It seems quite likely that the normal process of fetal lung biochemical maturation is delayed by maternal diabetes and that abnormalities in the pulmonary surfactant system are involved. The appearance of PG in amniotic fluid and possibly in fetal lung is impaired or at least delayed. The same is possibly true for DSPC, the main constituent of surfactant, but recent discrepant data call for further clarification of this specific point. Careful determination of the fetal lung phospholipid profile by amniotic fluid analysis helps predict and prevent RDS in IDM, along with a careful control of the maternal diabetic condition. A study of alveolar surfactant at birth, if it could be performed in addition to amniotic fluid analysis, would help to better characterize surfactant deficiency in IDM. On the basis of both in vivo and in vitro experimental approaches, it seems clear that hyperglycemia and fetal reactional hyperinsulinism are both involved in the processes delaying fetal lung maturation. Further advances in the understanding of cellular and molecular mechanisms leading to this delay will be conditional on the availability of animal models reproducing the features of the metabolic and hormonal environment of human fetuses in diabetic pregnancies. The appropriateness of in vivo models needs to be defined by two kinds of criteria: 1) presence of simultaneous hyperglycemia and hyperinsulinemia in the fetus; 2) the presence of delayed fetal lung maturation as judged by morphology and morphometry of epithelial lung cells, by physiological assessment of surfactant, and by the phospholipid composition of the lung (and including lung tissue per se, bronchoalveolar lavage fluid, lamellar bodies, and/or isolated surfactant fractions). Therefore, future studies must necessarily be comprehensive in scope and include information indicating that fetal growth, blood glucose, and circulating insulin are all increased. Such models already exist in rats and rabbits. Rat models are possibly not the best because of the high basal level of fetal blood insulin in this species and the relatively rapid rate of lung maturation that is not analogous to the human. Monkey models are of interest, because of their close relationship with the human pregnancy, and need to be studied further. They are particularly attractive also because primary fetal hyperinsulinism can be studied (268), as well as the combination of hyperglycemia and hyperinsulinemia in pregnancies of STZ-treated monkeys (152). An appropriate model of the diabetic pregnancy could provide answers to the following questions. Are the biosynthetic pathways of surfactant phospholipids directly impaired?(ABSTRACT TRUNCATED AT 400 WORDS)

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Fetal lung development in the diabetic pregnancy.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that is characterized by glucose intolerance, leads to dyslipidemia, and is aggravated by obesity. Cholesterol is taken up by the placenta as part of lipoproteins through the scavenger receptor class B type I receptor (SRBI), low-density lipoprotein receptor (LDLR), and very low density lipoprotein receptor (VLDLR), and its efflux is then mediated by ABCA1 and ABCG1. PCSK9 is involved in the degradation of LDLR and VLDLR. The goal of this study was to evaluate the impact of GDM and prepregnancy body mass index (BMI) on cholesterol transport through the modulation of the expression of several key players. Human full-term placenta, maternal, and venous cord blood samples were obtained at delivery from normal-weight women without GDM (n = 10), normal-weight women with GDM (n = 6), and overweight/obese women with GDM (n = 6). Lipids (total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, free fatty acids, apolipoprotein A1, apolipoprotein B100) levels were evaluated in blood samples. Messenger RNA and protein expression levels (LDLR, VLDLR, SRBI, ABCA1, ABCG1, proprotein convertase subtilisin/kexin type 9, liver x receptors, peroxisome proliferator-activated receptors) were assessed in human full-term placenta, respectively, by real-time RT-PCR and Western blots. Lipoprotein lipase activity was evaluated using a commercial kit on tissue homogenates. Overall, our study demonstrates that GDM affects the maternal and neonatal lipid profiles as well as different key players of placental cholesterol transfer from the maternal to the fetal circulation, depending on the maternal BMI. These changes could affect the fetal metabolism and predispose the fetus to future metabolic diseases.

https://bioone.org/journals/biology-of-reproduction/volume-88/issue-1/biolreprod.112.105619/Modulation-of-Cholesterol-Transport-by-Insulin-Treated-Gestational-Diabetes-Mellitus/10.1095/biolreprod.112.105619.pdf

Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta

Corticosteroid treatment of the fetus, which accelerates lung maturation, may mimic a modulating role of endogenous corticoids in normal development. To investigate this question, we determined the developmental pattern of plasma corticoids and their binding proteins in the rabbit, a commonly used species for studies of lung differentiation. The concentration of cortisol, the most potent glucocorticoid in the rabbit, was maximal at 23 days gestation (1.89 μg/dl), declining to 0.54 μg/dl at term (31 days). Levels of plasma corticosterone were always lower than those of cortisol. The adrenal content of corticoids, expressed per adrenal DNA or g BW, decreased during late gestation. Corticosteroid-binding globulin in fetal plasma decreased strikingly between day 23 (36 fig cortisol bound/dl) and day 31 (4.4 μg/dl; P < 0.001), whereas maternal levels increased about 10-fold during this time. Free cortisol in the fetus increased between 21 and 23 days (0.041 μg/dl) and then decreased somewhat until after day 29...

