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Gary D Lopaschuk - One of the best experts on this subject based on the ideXlab platform.
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failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and Glucose Oxidation
Cardiovascular Research, 2014Co-Authors: Waleed G T Masoud, John R. Ussher, Cory S. Wagg, Jagdip S. Jaswal, Wei Wang, Alexander S. Clanachan, Jason R B Dyck, Craig A Lygate, Stefan Neubauer, Gary D LopaschukAbstract:Aims To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and Glucose Oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency. Methods and results Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, Glucose Oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid Oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD-KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, Glucose Oxidation, proton production, and ATP production, indicative of improved efficiency. Conclusion CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and Glucose Oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization.
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foxo1 mediated upregulation of pyruvate dehydrogenase kinase 4 pdk4 decreases Glucose Oxidation and impairs right ventricular function in pulmonary hypertension therapeutic benefits of dichloroacetate
Journal of Molecular Medicine, 2013Co-Authors: Lin Piao, Vaninder K Sidhu, Yong Hu Fang, John J Ryan, Kishan S Parikh, Zhigang Hong, Peter T Toth, Erik Morrow, Shelby Kutty, Gary D LopaschukAbstract:Pyruvate dehydrogenase kinase (PDK) is activated in right ventricular hypertrophy (RVH), causing an increase in glycolysis relative to Glucose Oxidation that impairs right ventricular function. The stimulus for PDK upregulation, its isoform specificity, and the long-term effects of PDK inhibition are unknown. We hypothesize that FOXO1-mediated PDK4 upregulation causes bioenergetic impairment and RV dysfunction, which can be reversed by dichloroacetate. Adult male Fawn-Hooded rats (FHR) with pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH; age 6–12 months) were compared to age-matched controls. Glucose Oxidation (GO) and fatty acid Oxidation (FAO) were measured at baseline and after acute dichloroacetate (1 mM × 40 min) in isolated working hearts and in freshly dispersed RV myocytes. The effects of chronic dichloroacetate (0.75 g/L drinking water for 6 months) on cardiac output (CO) and exercise capacity were measured in vivo. Expression of PDK4 and its regulatory transcription factor, FOXO1, were also measured in FHR and RV specimens from PAH patients (n = 10). Microarray analysis of 168 genes related to Glucose or FA metabolism showed >4-fold upregulation of PDK4, aldolase B, and acyl-coenzyme A oxidase. FOXO1 was increased in FHR RV, whereas HIF-1α was unaltered. PDK4 expression was increased, and the inactivated form of FOXO1 decreased in human PAH RV (P < 0.01). Pyruvate dehydrogenase (PDH) inhibition in RVH increased proton production and reduced GO’s contribution to the tricarboxylic acid (TCA) cycle. Acutely, dichloroacetate reduced RV proton production and increased GO’s contribution (relative to FAO) to the TCA cycle and ATP production in FHR (P < 0.01). Chronically dichloroacetate decreased PDK4 and FOXO1, thereby activating PDH and increasing GO in FHR. These metabolic changes increased CO (84 ± 14 vs. 69 ± 14 ml/min, P < 0.05) and treadmill-walking distance (239 ± 20 vs. 171 ± 22 m, P < 0.05). Chronic dichloroacetate inhibits FOXO1-induced PDK4 upregulation and restores GO, leading to improved bioenergetics and RV function in RVH.
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agonist induced hypertrophy and diastolic dysfunction are associated with selective reduction in Glucose Oxidation a metabolic contribution to heart failure with normal ejection fraction
Circulation-heart Failure, 2012Co-Authors: Jun Mori, Gary D Lopaschuk, Cory S. Wagg, Liyan Zhang, Ratnadeep Basu, Brent A Mclean, Subhash K Das, Vaibhav B Patel, Zamaneh Kassiri, Gavin Y OuditAbstract:Background—Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the α-adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor. Methods and Results—Ang II (1.5 mg·kg−1·day−1) or PE (40 mg·kg−1·day−1) was administered to 9-week-old male C57/BL6 wild-type mice for 14 days via implanted microosmotic pumps. Echocardiography showed concentric hypertrophy and diastolic dysfunction, with preserved systolic function in Ang II- and PE-treated mice. Ang II induced marked reduction in cardiac Glucose Oxidation and lactate Oxidation, with no change in glycolysis and fatty acid β-Oxidation. Tricarboxylic acid acetyl coenzyme A production and ATP production were reduce...
