Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart

Newsholme, E. A.; Randle, P. J.

doi:10.1042/bj0930641

Cited by 191 publications

(45 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus increased plasma NEFA enhanced muscle glycogen deposition during the low-dose insulin clamp, an effect also seen in the heart (Table 4). Previous studies [15,20,39] have shown that enhanced glycogen synthesis in heart and red skeletal muscle when lipid oxidation is increased is associated with an increase in tissue glucose-6-phosphate secondary to inhibition of glycolysis at the level of phosphofructokinase [15,39,40]. Although we did not measure glucose-6-phosphate concentrations, increased muscle glycogen deposition but unchanged glucose turnover at low-dose insulin is consistent with an inhibition of glycolytic flux by increased fatty acid availability.…”

Section: ]mentioning

confidence: 51%

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

1990

View full text Add to dashboard Cite

Summary. Fatty acids in cardiac muscle compete with glucose for oxidation, thereby inhibiting glucose utilisation. It is not clear whether a similar mechanism is important in resting skeletal muscle. We used the hyperinsulinaemic euglycaemic clamp technique in conscious rats fasted for 20 h to examine the effects of increased plasma non-esterifled fatty acid levels (-1 mmol/1) on glucose metabolism. Insulin was infused at 75mU/h (plasma insulin, 2.27 + 0.21 gg/1) or 300 mU/h (16.41 + 0.47 gg/1). An increase in non-esterified fatty acid levels decreased clamp glucose requirement and 3-~H-glucose turnover by 35% (p < 0.001) when the higher insulin dose was used but there was no change at the lower dose. At both insulin infusion rates, clamp blood lactate and pyruvate responses suggested inhibition of muscle glycolysis by elevated plasma non-esterified fatty acid concentrations. Quadriceps muscle glycogen deposition during the clamps was enhanced by increased non-esterified fatty acid availability at the lower insulin dose (p < 0.001) but not at the higher insulin concentration. Activation of pyruvate dehyrogenase during the clamps was partially inhibited by increased plasma non-esterified fatty acid in the heart, adipose tissue and quadriceps muscle. This was evident at both insulin levels in heart but only at the higher insulin concentration in muscle (p < 0.002). The findings are consistent with an inhibition of glycolysis in skeletal muscle of mixed fibre type as a result of increased fatty acid availability. At low rates of glucose flux glycogen synthesis may compensate for decreased glycolysis so that glucose turnover is not decreased. The role of pyruvate dehydrogenase in the "glucose-fatty acid cycle" in muscle may depend on the prevailing plasma insulin concentration and the degree of activation of this enzyme.Key words: Glucose-fatty acid cycle, non-esterified fatty acids, rat, glucose clamp, glycogen, glycogen synthase, pyruvate dehydrogenase, intermediary metabolites, glucose turnover.Inhibition of glucose uptake and oxidation in rat diaphragm and cardiac muscle by increased fatty acid oxidation was first demonstrated by Randle and colleagues [1]. They coined the term "glucose-fatty acid cycle" and suggested that increased availability of non-esterified fatty acids (NEFA) in obesity and diabetes may play an important role in the glucose intolerance and tissue insensitivity to insulin [2].Glucose tolerance was impaired when plasma NEFA concentrations were raised in normal man, by infusion of lipids [3,4] or administration of heparin with a fat meal [5]. As liver and skeletal muscle are quantitatively the most important tissues for disposal of an oral glucose load [6,7], it is necessary to postulate that increased fatty acid availability impairs glucose uptake by these tissues. Decreased insulin-stimulated muscle glucose uptake and impaired suppression of hepatic glucose production by insulin in rats fed a high fat diet for several weeks would support this [8,9]. However, the effects of an acute increase ...

show abstract

Section: ]mentioning

confidence: 51%

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

1990

View full text Add to dashboard Cite

show abstract

“…During increased cardiac power we observed that diabetic pigs have decreased PDH activity and lactate uptake and enhanced ␤-hydroxybutyrate uptake compared with healthy animals (19). It is generally postulated that impaired pyruvate oxidation in the diabetic heart is partially due to an increase in mitochondrial NADH/NAD ϩ (19,32,33,40); however, evidence for this is lacking due to the inability to measure mitochondrial NADH and NAD ϩ in the intact heart. The overall goal of the present study was to 1) assess the role of parallel activation of multiple metabolic steps in the regulation of cytosolic and mitochondrial NADH/NAD ϩ during the dynamic transition from resting conditions to high rates of cardiac energy expenditure, as observed with exercise; 2) investigate the effects of elevated arterial lactate concentration on mitochondrial pyruvate and fatty acid oxidation and the cytosolic and mitochondrial NADH/NAD ϩ ratios; and 3) determine whether impaired pyruvate oxidation under diabetic conditions requires an increase in mitochondrial NADH/ NAD ϩ .…”

