Glucose and Alanine Metabolism in Children with Maple Syrup Urine Disease (original) (raw)
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Journal of Inherited Metabolic Disease, 2000
Neurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of this disorder are poorly understood. We determined the concentrations of all amino acids in plasma of patients with MSUD during crises (with severe CNS symptoms) and after recovery in the hope of detecting possible alterations of these levels during metabolic decompensation. Blood samples obtained from 11 children with MSUD aged 1 month to 7 years and from 10 age-matched controls (5 months to 6 years) with no evidence of metabolic disease were examined for their amino acid content by high-performance liquid chromatography. We observed that leucine, isoleucine and valine concentrations were respectively 30, 9 and 3 times higher than normal values, whereas the concentrations of the large neutral amino acids (LNAA) phenylalanine, tyrosine, tryptophan and methionine were significantly lower during metabolic decompensation as compared to the controls. In addition, concentrations of leucine, but not of valine or isoleucine, were inversely related to the LNAA concentrations in plasma. The concentrations of these amino acids in plasma returned to normal values when patients were clinically well. CSF amino acid concentrations also showed decreased amounts of LNAA and increased concentrations of branched-chain amino acids. It is possible that the decrease in plasma concentrations of LNAA may lead to a deficit of these essential amino acids in the brain as well as of their products such as proteins and neurotransmitters, a fact that might be related to the neurological dysfunction of MSUD.
Metabolism, 1982
We have explored interrelationships between the dynamic aspects of whole body glucose and alanine and glycine metabolism in adult humans. Using a primed, continuous intravenous infusion of [1-"C] leucine or lysine given simultaneously with ['H3] or ["Nlalanine or ["N]glycine. respectively, whole body alanine and glycine fluxes and their rates of de novo synthesis were determined in three experiments with healthy young men. Subjects were studied in the post-absorptive state and during a 150 min period of an intravenous infusion with unlabeled glucose, at a rate of 4 mg.kg-'min-'. In one experiment, insulin was given together with the glucose infusion to maintain normoglycemia. In the other two studies, subjects received glucose alone. For the post-absorptive state, alanine flux (mean lr SEMI was 381 * 28 and 317 T 18 fimole.kg-'hr-'. 'n two separate experiments and glycine flux was 240 + 22 wmole.kg-'hr-'. De novo synthesis of alanine and glycine accounted for 75%-81% and 81% of flux, respectively. Infusion with glucose alone raised plasma glucose to a mean level of 152 mg/dl and increased alanine flux, due to a rise in alanine synthesis of 98 Mmole.kg-'hr-' (p < 0.01). Glycine flux and synthesis rate were unaffected by the glucose infusion. When insulin was given with glucose to maintain normoglycemia, the rate of alanine synthesis was unchanged. Because glucose uptake rate. measured with [8,8-*Hz] glucose was the same whether glucose was infused along or with exogenous insulin, these results support the view that the circulating plasma glucose level itself may affect alanine synthesis and that the hyperglycemic state is an important factor in regulating interorgan nitrogen transfer, via alanine. in various pathophysiologic states.
Molecular Genetics and Metabolism Reports, 2016
Background: Maple syrup urine disease (MSUD) is the most common inborn error of metabolism in the country. The cause of the neuropathology is still not well established although accumulation of branched chain amino acids (BCAA) and alteration in large neutral amino acids (LNAA) as well as energy deprivation are suggested. It is therefore the aim of this study to determine the plasma amino acid and urine organic acid profiles of patients with MSUD and correlate the findings with their neurologic features. Methodology: Twenty six Filipino patients with MSUD were studied in terms of their plasma amino acid and urine organic acid profiles. Their results were compared with 26 age and sex matched controls. The neurologic features were correlated with the results of the plasma amino acids and urine organic acids. Results: Majority of the patients with MSUD had developmental delay/intellectual disability (88%), speech delay (69%), and seizures (65%). Their amino acid profiles revealed low glutamine and alanine with high levels of leucine, isoleucine, phenylalanine, threonine and alloisoleucine compared to controls (p b 0.05). The urine organic acids showed significantly elevated excretion of the branched chain ketoacids and succinate (p b 0.05). However there were no biochemical markers that correlated significantly with the neurologic features. Conclusion: The findings suggest that there could still be altered LNAA metabolism among patients with MSUD when the BCAAs are elevated. Although the biochemical findings were not significantly correlated with the neurologic features, the study showed that prevention and avoidance of neurologic disturbances may still rely primarily on early diagnosis and prompt institution of treatment, along with strict compliance with the dietary regimen and maintenance of good metabolic control over time.
