Effects Of Maternal Diabetes Research Articles

Effects of maternal diabetes on the levels, synthetic rates and activities of synthetic enzymes of surface-active phospholipids in perinatal rat lung

Streptozotocin-induced maternal diabetes in the rat has been found to reduce selectively the content and synthetic rates of disaturated phosphatidylcholine and lysophosphatidylcholine in the lungs of term fetuses. Furthermore, the elevations in these parameters which occur during normal pulmonary maturation between the final gestational day and the first neonatal day are abolished or markedly curtailed, resulting in significantly reduced levels and synthetic rates of surfactant and its immediate precursor in the neonatal lung. In addition, complete or partial inhibition of the perinatal developmental rise in the activities of key enzymes catalyzing de novo phosphatidylcholine synthesis in the lung, viz., cholinephosphate cytidylyltransferase and cholinephosphotransferase and of enzymes catalyzing reacylation of unsaturated to disaturated phospholipid, viz., lysophosphatidic acid and lysophosphatidylcholine acyltransferases, has been observed, resulting in reduced activities of these enzymes in the neonate. The observed reductions in surface-active phospholipid synthesis in the lungs of offspring of diabetic mothers may be related to these lowered enzyme activities, as well as to deficiencies in carbohydrate precursors available for phospholipid synthesis, as reported in previous studies. It is suggested that the hyperinsulinemia manifested in fetuses of diabetic mothers opposes the tendency of corticosteroids to enhance surface-active phospholipid synthesis, resulting in pulmonary surfactant deficiency and thus the propensity for neonatal respiratory distress.

Developmental-stage-dependent teratogenic effects of maternal spontaneous diabetes in the chinese hamster.

The effect of maternal diabetes on teratogenesis was examined utilizing female Chinese hamsters with typical diabetic symptoms from our closed colony (CHA) and F13-F19 of the brother-sister mating generations of a diabetic strain (CHAD). Both groups were mated with nondiabetic males from CHA. Embryologic studies on day 2.5, 4.5, and 18.5 of gestation were performed with 30, 31, 71 diabetic females that were impregnated during a normal 4-day estrous cycle. The preimplantation embryos of day 2.5 and 4.5 were also karyotyped. The results indicated that: (1) There was no decrease in the number of ovulated ova, of collected embryos, and of implantation sites in the diabetic females. (2) As far as the preimplantation stages were concerned, there was no decrease in the cleavage activity and no increase in the incidence of developmental anomalies. (3) There was no increase of chromosomal aberrations in the preimplantation embryos. (4) With respect to the postimplantation development, however, there were significant increases in embryonic death (P less than 0.001), gross malformation (P less than 0.001), and fetal hypoplasia (P less than 0.001). Results (1), (2), and (3) indicated that in diabetic females capable of conceiving during a normal estrous cycle, the maternal diabetic milieu did not affect oogenesis, ovulation, fertilization, cleavage division, implantation, and chromosomal behavior. Result (4), however, showed definitely that maternal diabetes exerted deleterious effects on fetal development during the stage of organogenesis, and also markedly reduced fetal growth during later developmental stages.

The effects of maternal diabetes on fetal maturation and neonatal health

This investigation focused on the relation between metabolic control of maternal diabetes in pregnancy and the health status of the fetus and newborn in the spontaneously diabetic BB rat. The basic hypothesis tested was that "tight" control of maternal diabetes before conception and during pregnancy should result in diminished fetal and neonatal morbidity and mortality. Behavioral teratologic tests were employed to evaluate the possible long-term effects of diabetes in pregnancy on postnatal development. The results demonstrated that approximation to glucose homeostasis in diabetic BB dams was associated with increased litter and fetal size, decreased perinatal mortality, and a significant reduction in the incidence of congenital malformation. Postnatal growth and neurologic function were also enhanced. These findings are supportive of efforts to initiate diabetic control prior to conception and especially during the critical period of fetal organogenesis during the first 8 weeks of human pregnancy.

Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate.