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cardiac diacylglycerol accumulation in high fat fed mice is associated with impaired insulin stimulated Glucose Oxidation
Cardiovascular Research, 2011Co-Authors: Liyan Zhang, John R. Ussher, Cory S. Wagg, Tatsujiro Oka, Virgilio J J Cadete, Gary D LopaschukAbstract:Aims The molecular processes leading to cardiac insulin resistance induced via a high-fat diet (HFD) remain unclear. We examined the changes in cardiac insulin sensitivity and the potential mechanism(s) involved following HFD in mice. Methods and results C57BL/6 mice were fed either a low-fat diet (LFD, 4% kcal fat) or a HFD (60% kcal fat) for 3 or 10 weeks. Insulin-stimulated Glucose Oxidation in isolated working hearts was decreased at 10 weeks of HFD compared with mice on LFD (249 ± 19 to 399 ± 46 vs. 551 ± 97 to 1464 ± 243 nmol/g dry wt/min; P < 0.05). The accumulation of myocardial diacylglycerol (DAG; 479 ± 174 vs. 266 ± 29 µmol/g wet wt; P < 0.05), but not long-chain acyl CoA, ceramide, or triacylglycerol, correlated with the development of insulin resistance. The accumulation of DAG occurred concomitantly with an increase in glycerol phosphate acyltransferase activity, a decrease in DAG acyltransferase activity, as well as an increase in the translocation of protein kinase C-α (PKCα) and phosphorylation of p70s6k. Neither HFD-induced accumulation of cardiac DAG nor up-regulation of phosphorylated p70s6k occurred in mice lacking malonyl CoA decarboxylase which are resistant to the development of HFD-induced insulin resistance. Conclusion The activation of myocardial p70s6k and PKCα is closely associated with cardiac insulin resistance in which the accumulation of intra-myocardial DAG could be responsible.
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insulin stimulated cardiac Glucose Oxidation is increased in high fat diet induced obese mice lacking malonyl coa decarboxylase
Diabetes, 2009Co-Authors: John R. Ussher, Jagdip S. Jaswal, Jason R B Dyck, Timothy R Koves, Liyan Zhang, Olga Ilkayeva, Deborah M Muoio, Gary D LopaschukAbstract:OBJECTIVE Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid Oxidation could also impair Glucose metabolism and function. We therefore determined the effects of diet-induced obesity (DIO) in wild-type (WT) mice and mice deficient for malonyl CoA decarboxylase (MCD −/− ; an enzyme promoting mitochondrial fatty acid Oxidation) on insulin-sensitive cardiac Glucose Oxidation. RESEARCH DESIGN AND METHODS WT and MCD −/− mice were fed a low- or high-fat diet for 12 weeks, and intramyocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nanomoles per gram of dry weight per minute) in isolated working hearts (+/– insulin). RESULTS DIO markedly reduced insulin-stimulated Glucose Oxidation compared with low fat–fed WT mice (167 ± 31 vs. 734 ± 125; P −/− mice subjected to DIO displayed a more robust insulin-stimulated Glucose Oxidation (554 ± 82 vs. 167 ± 31; P −/− mice had long-chain acyl CoAs similar to those of WT mice subjected to DIO but had increased triacylglycerol levels (10.92 ± 3.72 vs. 3.29 ± 0.62 μmol/g wet wt; P CONCLUSIONS DIO does not impair cardiac fatty acid Oxidation or function, and there exists disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.
Jason R B Dyck - One of the best experts on this subject based on the ideXlab platform.
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failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and Glucose Oxidation
Cardiovascular Research, 2014Co-Authors: Waleed G T Masoud, John R. Ussher, Cory S. Wagg, Jagdip S. Jaswal, Wei Wang, Alexander S. Clanachan, Jason R B Dyck, Craig A Lygate, Stefan Neubauer, Gary D LopaschukAbstract:Aims To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and Glucose Oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency. Methods and results Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, Glucose Oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid Oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD-KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, Glucose Oxidation, proton production, and ATP production, indicative of improved efficiency. Conclusion CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and Glucose Oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization.