Amino Acid Plasma Concentrations and Urinary Excretion in Young Diabetics
InTech eBooks, 2018
The aim of this study is to analyze amino acid plasma profile in a group of young diabetics and to evaluate its application as markers of metabolic control of the disease, as well as to analyze the urinary excretion of amino acids in these patients. A clinical assessment and metabolic study (amino acid serum concentrations and urinary excretion of amino acids) was accomplished in a group of 49 children diagnosed with diabetes, and a group of 48 healthy children (control group). The plasma levels of total amino acids as well as branchedchain, glucogenic and ketogenic amino acids were significantly higher (p < 0.05) in the diabetic group with respect to the control group. Total as well as branched-chain, glucogenic and ketogenic amino acids urinary levels were significantly lower (p < 0.05) in the diabetic group compared to the control group. The study of the amino acid plasma in the young diabetic reflect disturbances in protein/amino acid metabolism and, consequently, in metabolic control of the disease. The study of amino acid urinary excretion might have interest not only in the context of diabetic nephropathy, but also in the revealing of partial aspects of amino acid metabolism and, probably, in the metabolic control of the disease.
Journal of Clinical Investigation, 1980
study the effects of hyperglycemia on the metabolism of alanine and lactate independent of changes in plasma insulin and glucagon, glucose was infused into five 36-h-fasted dogs along with somatostatin and constant replacement amounts ofboth insulin and glucagon. Hepatic uptakes of alanine and lactate were calculated using the arteriovenious difference technique. [14C]Alanine was infused to measure the conversion of alanine and lactate into glucose. Hyperglycemia (M115 mg/dl) of 2 h duration caused the plasma alanine level to increase by over 50%. This change was caused by an increase in the inflow of alanine into plasma since the net hepatic uptake of the amino acid did not change. Taken together, the above findings indicate that glucose per se can significantly impair the fractional extraction of alanine by the liver. Hepatic extraction oflactate was also affected by hyperglycemia and had fallen to zero within 90 min ofstarting the glucose infusion. This fall was associated with a doubling of arterial lactate level. Conversion of [14C]alanine and ['4C]lactate into [14C]glucose was suppressed by 60±11 % after 2 h of hyperglycemia, and because this fall could not be entirely accounted for by decreased lactate extraction an inhibitory effect of glucose on gluconeogenesis within the liver is suggested. These studies indicate that the plasma glucose level per se can be an important determinant of the level of alanine and lactate in plasma as well as the rate at which they are converted to glucose.
Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders
Human molecular genetics, 2014
Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.
Neurochemical Research, 2008
Neurological dysfunction is a common finding in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of brain damage in this disorder are poorly known. In the present study, we investigated the effect of the in vitro effect of the branched chain a-keto acids (BCKA) accumulating in MSUD on some parameters of energy metabolism in cerebral cortex of rats. [ 14 CO 2 ] production from [ 14 C] acetate, glucose uptake and lactate release from glucose were evaluated by incubating cortical prisms from 30-day-old rats in Krebs -Ringer bicarbonate buffer, pH 7.4, in the absence (controls) or presence of 1 -5 mM of a-ketoisocaproic acid (KIC), a-keto-h-methylvaleric acid (KMV) or a-ketoisovaleric acid (KIV). All keto acids significantly reduced 14 CO 2 production by around 40%, in contrast to lactate release and glucose utilization, which were significantly increased by the metabolites by around 42% in cortical prisms. Furthermore, the activity of the respiratory chain complex I -III was significantly inhibited by 60%, whereas the other activities of the electron transport chain, namely complexes II, II -III, III and IV, as well as succinate dehydrogenase were not affected by the keto acids.