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Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice.
Isolated perfused hearts from type 2 diabetic (db/db) mice show impaired ventricular function, as well as altered cardiac metabolism. Assessment of the relationship between myocardial oxygen consumption (MVO(2)) and ventricular pressure-volume area (PVA) has also demonstrated reduced cardiac efficiency in db/db hearts. We hypothesized that lowering the plasma fatty acid supply and subsequent normalization of altered cardiac metabolism by chronic treatment with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist will improve cardiac efficiency in db/db hearts. Rosiglitazone (23 mg/kg body weight/day) was administered as a food admixture to db/db mice for five weeks. Ventricular function and PVA were assessed using a miniaturized (1.4 Fr) pressure-volume catheter; MVO(2) was measured using a fibre-optic oxygen sensor. Chronic rosiglitazone treatment of db/db mice normalized plasma glucose and lipid concentrations, restored rates of cardiac glucose and fatty acid oxidation, and improved cardiac efficiency. The improved cardiac efficiency was due to a significant decrease in unloaded MVO(2), while contractile efficiency was unchanged. Rosiglitazone treatment also improved functional recovery after low-flow ischemia. In conclusion, the present study demonstrates that in vivo PPARgamma-treatment restores cardiac efficiency and improves ventricular function in perfused hearts from type 2 diabetic mice.
Modification of myocardial substrate use as a therapy for heart failure.
Despite advances in treatment, chronic heart failure is still associated with significant morbidity and a poor prognosis. The scope for further advances based on additional neurohumoral blockade is small. Effective adjunctive therapies acting via a different cellular mechanism would, therefore, be attractive. Energetic impairment seems to contribute to the pathogenesis of heart failure. The findings from several studies have shown that the so-called metabolic agents could have potential as adjunctive therapies in heart failure. These agents cause a shift in the substrate used by the heart away from free fatty acids, the oxidation of which normally provides around 70% of the energy needed, towards glucose. The oxygen cost of energy generation is lessened when glucose is used as the substrate. In this review we aim to draw attention to the metabolic alteration in heart failure and we present evidence supporting the use of metabolic therapy in heart failure.
Gender differences in hypertrophy, insulin resistance and ischemic injury in the aging type 2 diabetic rat heart.
Aging and diabetes in women increase their susceptibility to myocardial ischemic injury, but the cellular mechanisms involved are not understood. Consequently, we studied the influence of gender on cardiac insulin resistance and ischemic injury in the aging of Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Male and female GK rats had heart/body weight ratios 29% (P < 0.0001) and 53% (P < 0.0001) higher, respectively, than their sex-matched controls, with the female GK rat hearts significantly more hypertrophied than the male (P < 0.001). Glucose transporter (GLUT) 1 protein levels were the same in all hearts, but GLUT4 protein levels were 28% lower (P < 0.01) in all GK rat hearts compared with their sex-matched controls. In isolated, perfused hearts, insulin-stimulated (3)H-glucose uptake rates were decreased by 23% (P < 0.05) and 40% (P < 0.05) in male and female GK rat hearts, respectively, compared with their controls, with the female significantly more insulin resistant than the male GK rat hearts (P < 0.05). Protein kinase B protein levels and insulin-stimulated phosphorylation were the same in all hearts. During low-flow ischemia, glucose uptake was 59% lower (P < 0.001) in female, but the same as controls in male, GK rat hearts. Consequently, recovery of contractile function during reperfusion was 30% lower (P < 0.05) in female, but the same as controls in male GK rat hearts. We conclude that the aging female type 2 diabetic rat heart has increased insulin resistance and greater susceptibility to ischemic injury, than non-diabetic or male type 2 diabetic rat hearts.
Metabolite and water apparent diffusion coefficients in the isolated rat heart: effects of ischemia.
A decrease in the apparent diffusion coefficient (ADC) of water is important in the detection of acute brain disorders, yet it is unknown whether changes in myocardial ADCs hold similar potential. Consequently, in this study a STEAM pulse sequence was modified in order to measure the ADCs of water and the (1)H-NMR detectable metabolites, taurine (an inert marker) and creatine, during perfusion, ischemia, and reperfusion in the isolated rat heart. At the short diffusion time of 50 ms, myocardial ADCs were (1.06 +/- 0. 07) x 10(-3) mm(2)/s for water, (0.29 +/- 0.01) x 10(-3) mm(2)/s for taurine and (0.26 +/- 0.01) x 10(-3) mm(2)/s for creatine. Heart water and taurine ADCs remained constant during ischemia, yet the total creatine ADC increased by 35% owing to the hydrolysis of PCr to creatine. The average cardiomyocyte diameter, calculated from taurine ADC values measured at diffusion times between 50 ms and 1510 ms, was 40 microm in the perfused heart and 27 microm by the end of ischemia. It is concluded that the taurine ADC measured at short diffusion times does not reveal ischemic injury in the heart, but at long diffusion times may be used to calculate changes in myocyte diameter. Magn Reson Med 44:208-214, 2000.
microMRI-HREM pipeline for high-throughput, high-resolution phenotyping of murine embryos.
Rapid and precise phenotyping analysis of large numbers of wild-type and mutant mouse embryos is essential for characterizing the genetic and epigenetic factors regulating embryogenesis. We present a novel methodology that permits precise high-throughput screening of the phenotype of embryos with both targeted and randomly generated mutations. To demonstrate the potential of this methodology we show embryo phenotyping results produced in a large-scale ENU-mutagenesis study. In essence this represents an analysis pipeline, which starts with simultaneous micro-magentic resonance imaging (microMRI) screening (voxel size: 25.4 x 25.4 x 24.4 microm) of 32 embryos in one run. Embryos with an indistinct phenotype are then cut into parts and suspect organs and structures are analysed with HREM (high-resolution episcopic microscopy). HREM is an imaging technique that employs 'positive' eosin staining and episcopic imaging for generating three-dimensional (3D) high-resolution (voxel size: 1.07 x 1.07 x 2 microm) digital data of near histological contrast and quality. The results show that our method guarantees the rapid availability of comprehensive phenotype information for high numbers of embryos in, if necessary, histological quality and detail. The combination of high-throughput microMRI with HREM provides an alternative screening pipeline with advantages over existing 3D phenotype screening methods as well as traditional histology. Thus, the microMRI-HREM phenotype analysis pipeline recommends itself as a routine tool for analysing the phenotype of transgenic and mutant embryos.
Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.
We measured the effects of a diet in which D-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [(18)F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.