Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury

Ussher, John R.; Wang, Wei; Gandhi, Manoj; Keung, Wendy; Samokhvalov, Victor; Oka, Tatsujiro; Wagg, Cory S.; Jaswal, Jagdip S.; Harris, Robert A.; Clanachan, Alexander S.; Dyck, Jason R.B.; Lopaschuk, Gary D.

doi:10.1093/cvr/cvs129

Cited by 163 publications

(150 citation statements)

References 48 publications

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“…4 Besides the myocardial accumulation of toxic lipid intermediates, 16 fatty acids inhibit pyruvate dehydrogenase (PDH), the enzyme that links glycolysis to subsequent glucose oxidation by converting pyruvate to acetyl coenzyme A (CoA) for entry into the tricarboxylic acid cycle (Figure 2). 15,20 Conversely, increased glucose use inhibits fatty acid oxidation at the level of the enzyme carnitine palmitoyl transferase 1 (CPT-1), whereas increased malonyl-CoA levels produced by increased glucose flux potently inhibit this enzyme, thus providing a mechanism whereby high rates of aerobic glycolysis inhibit the oxidation of FFAs (Figure 3). 15,20,21 Compared with glucose, the β-oxidation of 1 mol palmitate yields significantly more ATP (129 versus 38 ATP per 1 mol substrate) but consumes more oxygen.…”

Section: Metabolism Of the Normal And Ischemic Heartmentioning

confidence: 99%

“…15,20 Conversely, increased glucose use inhibits fatty acid oxidation at the level of the enzyme carnitine palmitoyl transferase 1 (CPT-1), whereas increased malonyl-CoA levels produced by increased glucose flux potently inhibit this enzyme, thus providing a mechanism whereby high rates of aerobic glycolysis inhibit the oxidation of FFAs (Figure 3). 15,20,21 Compared with glucose, the β-oxidation of 1 mol palmitate yields significantly more ATP (129 versus 38 ATP per 1 mol substrate) but consumes more oxygen. 22 FFAs are therefore the preferred substrate for the heart under normal conditions, and their uptake and use are determined primarily by their circulating concentrations.…”

Section: Metabolism Of the Normal And Ischemic Heartmentioning

confidence: 99%

“…Stimulation of glucose oxidation in rodent hearts decreased infarct size. 15 The application of these concepts to humans has been taken further by the recent study in which myocardial biopsies from patients given left ventricular assist devices showed decreased levels of toxic lipid intermediates. 16 Despite these results emphasizing the importance of timing of GIK supply during ischemia, over the years there has been only 1 clinical study, the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial, 17 covering administration in the first critical hours after the onset of symptoms in an acute coronary syndrome (ACS), a period when FFA levels are high.…”

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Glucose-Insulin-Potassium Revived

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Section: Metabolism Of the Normal And Ischemic Heartmentioning

confidence: 99%

Section: Metabolism Of the Normal And Ischemic Heartmentioning

confidence: 99%

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Glucose-Insulin-Potassium Revived

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“…‡P Ͻ 0.05 for high-ketone compared with low-ketone with the same insulin level, perfusion condition, and diet. infarction and reperfusion injury (42), and an increased FFA oxidation has been associated with reduced myocardial tolerance to ischemia-reperfusion (13); therefore, any increase in FFA and decrease in CHO or ketone oxidation induced by HFLCD might lead to worsened cardiac function during I/R. This has led to the concept that repressing myocardial FFA oxidation may be a therapeutic target to improve cardiac efficiency in the ischemic heart (40).…”

Section: Discussionmentioning

confidence: 99%

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Liu

Wang

Douglas

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Liu J, Wang P, Douglas SL, Tate JM, Sham S, Lloyd SG. Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 311: H1-H10, 2016. First published May 6, 2016; doi:10.1152/ajpheart.00809.2015.-High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulinketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels. diet; myocardial ischemia-reperfusion injury; insulin; metabolism NEW & NOTEWORTHYThe substrate oxidation and response to I/R are more dependent on diet than on physiologic range changes in circulating substrate and insulin. This was associated with altered insulin sensitivity. After I/R, there was a positive (with ketone) and negative (with FFA) correlation between recovery of function and substrate oxidation.HIGH-FAT, LOW-CARBOHYDRATE DIETS (HFLCD S ) are used by many people in an effort to lose weight. The effect of such diets on cardiovascular health has been the subject of intense investigation. Population studies evaluating the impact of HFLCD on cardiovascular clinical outcomes have provided a range of results, with some finding favorable changes in cardiovascular disease risk factors (9, 35, 37), and others showing an increased risk of adverse outcomes in both animal (29) and human studies, including in the setting of myocardial infarction (23). Consistent with this latter finding, we have p...

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“…Myocardial glucose uptake and metabolism are essential for maintaining myocardial energetics especially under circumstances of stress, such as myocardial ischemia or hypertrophy (Patterson et al 2009). Indeed, stimulating glucose oxidation protects against acute myocardial infarction and reperfusion injury and is a potential therapeutic target (Ussher et al 2012). This may be especially important in patients with insulin resistance or type 2 diabetes, as multiple studies have shown defective myocardial glucose uptake and insulin resistance in these patients using fluorine 18-labeled fluorodeoxyglucose approaches (Iozzo et al 2002;Yokoyama et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Genetic manipulation of cardiac Hsp72 levels does not alter substrate metabolism but reveals insights into high-fat feeding-induced cardiac insulin resistance

Henstridge

Estévez

Allen

et al. 2015

Cell Stress and Chaperones

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Heat shock protein 72 (Hsp72) protects cells against a variety of stressors, and multiple studies have suggested that Hsp72 plays a cardioprotective role. As skeletal muscle Hsp72 overexpression can protect against high-fat diet (HFD)-induced insulin resistance, alterations in substrate metabolism may be a mechanism by which Hsp72 is cardioprotective. We investigated the impact of transgenically overexpressing (Hsp72 Tg) or deleting Hsp72 (Hsp72 KO) on various aspects of cardiac metabolism. Mice were fed a normal chow (NC) or HFD for 12 weeks from 8 weeks of age to examine the impact of diet-induced obesity on metabolic parameters in the heart. The HFD resulted in an increase in cardiac fatty acid oxidation and a decrease in cardiac glucose oxidation and insulin-stimulated cardiac glucose clearance; however, there was no difference in Hsp72 Tg or Hsp72 KO mice in these rates compared with their respective wild-type control mice. Although HFD-induced cardiac insulin resistance was not rescued in the Hsp72 Tg mice, it was preserved in the skeletal muscle, suggesting tissue-specific effects of Hsp72 overexpression on substrate metabolism. Comparison of two different strains of mice (BALB/c vs. C57BL/6J) also identified strain-specific differences in regard to HFD-induced cardiac lipid accumulation and insulin resistance. These strain differences suggest that cardiac lipid accumulation can be dissociated from cardiac insulin resistance. Our study finds that genetic manipulation of Hsp72 does not lead to alterations in metabolic processes in cardiac tissue under resting conditions, but identifies mouse strain-specific differences in cardiac lipid accumulation and insulin-stimulated glucose clearance.

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Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury

Abstract: These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease.

Cited by 163 publications

References 48 publications

Glucose-Insulin-Potassium Revived

Glucose-Insulin-Potassium Revived

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Genetic manipulation of cardiac Hsp72 levels does not alter substrate metabolism but reveals insights into high-fat feeding-induced cardiac insulin resistance

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