Alanine and glutamine are the principal glucogenic amino acids. Most originate from muscles, where branched-chain amino acids (valine, leucine, and isoleucine) are nitrogen donors and, under exceptional circumstances, a source of carbons for glutamate synthesis. Glutamate is a nitrogen source for alanine synthesis from pyruvate and a substrate for glutamine synthesis by glutamine synthetase. The following differences between alanine and glutamine, which can play a role in their use in gluconeogenesis, are shown: (i) glutamine appearance in circulation is higher than that of alanine; (ii) the conversion to oxaloacetate, the starting substance for glucose synthesis, is an ATP-consuming reaction for alanine, which is energetically beneficial for glutamine; (iii) most alanine carbons, but not glutamine carbons, originate from glucose; and (iv) glutamine acts a substrate for gluconeogenesis in the liver, kidneys, and intestine, whereas alanine does so only in the liver. Alanine plays a significant role during early starvation, exposure to high-fat and high-protein diets, and diabetes. Glutamine plays a dominant role in gluconeogenesis in prolonged starvation, acidosis, liver cirrhosis, and severe illnesses like sepsis and acts as a substrate for alanine synthesis in the small intestine. Interactions among muscles and the liver, kidneys, and intestine ensuring optimal alanine and glutamine supply for gluconeogenesis are suggested.

• Keywords
• branched-chain amino acids, cirrhosis, diabetes, glucose, starvation,
• MeSH
• Alanine * metabolism   MeSH
• Gluconeogenesis * MeSH
• Glucose metabolism   MeSH
• Glutamine * metabolism   MeSH
• Liver * metabolism   MeSH
• Kidney * metabolism   MeSH
• Humans MeSH
• Intestine, Small * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Alanine * MeSH
• Glucose MeSH
• Glutamine * MeSH

Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.

• Keywords
• aspartame, aspartate and cell-to-cell interactions, branched-chain amino acids, gluconeogenesis, glutamate–glutamine cycle, malate–aspartate shuttle, neurotransmission, oxaloacetate, purine-nucleotide cycle, urea cycle,
• Publication type
• Journal Article MeSH
• Review MeSH

The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased.

• Keywords
• branched-chain amino acids, glycine, insulin resistance, serine,
• MeSH
• Amino Acids metabolism   MeSH
• Diabetes Mellitus, Type 2 * metabolism   MeSH
• Glycine metabolism   MeSH
• Glycolysis MeSH
• Pyruvic Acid MeSH
• Humans MeSH
• Serine metabolism   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amino Acids MeSH
• Glycine MeSH
• Pyruvic Acid MeSH
• Serine MeSH
• Amino Acids, Branched-Chain MeSH

The aim of the article is to examine side effects of increased dietary intake of amino acids, which are commonly used as a dietary supplement. In addition to toxicity, mutagenicity and carcinogenicity, attention is focused on renal and gastrointestinal tract functions, ammonia production, and consequences of a competition with other amino acids for a carrier at the cell membranes and enzymes responsible for their degradation. In alphabetic order are examined arginine, beta-alanine, branched-chain amino acids, carnosine, citrulline, creatine, glutamine, histidine, beta -hydroxy- beta -methylbutyrate, leucine, and tryptophan. In the article is shown that enhanced intake of most amino acid supplements may not be risk-free and can cause a number of detrimental side effects. Further research is necessary to elucidate effects of high doses and long-term consumption of amino acid supplements on immune system, brain function, muscle protein balance, synthesis of toxic metabolites, and tumor growth and examine their suitability under certain circumstances. These include elderly, childhood, pregnancy, nursing a baby, and medical condition, such as diabetes and liver disease. Studies are also needed to examine adaptive response to a long-term intake of any substance and consequences of discontinuation of supplementation.

• MeSH
• Amino Acids adverse effects   metabolism   MeSH
• Arginine pharmacology   MeSH
• Child MeSH
• Glutamine * metabolism   pharmacology   MeSH
• Histidine metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Humans MeSH
• Dietary Supplements * adverse effects   MeSH
• Aged MeSH
• Pregnancy MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Aged MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amino Acids MeSH
• Arginine MeSH
• Glutamine * MeSH
• Histidine MeSH

The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to alpha-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (alpha-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

• MeSH
• Diabetes Mellitus metabolism   MeSH
• Isoleucine metabolism   MeSH
• Liver Cirrhosis metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Leucine metabolism   MeSH
• Humans MeSH
• Metabolic Diseases metabolism   MeSH
• Valine metabolism   MeSH
• Amino Acids, Branched-Chain metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Isoleucine MeSH
• Leucine MeSH
• Valine MeSH
• Amino Acids, Branched-Chain MeSH

Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.

• Keywords
• ATP depletion, branched-chain amino acids, ketoglutarate, muscles, serine,
• MeSH
• Amino Acids administration & dosage   pharmacology   MeSH
• Diabetes Mellitus, Type 1 chemically induced   drug therapy   metabolism   MeSH
• Injections, Intraperitoneal MeSH
• Injections, Subcutaneous MeSH
• Liver drug effects   metabolism   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Streptozocin administration & dosage   MeSH
• Valerates administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amino Acids MeSH
• beta-hydroxyisovaleric acid MeSH Browser
• Streptozocin MeSH
• Valerates MeSH