Evaluation of folliculogenesis and oxidative stress parameters in type 1 diabetes mellitus women with different glycemic profiles.

BACKGROUND: Despite enormous advances in diabetes treatment, women with type 1 diabetes mellitus (DM) still experience delayed menarche, menstrual irregularities, fewer pregnancies, and a higher rate of stillbirths compared to women without the disease. Due to the fact that type 1 DM occurs at a young age, the preservation of reproductive health is one of the most important goals of treatment. AIMS: The aim of this study was to evaluate the relationship between different glycemic profiles and changes in the pro-oxidant-antioxidant balance and ovarian follicular apparatus in reproductive-age patients with type 1 DM. METHODS: We examined 50 reproductive-age (19-38 years) women with type 1 DM with a disease duration of at least ten years. Carbohydrate metabolism was assessed with the continuous glucose monitoring (CGM) system and glycated hemoglobin (HbA1c) concentration measurement. CGM was performed using the FreeStyle Libre flash glucose monitoring system (Abbott Diabetes Care, Witney, UK). In each patient, malondialdehyde level, catalase activity and 3-nitrotyrosine level in the blood serum were determined. To assess the ovarian function, we measured the ovarian volume, the antral follicle count, and the serum levels of anti-Müllerian hormone and follicle-stimulating hormone. All patients were divided into four groups (glucotypes) based on the CGM results. Group 1 included type 1 DM patients with satisfactory compensation of carbohydrate metabolism; group 2 consisted of patients with frequent hypoglycemic conditions and pathological glucose variability; group 3 included individuals with prolonged hyperglycemic conditions and maximum HbA1c levels; and group 4 comprised patients with the glycemic profile characterized by all the presented types of dysglycemia (intermittent glycemia). RESULTS: We revealed a negative correlation between serum catalase activity and time of hypoglycemic conditions in patients with type 1 DM based on the CGM results (rs = -0.47, p < 0.01). In group 4 (intermittent glycemia), patients demonstrated the lowest serum catalase activity and increased serum 3-nitrotyrosine level, while in group 3, women with chronic hyperglycemia (HbA1c 8.4 [8.1; 9.9]%; 68 [65; 85] mmol/mol) had a moderate change in antioxidant defense and oxidative stress parameters. Correlation analysis of ovarian volume, the antral follicle count, and the serum anti-Müllerian hormone level in type 1 DM women with different glycemic profiles established a negative relationship (rs = -0.82, p < 0.05) between the antral follicle count and glucose variability in group 1, a positive relationship (rs = 0.68, p < 0.05) between ovarian volume and glucose variability in group 2, and a positive relationship (rs = 0.88, p < 0.05) between ovarian volume and time of hypoglycemic conditions, which, according to the CGM results, amounted to a critical value of 57.5 [40.0; 82.0]%. CONCLUSIONS: The data obtained indicate the relationship between the ovarian volume, serum anti-Müllerian hormone level, the antral follicle count and oxidative stress parameters not only in patients with hyperglycemia, but also in those with hypoglycemic conditions, as well as with pathological glucose variability.

Maternal Hyperhomocysteinemia Induces Neuroinflammation and Neuronal Death in the Rat Offspring Cortex.

Maternal hyperhomocysteinemia is one of the common complications of pregnancy that causes offspring cognitive deficits during postnatal development. In the present work, we evaluated the effect of prenatal hyperhomocysteinemia on structural and ultrastructural organization, neuronal and glial cell number, apoptosis (caspase-3 content and activity), inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in the offspring brain cortex in early ontogenesis. Wistar female rats received methionine (0.6 g/kg body weight) by oral administration during pregnancy. Histological and biochemical analyses of 5- and 20-day-old pups' cortical tissue were performed. Lysosome accumulation and other neurodegenerative changes in neurons of animals with impaired embryonic development were investigated by electron microscopy. Neuronal staining (anti-NeuN) revealed a reduction in neuronal number, accompanied by increasing of caspase-3 active form protein level and activity. Maternal hyperhomocysteinemia also elevated the number of astroglial and microglial cells and increased expression of interleukin-1ß and p38 MAPK phosphorylation, which indicates the development of neuroinflammatory processes.

Neurotrophins of the Fetal Brain and Placenta in Prenatal Hyperhomocysteinemia.

Prenatal hyperhomocysteinemia (PHHC) in pregnant rats was induced by chronic L-methionine loading, resulting in a significant increase in the L-homocysteine content both in the mothers' blood and blood and brain of fetuses. Significant decrease in the weight of the placenta, fetus, and fetal brain was detected by the morphometric studies on day 20 of pregnancy. PHHC also activated maternal immune system due to the increase in the content of proinflammatory interleukin-1ß in the rat blood and fetal part of the placenta. PHHC elevated the levels of the brain-derived neurotrophic factor (BDNF, 29 kDa) and nerve growth factor (NGF, 31 kDa) precursors in the placenta and the content of the BDNF isoform (29 kDa) in the fetal brain. The content of neuregulin 1 (NRG1) decreased in the placenta and increased in the fetal brain on day 20 of embryonic development. An increase in the caspase-3 activity was detected in the brains of fetuses subjected to PHHC. It was suggested that changes in the processing of neurotrophins induced by PPHC, oxidative stress, and inflammatory processes initiated by it, as well as apoptosis, play an important role in the development of brain disorders in the offspring.

[Catecholamine content in the adrenal gland of rat offspring in the model of prenatal hyperhomocysteinemia].

Catecholamine content has been studied in the adrenal gland of rat females whose pregnant mothers were loaded daily with L-methionine administered per os during all the pregnancy period, on the first day of postnatal life, and in one and two months after birth. The animal model of hyperhomocysteinemia used in the experiment has been shown to result in the catecholamine content decreasing in the adrenal gland of both newly born rat offspring with high serum level of homocysteine and one-month old offspring with their homocysteine level decreased to the normal values. It was found that nitrotyrosine level increased significantly in the blood serum of the offspring aged one and two months. The data obtained may testify to oxidative stress development.