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insulin stimulated cardiac Glucose Oxidation is increased in high fat diet induced obese mice lacking malonyl coa decarboxylase
Diabetes, 2009Co-Authors: John R. Ussher, Jagdip S. Jaswal, Jason R B Dyck, Timothy R Koves, Liyan Zhang, Olga Ilkayeva, Deborah M Muoio, Gary D LopaschukAbstract:OBJECTIVE Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid Oxidation could also impair Glucose metabolism and function. We therefore determined the effects of diet-induced obesity (DIO) in wild-type (WT) mice and mice deficient for malonyl CoA decarboxylase (MCD −/− ; an enzyme promoting mitochondrial fatty acid Oxidation) on insulin-sensitive cardiac Glucose Oxidation. RESEARCH DESIGN AND METHODS WT and MCD −/− mice were fed a low- or high-fat diet for 12 weeks, and intramyocardial lipid metabolite accumulation was assessed. A parallel feeding study was performed to assess myocardial function and energy metabolism (nanomoles per gram of dry weight per minute) in isolated working hearts (+/– insulin). RESULTS DIO markedly reduced insulin-stimulated Glucose Oxidation compared with low fat–fed WT mice (167 ± 31 vs. 734 ± 125; P −/− mice subjected to DIO displayed a more robust insulin-stimulated Glucose Oxidation (554 ± 82 vs. 167 ± 31; P −/− mice had long-chain acyl CoAs similar to those of WT mice subjected to DIO but had increased triacylglycerol levels (10.92 ± 3.72 vs. 3.29 ± 0.62 μmol/g wet wt; P CONCLUSIONS DIO does not impair cardiac fatty acid Oxidation or function, and there exists disassociation between myocardial lipid accumulation and insulin sensitivity. Our results suggest that MCD deficiency is not detrimental to the heart in obesity.
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absence of malonyl coenzyme a decarboxylase in mice increases cardiac Glucose Oxidation and protects the heart from ischemic injury
Circulation, 2006Co-Authors: Jason R B Dyck, Sebastien Bonnet, Evangelos D Michelakis, Teresa A Hopkins, Martin E Young, Miho Watanabe, Yosuke Kawase, Kouichi Jishage, Gary D LopaschukAbstract:Background— Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid Oxidation and stimulating Glucose Oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection. Methods and Results— Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd−/− mice. Ex vivo working hearts from mcd−/− and wild-type mice displayed no significant differences in rates of fatty acid Oxidation, Glucose Oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despit...
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malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid Oxidation and stimulating Glucose Oxidation
Circulation Research, 2004Co-Authors: Jason R B Dyck, Jiefei Cheng, William C Stanley, Rick L Barr, Margaret P Chandler, Steven Brown, David Wallace, Thomas Arrhenius, Charles Harmon, Guang YangAbstract:Abnormally high rates of fatty acid Oxidation and low rates of Glucose Oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid Oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid Oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid Oxidation rates and an increase in Glucose Oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased Glucose Oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, Glucose Oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid Oxidation and accelerate Glucose Oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
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beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of Glucose Oxidation secondary to inhibition of long chain 3 ketoacyl coenzyme a thiolase
Circulation Research, 2003Co-Authors: Gary D Lopaschuk, Rick L Barr, Panakkezhum D Thomas, Jason R B DyckAbstract:High rates of fatty acid Oxidation in the heart and subsequent inhibition of Glucose Oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating Glucose Oxidation, either directly or secondary to an inhibition of fatty acid Oxidation. We recently demonstrated that trimetazidine stimulates Glucose Oxidation in the heart secondary to inhibition of fatty acid Oxidation. This inhibition of fatty acid Oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid β-Oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 μmol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 μmol/L even at high concentrations of trimetazidine (100 μmol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 μmol/L, a concentration that would completely overcome 100 μmol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 μmol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid Oxidation and stimulates Glucose Oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.
K Balasubramanian - One of the best experts on this subject based on the ideXlab platform.