The present study used the whole embryo culture technique to determine the effects of the ketone body, B-hydroxybutyrate (B-OHB), on organogenesis in mouse embryos. Embryos of two stages (3-4 and 5-6 somites) were exposed for 24 h to a racemic mixture of D-L B-OHB at levels of 8, 16, or 32 mM/L. An abnormal pattern of development resulted, consisting of growth reduction and inhibition or delay of neural tube closure in the cranial and/or caudal regions of the embryo. These effects were dose- and age-dependent, such that younger embryos were more frequently affected than older ones, and increasing doses produced a higher rate of malformation. Growth reduction as evidenced by embryonic protein showed similar relationships. Histologic analysis of embryos exposed to 32 mM/L B-OHB for 24 h revealed numerous cytoplasmic "vacuoles" widespread throughout the neuroepithelium, mesenchyme, and ectoderm. Ultrastructurally, these "vacuoles" proved to be mitochondria that had undergone high-amplitude swelling with a loss of matrix density and few identifiable cristae. No other consistent ultrastructural changes were noted, and the mitochondria of control tissues displayed a typical orthodox configuration. While this study does not conclusively limit the effects to the D-form of B-OHB, possible relationships exist between the ultrastructural alterations, ketone body metabolism, and abnormal morphogenesis.

Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate

Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate

Effects of maternal diabetes on the development of carbohydrate-metabolizing enzymes, glycogen deposition and surface active phospholipid levels in fetal rat lung.

Streptozotocin-induced maternal diabetes has been shown to alter developmental patterns of carbohydrate-metabolizing enzyme activities, glycogen deposition and surfactant levels in late fetal rat lung in a tissue-specific manner, as follows: (a) marked reduction in glycogen synthase a activity, due to aberrant interconversion between active and inactive forms of the enzyme; less glycogen was thus accumulated; (b) lowered activities of hexokinase, phosphofructokinase and pyruvate kinase at term; (c) reduced disaturated phosphatidylcholine (surfactant) concentrations. The diminished synthesis and accumulation of glycogen and glycolytic capacity in the lungs of fetuses of diabetic mothers has been related to reduction in surfactant level, which underlies respiratory distress syndrome frequently encountered in neonates of diabetic pregnancies.

The effect of maternal diabetes and fasting on fetal adipose tissue histochemistry in the pig.

The effects of maternal diabetes (induced d 78 of gestation) and food deprivation (last 20 d of gestation) on the histochemical disposition of fetal adipose tissue at 112 d of gestation were determined. In both cases, there was an increased number of fat cell clusters by comparison with the control. In the fetuses of diabetic pigs, there were striking effects on adipocyte size and the extent of lipid filling of presumptive adipose space. In these fetuses, the adipocytes were large and many were unilocular, whereas, those in the fetuses of control and fasted pigs were smaller. The adipose tissue space of the control was "empty" compared with that of fetuses of diabetic pigs. Adipocytes from fetuses of diabetic pigs contained intracellular glycogen deposits, which were not present in adipocytes of control and fasted progeny. Maternal fasting and diabetes increased the number of lipid-containing adipocytes in fetal adipose tissue. An additional effect of maternal diabetes was to increase fetal adipocyte size over that of fetuses of control and fasted pigs.

Effects of maternal diabetes on the development of carbohydrate metabolizing enzymes in fetal rat liver

Effects of streptozotocin-induced maternal diabetes on fetal hepatic carbohydrate-metabolizing enzyme development and hormonal status has been explored in the rat. Hepatic glycogen synthase a activity of the normal fetus rose to a maximum at 20 days of gestation, then fell prior to parturition. In fetuses of diabetic mothers, this prepartum decline was curtailed, resulting in enhanced synthase a activity and increased glycogen content in fetal livers at term. Elevation in hepatic synthase a in fetuses of diabetic mothers was due, not to altered interconversion between existing synthase a and b, but to equivalent increases in both forms of the enzyme. Both hepatic and free plasma corticosterone levels were elevated in fetuses of diabetic mothers and may be responsible for the enhanced development of total glycogen synthase observed in these fetuses. In normal fetuses hepatic phosphofructokinase and pyruvate kinase activities also rose to maxima at 20 days, then declined prior to term. In fetuses of diabetic mothers pyruvate kinase activity attained higher than normal maximal levels and phosphofructokinase activity fell more gradually, thus resulting in elevations in both enzyme activities at term. Augmentations in these glycolytic enzymes are compatible with hyperinsulinemia observed in fetuses of diabetic mothers. The following conclusions may be drawn from these findings. During late fetal life developmental patterns of rate-limiting hepatic glycogen-synthesizing and glycolytic enzymes are adapted to glucose utilization. In the normal fetus these patterns reverse at term, thereby promoting glucose mobilization, which prepares the fetus for abrupt deprivation of maternal glucose at birth. Maternal diabetes results in retardation of these reversal processes, presumably due to elevations in fetal glucocorticoid and insulin levels. Glycogenolytic and glucogenic capacities are thereby impaired in these fetuses.

