The insulin-sensitizing effect of rosiglitazone in type 2 diabetes mellitus patients does not require improved in vivo muscle mitochondrial function.

Aims: To investigate whether improved in vivo mitochondrial function in skeletal muscle and intramyocellular lipids (IMCL) contribute to the insulin-sensitizing effect of rosiglitazone. Methods: Eight overweight type 2 diabetic patients (BMI= 29.3 +/- 1.1 kg/m(2)) were treated with rosiglitazone for 8 weeks. Before and after treatment, insulin sensitivity was determined by a hyperinsulinaemic-euglycaemic clamp. Muscular mitochondrial function (half-time of phosphocreatine recovery after exercise) and IMCL content were measured by magnetic resonance spectroscopy. Results: Insulin sensitivity improved after rosiglitazone (GIR: 19.9+/-2.8 to 24.8+/-2.1 micromol/kg/min (P<0.05)). In vivo mitochondrial function (PCr recovery half-time: 23.8+/-3.5 to 20.0+/-1.7 s (P=0.23)) and IMCL content (0.93+/-0.18% to 1.37+/-0.40%, p=0.34) did not change. Interestingly, the changes in PCr half-time correlated/tended to correlate with changes in fasting insulin (R(2)=0.50, P=0.05), and glucose (R(2)=0.43, p=0.08) levels. Changes in PCr half-time did not correlate with changes in GIR (R(2)=0.08, P=0.49). Conclusion: The rosiglitazone-enhanced insulin sensitivity does not require improved muscular mitochondrial function

Geometrical models for cardiac MRI in rodents: comparison of quantification of left ventricular volumes and function by various geometrical models with a full-volume MRI data set in rodents.

van de Weijer T, van Ewijk PA, Zandbergen HR, Slenter JM, Kessels AG, Wildberger JE, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB, Kooi ME. Geometrical models for cardiac MRI in rodents: comparison of quantification of left ventricular volumes and function by various geometrical models with a full-volume MRI data set in rodents. Am J Physiol Heart Circ Physiol 302: H709-H715, 2012. First published November 18, 2011; doi:10.1152/ajpheart.00710.2011.-MRI has been proven to be an accurate method for noninvasive assessment of cardiac function. One of the current limitations of cardiac MRI is that it is time consuming. Therefore, various geometrical models are used, which can reduce scan and postprocessing time. It is unclear how appropriate their use is in rodents. Left ventricular (LV) volumes and ejection fraction (EF) were quantified based on 7.0 Tesla cine-MRI in 12 wild-type (WT) mice, 12 adipose triglyceride lipase knockout (ATGL(-/-)) mice (model of impaired cardiac function), and 11 rats in which we induced cardiac ischemia. The LV volumes and function were either assessed with parallel short-axis slices covering the full volume of the left ventricle (FV, gold standard) or with various geometrical models [modified Simpson rule (SR), biplane ellipsoid (BP), hemisphere cylinder (HC), single-plane ellipsoid (SP), and modified Teichholz Formula (TF)]. Reproducibility of the different models was tested and results were correlated with the gold standard (FV). All models and the FV data set provided reproducible results for the LV volumes and EF, with interclass correlation coefficients >= 0.87. All models significantly over-or underestimated EF, except for SR. Good correlation was found for all volumes and EF for the SR model compared with the FV data set (R-2 ranged between 0.59-0.95 for all parameters). The HC model and BP model also predicted EF well (R-2 >= 0.85), although proved to be less useful for quantitative analysis. The SP and TF models correlated poorly with the FV data set (R-2 >= 0.45 for EF and R-2 >= 0.29 for EF, respectively). For the reduction in acquisition and postprocessing time, only the SR model proved to be a valuable method for calculating LV volumes, stroke volume, and EF

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 ± 2.8% (P <0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 ± 9.7%; P <0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 ± 6 to 1,450 ± 55 and 57 ± 11 to 474 ± 54 µM, respectively; P <0.001), whereas plasma triglyceride concentrations were decreased (from 1,498 ± 39 to 703 ± 7 µM; P <0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle

