The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

Mowbray, John; Ottaway, J. H.

doi:10.1111/j.1432-1033.1973.tb02921.x

Cited by 34 publications

(6 citation statements)

References 51 publications

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“…Consequently, we have proposed that, in the presence of exogenous lactate, glucose-derived pyruvate formation is tightly coupled to lactate production and subsequent transport out of the cell, whereas exogenous lactate-derived pyruvate is preferentially oxidized in the mitochondria. This model accounts for the observations of separate pyruvate pools in the isolated perfused heart (8,28,31,35) and the reports of simultaneous myocardial lactate uptake and efflux observed in vivo and in vitro (1,2,19,20,30,40,49). It is also consistent with the intracellular lactate shuttle hypothesis (6,7).…”

Section: Discussionsupporting

confidence: 85%

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Evidence of separate pathways for lactate uptake and release by the perfused rat heart

Chatham

Rosiers

Forder

2001

American Journal of Physiology-Endocrinology and Metabolism

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The simultaneous release and uptake of lactate by the heart has been observed both in vivo and ex vivo; however, the pathways underlying these observations have not been satisfactorily explained. Consequently, the purpose of this study was to test the hypothesis that hearts release lactate from glycolysis while simultaneously taking up exogenous lactate. Therefore, we determined the effects of fatty acids and diabetes on the regulation of lactate uptake and release. Hearts from control and 1-wk diabetic animals were perfused with 5 mM glucose, 0.5 mM [3-(13)C]lactate, and 0, 0.1, 0.32, or 1.0 mM palmitate. Parameters measured include perfusate lactate concentrations, fractional enrichment, and coronary flow rates, which enabled the simultaneous, but independent, measurements of the rates of 1) uptake of exogenous [(13)C]lactate and 2) efflux of unlabeled lactate from metabolism of glucose. Although the rates of lactate uptake and efflux were both similarly inhibited by the addition of palmitate, (i.e., the ratio of lactate uptake to efflux remained constant), the ratio of lactate uptake to efflux was significantly higher in the controls compared with the diabetic group (1.00 +/- 0.14 vs. 0.50 +/- 0.07, P < 0.002). These data, combined with heterogeneous (13)C enrichment of tissue lactate, pyruvate, and alanine, suggest that glycolytically derived lactate production and oxidation of exogenous lactate operate as functionally separate metabolic pathways. These results are consistent with the concept of an intracellular lactate shuttle.

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Section: Discussionsupporting

confidence: 85%

“…6. We believe that this model provides a framework for integrating the observations of myocardial lactate uptake and release in vivo and in vitro (1,2,19,20,30,40,49) with earlier reports of pyruvate compartmentation in the heart (8,28,31,35,46).…”

Section: Discussionmentioning

confidence: 76%

Evidence of separate pathways for lactate uptake and release by the perfused rat heart

Chatham

Rosiers

Forder

2001

American Journal of Physiology-Endocrinology and Metabolism

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“…Based on studies at tracer concentrations of pyruvate, these results were most consistent with two functional pools of pyruvate in the cytosol of the heart, one in communication with pyruvate from glycolysis and the other in communication with extracellular pyruvate [21]. In the presence of [2-14 C]lactate, not all pyruvate in the heart exchanges with lactate [22]. 13 C and 1 H NMR methods found differing enrichments in lactate and alanine when the tracer originated in glucose [23].…”

Section: Functional Compartmentation Of Pyruvate Is Detected By 2 H Dmentioning

confidence: 52%

Effects of deuteration on transamination and oxidation of hyperpolarized 13C-Pyruvate in the isolated heart

