Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia

King, Linda M.; Sidell, Robert J.; Wilding, James R.; Radda, George K.; Clarke, Kieran

doi:10.1152/ajpheart.2001.280.3.h1173

Cited by 27 publications

(32 citation statements)

References 37 publications

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“…Thus, the availability of other substrates may have significantly altered the response to ischemia. Indeed, we have demonstrated that the addition of palmitate to the perfusate improved recovery of contractile function in diabetic rat hearts (25). Furthermore, the availability of other substrates can also affect glucose uptake; thus, the differences seen here in the 12-month-old Zucker rats may not be apparent under in vivo conditions, in which circulating substrate levels also differ.…”

Section: Coronary Flowmentioning

confidence: 74%

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Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Sidell

Cole²,

Draper³

et al. 2002

Diabetes

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149

128

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Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml ⅐ min ؊1 ⅐ grams wet wt ؊1 and reperfusion. D[2-3 H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.

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Section: Coronary Flowmentioning

confidence: 74%

“…Glucose uptake was measured in two other groups of hearts as the rate of cleavage of H ϩ from glucose, as previously described (25). Hearts were perfused with 250 ml recirculating Krebs-Henseleit buffer containing 11 mmol/l glucose and…”

Section: Animalsmentioning

confidence: 99%

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Sidell

Cole²,

Draper³

et al. 2002

Diabetes

Self Cite

149

128

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“…Furthermore, whereas oxidative energy production is minimal during zero-flow ischemia, we have recently shown that oxidative energy metabolism contributes 30% to 50% of ATP production during the LFI protocol used here. 13 Interestingly, King et al 34 showed that the provision of additional oxidizable substrates such as long-chain fatty acids improved functional recovery after a similar LFI protocol compared with situations when glucose was the only available substrate. We believe that using an LFI protocol is relevant because, in both large animal studies and patients, there is considerable residual flow in the infarct zone.…”

Section: Wang Et Al Cardiac Metabolism and Function After Ischemia 2069mentioning

confidence: 99%

Impact of High Glucose/High Insulin and Dichloroacetate Treatment on Carbohydrate Oxidation and Functional Recovery After Low-Flow Ischemia and Reperfusion in the Isolated Perfused Rat Heart

Wang¹,

Lloyd²,

Chatham³

2005

Circulation

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Background-It is believed that increasing cardiac glucose metabolism in the setting of ischemia and reperfusion is protective because of the resulting decrease in fatty acid oxidation, which improves cardiac efficiency and increases glucose oxidation relative to glycolysis; however, these conclusions are based primarily on studies in which glucose is the only carbohydrate provided. The goal of this study was to examine the effect of stimulating myocardial carbohydrate use either by increasing glucose and insulin levels or by using dichloroacetate on the response to ischemia and reperfusion in hearts perfused with physiological concentrations of lactate and pyruvate plus glucose and fatty acids. Methods and Results-Metabolic fluxes were determined in hearts from male Sprague-Dawley rats perfused with 13 C-labeled substrates using 13 C/ 1 H-NMR isotopomer analysis after 30 minutes of low-flow ischemia (0.3 mL/min) and 60 minutes of reperfusion. Measurements were made under control conditions: 5 mmol/L glucose, 1 mmol/L lactate, 0.1 mmol/L pyruvate, 0.3 mmol/L palmitate, and 50 U/mL insulin plus dichloroacetate 5 mmol/L or glucose and insulin increased to 30 mmol/L and 1000 U/mL, respectively. Dichloroacetate increased carbohydrate oxidation and the ratio of glucose oxidation to glycolysis but did not improve functional recovery or cardiac efficiency; however, elevated glucose and insulin levels improved functional recovery and cardiac efficiency but did not increase carbohydrate oxidation or the ratio of glucose oxidation to glycolysis. Conclusions-These data support the notion that increasing myocardial glucose use is beneficial in the setting of ischemia and reperfusion; however, the protective effect appears not to be mediated by shifting the balance between carbohydrate and fatty acid oxidation.

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“…The initiation of therapy during this time may provide valuable additional cell survival advantages. King et al (26) demonstrated that, in a LFI-and-reperfusion protocol, perfusion of diabetic hearts with glucose and palmitate resulted in improved recovery of function compared with glucose alone. They speculated that this improvement could be due to palmitate oxidation, leading to increased ATP production during LFI, which is clearly counter to the concept that increasing carbohydrate use at the expense of fatty acids is beneficial in the setting of ischemia.…”

mentioning

confidence: 99%

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

Lloyd

Wang

Zeng

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used 1 H and 13 C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and 13 C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a ϳ50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and ϳ30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia. nuclear magnetic resonance spectroscopy; energy metabolism; lactate; pyruvate; ATP

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Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia

Cited by 27 publications

References 37 publications

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Impact of High Glucose/High Insulin and Dichloroacetate Treatment on Carbohydrate Oxidation and Functional Recovery After Low-Flow Ischemia and Reperfusion in the Isolated Perfused Rat Heart

Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

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