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ABSTRACT Background Muscular 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 [...]

Phosphorus (31P) MRS is a powerful tool for the non-invasive investigation of human liver metabolism. Four in vivo 31P localization approaches (single voxel image selected in vivo spectroscopy (3D-ISIS), slab selective 1D-ISIS, 2D chemical shift imaging (CSI), and 3D-CSI) with different voxel volumes and acquisition times were demonstrated in nine healthy volunteers. Localization techniques provided comparable signal-to-noise ratios normalized for voxel volume and acquisition time differences, Cramer-Rao lower bounds (8.7 ± 3.3%1D-ISIS, 7.6 ± 2.5%3D-ISIS, 8.6 ± 4.2%2D-CSI, 10.3 ± 2.7%3D-CSI), and linewidths (50 ± 24 Hz1D-ISIS, 34 ± 10 Hz3D-ISIS, 33 ± 10 Hz2D-CSI, 34 ± 11 Hz3D-CSI). Longitudinal ( T1) relaxation times of human liver metabolites at 7 T were assessed by 1D-ISIS inversion recovery in the same volunteers ( n = 9). T1 relaxation times of hepatic 31P metabolites at 7 T were the following: phosphorylethanolamine - 4.41 ± 1.55 s; phosphorylcholine - 3.74 ± 1.31 s; inorganic phosphate - 0.70 ± 0.33 s; glycerol 3-phosphorylethanolamine - 6.19 ± 0.91 s; glycerol 3-phosphorylcholine - 5.94 ± 0.73 s; γ-adenosine triphosphate (ATP) - 0.50 ± 0.08 s; α-ATP - 0.46 ± 0.07 s; β-ATP - 0.56 ± 0.07 s. The improved spectral resolution at 7 T enabled separation of resonances in the phosphomonoester and phosphodiester spectral region as well as nicotinamide adenine dinucleotide and uridine diphosphoglucose signals. An additional resonance at 2.06 ppm previously assigned to phosphoenolpyruvate or phosphatidylcholine is also detectable. These are the first 31P metabolite relaxation time measurements at 7 T in human liver, and they will help in the exploration of new, exciting questions in metabolic research with 7 T MR. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Phosphorus MRSI (31P–MRSI) using a spiral‐trajectory readout at 7 T was developed for high temporal resolution mapping of the mitochondrial capacity of exercising human skeletal muscle. The sensitivity and localization accuracy of the method was investigated in phantoms. In vivo performance was assessed in 12 volunteers, who performed a plantar flexion exercise inside a whole‐body 7 T MR scanner using an MR‐compatible ergometer and a surface coil. In five volunteers the knee was flexed (~60°) to shift the major workload from the gastrocnemii to the soleus muscle. Spiral‐encoded MRSI provided 16–25 times faster mapping with a better point spread function than elliptical phase‐encoded MRSI with the same matrix size. The inevitable trade‐off for the increased temporal resolution was a reduced signal‐to‐noise ratio, but this was acceptable. The phosphocreatine (PCr) depletion caused by exercise at 0° knee angulation was significantly higher in both gastrocnemii than in the soleus (i.e. 64.8 ± 19.6% and 65.9 ± 23.6% in gastrocnemius lateralis and medialis versus 15.3 ± 8.4% in the soleus). Spiral‐encoded 31P–MRSI is a powerful tool for dynamic mapping of exercising muscle oxidative metabolism, including localized assessment of PCr concentrations, pH and maximal oxidative flux with high temporal and spatial resolution.

REL feature impaired glucose transport which relates to reduced myocellular ATP synthesis (fATP). We hypothesized that exercise stimulates fATP, decreases intramyocellular lipids (IMCL) and so improves insulin action. Glucose tolerant REL (4f/6m, age: 39±4a, BMI: 24±lkg/m²) and CON (4f/6m, 38±4a, 24±1 kg/m²) with comparable O2[sub 2] uptake at respiratory compensation (VO[sub 2]rcp; REL:25±2, CON:26±1ml.kg[sup -1].min[sup -1];ns) underwent OGTT to measure insulin sensitivity (OGIS) and ¹H/[sup 31]P MR spectroscopy to assess IMCL and ATP synthesis from P-creatine (fPCR) and inorganic phosphate (fATP). Both tests were done before and after 1-week cycling training (2x40 min, 90% VO[sub 2]rcp). OGIS (ml.min[sup -1].m[sup -2]) was 13% lower in REL (370±20 vs 424±8;P<.05) without changes alter exercise. Basal fATP was similar but exercise increased fATP by 20% in CON (P=10[sup -4]) being 21% higher than in REL (12±1 vs 15±2µmol.ml[sup -1] min[sup -1]; P<.05). Basal fATP/fPCR ratios were 23% higher in REL (30±2, 36±2;P=.02) and decreased (P<.005) being comparable after exercise as was IMCL. VO[sub 2]max and VO[sub 2]rcp correlated with fATP (R=.617, P=.004; R=.748; P=10[sup -4]) with VO[sub 2]max independently explaining 40% (P=.004) of fATP variation. Short-term exercise training increases ATP synthesis despite unchanged insulin sensitivity in CON suggesting that stimulation of mitochondrial function precedes training effects on insulin sensitivity. In REL, impaired ATP synthesis remains despite exercise-induced normalization of the equilibrium of energy generating processes supporting the concept of inherited mitochondrial dysfunction beyond reduced mitochondrial contents. [ABSTRACT FROM AUTHOR]