The increase in intramyocellular lipid content is a very early response to training

The present study investigated the influences of a 2-wk training program on intramyocellular lipid (IMCL) content, IMCL decrease during exercise, fat oxidation, and insulin sensitivity. Nine untrained men (age, 23.3 ± 3.2 yr; body mass index, 22.6 ± 2.6 kg/m2; maximal power output, 3.8 ± 0.6 W/kg body weight) trained for 2 wk. Before and after training, subjects cycled for 3 h while substrate oxidation was measured. IMCL content in the vastus lateralis muscle was determined before and after cycling by proton magnetic resonance spectroscopy. Before and after training, insulin sensitivity was assessed by an insulin tolerance test. The training period resulted in a significant increase in IMCL content by 42 ± 14%. IMCL content decreased significantly during cycling. However, 2 wk of training were not sufficient to achieve increases in fat oxidation and/or use of IMCL during exercise. All markers used to test insulin sensitivity point toward improved insulin sensitivity, albeit not significant. We conclude that the increase in IMCL content is a very early response to training, preceding significant changes in insulin sensitivity. The results suggest that the presence of triglycerides alone does not necessarily have detrimental effects on insulin sensitivity. We confirm earlier reports that IMCL contributes to the energy used during prolonged submaximal exercise

Dynamic Contrast-enhanced MR Imaging of Carotid Atherosclerotic Plaque: Model Selection, Reproducibility, and Validation.

Purpose: compare four known pharmacokinetic models for their ability to describe dynamic contrast material-enhanced magnetic resonance (MR) imaging of carotid atherosclerotic plaques, to determine reproducibility, and to validate the results with histologic findings. Materials and Methods: The study was approved by the institutional medical ethics committee. Written informed consent was obtained from all patients. Forty-five patients with 30%-99% carotid stenosis underwent dynamic contrast-enhanced MR imaging. Plaque enhancement was measured at 16 time points at approximately 25-second image intervals by using a gadolinium-based contrast material. Pharmacokinetic parameters (volume transfer constant, Ktrans; extracellular extravascular volume fraction, v e; and blood plasma fraction, v p) were determined by fitting a two-compartment model to plaque and blood gadolinium concentration curves. The relative fit errors and parameter uncertainties were determined to find the most suitable model. Sixteen patients underwent imaging twice to determine reproducibility. Carotid endarterectomy specimens from 16 patients who were scheduled for surgery were collected for histologic validation. Parameter uncertainties were compared with the Wilcoxon signed rank test. Reproducibility was assessed by using the coefficient of variation. Correlation with histologic findings was evaluated with the Pearson correlation coefficient. Results: The mean relative fit uncertainty (+/- standard error) for Ktrans was 10% +/- 1 with the Patlak model, which was significantly lower than that with the Tofts (20% +/- 1), extended Tofts (33% +/- 3), and extended graphical (29% +/- 3) models (P <.001). The relative uncertainty for v p was 20% 6 2 with the Patlak model and was significantly higher with the extended Tofts (46% +/- 9) and extended graphical (35% +/- 5) models (P <.001). The reproducibility (coefficient of variation) for the Patlak model was 16% for Ktrans and 26% for v p. Significant positive correlations were found between Ktrans and the endothelial microvessel content determined on histologic slices (Pearson r = 0.72, P = .005). Conclusion: The Patlak model is most suited for describing carotid plaque enhancement. Correlation with histologic findings validated Ktrans as an indicator of plaque microvasculature, and the reproducibility of Ktrans was good. (C)RSNA, 201

Roadmap Consensus on Carotid Artery Plaque Imaging and Impact on Therapy Strategies and Guidelines: An International, Multispecialty, Expert Review and Position Statement

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant information to guidelines currently based on the quantification of stenosis.</p