Regulation of Leucine Metabolism in Man: A Stable Isotope Study

Matthews, Dwight E.; Bier, Dennis M.; Rennie, M. J.; Edwards, R. H. T.; Halliday, D.; Millward, D. J.; Clugston, Graeme

doi:10.1126/science.7302583

Cited by 180 publications

(70 citation statements)

References 8 publications

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“…The first step is reversible and is catalysed by branched-chain aminotransferase (BCAT), whereas the second step is an irreversible oxidative decarboxylation involving a multienzyme complex (a decarboxylase, a transacylase and a dehydrogenase). The regulation of this complex determines BCAA homeostasis and is assumed to be the rate-limiting step of BCAA catabolism (Matthews et al, 1981). An increased supply of Leu is known to stimulate the activity of the enzyme complex and may therefore increase the catabolism of Val and Ile (Wiltafsky et al, 2010) and thus their requirements.…”

Section: Introductionmentioning

confidence: 99%

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Gloaguen

Floc'H

Brossard

et al. 2011

Animal

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The branched-chain amino acids (BCAA) valine (Val) and isoleucine (Ile) are considered to be among the next-limiting amino acids for growth in piglets. In earlier studies, we estimated the standardized ileal digestible (SID) Val : Lys (lysine) requirement to be at least 70%, whereas the Ile : Lys requirement may be as low as 50%. Because the BCAA partially share a common route of catabolism, the supply of one BCAA may affect the availability of the other BCAA. Four experiments were conducted to determine the response of 6-week-old piglets to the Val supply in relation to the other BCAA. A deficient supply of Val or Ile typically results in a reduction in average daily feed intake (ADFI). Experiment 1 was designed to determine the effect of a limiting Val supply, independent of the effect on feed intake. In a dose-response study using restrictively fed piglets, nitrogen retention did not increase for an SID Val : Lys supply greater than 64%. In the remaining experiments, piglets were offered feed ad libitum using ADFI, average daily gain (ADG) and gain-to-feed ratio as response criteria. The interaction between the Val and leucine (Leu) was studied in Experiment 2 in a 2 3 2 factorial design (60% and 70% SID Val : Lys, and 111% and 165% SID Leu : Lys). Performance was considerably lower in piglets receiving 60% Val : Lys compared with those receiving 70% Val : Lys and was lowest in piglets receiving the diet with low Val and high Leu content. To further evaluate the interaction between Val and Leu, a dose-response study was carried out in which the response to Val supply was studied in combination with high Leu supply (165% Leu : Lys). Using a curvilinear-plateau model, the average SID Val : Lys requirement was 72%. However, low Val supply (60% SID Val : Lys) reduced performance by 13% to 38%, which was much greater than what we observed in earlier studies. Experiment 4 was carried out to test the hypothesis that the Val requirement is not affected by low Ile supply (50% SID Ile : Lys). Performance was not improved for Val : Lys supplies greater than 65%, which may indicate that Ile (and not Lys) was second-limiting in this study. In conclusion, the first response of piglets to deficient Val supply appears to be a reduction in ADFI, rather than a reduction in ADG or nitrogen retention. A large supply of Leu may not affect the Val requirement per se, but may aggravate the consequences of Val deficiency.

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Section: Introductionmentioning

confidence: 99%

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Gloaguen

Floc'H

Brossard

et al. 2011

Animal

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“…13 C]KIC were used because this measurement better represents the intracellular leucine environment than that of plasma leucine (36,44), whereas for leucine nitrogen flux (Qn calculation), the isotopic enrichment of [1-13 C, 15 N]leucine at plateau was used (2,45,46). The reversible transamination of leucine, deamination into KIC (Xo), and reamination of KIC (Xn) back to leucine molecules was calculated with the following formula: Qn Ϫ Qc ϭ Xn ϭ Xo Ϫ C. Based on this equation, we estimated Xn and Xo, since we had measured Qn, Qc, and C. Phenylalanine kinetics.…”

Section: Methodsmentioning

confidence: 99%

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

et al. 2002

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Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO 2max . We investigated the effect of 11 days of intensive insulin treatment (T 2 D؉) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T 2 D؊) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T 2 D؊. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.

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“…Comparison with the reported rate of leucine incorporation into protein, 0.19-0.37 jimol/g/h, strongly suggests that, under physiological conditions, the flux of leucine through the BCAT pathway is two-to threefold faster than the flux into protein synthesis. It is interesting that the rate of leucine-a-ketoglutarate transamination measured in whole human body by intravenous infusion of trace [1-' 3C, I5N I leucine and analyses of isotopic enrichments of blood leucine and exhaled CO 2 showed the rate to be 111-152 jimol/kg/h, corresponding to 0.11-0.15 j.tmol/g/h (Matthews et al, 1981). Although the whole-body rate reflects mainly the rates in large organs such as the liver and the muscle, it is interesting that the rate in the brain measured in the present work is of the same order of magnitude.…”

Section: Effects Of Substrate Concentrations On Bcat Activitymentioning

confidence: 99%

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Kanamori

Ross

Kondrat

1998

Journal of Neurochemistry

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Abstract:The rate of glutamate synthesis from leucine by the branched-chain aminotransferase was measured in rat brain in vivo at steady state. The rats were fed exclusively by intravenous infusion of a nutrient solution containing [15N]leucine. The rate of glutamate synthesis from leucine, determined from the rate of increase of brain [15N]glutamate measured by 15N NMR and the 15N enrichments of brain and blood leucine analyzed by gas chromatography-mass spectrometry, was 0.7-1.8 j.tmol/g/ h at a steady-state brain leucine concentration of 0.25 mol/g. A comparison of the observed fractional 15N enrichments of brain leucine (0.42 ±0.03) and glutamate (0.21 ±0.015) showed that leucine provides '-.~50%of glutamate nitrogen under our experimental condition. From the observed rate (0.7-1.8 j.imol/g) and the known Km of the branched-chain aminotransferase for leucine (1.2 mM), the rate of glutamate synthesis from leucine at physiological brain leucine concentration (0.11~mol/ g) was estimated to be 0.35-0.9~mol/g/h, with leucine providing~25% of glutamate nitrogen. The results strongly suggest that plasma leucine from dietary source, transported into the brain, is an important external source of nitrogen for replenishment of brain glutamate in vivo. Implications of the results for treatment of maple-syrup urine disease patients with leucine-restricted diet are discussed. Key Words: Leucine-Glutamate-BrainBranched-chain aminotransferase-1 5N NMR-In vivo. J. Neurochem. 70, 1304Neurochem. 70, -1315Neurochem. 70, (1998.The branched-chain amino acids (BCAA) -leucine, isoleucine, and valine-are essential amino acids that readily cross the blood-brain barrier. Leucine is the predominant BCAA in most dietary proteins (Berry et al., 1989) and has the highest influx rate into the brain (Smith et al., 1987). In the brain, leucine has two metabolic fates: (a) incorporation into proteins and (b) transamination to a-ketoglutarate to form glutamate, catalyzed by branched-chain aminotransferase (BCAT; EC 2.6.1.42):

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Regulation of Leucine Metabolism in Man: A Stable Isotope Study

Cited by 180 publications

References 8 publications

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

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Regulation of Leucine Metabolism in Man: A Stable Isotope Study

Cited by 180 publications

References 8 publications

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Response of piglets to the valine content in diet in combination with the supply of other branched-chain amino acids

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR

Contact Info

Product

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Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR