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Amino acid metabolism during prolonged starvation.

Plasma concentration, splanchnic and renal exchange, and urinary excretion of 20 amino acids were studied in obese subjects during prolonged (5-6 wk) starvation. Splanchnic amino acid uptake was also investigated in postabsorptive and briefly (36-48 hr) fasted subjects.A transient increase in plasma valine, leucine, isoleucine, methionine, and alpha-aminobutyrate was noted during the 1st wk of starvation. A delayed, progressive increase in glycine, threonine, and serine occurred after the 1st 5 days. 13 of the amino acids ultimately decreased in starvation, but the magnitude of this diminution was greatest for alanine which decreased most rapidly during the 1st week of fasting. In all subjects alanine was extracted by the splanchnic circulation to a greater extent than all other amino acids combined. Brief fasting resulted in an increased arterio-hepatic venous difference for alanine due to increased fractional extraction. After 5-6 wk of starvation, a marked falloff in splanchnic alanine uptake was attributable to the decreased arterial concentration. Prolonged fasting resulted in increased glycine utilization by the kidney and in net renal uptake of alanine. It is concluded that the marked decrease in plasma alanine is due to augmented and preferential splanchnic utilization of this amino acid in early starvation resulting in substrate depletion. Maintenance of the hypoalaninemia ultimately serves to diminish splanchnic uptake of this key glycogenic amino acid and is thus an important component of the regulatory mechanism whereby hepatic gluconeogenesis is diminished and protein catabolism is minimized in prolonged fasting. The altered renal extraction of glycine and alanine is not due to increased urinary excretion but may be secondary to the increased rate of renal gluconeogenesis observed in prolonged starvation.

Adolescent↗

Amino acid metabolism during starvation in human pregnancy.

To evaluate the factors regulating gluconeogenesis in pregnancy, plasma amino acid levels were determined during the course of an 84-90 hr fast in physically healthy women studied during wk 16-22 of gestation (before undergoing therapeutic abortion), and in nonpregnant controls. The effect of pregnancy on the glycemic response to exogenous alanine administration during starvation was also investigated. In the nonpregnant group fasting resulted in a 2- to 3-fold increase in the levels of plasma valine, leucine, isoleucine, and alpha-aminobutyrate, while the concentration of alanine and glycine fell. In the pregnant group, the levels of most amino acids were significantly reduced in the postabsorptive state. With starvation, the plasma concentration of alanine fell more rapidly in the pregnant group and was significantly below that of the nonpregnant subjects for the first 60 hr of the fast. In contrast, a significant elevation in plasma glycine, serine, and threonine was observed in the pregnant group after 84 hr of fasting, whereas similar increments were not demonstrable until after 10 days of fasting in previously studied nonpregnant obese subjects. Paralleling the changes in maternal plasma, amniotic fluid levels of valine, leucine, and isoleucine increased while that of alanine fell during the fast. Although the plasma glucose concentration was lower in the pregnant group at termination of the fast, intravenous alanine administration (0.15 g/kg), resulted in a prompt, comparable increase (20-25 mg/100 ml) in plasma glucose in both groups of subjects. It is concluded that (a) pregnancy accelerates and exaggerates the hypoalaninemic and hyperglycinemic effects of starvation; (b) lack of key endogenous substrate rather than altered intrahepatic processes may limit hepatic gluconeogenesis in pregnancy and contribute to gestational hypoglycemia; (c) maternal caloric deprivation profoundly alters the levels of amino acids in amniotic fluid.

Adolescent↗

Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus.

Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min. In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 1(1/2)-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two- to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of alterations in splanchnic or peripheral exchange of these amino acids. Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion. It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion.

Abdomen↗

[Amino acids metabolism and nutritional support in acute renal failure].

It has been claimed that conventional essential amino acid (EAA) solution may give rise to adverse effects such as hyperammonemia, in acute renal failure (ARF). On the other hand the majority the ARF treated recently have been complicated by multiple organ failure (MOF). These data indicate that a new regimen in nutritional support should be applied to those patients. A new amino acid solution for renal failure, containing not only EAA but also branched chain and non-essential amino acids, has been developed. We administered this solution as total parenteral nutrition (TPN) to ARF patients complicated by MOF. Continuous hemodiafiltration is simultaneously applied to remove excess water. The nutritional status and the deranged aminogram are improved by this treatment. We believe that an ARF patient complicated by MOF should be nutritionally supported with this new regimen.

Acute Kidney Injury↗

An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.

Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.

Activating Transcription Factor 4↗

[Protein and amino acid metabolism in the intestinal tract of growing young bulls. 7. Protein estimation and evaluation of protein supply in growing ruminants by the apparently digestible total protein in the duodenum based on rations].

The following values were derived from experimental studies of the crude protein (CP) and amino acid (AA) metabolism of growing fattening bulls, the detailed results of which were described in installments 1-6, for the ascertainment of the content of apparently digestible total protein at the duodenum (ADTPD): a) partial method: Degradation quotaCP = NPN + 0.69 X g pure protein/CP; g AD feed PD = g CP (1 -decomposition quotaCP) X 0.72 or g AD feed PD = 0.31 X g pure protein X 0.72; g ADBPDE = 0.149 X g AD org. matter X 0.80 X 0.72 (ADBPDE = apparently digestible pure bacteria protein at the duodenum, dependent on energy release in the reticulo-rumen; g ADBPDN = g CP X (degradation quotaCP) X 0.80 X 0.72 (ADBPDN = apparently digestible pure bacteria protein at the duodenum, dependent on CP supply of rumen microbes); g AD total PD = g AD feed PD + ADBPDE g AD total PD = g AD feed PD + ADBPDN; b) summarizing method: AD total PD = 0.429 + 10.9 X 0.80/CP in % AD org. matter X (CP intake) X 0.72; AD total PD = 0.196 + 16.6 X 0.80/pure protein % AD org. m. X pure pr. intake X 0.72. The requirement of AD total PD was calculated under consideration of the endogenous urine N, skin N and hair N losses as well as protein retention per kg live weight assuming a utilization of 0.70 for this partial performance. The practical application of this balance method is demonstrated in comparison to the digestible CP-system.

Amino Acids↗

[Animal experiment studies of chronic thiamine deficiency. Changes in carbohydrate and amino acid metabolism under resting and load conditions].

The metabolic effects of thiamine deficiency on the metabolism of lactate, acid-base and amino acids were evaluated both with and without muscular exercise in a controlled animal experiment. Thiamine deficiency - in good correlation with its biologic halftime and also with reports in the literature - caused with a latency of 17-56 days and statistically proven in parallel the following effects: hyperlactemia; in comparison to controls elevated plasma concentrations of threonine, alanine, glutamic acid, glutamine, histidine, methionine, taurine, valine, isoleucine and leucine; distinctly lowered - also in comparison to controls - plasma concentrations of arginine and tryptophan. Furthermore, in the thiamine deficient rats predetermined muscular exercise caused the following effects, also occurring concomitantly: life threatening lactacidosis; marked - statistically prover - disturbance of the homeostasis of alanine, glycine, methionine and arginine; distinctly - and statistically significant - elevated plasma concentration of proline; statistically significantly lowered plasma concentrations of taurine. The reasons for all these changes under thiamine deficiency is most likely a metabolic one primarily due to a disturbance of the utilization of pyruvate in the liver. An additional disturbance of both the transsulfuration pathway and the Krebs-Henseleit-cycle seems probable. The physiologic regulation of pyruvate, lactate, alanine, serine and tyrosine during muscular exercise in correlation to the controls is being discussed.

Amino Acids↗

[The effect of work load on amino acid metabolism].

The results of a comprehensive investigation of the effect of a 20-minute submaximal (Z1) and exhausting (Z2) work load in a group of 8 healthy volunteers on the amino acid and nitrogen metabolism indicate that, as compared with the mild and significant increase of alanine and drop of leucine (all P < 0.05) during the minor load, after an exhausting load a significant rise and concurrent drop of isoleucine, threonine, ornithine, leucine, serine, glycine, asparagine and glutamine (P < 0.01) occurs and a slightly significant drop of methionine and citrulline, while the total amino acid level is practically unaltered. The rise of alanine suggests the existence of a glucose-alanine cycle. The drop of branched amino acids is probably due to their enhanced entry into muscles, the drop of ornithine and citrulline is most probably due to inhibition of ureogenesis in the liver due to lactate and pyruvate accumulation. Exercise caused moreover a significant rise of serum ammonia and uric acid. N-urea changed only little and on average had a declining tendency. The results support data, that intense exercise increases the demands of the human organism for high quality dietary protein intake.

Adult↗

[Effect of gamma- and gamma-neutron irradiation on the composition of the metabolic amino acid pool, blood antiprotease activity and the life-span of animals].

A study was made of the effect of gamma- and gamma-neutron-radiation, with neutron energy of 0.9 MeV, on the free amino acid composition and antiprotease activity of blood as well as on the life span of albino mongrel rats. The data obtained indicate that changes in the metabolic pool of blood amino acids and inhibitory capacity of blood with respect to alpha 2-macroglobulin depend upon the type and dose of radiation. An attempt is made to find a correlation between early changes in the metabolic pool of amino acids and antiprotease activity and the degree of life span shortening after gamma- and gamma-neutron irradiation.

