Early pregnancy urinary biomarkers of fatty acid and carbohydrate metabolism in pregnancies complicated by gestational diabetes.

AIMS: Alterations in organic acid biomarkers from fatty acid and carbohydrate metabolism have been documented in type 2 diabetes patients. However, their association with gestational diabetes mellitus (GDM) is largely unknown. METHODS: Participants were 25 GDM cases and 25 non-GDM controls. Biomarkers of fatty acid (adipate, suberate and ethylmalonate) and carbohydrate (pyruvate, l-lactate and ß-hydroxybutyrate) metabolism were measured in maternal urine samples collected in early pregnancy (17 weeks) using liquid chromatography-mass spectrometry methods. Logistic regression were used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: GDM cases and controls differed in median urinary concentrations of ethylmalonate (3.0 vs. 2.3µg/mg creatinine), pyruvate (7.4 vs. 2.1µg/mg creatinine), and adipate (4.6 vs. 7.3µg/mg creatinine) (all p-values <0.05). Women in the highest tertile for ethylmalonate or pyruvate concentrations had 11.4-fold (95%CI 1.10-117.48) and 3.27-fold (95%CI 0.72-14.79) increased risk of GDM compared with women in the lowest tertile for ethylmalonate and pyruvate concentrations, respectively. Women in the highest tertile for adipate concentrations, compared with women in the lowest tertile, had an 86% reduction in GDM risk (95%CI 0.02-0.97). CONCLUSIONS: These preliminary findings underscore the importance of altered fatty acid and carbohydrate metabolism in the pathogenesis of GDM.

Effects of birth asphyxia on urinary organic acid excretion.

Using capillary gas chromatography-mass spectrometry, the effects of birth asphyxia on the urinary organic acid profile of term babies was investigated. Random urine samples were collected on days 1 and 8 from 19 babies with fetal distress, 19 with moderate birth asphyxia and 12 with severe asphyxia causing encephalopathy. Controls were 27 well neonates. Statistically significant abnormalities were found only for the severely asphyxiated group: increased concentrations of lactic, pyruvic, 3-hydroxybutyric, 4-hydroxyphenyllactic and 4-hydroxy-3-methoxymandelic acids, and excretion of four abnormal metabolites, 2-hydroxybutyric, 2-oxoisocaproic, 2-hydroxyisovaleric and 2-oxo-3-methylvaleric acids. Six other babies had increased lactic acid excretion, associated in four with transient 'jitterness' or hypotonia. Organic acid studies may help to grade the severity of perinatal asphyxia in the outcome or intervention studies.

Pyruvate metabolism in Lafora disease.

Lafora disease is an autosomal recessive and progressive degenerative disorder of the central nervous system (CNS). The pathogenic mechanism has been presumed to be an inborn error of carbohydrate metabolism, although this has never been proved. In a case of proven Lafora disease, pyruvate metabolism, which has a central position in carbohydrate metabolism, was studied in body fluids under various conditions and in brain biopsy material. No abnormalities in this metabolic pathway were found. This finding plus earlier reports in the literature exclude a defect in glycolysis; thus, a disturbance of carbohydrate metabolism as the pathogenic mechanism of Lafora disease is unlikely.

Nephrotoxicity of mercapturic acids of three structurally related 2,2-difluoroethylenes in the rat. Indications for different bioactivation mechanisms.