mentioning

confidence: 80%

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Zhou

Cabrera²,

Okere³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

. Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies. Am J Physiol Heart Circ Physiol 291: H1036-H1046, 2006. First published April 21, 2006 doi:10.1152/ajpheart.01382.2005.-In response to exercise, the heart increases its metabolic rate severalfold while maintaining energy species (e.g., ATP, ADP, and Pi) concentrations constant; however, the mechanisms that regulate this response are unclear. Limited experimental studies show that the classic regulatory species NADH and NAD ϩ are also maintained nearly constant with increased cardiac power generation, but current measurements lump the cytosol and mitochondria and do not provide dynamic information during the early phase of the transition from low to high work states. In the present study, we modified our previously published computational model of cardiac metabolism by incorporating parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and oxidative phosphorylation, and simulated the metabolic responses of the heart to an abrupt increase in energy expenditure. Model simulations showed that myocardial oxygen consumption, pyruvate oxidation, fatty acids oxidation, and ATP generation were all increased with increased energy expenditure, whereas ATP and ADP remained constant. Both cytosolic and mitochondrial NADH/NAD ϩ increased during the first minutes (by 40% and 20%, respectively) and returned to the resting values by 10 -15 min. Furthermore, model simulations showed that an altered substrate selection, induced by either elevated arterial lactate or diabetic conditions, affected cytosolic NADH/NAD ϩ but had minimal effects on the mitochondrial NADH/NAD ϩ , myocardial oxygen consumption, or ATP production. In conclusion, these results support the concept of parallel activation of metabolic processes generating reducing equivalents during an abrupt increase in cardiac energy expenditure and suggest there is a transient increase in the mitochondrial NADH/NAD ϩ ratio that is independent of substrate supply.diabetes; exercise; heart; lactate; mitochondria; modeling CARDIAC PUMP FUNCTION is fueled by ATP hydrolysis, which is precisely matched by ATP formation, primarily in the mitochondria (42). In the transition from rest to intense exercise, there is a three-to sixfold increase in the rate of cardiac power generation, myocardial oxygen consumption (MV O 2 ), and ATP turnover (25). Nevertheless, at high work states the myocardial ATP and ADP concentrations are maintained at a relatively constant level (2, 4, 36). There is rapid activation of NADH generation in the mitochondria, flux through the electron transport chain (ETC), and ATP production by oxidative phosphorylation to match exactly ATP breakdown in the cytosol. Studies in isolated mitochondria show that the generation of NADH from carbon substrates, oxygen consumption, and oxidative phosphorylation are turned on by feedback from an increase in ADP concentration (9); however, the regul...

show abstract

“…The overall effect of activated AMPK is to increase ATP supply by accelerating the rates of fatty acid oxidation and glycolysis. However, high rates of fatty acid oxidation dramatically inhibit glucose oxidation rates via the Randle cycle (102). That is, fatty acid-derived acetyl CoA is able to decrease the production of glucose-derived acetyl CoA via inhibition of the pyruvate dehydrogenase complex (66).…”

Section: Regulation Of Myocardial Energy Utilizationmentioning

confidence: 99%

Role of AMP-activated protein kinase in healthy and diseased hearts

Dolinsky¹,

Dyck²

2006

American Journal of Physiology-Heart and Circulatory Physiology

117

105

View full text Add to dashboard Cite

Dolinsky, Vernon W., and Jason R. B. Dyck. Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291: H2557-H2569, 2006. First published July 14, 2006 doi:10.1152/ajpheart.00329.2006.-The heart is capable of utilizing a variety of substrates to produce the necessary ATP for cardiac function. AMP-activated protein kinase (AMPK) has emerged as a key regulator of cellular energy homeostasis and coordinates multiple catabolic and anabolic pathways in the heart. During times of acute metabolic stresses, cardiac AMPK activation seems to be primarily involved in increasing energy-generating pathways to maintain or restore intracellular ATP levels. In acute situations such as mild ischemia or short durations of severe ischemia, activation of cardiac AMPK appears to be necessary for cardiac myocyte function and survival by stimulating ATP generation via increased glycolysis and accelerated fatty acid oxidation. Whereas AMPK activation may be essential for adaptation of cardiac energy metabolism to acute and/or minor metabolic stresses, it is unknown whether AMPK activation becomes maladaptive in certain chronic disease states and/or extreme energetic stresses. However, alterations in cardiac AMPK activity are associated with a number of cardiovascular-related diseases such as pathological cardiac hypertrophy, myocardial ischemia, glycogen storage cardiomyopathy, and Wolff-Parkinson-White syndrome, suggesting the possibility of a maladaptive role. Although the precise role AMPK plays in the diseased heart is still in question, it is clear that AMPK is a major regulator of cardiac energy metabolism. The consequences of alterations in AMPK activity and subsequent cardiac energy metabolism in the healthy and the diseased heart will be discussed. ischemia; cardiac hypertrophy; cardiac energy metabolism; glycogen THE HEART is capable of utilizing a variety of substrates to meet its immense demand for energy. Under normal physiological circumstances, cardiac function is dependent on the production of intracellular ATP derived primarily by the utilization of fatty acids, glucose, and lactate (123). A variety of transport proteins and regulatory enzymes control the uptake and subsequent metabolism of these energy substrates. Whereas many of these enzymes are regulated through substrate supply and/or energy demand, covalent modification of a number of these enzymes is also important. These regulatory mechanisms mediate substrate utilization and are essential for proper cardiac function.Fatty acids provide a concentrated supply of energy accounting for ϳ50 -75% of the myocardial acetyl CoA-derived ATP (84). Upon entering the cardiac myocyte, fatty acids are transported into the mitochondria and undergo ␤-oxidation to produce acetyl CoA that is eventually used to produce ATP. Glucose is transported into the cell via glucose transporters (GLUT) and can undergo glycolytic metabolism to generate pyruvate and ATP. This can occur in the absence of oxygen while still producing ATP. However, i...

show abstract

Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart

Abstract: Newsholme & Randle (1961) found that the concentrations of glucose 6-phosphate and fructose 6-phosphate were decreased and that of fructose * Part 6: Newsholme & Randle (1962).

Cited by 191 publications

References 13 publications

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

Effects of non-esterified fatty acid availability on insulin stimulated glucose utilisation and tissue pyruvate dehydrogenase activity in the rat

Regulation of myocardial substrate metabolism during increased energy expenditure: insights from computational studies

Role of AMP-activated protein kinase in healthy and diseased hearts

Contact Info

Product

Resources

About