed by employing three-dimensional (3D) k-space weighted spectroscopic imaging (MRSI) with B 1 -insensitive adiabatic excitation. The protocol allowed for high spatial resolution of 17.8 ؎ 0.22 cm 3 in 34 min at 3 T. No pulse adjustment prior to MRSI measurement was necessary due to adiabatic excitation. The protocol geometry was identical for all measurements so that one calibration data set, acquired from phantom replacement measurement, was applied for all quantifications. The protocol was tested in 10 young, healthy volunteers, for whom 57 ؎ 7 spectra were quantified. Concentrations per liter of liver volume (reproducibilities) were 2.24 ؎ 0.10 mmol/L (1.8%) for phosphomonoesters (PME), 1.37 ؎ 0.07 mmol/L (7.9%) for inorganic phosphate (Pi), 11.40 ؎ 0.96 mmol/L (2.9%) for phosphodiesters (PDE), and 2.14 ؎ 0.10 mmol/L (1.6%) for adenosine triphosphate (ATP), respectively. Taken Key words: spectroscopic imaging; 31 P metabolites; human liver; absolute concentration; concentration distribution Alterations in hepatic energy metabolism are typical for inflammatory and neoplastic liver diseases (1-3). Recently, evidence has shown that abnormalities in energy metabolism can also underlie non-alcoholic fatty liver in insulin-resistant and/or type 2 diabetic patients (4). Thus, information on regional alterations in liver metabolism may contribute to early diagnosis of various liver diseases in humans.During the past decade, in vivo phosphorus magnetic resonance spectroscopy ( 31 P-MRS) has been shown to be a valuable non-invasive research tool to investigate metabolic changes in the liver, specifically with regard to diffuse liver disease (5), viral (6) and alcoholic liver disease (7), cirrhosis (8 -11), and liver metastases (12,13). These studies used metabolite peak ratios as a surrogate for energy metabolism in the human liver. 31 P-MRS has also been used as a tool for determining absolute concentrations of metabolites in the healthy human liver (14 -18) and can yield more detailed information on liver function than metabolite peak ratios.Despite the increasing use of this approach there are discrepancies between the reported results (14 -18), which may reflect different signal acquisition schemes, different corrections of partial longitudinal saturation effects, as well as differences in postprocessing and quantification protocols (16). Thus, there is a need for a robust, simple, and reproducible method for acquiring 31 P metabolite concentrations in the human liver.The most promising approach is currently magnetic resonance spectroscopic imaging (MRSI). The main advantage of multivoxel MRSI resides in the ability to provide a measure of the spatial distribution of metabolites. On the other hand, time demands of typical ...