The effect of insulin on pyruvate dehydrogenase interconversion in heart muscle of alloxan-diabetic rats

A B S T R A C T Pyruvate dehydrogenase complex (PDC) activity in human skin fibroblasts appears to be regulated by a phosphorylation-dephosphorylation mechanism, as is the case with other animal cells. The enzyme can be activated by pretreating the cells with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, before they are disrupted for measurement of PDC activity. With such treatment, the activity reaches 5-6 nmol/min per mg of protein at 37°C with fibroblasts from infants. Such values represent an activation of about 5-20-fold over those observed with untreated cells. That this assay, based on [1-_4C]pyruvate decarboxylation, represents a valid measurement of the overall PDC reaction is shown by the dependence of 14CO2 production on the presence ofthiamin-PP, coenzyme A (CoA), Mg++, and NAD+. Also, it has been shown that acetyl-CoA and '4CO2 are formed in a 1:1 ratio. A similar degree of activation of PDC can also be achieved by adding purified pyruvate dehydrogenase phosphatase and high concentrations ofMg++ and Ca++, or in some cases by adding the metal ions alone to the cell homogenate after disruption. These results strongly suggest that activation is due to dephosphorylation. Addition of NaF, which inhibits dephosphorylation, leads to almost complete loss of PDC activity.Assays of completely activated PDC were performed on two cell lines originating from patients reported to be deficient in this enzyme (Blass, J. P.,

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“…[46]). The results shown in Table III (51,52); about 60% in rat heart and adipose tissue (51,(53)(54)(55)(56)(57).…”

Section: Resultsmentioning

confidence: 92%

Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

Sheu¹,

Hu²,

Utter³

1981

J. Clin. Invest.

140

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“…3) [8]. Finally, in perfused hearts, the addition of insulin has no clear effect on PDH activity [131,142]. This is in contrast with adipose tissue, where the activation of PDH by insulin is well documented [143,144].…”

Section: Bradykininmentioning

confidence: 99%

Mechanisms of control of heart glycolysis

Depré

Rider

Hue

1998

European Journal of Biochemistry

143

124

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This review focuses on the mechanisms of control of heart glycolysis under conditions of normal and reduced oxygen supply. The kinetic properties and the biochemical characteristics of control steps (glucose transporters, hexokinase, glycogen phosphorylase and phosphofructokinases) in the heart are reviewed in the light of recent findings and are considered together to explain the control of glycolysis by substrate supply and availability, energy demand, oxygen deprivation and hormones. The role of fructose 2,6-bisphosphate in the control of glycolysis is analysed in detail. This regulator participates in the stimulation of heart glycolysis in response to glucose, workload, insulin and adrenaline, and it decreases the glycolytic flux when alternative fuels are oxidized. Fructose 2,6-bisphosphate integrates information from various metabolic and signalling pathways and acts as a glycolytic signal. Moreover, a hierarchy in the control of glycolysis occurs and is evidenced in the presence of adrenaline or cyclic AMP, which relieve the inhibition of glycolysis by alternative fuels and stimulate fatty acid oxidation. Insulin and glucose also stimulate glycolysis, but inhibit fatty acid oxidation. The mechanisms of control underlying this fuel selection are discussed. Finally, the study of the metabolic adaptation of glucose metabolism to oxygen deprivation revealed the implication of nitric oxide and cyclic GMP in the control of heart glucose metabolism.Keywords : fructose 2,6-bisphosphate; glycolysis ; heart; hormones; ischaemia.The working heart requires a continous supply of energy to support its contractile activity. Most of its energy requirements are met by the oxidation of exogenous substrates (fatty acids, glucose, lactate and ketone bodies) and the relative contribution of these fuels to energy provision depends on several parameters. In the postprandial state, when blood glucose and insulin levels are elevated, glucose utilization is dominant, whereas in the fasted state, glycolysis is inhibited by other substrates [1,2]. Therefore, a characteristic feature of the heart is fuel selection.

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“…We suggest that the lack of an insulin effect in hearts from normal rats is due to the limited availability of triacylglycerols in those hearts. It has been demon strated that insulin is not able to inhibit the hormone stimulation of adenylate cyclase in heart (37) or skeletal muscle (38), while an insulin activation of the pyruvate dehydroge nase reaction has been demonstrated in hearts from alloxan-diabetic rats (39). We propose that glucose cum insulin, by a similar stimulation of the pyruvate dehydrogenase reaction (39), may decrease the intracellular CoA concentration which thereby becomes rate-limiting for fatty acid activation.…”

Section: Discussionmentioning

confidence: 99%

Control of Lipolysis in Triglyceride-Enriched Rat Hearts

Stam

Hülsmann²

1981

Ann Nutr Metab

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Hormonal and metabolic regulation of endogenous triglyceride hydrolysis was studied in triglyceride-enriched hearts obtained from rats fed 3 days with a trierucate-rich diet. Endogenous lipolysis was determined by measuring glycerol release during in vitro perfusion of the hearts. It appeared that there was a direct relation between the contractile state of the heart, the rate of glycerol release in the coronary effluent and the Ca²⁺ concentration in the perfusion medium. During Ca²⁺-free perfusion, 2,4-dinitrophenol stimulated oleate oxidation and this, as well as the addition of 2 • 10^–7M glucagon, induced a marked stimulation of lipolysis. Insulin did not affect glucagon- and norepinephrine-stimulated lipolysis during substrate-free perfusion. The presented experiments point out that in lipid-enriched rat hearts the activity of the tissue lipase may be controlled by the rate of β-oxidation and re-esterification of the liberated fatty acids, as well as by a shift to utilization of carbohydrate instead of fatty acids for energy supply.

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The effect of insulin on pyruvate dehydrogenase interconversion in heart muscle of alloxan-diabetic rats

Cited by 22 publications

References 35 publications

Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts

Mechanisms of control of heart glycolysis

Control of Lipolysis in Triglyceride-Enriched Rat Hearts

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