Endogenous corticoids and lung development in the fetal rabbit.

Delayed fetal lung development is a feature of the diabetic pregnancy. Since fetal glucocorticoids are important in the regulation of lung maturation, we measured corticosterone and corticosteroid-binding globulin binding capacity in streptozotocin-diabetic pregnant rats and their fetuses. Previous studies have demonstrated delayed fetal lung maturation in this animal model. In control fetuses, total corticosterone concentration increased through day 20 of gestation, then declined until day 22 (term). The unbound steroid, which accounted for 5-10% of the total, increased approximately 3-fold from day 18 to term. Corticosteroid-binding globulin binding capacity peaked on day 19 after which it decreased. Maternal total and unbound corticosterone levels and corticosteroid-binding globulin binding capacity remained relatively constant throughout the final week of normal gestation. When compared to controls, fetuses from diabetic pregnancies had significantly lower total corticosterone from day 19 through 22. Corticosteroid-binding globulin binding capacity was also significantly decreased in these fetuses for the last 4 days of gestation. Similar differences were noted in maternal samples. However, no significant differences in unbound, biologically active, corticosterone were seen when diabetic and control groups were compared. Thus, delayed fetal lung maturation observed in fetuses of streptozotocin-diabetic rats is associated with a decrease in total circulating corticosteroid levels late in gestation. However, since unbound corticosteroid levels were similar in fetuses of control and diabetic animals, it is likely that other mechanisms may be responsible for the observed delay in lung development in fetuses of diabetic pregnancies.

/pdf/fetal-and-maternal-corticosterone-and-corticosteroid-binding-512tqgk93k.pdf

Fetal and maternal corticosterone and corticosteroid binding globulin in the diabetic rat gestation.

The lungs of fetuses of streptozotocin-diabetic rats were examined for their ability to incorporate U-14C-glucose into phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inositol and lysophosphatidyl choline. In the lungs of control rats an increased biosynthesis of phosphatidyl glycerol in late pregnancy suggested a close association between the production of this phospholipid and the terminal maturation of the fetal lung. In the offspring of diabetic rats the incorporation of 14C-glucose into phosphatidyl choline, lysophosphatidyl choline and phosphatidyl glycerol was markedly decreased compared with the control rats on gestational day 20, whereas no difference was seen at day 22. Insulin treatment of the pregnant rats restored the biosynthesis of phosphatidyl choline and lysophosphatidyl choline towards normal on gestational day 20, while the ratio of phosphatidyl glycerol to phosphatidyl inositol incorporation of 14C-glucose was decreased, suggesting that the biosynthesis of phosphatidyl glycerol is more sensitive than that of phosphatidyl choline and lysophosphatidyl choline to the metabolic disturbances inherent in maternal diabetes. The delayed fetal pulmonary maturation occurred without fetal hyperinsulinism which suggests that this latter feature may not be of crucial significance in the aetiology of the respiratory distress syndrome.

https://link.springer.com/content/pdf/10.1007/BF00250162.pdf

Development of phosphatidyl glycerol biosynthesis in the lungs of fetuses of diabetic rats.

To investigate whether maternal or fetal glucocorticoid secretion is altered during pregnancy complicated by diabetes mellitus, in vitro production of corticosterone (B) and cortisol (F) was measured on day 28 of gestation in rabbits made alloxan diabetic prior to pregnancy. In addition, plasma B and F were followed throughout the experimental period. Fetuses of diabetic mothers were hyperglycemic and hyperinsulinemic, and mortality was much higher (18%) than that of control animals (1.5%). No significant differences were found in maternal plasma B or F during gestation, whereas F was significantly lower in fetuses of diabetic mothers. In vitro production of both B and F by maternal and fetal adrenals was lower in the diabetic animals, and responses to ACTH or insulin added to the incubation were the same in both groups. These results suggest that the ability of the adrenal cortex to secrete glucocorticoids may be impaired both in the mother and fetus when maternal diabetes is present. This could have effects both on maturational events in the fetus that are accelerated by glucocorticoids and on the ability to respond to stress.

R. R. Beck

Papers

Maternal and fetal adrenocortical function in the diabetic rabbit.