Amino Acids↗

Perinatal changes in amino acid metabolism of rat brain, especially alanine and glutamic acid.

The changes in both the levels of some free amino acids and their metabolism in the rat brain during the first 24 hr of postnatal life were studied. The content of glutamic acid decreased for the first 2 hr; it remained at the lowest level for the next 4 hr, when it began to increase. The content of alanine decreased for the first 6 hr and approached the adult level. Oxygen consumption, glucose oxidation, and pyruvate formation in the cerebral slices of the 24-hr-old rats were as much as 150% of that of the 19-day-old fetus. The distribution profile of radioactivity incorporated into the cerebral amino acids from the subarachnoid-injected [U-14C]glucose was also changed. In the 2- and 6-hr-old rats, 50% of the total radioactivity recovered in the free amino acids was in alanine. Its rate decreased to 30% in the 24-hr-old and was 2% in the adult, while the radioactivity incorporated into glutamic acid increased. Alanine aminotransferase activity started to increase at birth and had the highest level at 24 hr after birth. It then decreased and finally reached the same level as shown at birth. However, aspartate aminotransferase increased during the first 6 hr after birth and did not change until the end of the first day of life.

Aging↗

Glucocorticoid regulation of muscle branched-chain amino acid metabolism.

Branched-chain alpha-keto acid dehydrogenase (BCKAD) is a multisubunit complex regulated by phosphorylation and is considered to be rate-limiting for branched-chain amino acid (BCAA) metabolism in skeletal muscle. Glucocorticoids increase net protein degradation in muscle; associated with this increased breakdown of muscle protein is an elevated rate of BCAA oxidation. The effects of glucocorticoids on skeletal muscle BCKAD were investigated in different rat models. BCKAD was activated after glucocorticoid treatment (both acutely, within 2 h, and chronically). The amount of enzyme per muscle cell increased after 5 d of cortisone acetate treatment. Insulin administration partially blocked the acute effects of glucocorticoids on muscle BCKAD. Activation was also observed during metabolic acidosis, insulinopenic diabetes mellitus, and endotoxic shock, three conditions characterized by elevated circulating glucocorticoids, increased BCAA oxidation, and increased net protein breakdown. Activation of BCKAD may account for the increased oxidation of BCAA observed during hypercortisolemia. The sequelae of this accelerated catabolism may include increased glutamine and alanine production for gluconeogenesis and provision of ATP for muscle work.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

Interactions between ruminal degradable nitrogen intake and in vitro addition of substrates on patterns of amino acid metabolism in isolated ovine hepatocytes.

The effects of ammonia (as NH4Cl) and propionate on the partitioning of amino acids between oxidation and gluconeogenesis were determined in isolated hepatocytes obtained from sheep fed a basal diet (50:50 bromegrass hay:corn; asfed basis) with or without urea. Hepatocyte suspensions were incubated with NH4Cl (0, 1.25, 2.5 and 5.0 mmol/L) and/or propionate (0, 2.5 and 5.0 mmol/L), in the presence of either 2.5 mmol/L L-alanine and 18.5 kBq L-[1-14C]alanine or 2.5 mmol/L L-glutamate and 18.5 kBq L-[1-14C]glutamate. Increasing the level of ruminal degradable nitrogen with urea increased in vitro rates of oxidation to 14CO2 of [1-14C]alanine, but not [1-14C]glutamate. Increasing in vitro concentrations of NH4Cl and propionate between 0 and 5 mmol/L reduced the rates of oxidation to 14CO2 of both [1-14C]alanine and [1-14C]glutamate. Synthesis of [14C]glucose with [1-14C]alanine, but not [1-14C]glutamate as the substrate, was increased 100% by feeding urea. Increasing in vitro levels of NH4Cl between 0 and 5 mmol/L reduced the rates of conversion of [1-14C]alanine and [1-14C]glutamate to [14C]glucose in hepatocytes isolated from sheep fed both diets. Increasing in vitro levels of propionate between 0 and 2.5 mmol/L elevated production rates of [14C]glucose from both radiotracers, but from 2.5 to 5.0 mmol/L propionate no further increase was evident. Feeding urea increased in vitro rates of urea nitrogen production. Increasing propionate levels between 0 and 5 mmol/L reduced ureagenic rates in liver cells isolated from sheep fed both diets. Oxygen (O2) uptake was unaffected by diet and NH4Cl; however, increasing propionate between 0 and 5 mmol/L increased rates of O2 uptake. It is concluded that in isolated sheep hepatocytes, detoxification of excessive ammonia may cause a repartitioning of alanine and glutamate metabolism towards oxidation and gluconeogenesis.

Alanine↗