Gestational Diabetes Abstracts 1

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Biochemistry of tryptophan in health and disease.
            (Bender, 1983) Download

Improvement of oral glucose tolerance in gestational diabetes by pyridoxine.
            (Bennink and Schreurs, 1975) Download
Fourteen pregnant women were shown by the oral glucose tolerance test to have gestational diabetes. In 13 an increased urinary xanthurenic-acid excretion after an oral load of L-tryptophan indicated a relative pyridoxine deficiency. All patients were treated with vitamin B6 (pyridoxine) 100 mg/day for 14 days by mouth, after which the pyridoxine deficiency disappeared and the oral glucose tolerance improved considerably. Only two patients then had sufficiently impaired glucose tolerance to justify the diagnosis of gestational diabetes; Our results substantiated our hypothesis that increased xanthurenic-acid synthesis during pregnancy may cause gestational diabetes. Treatment with vitamin B6 makes the production of xanthurenic-acid normal by restoring tryptophan metabolism and improves the oral glucose tolerance in patients with gestational diabetes.

Letter: Pyridoxine and oestrogen-induced glucose intolerance.
            (Cornish and Tesoriero, 1975) Download

Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women.
            (da Silva et al., 2013) Download
Suboptimal vitamin B-6 status, as reflected by low plasma pyridoxal 5'-phosphate (PLP) concentration, is associated with increased risk of vascular disease. PLP plays many roles, including in one-carbon metabolism for the acquisition and transfer of carbon units and in the transsulfuration pathway. PLP also serves as a coenzyme in the catabolism of tryptophan. We hypothesize that the pattern of these metabolites can provide information reflecting the functional impact of marginal vitamin B-6 deficiency. We report here the concentration of major constituents of one-carbon metabolic processes and the tryptophan catabolic pathway in plasma from 23 healthy men and women before and after a 28-d controlled dietary vitamin B-6 restriction (<0.35 mg/d). liquid chromatography-tandem mass spectrometry analysis of the compounds relevant to one-carbon metabolism showed that vitamin B-6 restriction yielded increased cystathionine (53% pre- and 76% postprandial; P < 0.0001) and serine (12% preprandial; P < 0.05), and lower creatine (40% pre- and postprandial; P < 0.0001), creatinine (9% postprandial; P < 0.05), and dimethylglycine (16% postprandial; P < 0.05) relative to the vitamin B-6-adequate state. In the tryptophan pathway, vitamin B-6 restriction yielded lower kynurenic acid (22% pre- and 20% postprandial; P < 0.01) and higher 3-hydroxykynurenine (39% pre- and 34% postprandial; P < 0.01). Multivariate ANOVA analysis showed a significant global effect of vitamin B-6 restriction and multilevel partial least squares-discriminant analysis supported this conclusion. Thus, plasma concentrations of creatine, cystathionine, kynurenic acid, and 3-hydroxykynurenine jointly reveal effects of vitamin B-6 restriction on the profiles of one-carbon and tryptophan metabolites and serve as biomarkers of functional effects of marginal vitamin B-6 deficiency.

Pyridoxine treatment of chemical diabetes in pregnancy.
            (Gillmer and Mazibuko, 1979) Download
Thirteen women with chemical diabetes diagnosed in late pregnancy were found to excrete excessive amounts of urinary xanthurenic acid after a tryptophan load, indicative of a relative pyridoxine (vitamin B6) deficiency. Treatment with 100 mg pyridoxine daily for 14 to 23 days restored the urinary xanthurenic acid excretion to normal in all patients. Improvement of glucose tolerance was observed in only two of the patients studied, deterioration in six, and no significant change in the remaining five. The insulin response to glucose was unaltered during pyridoxine therapy.

The physiological significance of the xanthurenic acid-insulin comples.
            (Kotake et al., 1975) Download
The xanthurenic acid-insulin complex was found to have similar immunological properties to native Zn-insulin. This complex showed less hormonal activity on glucose metabolism in adipose tissue than native An-insulin, but its activity was increased by addition of Zn2+ ions.


 

Vitamin B6 requirements of women using oral contraceptives.
            (Leklem et al., 1975) Download
Fifteen women who used combined estrogen-progestogen oral contraceptives and nine control women were given a vitamin B6-deficient diet for 4 weeks and the same diet supplemented with 0.8, 2.0, or 20.0 mg of pyridoxine hydrochloride for an additional 4 weeks. At weekly intervals a variety of indices of vitamin B6 nutrition were measured to determine rates of depletion and repletion. The tryptophan load test (2.0 g) was significantly different in the contraceptive users. However, other indices, including urinary cystathionine (3.0 g L-methionine load), urinary 4-pyridoxic acid, plasma phosphate, and erythrocyte alanine and aspartate aminotransferases, were not significantly different. Since altered tryptophan metabolism persisted in contraceptive users even when other indices of vitamin B6 nutrition were normal, we suggest that the use of oral contraceptives specifically affects tryptophan metabolism by some means other than through a vitamin B6 deficiency.