Funk

Wen

Hever

et al. 2019

Journal of Magnetic Resonance

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This study was designed to determine the effects of deuteration in pyruvate on exchange reactions in alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and flux through pyruvate dehydrogenase (PDH). Although deuteration of a 13 C enriched substrate is commonly used to increase the lifetime of a probe for hyperpolarization experiments, the potential impact of kinetic isotope effects on such substitutions has not been studied in detail. Metabolism of deuterated pyruvate was investigated in isolated rat hearts. Hearts were perfused with a 1:1 mixture of [U-13 C 3 ]pyruvate and [2-13 C 1 ]pyruvate or a 1:1 mixture of [U-13 C 3 ]pyruvate plus [2-13 C 1 , U-2 H 3 ]pyruvate for 30 min before being freeze clamped. Another set of hearts received [2-13 C 1 , U-2 H 3 ]pyruvate and was freeze-clamped at 3 min or 6 min. Tissue extracts were analyzed by 1 H and 13 C{ 1 H} NMR spectroscopy. The chemical shift isotope effect of 2 H was monitored in the 13 C NMR spectra of the C2 resonance of lactate and alanine plus the C5 of glutamate. There was little kinetic isotope effect of 2 H in pyruvate on flux through PDH, LDH or ALT as detected by the distribution of 13 C, but the distribution of 2 H differed markedly between alanine and lactate. At steady-state, alanine was a mixture of deuterated species, while lactate was largely perdeuterated. Consistent with results at steady-state, hearts freeze-clamped at 3 min or 6 min showed rapid removal of deuterium in alanine but not in lactate. Metabolism of hyperpolarized [l-13 C 1 ]pyruvate was compared to [l-13 C 1 ,U-2 H 3 ]pyruvate in isolated hearts. Consistent with the results from tissue extracts, there was little effect of deuteration on the kinetics of appearance of lactate, alanine or bicarbonate, but there was a small, time-dependent upfield chemical shift in the HP[l-13 C 1 ]alanine signal reflecting exchange of methyl deuterons with water protons. Together, these results

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“…1 One example of possible functional compartmentation came from the early work of Mowbray and Ottaway, [2][3][4][5] who first presented evidence for multiple, metabolic pools of pyruvate. Most early evidence for compartmentation came from differences in 14 C specific activities of alanine vs lactate, metabolites that share pyruvate as a 3-carbon precursor.…”

Section: Introductionmentioning

confidence: 99%

Compartmentation of glycolysis and glycogenolysis in the perfused rat heart

et al. 2004

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Developing methods that can detect compartmentation of metabolic pathways in intact tissues may be important for understanding energy demand and supply. In this study, we investigated compartmentation of glycolysis and glycogenolysis in the isolated perfused rat heart using (13)C NMR isotopomer analysis. Rat hearts previously depleted of myocardial glycogen were perfused with 5.5 mm [U-(13)C]glucose plus 50 mU/mL insulin until newly synthesized glycogen recovered to new steady-state levels ( approximately 60% of pre-depleted values). After a short wash-out period, the perfusate glucose was then switched to [1-(13)C]glucose, and glycolysis and glycogenolysis were stimulated by addition of glucagon (1 microg/ml). A (13)C NMR multiplet analysis of the methyl resonance of lactate provided an estimate of pyruvate derived from glucose vs glycogen while a multiplet analysis of the C4 resonance of glutamate provided an estimate of acetyl-CoA derived from glycolytic pyruvate vs glycogenolytic pyruvate. These two indices were not equivalent and their difference was further magnified in the presence of insulin during the stimulation phase. These combined observations are consistent with functional compartmentation of glycolytic and glycogenolytic enzymes that allows pyruvate generated by these two processes to be distinguished at the level of lactate and acetyl-CoA.

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The Effect of Insulin and Growth Hormone on the Flux of Tracer from Labelled Lactate in Perfused Rat Heart

Cited by 34 publications

References 51 publications

Evidence of separate pathways for lactate uptake and release by the perfused rat heart

Evidence of separate pathways for lactate uptake and release by the perfused rat heart

Effects of deuteration on transamination and oxidation of hyperpolarized 13C-Pyruvate in the isolated heart

Compartmentation of glycolysis and glycogenolysis in the perfused rat heart

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