Fetal rat lung phosphatidylcholine synthesis in diabetic and normal pregnancies: A comparison of prenatal dexamethasone treatments

The effects of maternal diabetes upon fetal lung surfactant phospholipid metabolism were studied using 19-day gestational age fetal rats from mothers with streptozotocin-induced diabetes mellitus. In this experimental animal model, maternal glucose intolerance significantly impaired fetal body and lung development. However, incorporation of [ 14C]palmitate and [ 3H]choline into lung total and disaturated phosphatidylcholine was unimpaired in offspring of diabetic mothers. Dexamethasone, which is known to promote fetal lung maturation in normal pregnancies, was administered to diabetic and control mothers during late gestation. Prenatal dexamethasone inhibited lung growth in both diabetic and control pregnancies. While this agent slightly stimulated [ 14C]palmitate incorporation into total phosphatidylcholine and markedly enhanced [ 3H]choline incorporation into both disaturated and total phosphatidylcholine in control pregnancies, it failed to stimulate incorporation of either precursor into fetal lung from diabetic pregnancies.

Effect of Maternal Diabetes on Response to Hypoxia in the Newborn Rabbit

We tested the hypothesis that maternal diabetes is associated with a decreased ability of the newborn to tolerate hypoxia by measuring the time to last gasp of rabbit pups born to diabetic and control does and placed in 100% N2. Rabbits were made diabetic by injection of 100 mg/kg alloxan i.v. The alloxan-treated mothers had significantly elevated blood glucose during pregnancy and at delivery (132 vs. 90 mg/dl, p less than 0.001). Pups were delivered at 30 day's gestation by hysterectomy under local anesthesia. Half of each litter were immediately sacrificed and the remaining pups placed in 100% Ns. The pups from the alloxan-treated mothers showed a higher pre-asphyxial mean blood glucose (97 vs. 73 mg/dl, p less than 0.025) and a lower mean survival time (18.4 vs. 21.1 min, p less than 0.005).

Effects of maternal diabetes on early embryogenesis: I. The teratogenic potential of diabetic serum.

AbstractEffects of maternal diabetes on initial stages of organogenesis was examined by culturing early somite stage mouse embryos in the presence of diabetic serum. Serum for the cultures was prepared from rats which had been made mildly or severely diabetic by the intraperitoneal administration of 50 mg/kg or 75 mg/kg streptozotocin, respectively. Effects of this diabetic serum were age‐and dose‐related, with a higher incidence of malformations occurring among younger (2–3 vs 4–6 somite) embryos and among embryos exposed to serum from severely diabetic animals. The most commonly occuring anomaly was inhibition of neural tube closure which involved cranial (exencephaly) regions only, and was accompanied by growth inhibition in embryos exposed to severely diabetic serum. Histologically, embryos cultured in diabetic serum exhibited a wave of cell necrosis which occurred during the first 4–8 h of culture and was primarily restricted to neuroepithelial and prospective neural crest cells. However, by 24 h the neurotic debris had disappeared, even in severely malformed embryos. These abnormalities are similar to central nervous system defects described for offspring from diabetic mothers. Furthermore, the severity of diabetes produced by streptozotocin treatment promoted glucose and insulin levels comparable to those observed in diabetic patients.

Influence of maternal diabetes on lipid metabolism in neonatal rat lung

The effect of maternal diabetes on tissue constituents, lipid metabolism and glucose utilization was examined in 1-day old rat lungs. Maternal diabetes was induced by intravenous injection of streptozotocin (50 mg/kg body weight) into pregnant Long-Evans hooded rats on the 10th day of gestation resulting in a maternal serum glucose concentration which was 3-fold higher than that of controls. Neonates from diabetic mothers showed a significant decrease in body weight (14%), lung weight (32%) and lung protein concentration (30%). Glycogen, DNA and lipid content of the lungs were significantly elevated in neonates from diabetic mothers. The percent of total phospholipid made up of phosphatidylcholine was not altered, but the percentage of disaturated phosphatidylcholine was decreased (25%). The activity of the CDPcholine pathway enzymes (choline kinase, cholinephosphate cytidylyltransferase and choline phosphotransferase) also showed a marked increase in lungs of neonates from diabetic mothers. Lung slices of neonates from diabetic mothers showed depressed in vitro incorporation of [U- 14C]glucose into neutral lipids and decreased oxidation to CO 2. The results of these investigations show that maternal diabetes interferes with the structural and metabolic processes by which the undifferentiated lung becomes functional at birth.