 

Maternal tryptophan and kynurenine pathway metabolites and risk of preeclampsia.
            (Nilsen et al., 2012) Download
OBJECTIVE: To estimate the association of maternal plasma concentrations of tryptophan and six kynurenine pathway metabolites with the risk of preeclampsia. METHODS: The study was based on a subsample of 2,936 pregnant women who delivered singleton neonates in the Norwegian Mother and Child Cohort Study in 2002-2003. Maternal blood plasma was obtained at approximately gestational week 18 and was measured for tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid. RESULTS: Of the 2,936 pregnant women included in this study, 116 (4.0%, 95% confidence interval [CI] 3.2-4.7) had preeclampsia subsequently diagnosed. The prevalence of preeclampsia was significantly higher among women with plasma kynurenic acid concentrations greater than the 95th percentile than among those with concentrations in the 25th-75th percentile (11.0% compared with 3.3%, P<.001; adjusted odds ratio 3.6, 95% CI 1.9-6.8). This association was significantly stronger in women with prepregnancy body mass index of 25 or more (P for interaction=.03; 20.4% compared with 4.2%; P<.001). No statistically significant associations of preeclampsia with other tryptophan metabolites were found. CONCLUSION: Elevated maternal plasma kynurenic acid concentrations in early pregnancy are associated with a substantial increased risk of preeclampsia in obese women. LEVEL OF EVIDENCE: II.

Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways.
            (Oxenkrug, 2013) Download
Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)-kynurenine (KYN) and KYN-nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP-KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN-NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a cofactor. Deficiency of P5P diverts KYN-NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced upregulation of TRP-KYN metabolism in combination with P5P deficiency-induced diversion of KYN-NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP-KYN and KYN-NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B6, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.

Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism.
            (Rose et al., 1975) Download
Oral glucose tolerance, urinary xanthurenic acid excretion, and plasma pyridoxal phosphate concentrations were determined in nine women taking oral contraceptives and in four controls. The tests were repeated after 4 weeks ingestion of a vitamin B6-deficient diet, and again after pyridoxine supplementation. Vitamin B6 deficiency, as judged by an increased xanthurenic acid excretion and reduced plasma pyridoxal phosphate, was associated with a deterioration in the glucose tolerance of the contraceptive steroid-treated group despite normal or elevated plasma insulin levels. This abnormality was reversed by pyridoxine. There was no change in the glucose tolerance of the vitamin B6-deficient controls. The observed pyridoxine-responsive alteration in carbohydrate metabolism may involve the complexing of insulin with xanthurenic acid with a consequent loss of biological activity. In addition, oral contraceptives may enhance gluconeogensis.

Pyridoxal 5'-phosphate (PLP) deficiency might contribute to the onset of type I diabetes.
            (Rubi, 2012) Download
The incidence of type I diabetes is rising worldwide, particularly in young children. Type I diabetes is considered a multifactorial disease with genetic predisposition and environmental factors participating. Currently, despite years of research, there is no consensus regarding the factors that initiate the autoimmune response. Type I diabetes is preceded by autoimmunity to islet antigens, among them the protein glutamic acid decarboxylase, GAD-65. Pyridoxal 5'-phosphate (PLP) is formed from vitamin B6 by the action of pyridoxal kinase. Interaction of GAD65 with PLP is necessary for GAD65-mediated synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). PLP is also a required cofactor for dopamine synthesis by L-aromatic decarboxylase (L-AADC). Both GAD65 and L-AADC are expressed in pancreatic islets. Here it is proposed that lack of the vitamin B6 derivative pyridoxal 5'-phosphate might contribute to the appearance of pancreatic islet autoimmunity and type I diabetes onset.

Vitamin B6 treatment of gestational diabetes mellitus: studies of blood glucose and plasma insulin.
            (Spellacy et al., 1977) Download
Thirteen women with late pregnancy gestational diabetes mellitus were tested with an intravenous glucose tolerance test and both blood glucose and plasma insulin levels were measured. Each woman was then treated with 100 mg. of vitamin B6 per day for 2 weeks and the intravenous glucose tolerance test was then repeated. There was a statistically significant improvement in the glucose tolerance curve after the vitamin B6 treatment, with a lowering of blood glucose levels at all points on the curve except for the 5 minute value. This glucose effect occurred despite an unchanged or lowered plasma insulin level. These results suggest that a relative deficiency in vitamin B6 is associated with some cases of gestational diabetes mellitus and that the replacement of this vitamin improves the metabolic state. The low vitamin B6 levels appear to alter metabolic pathways which result in a lowering of the biologic activity of endogenous insulin.