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effect of bisphenol a on insulin signal transduction and Glucose Oxidation in liver of adult male albino rat
Environmental Toxicology and Pharmacology, 2013Co-Authors: Shankar Jayashree, Dhananjayan Indumathi, Narasimhan Akilavalli, Sampath Sathish, Jayaraman Selvaraj, K BalasubramanianAbstract:Abstract Bisphenol-A (BPA) has been classified as an endocrine disruptor which disrupts normal cell function by acting as an estrogen agonist. Environmentally relevant doses of the Bisphenol-A have profound effects on rat endocrine pancreas, an essential organ involved in Glucose homeostasis. Bisphenol-A acts on insulin releasing β-cells whereby it increases the pancreatic insulin content and secretion and also favours post prandial hyperinsulinemia and insulin resistance in male mice. Liver plays a central role in the control of Glucose production and regulation of insulin secretion. It is one of the primary organs that are initially confronted by damage from toxic substances, xenobiotics and environmental hormones. The present study was designed to assess the effect of Bisphenol-A on insulin signal transduction and Glucose Oxidation in liver of adult male albino rat. Wistar strain albino rats were selected and divided into three groups, Group-I: Control, Group-II: 20 mg BPA treated, Group-III: 200 mg BPA treated. The IR (insulin receptor) and Akt (PKB: protein kinase B) mRNA and protein showed a decreased expression pattern in the high dose group. Eventhough there was an increase in serum insulin and a decrease in serum testosterone levels in the high dose group, the fasting blood Glucose level remained unaltered. Glucose Oxidation and glycogen content were found to be decreased in both high and low dose treated groups. Results of this study suggest that Bisphenol-A treatment impairs hepatic Glucose Oxidation and glycogen content through defective insulin signal transduction.
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effect of bisphenol a on insulin signal transduction and Glucose Oxidation in skeletal muscle of adult male albino rat
Human & Experimental Toxicology, 2013Co-Authors: Dhananjayan Indumathi, Shankar Jayashree, Narasimhan Akilavalli, Sampath Sathish, Jayaraman Selvaraj, Chinnaiyan Mayilvanan, K BalasubramanianAbstract:The estrogenic monomer bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of epoxy resins, plastic food and beverage containers, leading to ubiquitous human exposure. Environmentally relevant doses of BPA have profound effects on mice endocrine pancreas. It increases pancreatic insulin content and favors postprandial hyperinsulinemia and insulin resistance in male mice. Skeletal muscle plays a crucial role in maintaining systemic Glucose metabolism. In the present study, we investigated the possible effects of BPA on insulin-signaling molecules and Glucose Oxidation in skeletal muscle of male rat. Adult male Wistar albino rats were divided into three groups. Group I: control (vehicle treated) and groups II and III were administered with BPA orally (20 and 200 mg/kg bw/day, respectively). Although there was no change in the levels of insulin receptor (IR), Akt (protein kinase B) and Glucose transporter-4 (GLUT4) messenger RNA, BPA significantly decreased the IR, Akt and GLUT4 prot...
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insulin mimetic impact of catechin isolated from cassia fistula on the Glucose Oxidation and molecular mechanisms of Glucose uptake on streptozotocin induced diabetic wistar rats
Phytomedicine, 2010Co-Authors: Pitchai Daisy, K Balasubramanian, Manikkam Rajalakshmi, J Eliza, J SelvarajAbstract:Abstract Diabetes mellitus is the most common and serious metabolic disorder among people all over the world. Many plants have successfully been used to overcome this problem. Cassia fistula , an ethnomedicnal plant, is widely used in Indian medicine to treat diabetes. Methanol extract of stem of plant, reduced the blood Glucose levels in Streptozotocin-induced diabetic rats. Bioassay guided fractionation was followed to isolate Catechin from methanol extract. Catechin was administered to Streptozotocin (60 mg/kg b.w.)-induced diabetic male Wistar rats at different doses (5, 10, 20 mg/kg b.w.) for 6 weeks to assess its effect on fasting plasma Glucose. The plasma Glucose was significantly ( p 14 C-Glucose Oxidation without any change in plasma insulin and C-peptide. Catechin restored the altered Glucokinase, Glucose-6 Phosphatase, Glycogen Synthase and Glycogen Phosphorylase levels to near normal. GLUT4 mRNA and protein expression were enhanced after Catechin treatment. The results of this experimental study indicated that Catechin possesses hypo-glycemic, Glucose oxidizing and insulin mimetic activities and hence it could be used as a drug for treating diabetes.
