Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies.

Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of 'catch up' growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity. Vitamin B12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin's transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

Embryonic fatty acid metabolism in diabetic pregnancy: the difference between embryoblasts and trophoblasts.

During the first days of development the preimplantation embryo is supplied with nutrients from the surrounding milieu. Maternal diabetes mellitus affects the uterine microenvironment, leading to a metabolic adaptation processes in the embryo. We analysed embryonic fatty acid (FA) profiles and expression of processing genes in rabbit blastocysts, separately in embryoblasts (EBs) and trophoblasts (TBs), to determine the potential consequences of maternal diabetes mellitus on intracellular FA metabolism. Insulin-dependent diabetes was induced by alloxan in female rabbits. On Day 6 post coitum, FA profiles in blastocysts (EB, TB and blastocoel fluid) and maternal blood were analysed by gas chromatography. The expression levels of molecules involved in FA elongation (fatty acid elongases, ELOVLs) and desaturation (fatty acid desaturases, FADSs) were measured in EB and TB. Maternal diabetes mellitus influenced the FA profile in maternal plasma and blastocysts. Independent from metabolic changes, rabbit blastocysts contained a higher level of saturated fatty acids (SFAs) and a lower level of polyunsaturated fatty acids (PUFAs) compared to the FA profile of the maternal plasma. Furthermore, the FA profile was altered in the EB and TB, differently. While SFAs (palmitic and stearic acid) were elevated in EB of diabetic rabbits, PUFAs, such as docosahexaenoic acid, were decreased. In contrast, in the TB, lower levels of SFAs and higher levels of oleic acid were observed. EB and TB specific alterations in gene expression were found for ELOVLs and FADSs, key enzymes for FA elongation and desaturation. In conclusion, maternal diabetes mellitus alters embryonic FA metabolism differently in EB and TB, indicating a lineage-specific metabolic adaptive response.

Adiponectin stimulates lipid metabolism via AMPK in rabbit blastocysts.

STUDY QUESTION: How does a maternal diabetic hyperadiponectineamia affect signal transduction and lipid metabolism in rabbit preimplantation blastocysts? SUMMARY ANSWER: In a diabetic pregnancy increased levels of adiponectin led to a switch in embryonic metabolism towards a fatty acid-dependent energy metabolism, mainly affecting genes that are responsible for fatty acid uptake and turnover. WHAT IS KNOWN ALREADY: Although studies in cell culture experiments have shown that adiponectin is able to regulate lipid metabolism via 5'-AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα), data on the effects of adiponectin on embryonic lipid metabolism are not available. In a diabetic pregnancy in rabbits, maternal adiponectin levels are elevated fourfold and are accompanied by an increase in intracellular lipid droplets in blastocysts, implying consequences for the embryonic hormonal and metabolic environment. STUDY DESIGN, SIZE, DURATION: Rabbit blastocysts were cultured in vitro with adiponectin (1 µg/ml) and with the specific AMPK-inhibitor Compound C for 15 min, 1 h and 4 h (N ≥ 3 independent experiments: for RNA analysis, n ≥ 4 blastocysts per treatment group; for protein analysis three blastocysts pooled per sample and three samples used per experiment). Adiponectin signalling was verified in blastocysts grown in vivo from diabetic rabbits with a hyperadiponectinaemia (N ≥ 3 independent experiments, n ≥ 4 samples per treatment group, eight blastocysts pooled per sample). PARTICIPANTS/MATERIALS, SETTING, METHODS: In these blastocysts, expression of molecules involved in adiponectin signalling [adaptor protein 1 (APPL1), AMPK, acetyl-CoA carboxylase (ACC), p38 mitogen-activated protein kinases (p38 MAPK)], lipid metabolism [PPARα, cluster of differentiation 36 (CD36), fatty acid transport protein 4 (FATP4), fatty acid binding protein (FABP4), carnitine palmityl transferase 1 (CPT1), hormone-senstive lipase (HSL), lipoprotein lipase (LPL)] and members of the insulin/insulin-like growth factor (IGF)-system [IGF1, IGF2, insulin receptor (InsR), IGF1 receptor (IGF1R)] were analyzed by quantitative RT-PCR and western blot. Analyses were performed in both models, i.e. adiponectin stimulated blastocysts (in vitro) and in blastocysts grown in vivo under increased adiponectin levels caused by a maternal diabetes mellitus. MAIN RESULTS AND THE ROLE OF CHANCE: In both in vitro and in vivo models adiponectin increased AMPK and ACC phosphorylation, followed by an activation of the transcription factor PPARα, and CPT1, the key enzyme of ß-oxidation (all P < 0.05 versus control). Moreover, mRNA levels of the fatty acid transporters CD36, FATP4 and FABP4, and HSL were upregulated by adiponectin/AMPK signalling (all P < 0.05 versus control). Under diabetic developmental conditions the amount of p38 MAPK was upregulated (P < 0.01 versus non-diabetic), which was not observed in blastocysts cultured in vitro with adiponectin, indicating that the elevated p38 MAPK was not related to adiponectin. However, a second effect of adiponectin has to be noted: its intensification of insulin sensitivity, by regulating IGF availability and InsR/IGF1R expression. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: There are two main limitations for our study. First, human and rabbit embryogenesis can only be compared during blastocyst development. Therefore, the inferences from our findings are limited to the embryonic stages investigated here. Second, the increased adiponectin levels and lack of maternal insulin is only typical for a diabetes mellitus type one model. WIDER IMPLICATIONS OF THE FINDINGS: This is the first mechanistic study demonstrating a direct influence of adiponectin on lipid metabolism in preimplantation embryos. The numbers of young women with a diabetes mellitus type one are increasing steadily. We have shown that preimplantation embryos are able to adapt to changes in the uterine milieu, which is mediated by the adiponectin/AMPK signalling. A tightly hormonal control during pregnancy is essential for survival and proper development. In this control process, adiponectin plays a more important role than known so far. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Council (DFG RTG ProMoAge 2155), the EU (FP7 Epihealth No. 278418, FP7-EpiHealthNet N°317146), COST Action EpiConcept FA 1201 and SALAAM BM 1308. The authors have no conflict(s) of interest to disclose.