Mitochondrial gene mutations lead to mitochondrial diabetes with defects of insulin secretion and sensitivity. Mitochondrial dysfunction is also involved in common insulin resistance, but secondary metabolic events may be confounding the metabolic picture in overt type 2 diabetes. Acromegaly is associated with alterations of energy expenditure and insulin action and might serve as model to investigate the role of mitochondrial function. Thus, we examined glucose metabolism, intracellular fat deposition and mitochondrial function in patients with a history of acromegaly (AM). Six AM (4f/2m, age: 49±4 years, body mass index, BMI: 27±1 kg/m²) with an at least 7-years history of successful treatment and age-/BMI-matched healthy volunteers (CON: 3 f/3m, 43±5 years, 26±2 kg/m²) were studied. Insulin sensitivity (OGIS), first-phase and adaptive insulin secretion were assessed from the frequently sampled OGTT (insulinogenic index, ISEC, adaptation index ADAP). Fasting mitochondrial function was assessed from ATP synthetic flux (fATP) using [sup 31]P magnetic resonance spectroscopy (MRS) of calf muscle. Intracellular lipid contents of tibialis anterior (IMCLt) and soleus muscles (IMCLs) as well as liver (HCL) were measured with [sup 1]H MRS. IGF-1 did not differ between groups (AM: 1774-36; CON: 145±21 ng/ml). Fasting plasma glucose was ∼16% higher in AM than in CON (99±3 vs. 85±2 mg/dl, p<0.05). OGIS was comparable (AM: 395±30, CON: 415±6 ml.min[sup -1].m[sup -2]), whereas ISEC was ∼87% (AM: 0.9±0.4, CON: 6.7±1.7 pmol/mmol, p<0.05) and ADAP was ∼84% lower in AM (0.44±0.19, CON: 2.77∼0.7 min[sup -2]/mmol.l[sup -1] p<0.05), fATP was ∼22% lower in AM (10.1±0.6 vs. 12.9±1.0 mmol.l[sup -1]min[sup -1], p<0.05) and related positively to ISEC (r=.687, p<0.01) and ADAP (r=0.744, p<0.005). IMCLt, IMCLs and HCL were not different between groups. IMCLs related negatively to insulin sensitivity (r=-0.745, p=0.005). Patients with a history of acromegaly exhibit reduced β cell and muscle mitochondrial function despite normal insulin sensitivity. Previous long-term exposure to high growth hormone and IGF concentrations and/or chronic increases in plasma glucose concentrations could lead to similar abnormalities in both tissues. [ABSTRACT FROM AUTHOR]

Phosphorus ((31) P) MRS is a powerful tool for the non-invasive investigation of human liver metabolism. Four in vivo (31) P localization approaches (single voxel image selected in vivo spectroscopy (3D-ISIS), slab selective 1D-ISIS, 2D chemical shift imaging (CSI), and 3D-CSI) with different voxel volumes and acquisition times were demonstrated in nine healthy volunteers. Localization techniques provided comparable signal-to-noise ratios normalized for voxel volume and acquisition time differences, Cramer-Rao lower bounds (8.7 ± 3.3%1D-ISIS , 7.6 ± 2.5%3D-ISIS , 8.6 ± 4.2%2D-CSI , 10.3 ± 2.7%3D-CSI ), and linewidths (50 ± 24 Hz1D-ISIS , 34 ± 10 Hz3D-ISIS , 33 ± 10 Hz2D-CSI , 34 ± 11 Hz3D-CSI ). Longitudinal (T1 ) relaxation times of human liver metabolites at 7 T were assessed by 1D-ISIS inversion recovery in the same volunteers (n = 9). T1 relaxation times of hepatic (31) P metabolites at 7 T were the following: phosphorylethanolamine - 4.41 ± 1.55 s; phosphorylcholine - 3.74 ± 1.31 s; inorganic phosphate - 0.70 ± 0.33 s; glycerol 3-phosphorylethanolamine - 6.19 ± 0.91 s; glycerol 3-phosphorylcholine - 5.94 ± 0.73 s; γ-adenosine triphosphate (ATP) - 0.50 ± 0.08 s; α-ATP - 0.46 ± 0.07 s; β-ATP - 0.56 ± 0.07 s. The improved spectral resolution at 7 T enabled separation of resonances in the phosphomonoester and phosphodiester spectral region as well as nicotinamide adenine dinucleotide and uridine diphosphoglucose signals. An additional resonance at 2.06 ppm previously assigned to phosphoenolpyruvate or phosphatidylcholine is also detectable. These are the first (31) P metabolite relaxation time measurements at 7 T in human liver, and they will help in the exploration of new, exciting questions in metabolic research with 7 T MR., (Copyright © 2014 John Wiley & Sons, Ltd.)