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insulin mimetic impact of catechin isolated from cassia fistula on the Glucose Oxidation and molecular mechanisms of Glucose uptake on streptozotocin induced diabetic wistar rats
Phytomedicine, 2010Co-Authors: Pitchai Daisy, K Balasubramanian, Manikkam Rajalakshmi, J Eliza, J SelvarajAbstract:Diabetes mellitus is the most common and serious metabolic disorder among people all over the world. Many plants have successfully been used to overcome this problem. Cassia fistula, an ethnomedicnal plant, is widely used in Indian medicine to treat diabetes. Methanol extract of stem of plant, reduced the blood Glucose levels in Streptozotocin-induced diabetic rats. Bioassay guided fractionation was followed to isolate Catechin from methanol extract. Catechin was administered to Streptozotocin (60mg/kg b.w.)-induced diabetic male Wistar rats at different doses (5, 10, 20mg/kg b.w.) for 6 weeks to assess its effect on fasting plasma Glucose. The plasma Glucose was significantly (p<0.05) reduced when compared to the control. Oral administration of Catechin (20mg/kg b.w.) markedly increased tissue glycogen, and (14)C-Glucose Oxidation without any change in plasma insulin and C-peptide. Catechin restored the altered Glucokinase, Glucose-6 Phosphatase, Glycogen Synthase and Glycogen Phosphorylase levels to near normal. GLUT4 mRNA and protein expression were enhanced after Catechin treatment. The results of this experimental study indicated that Catechin possesses hypo-glycemic, Glucose oxidizing and insulin mimetic activities and hence it could be used as a drug for treating diabetes.
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corticosterone has direct inhibitory effect on the expression of peptide hormone receptors 11β hsd and Glucose Oxidation in cultured adult rat leydig cells
Molecular and Cellular Endocrinology, 2007Co-Authors: Srinivasan Rengarajan, K BalasubramanianAbstract:Abstract The present study was designed to investigate the dose-dependent direct effect of corticosterone on the expression of peptide hormone receptors, 11β-hydroxysteroid dehydrogenase (11β-HSD) and Glucose Oxidation in cultured adult rat Leydig cells. Leydig cells were isolated from the testis of normal adult male albino rats, purified on discontinuous Percoll gradient and plated in culture plates/flasks overnight at 34 °C in a CO2 incubator under 95% air and 5% CO2 using DME/F12 medium containing 1% fetal bovine serum. After the attachment of cells, serum containing medium was removed and cells were exposed to different doses (0, 50, 100, 200, 400 and 800 nM) of corticosterone using serum-free fresh medium for 24 h at 34 °C. At the end of exposure period, cells were utilized for the quantification of cell-surface LH, prolactin, insulin receptors and their mRNA expression, the activity and mRNA expression of 11β-HSD and Glucose Oxidation. Testosterone production was estimated in cell pellets and in culture media. At all doses employed, corticosterone significantly decreased the production of testosterone by Leydig cells. The concentration of cell-surface LH and prolactin receptors were significantly reduced after corticosterone exposure whereas the concentration of insulin receptor was diminished only at 200–800 nM doses of corticosterone. The levels of LH and prolactin receptor mRNAs were significantly decreased after corticosterone (100–800 nM) exposure whereas the mRNA level of insulin receptor was significantly reduced only at 800 nM dose of corticosterone. 11β-HSD mRNA expression as well as the activity was significantly inhibited by corticosterone treatment. Glucose Oxidation was markedly inhibited by corticosterone exposure in a dose-dependent manner. It is concluded from this in vitro study that corticosterone induces steroidogenic lesion in testicular Leydig cells by decreasing the number of cell-surface LH, prolactin and insulin receptors, the activity of 11β-HSD and their mRNA levels and Glucose Oxidation.
Rick L Barr - One of the best experts on this subject based on the ideXlab platform.
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malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid Oxidation and stimulating Glucose Oxidation
Circulation Research, 2004Co-Authors: Jason R B Dyck, Jiefei Cheng, William C Stanley, Rick L Barr, Margaret P Chandler, Steven Brown, David Wallace, Thomas Arrhenius, Charles Harmon, Guang YangAbstract:Abnormally high rates of fatty acid Oxidation and low rates of Glucose Oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid Oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid Oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid Oxidation rates and an increase in Glucose Oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased Glucose Oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, Glucose Oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid Oxidation and accelerate Glucose Oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
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beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of Glucose Oxidation secondary to inhibition of long chain 3 ketoacyl coenzyme a thiolase
Circulation Research, 2003Co-Authors: Gary D Lopaschuk, Rick L Barr, Panakkezhum D Thomas, Jason R B DyckAbstract:High rates of fatty acid Oxidation in the heart and subsequent inhibition of Glucose Oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating Glucose Oxidation, either directly or secondary to an inhibition of fatty acid Oxidation. We recently demonstrated that trimetazidine stimulates Glucose Oxidation in the heart secondary to inhibition of fatty acid Oxidation. This inhibition of fatty acid Oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid β-Oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 μmol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 μmol/L even at high concentrations of trimetazidine (100 μmol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 μmol/L, a concentration that would completely overcome 100 μmol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 μmol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid Oxidation and stimulates Glucose Oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.