SUBCUTANEOUS FAT IN NEWBORN INFANTS OF DIABETIC MOTHERS: AN INDICATION OF QUALITY OF DIABETIC CONTROL

Biceps, triceps, subscapular, and suprailiac skinfolds were measured in 40 newborn infants of diabetic mothers. Maternal fasting blood-glucose and mean blood-glucose in the third trimester correlated significantly with neonatal skinfold thickness. Skinfold measurement, when compared with a reference range for gestational age, may be a convenient way of assessing one effect of maternal diabetes on the fetus. Gluteal adipose-cell diameter was measured in 31 infants of diabetic mothers. The fattest babies had the largest adipose cells and there was a significant positive correlation between maternal fasting blood-glucose and neonatal adipose cell diameter. These findings are consistent with the hypothesis that in diabetic pregnancy fetal hyperglycæmia and hyperinsulinism stimulate increased triglyceride synthesis in adipose cells and enlargement of adipose cells and lead to an increase in fetal subcutaneous fat.

Insulin Response to Arginine in Normal Newborn Infants and Infants of Diabetic Mothers

The effect of maternal diabetes during pregnancy on insulin release of the newborn infant was examined employing arginine infusion as stimulus. At age two hours, eight normal newborn infants, six of gestationally diabetic mothers (IGDM) and four of insulin-dependent diabetic mothers (IDM) were infused with arginine hyd-rochloride 0.5 gm. per kilogram body weight for thirty minutes. Eight additional normal newborn infants were infused with isotonic saline. A small but definite rise in plasma IRI was observed in the normal newborns receiving arginine; however, the infants of gestationally diabetic mothers responded with an enhanced blood glucose and plasma insulin rise compared with the normal newborns. It seemed that intermittent or sustained hyperglycemia in utero may have potentiated the neonatal insulin response to arginine.

The effect of maternal diabetes on adipose tissue cellularity in man and rat.

It is well recognised that the newborn of diabetic mothers may be overweight and obese, presumably due to excessive glucose and insulin levels in the fetus. Since recent evidence indicates that the number of fat cells is established early in life, we studied the effect of intrauterine hyperglycaemia and hyperinsulinaemia on adipose tissue cellularity. Six men (age range 21–26 years) and six women (age range 18–24 years) were investigated. Their weights at birth generally exceeded the average value by 2 S.D. As a group they were not obese at the time of the investigation and neither total number of fat cells, average cell size nor body fat differed significantly from controls of the same age. There was no correlation between the number of fat cells and the weight at birth. The adipose tissue cellularity in the offspring of alloxan-diabetic rats (AX) and in controls (C) of equal weight was also studied. When sacrificed (after 40 days) body weights and the weights of the epididymal and retroperitoneal fat pads were similar in the AX and C groups. However, the number of fat cells of the retroperitoneal fat pad was significantly increased in the AX group, while the cell size was slightly diminished. Cell data of the epididymal fat pads were not significantly different. The results indicate that excessive glucose and insulin levels in utero may influence the number of fat cells, but, in man, they do not seem to lead to a permanent hyperplasia of the adipose tissue.

Mayer and Camara: The Effect of Maternal Diabetes on the Developing Fetus

Mayer and Camara: The Effect of Maternal Diabetes on the Developing Fetus

SUBCLINICAL AND CLINICAL DIABETES COMPLICATING PREGNANCY.

Evidence shows that untreated maternal diabetes results in a high stillbirth rate and a neonatal mortality of approximately 30 per cent.A diabetic detection program for gravid women has not been accepted because of differing opinions on the effects of pregnancy on carbohydrate tolerance in normal women and on the most reliable testing method to be used during gestation.The oral glucose tolerance test is the most widely employed. It is suggested that in addition the cortisone-modified glucose tolerance test should be used in the late puerperium of patients in the suspect and latent diabetes groups.Clinical observations in diabetic pregnancies discussed by the author include increased insulin resistance and susceptibility to toxemia and urinary tract infection, effects of maternal diabetes on the fetus, and optimal timing and mode of delivery.