 

Effect of natural oestrogens on tryptophan metabolism: evidence for interference of oestrogens with kynureninase.
            (Wolf et al., 1980) Download
Urinary excretion of metabolites of the tryptophan-nicotinic acid ribonucleotide pathway, urinary excretion of 4-pyridoxic acid and blood concentrations of oestradiol and pyridoxal phosphate were studied in groups of post-menopausal women before or during treatment with natural oestrogens, i.e. oestradiol and oestriol, before and after loading doses of 9800 mumol L-tryptophan or 700 mumol L-kynurenine sulphate. Natural oestrogens induced abnormalities of tryptophan metabolism similar to those induced by synthetic oestrogens, and there was a dose related increase in urinary excretion of metabolites of the tryptophan-nicotinic acid ribonucleotide pathway before the kynureninase step. The increase in urinary excretion of these metabolites also after a loading dose of 700 mumol L-kynurenine indicates an inhibitory effect of oestrogens on kynureninase in vivo. Evidence is presented that this inhibition is an effect mediated through decreased availability of vitamin B6, the coenzyme of kynureninase, although the possibility of a direct effect of oestrogens on kynureninase can not be excluded.

Association of maternal diabetes with autism in offspring.
            (Xiang et al., 2015) Download
IMPORTANCE: Information about the association of maternal diabetes and autism spectrum disorders (ASDs) in offspring is limited, with no report on the importance of timing of exposure during gestation. OBJECTIVE: To assess ASD risk associated with intrauterine exposure to preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by gestational age at GDM diagnosis. DESIGN, SETTING, AND PATIENTS: Retrospective longitudinal cohort study including 322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012. Relative risks of ASD were estimated by hazard ratios (HRs) using Cox regression models adjusted for birth year. EXPOSURES: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26 weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579), or no diabetes (n = 290 792) during the index pregnancy. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of ASD in offspring. RESULTS: During follow-up, 3388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at </=26 weeks, 180 exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68 512) did not affect the results. CONCLUSIONS AND RELEVANCE: In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.

The interaction of pyridoxal phosphate with alcohol dehydrogenase.
            (Yamada et al., 1967) Download

 


References

Bender, DA (1983), ‘Biochemistry of tryptophan in health and disease.’, Mol Aspects Med, 6 (2), 101-97. PubMedID: 6371429
Bennink, H. J. and W. H. Schreurs (1975), ‘Improvement of oral glucose tolerance in gestational diabetes by pyridoxine’, Br Med J, 3 (5974), 13-15. PubMedID: 1131652
Cornish, EJ and W Tesoriero (1975), ‘Letter: Pyridoxine and oestrogen-induced glucose intolerance.’, Br Med J, 3 (5984), 649-50. PubMedID: 1164654
da Silva, VR, et al. (2013), ‘Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women.’, J Nutr, 143 (11), 1719-27. PubMedID: 23966327
Gillmer, MD and D Mazibuko (1979), ‘Pyridoxine treatment of chemical diabetes in pregnancy.’, Am J Obstet Gynecol, 133 (5), 499-502. PubMedID: 443288
Kotake, Y, et al. (1975), ‘The physiological significance of the xanthurenic acid-insulin comples.’, J Biochem, 77 (3), 685-87. PubMedID: 1150636
Leklem, JE, et al. (1975), ‘Vitamin B6 requirements of women using oral contraceptives.’, Am J Clin Nutr, 28 (5), 535-41. PubMedID: 1130311
Nilsen, RM, et al. (2012), ‘Maternal tryptophan and kynurenine pathway metabolites and risk of preeclampsia.’, Obstet Gynecol, 119 (6), 1243-50. PubMedID: 22617590
Oxenkrug, G (2013), ‘Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways.’, Mol Neurobiol, 48 (2), 294-301. PubMedID: 23813101
Rose, DP, et al. (1975), ‘Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism.’, Am J Clin Nutr, 28 (8), 872-78. PubMedID: 1146747
Rubi, B (2012), ‘Pyridoxal 5’-phosphate (PLP) deficiency might contribute to the onset of type I diabetes.’, Med Hypotheses, 78 (1), 179-82. PubMedID: 22088923
Spellacy, W. N., W. C. Buhi, and S. A. Birk (1977), ‘Vitamin B6 treatment of gestational diabetes mellitus: studies of blood glucose and plasma insulin’, Am J Obstet Gynecol, 127 (6), 599-602. PubMedID: 842585
Wolf, H, et al. (1980), ‘Effect of natural oestrogens on tryptophan metabolism: evidence for interference of oestrogens with kynureninase.’, Scand J Clin Lab Invest, 40 (1), 15-22. PubMedID: 7367807
Xiang, AH, et al. (2015), ‘Association of maternal diabetes with autism in offspring.’, JAMA, 313 (14), 1425-34. PubMedID: 25871668
Yamada, K, S Sawaki, and H Hattori (1967), ‘The interaction of pyridoxal phosphate with alcohol dehydrogenase.’, J Vitaminol (Kyoto), 13 (4), 309-12. PubMedID: 5591023