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beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of Glucose Oxidation secondary to inhibition of long chain 3 ketoacyl coenzyme a thiolase
Circulation Research, 2003Co-Authors: Gary D Lopaschuk, Rick L Barr, Panakkezhum D Thomas, Jason R B DyckAbstract:High rates of fatty acid Oxidation in the heart and subsequent inhibition of Glucose Oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating Glucose Oxidation, either directly or secondary to an inhibition of fatty acid Oxidation. We recently demonstrated that trimetazidine stimulates Glucose Oxidation in the heart secondary to inhibition of fatty acid Oxidation. This inhibition of fatty acid Oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid beta-Oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 micromol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 micromol/L even at high concentrations of trimetazidine (100 micromol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 micromol/L, a concentration that would completely overcome 100 micromol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 micromol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid Oxidation and stimulates Glucose Oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.
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ranolazine stimulates Glucose Oxidation in normoxic ischemic and reperfused ischemic rat hearts
Circulation, 1996Co-Authors: James G Mccormack, Rick L Barr, Andrew Wolff, Gary D LopaschukAbstract:Background Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase Glucose and decrease fatty acid (FA) Oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on Glucose and palmitate Oxidation and glycolysis were assessed in isolated rat hearts. Methods and Results Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate); with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) Glucose Oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and Glucose oxida...
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calixarene based ni18 coordination wheel highly efficient electrocatalyst for the Glucose Oxidation and template for the homogenous cluster fabrication
Journal of the American Chemical Society, 2018Co-Authors: Shentang Wang, Xiaohui Gao, Xinxin Hang, Xiaofei Zhu, Haitao Han, Wuping Liao, Wei ChenAbstract:Catalyst plays a very important role in the exploration of new energy. To obtain a highly efficient electrocatalyst for the Glucose Oxidation and tiny metal nanocluster catalysts, a calixarene-based {Ni18} coordination wheel with sulfur atoms on the cavity surface was designed, synthesized, and used as the porous template. Contributing from the active sites of nickel cations, the as-synthesized coordination wheels can efficiently catalyze the electrochemical Oxidation of Glucose with the onset and peak potentials of 0.3 and 0.46 V in alkaline medium, and the catalysis does not depend on the atmosphere (N2, air, or O2), which indicates that the coordination wheel will be a promising electrocatalyst candidate for the compartmentless Glucose–air fuel cell. Meanwhile, benefiting from its confined cavity and inner sulfur surface, such a coordination wheel can serve as a general template for the fabrication and encapsulation of tiny metal nanoclusters of Au, Pd, Ir, Ru, Rh, Pt, and AuPd. In electrochemical exam...
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Calixarene-Based {Ni18} Coordination Wheel: Highly Efficient Electrocatalyst for the Glucose Oxidation and Template for the Homogenous Cluster Fabrication
2018Co-Authors: Shentang Wang, Xiaohui Gao, Xinxin Hang, Xiaofei Zhu, Haitao Han, Wuping Liao, Wei ChenAbstract:Catalyst plays a very important role in the exploration of new energy. To obtain a highly efficient electrocatalyst for the Glucose Oxidation and tiny metal nanocluster catalysts, a calixarene-based {Ni18} coordination wheel with sulfur atoms on the cavity surface was designed, synthesized, and used as the porous template. Contributing from the active sites of nickel cations, the as-synthesized coordination wheels can efficiently catalyze the electrochemical Oxidation of Glucose with the onset and peak potentials of 0.3 and 0.46 V in alkaline medium, and the catalysis does not depend on the atmosphere (N2, air, or O2), which indicates that the coordination wheel will be a promising electrocatalyst candidate for the compartmentless Glucose–air fuel cell. Meanwhile, benefiting from its confined cavity and inner sulfur surface, such a coordination wheel can serve as a general template for the fabrication and encapsulation of tiny metal nanoclusters of Au, Pd, Ir, Ru, Rh, Pt, and AuPd. In electrochemical examinations, the bimetallic AuPd clusters confined in the coordination wheel show higher current density than commercial Pt/C toward hydrogen evolution reaction (HER). The present study shows that the designed coordination wheel can be used as not only a type of novel catalyst itself but also a class of templates for metal cluster catalysts