The biotransformation and the hepato- and nephrotoxicity of the mercapturic acids (N-acetyl-1-cysteine S-conjugates) of three structurally related 2,2-difluoroethylenes were investigated in vivo in the rat. All mercapturic acids appeared to cause nephrotoxicity, without any measureable effect on the liver. The mercapturic acid of tetrafluoroethylene (TFE-NAC) appeared to be the most potent nephrotoxin, causing toxicity upon an i.p. dose of 50 mumol/kg. The mercapturic acids of 1,1-dichloro-2,2-difluoroethylene (DCDFE-NAC) and 1,1-dibromo-2,2-difluoroethylene (DBDFE-NAC) were nephrotoxic at slightly higher doses, i.e. at 75 and 100 mumol/kg, respectively. In the urine of TFE-NAC-treated rats significant amounts of difluoroacetic acid (DFAA) could be detected. With increasing doses, the relative amount of DFAA in urine increased progressively (5-18% of dose). In urine of rats treated with DCDFE-NAC and DBDFE-NAC, however, the corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected. Formation of DFAA and pyruvate could also be observed during in vitro metabolism of the cysteine conjugate of tetrafluoroethylene (TFE-CYS) by rat renal cytosol. Inhibition by aminooxyacetic acid (AOA) pointed to a beta-lyase dependency for the DFAA-formation. Next to DFAA and pyruvate, also formation of hydrogen sulfide and thiosulfate could be detected. These results suggest that TFE-CYS is bioactivated to a significant extent to difluorothionacyl fluoride, which most likely is subsequently hydrolysed to difluorothio(no)acetic acid and difluoroacetic acid. According to formation of pyruvate, the cysteine conjugates derived from DCDFE-NAC and DBDFE-NAC also were efficiently metabolized by rat renal beta-lyase. However, the formation of corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected in vitro at all. Only very small amounts of hydrogen sulfide and thiosulfate were detected. These results suggest that bioactivation of the latter two conjugates to a dichloro- or dibromothionoacyl fluoride represents only a minor route. Because of better leaving group abilities of chloride and bromide compared to fluoride, rearrangement of the initially formed ethanethiol to a thiirane might be favoured. Based on the present in vivo and in vitro data, it is concluded that the nephrotoxicity of the structurally related mercapturic acids of 2,2-difluoroethylenes is dependent on halogen substitution and presumably the result of at least two different mechanisms of bioactivation.

Changes in albumin levels in blood and urine of Microtus montanus chronically infected with Trypanosoma brucei gambiense.

Serum albumin and glucose concentrations and urinary excretion of alpha-keto acids and proteins were determined in samples obtained throughout a chronic Trypanosoma brucei gambiense infection in Microtus montanus. An increase in urinary excretion of alpha-keto acids and proteins during the terminal stage of disease was accompanied by a decrease in serum glucose concentration. This terminal hypoglycemia reflected a depletion of liver glycogen in most animals. In contrast (and the major focus of this study) serum albumin concentration was decreased by the second week of infection and in the final sample obtained was less than 50% of that measured in preinfection samples. Female animals survived approximately 1 wk longer than males and were less susceptible during the acute phase of disease. This relative resistance was most likely due to the fact that female animals were relatively more efficient in limiting parasitemia during the first week of infection. The similarity between humans and voles in terms of protein and alpha-keto acid excretion and changes in serum concentrations of glucose and albumin during trypanosome infection further validate the use of Microtus as an experimental model for trypanosomiasis in humans.

Measurement of urinary lactic, 3-hydroxybutyric, pyruvic and acetoacetic acids in a single analysis using selected ion monitoring and stable isotope labelling techniques.

Sodium borodeuteride treatment of urine expected to have large concentrations of pyruvic and acetoacetic acids produces lactic and 3-hydroxybutyric acids labelled with deuterium. Mass fragmentographic techniques applied to the trimethylsilyated extract of the urine spiked with more extensively labelled analogues as internal standards permit the reliable determination of lactic, pyruvic, 3-hydroxybutyric and acetoacetic acids in a single analysis.

Renal effects of dichloroacetate in vivo.

We have investigated the effect of dichloroacetate (DCA) on the urinary excretion of lactate and pyruvate in a patient with congenital lactic acidosis and in healthy human controls. DCA administered orally in doses of 50 mg/kg and 30 mg/kg decreased plasma lactate and pyruvate of both the patient and the controls, while the urinary excretion of lactate and pyruvate was increased. However, these urinary increments were too small to contribute to the decrease of plasma lactate and pyruvate.

Acute encephalopathy with hyperammonemia and dicarboxylic aciduria during calcium hopantenate therapy: a patient report.

We report a 3-year-old Japanese girl who developed acute encephalopathy while receiving calcium hopantenate (Calcium D-(+)-4-(2, 4-dihydroxy-3,3-dimethylbutyramido) butyrate hemihydrate). She had hyperammonemia, elevated CPK, lactic acidemia and pyruvic acidemia, however, she did not show elevated SGOT or SGPT. Calcium hopantenate has been used in Japan for the treatment of mental retardation with behavior abnormalities. Recently there have been three reports on the occurrence of Reye-like syndrome in patients receiving this drug. Clinical signs and laboratory data of these patients are similar to those of Reye syndrome. Calcium hopantenate causes pantothenic acid deficiency in the young rat, which may reduce the content of coenzyme A. If this drug decreases coenzyme A biosynthesis, it may reduce beta-oxidation of fatty acids and levels of dicarboxylic acids would increase because of increasing omega-oxidation. We suspect that there is a possible relationship between the occurrence of acute encephalopathy and calcium hopantenate therapy.

Multiple alpha-keto aciduria in Microtus montanus chronically infected with Trypanosoma brucei gambiense.

Microtus montanus chronically infected with a monomorphic strain of Trypanosoma brucei gambiense excreted in urine greatly elevated quantities of not only the aromatic alpha-keto acids, phenylpyruvic and 4-hydroxyphenylpyruvic acids, but also two aliphatic alpha-keto acids, pyruvic and alpha-ketoglutaric acids. Elevated keto acid excretion began approximately midway through infection and quantities remained elevated until death. Daily keto acid excretion did not correlate with daily parasitemia. Thus, a large metabolic disturbance exists in laboratory animals infected with African trypanosomes. The multiple alpha-keto aciduria potentially contributes to the pathogenesis of chronic African trypanosomiasis.

[Changes in carbohydrate metabolism indices in patients with hemorrhagic fever associated with renal syndrome]. / Izmeneniia pokazatelei uglevodnogo obmena u bol'nykh gemorragicheskoi likhoradkoi s pochechnym sindromom.

Metabolism of carbohydrates was impaired in 80 patients with hemorrhagic fever accompanied by renal syndrome, in which activation of glycolysis occurred due to a decrease in aerobic oxidation and development of metabolic acidosis. Lactacidemia and activation of LDH in blood serum were considered as criteria of the degree of hypoxia and of the severity of the disease. Estimation of lactate and pyruvate in blood serum and urine might be used for diagnosis and for evaluation of the treatment efficiency.

Analysis of the oxocarboxylic acid fraction in serum and urine as O-methyloximes by thermionic specific detection.

After O-methyloximation of the carbonyl functions, the organic acids in serum and urine are extracted by anion-exchange chromatography, transformed into the methyl esters and pre-fractionated by thin-layer chromatography. In one of the four fractions and on the basis of the nitrogen in the O-methyloxime esters, the profiles of the oxocarboxylic acids are analyzed by gas chromatography with thermionic specific detection. The method has good specificity for the oxocarboxylic acids and is suitable for comparative studies. During diabetic or fasting ketoacidosis the serum concentrations of 3-oxobutyric acid and of the amino acid metabolites 2-oxobutyric, 2-oxoisovaleric and especially 2-oxo-3-methylvaleric and 2-oxoisocaproic acid are increased. In urine mainly 3-oxobutyric acid and only small amounts of the 2-oxocarboxylic acids are excreted.

[Thiamine allowance of animals receiving rye and wheat grains grown with the use of herbicides from the phenoxy acid chlorine derivative group]. / Obespechennost' tiaminom zhivotnykh, poluchavshikh zerno rzhi i pshenitsy, vyrashchennykh s primeneniem gerbitsidov gruppy khlorproizvodnykh fenoksikislot.

Investigations carried out for several years have shown that the treatment of rye and wheat crops with an amine salt of 2,4-dichlorophenoxyacetic acid and dialene produces sometimes a decrease in the grain thiamine content of these cereals. Feeding of rye and wheat grains grown with the use of the amine salt of 2,4-dichlorophenoxyacetic acid to growing ratlings has demonstrated that the thiamine content in the liver of ratlings is directly proportional to thiamine supply to their body with food.

Organic acids in urine from preterm infants.

The organic acid excretion was studied in urine samples from 26 preterm infants on the 1st and 5th days of life and the results compared to those obtained in 5 samples from full-term neonates. Gas-chromatography-mass spectrometry with a computer system was the method used in this work. The acids tabulated were those more closely related to lactic acidosis and the Krebs cycle. Great variations were found in the excretion of these acids in preterm infants in contrast to the very homogeneous pattern obtained in full-term neonates.