Impaired prenatal development and glycemic status in the offspring of rats with experimental streptozotocin-induced diabetes and their correction with afobazole.

Diabetes mellitus was simulated in rats on gestation day 1 by a single intraperitoneal injection of streptozotocin in doses of 40 and 50 mg/kg. Pregnant females showed increased glucose concentrations n the blood and urine, embryonic developmental disorders, such as tongue protrusion, edema, and skin hyperemia with concomitant vascular damage (hemorrhage, hematoma) as well as pre- and post-implantation embryo loss. Afobazole administered orally in doses of 10 and 50 mg/kg to pregnant rats with streptozotocin-induced diabetes significantly decreased prenatal developmental disorders and pre- and post-implantation embryo loss rate. Afobazole in a dose of 50 mg/kg produced maximum protective effect: in rats receiving 40 mg/kg streptozotocin, post-implantation embryo loss decreased by 14.7 times. Afobazole in doses of 10 and 50 mg/kg significantly reduced blood glucose concentration in pregnant rats and normalized glycemia in 90-day-old male offspring.

Maternal-fetal outcomes of pregnant women with type 1 diabetes treated with continuous subcutaneous insulin infusion or multiple daily injections during pregnancy - A Brazilian health care referral center cohort study.

Objective: Pregnant women with type 1 diabetes (T1D) have an increased risk of maternal-fetal complications. Regarding treatment, continuous subcutaneous insulin infusion (CSII) has advantages compared to multiple daily injections (MDI), but data about the best option during pregnancy are limited. This study's aim was to compare maternal-fetal outcomes among T1D patients treated with CSII or MDI during pregnancy. Subjects and methods: This study evaluated 174 pregnancies of T1D patients. Variables of interest were compared between the groups (CSII versus MDI), and logistic regression analysis was performed (p < 0.05). Results: Of the 174 included pregnancies, CSII was used in 21.3% (37) and MDI were used in 78.7% (137). HbA1c values improved throughout gestation in both groups, with no difference in the first and third trimesters. The frequency of cesarean section was significantly higher in the CSII group [94.1 vs. 75.4%, p = 0.017], but there was no significant difference in the frequency of other complications, such as miscarriage, premature delivery and preeclampsia. The mean birth weight and occurrence of neonatal complications were also similar, except for the proportion of congenital malformations, which was significantly lower in the CSII group [2.9 vs. 15.6%, p = 0.048]. In regression analysis, the association of CSII with cesarean section and malformations lost significance after adjusting for HbA1c and other covariates of interest. Conclusion: In this study, we observed a higher frequency of cesarean section and a lower occurrence of congenital malformations in the CSII group, but the adjusted results might indicate that these associations are influenced by glycemic control.

Evaluation of blood pressure and aortic elasticity of offspring of diabetic Wistar rats who have consumed flaxseed oil during pregnancy and lactation.

OBJECTIVE: This study aimed to investigate whether maternal use of flaxseed oil has effects on blood pressure and aorta elastic fibre in female offspring of diabetic mothers. METHODS: Diabetes was induced into the rats (n = 18) by a high-fat diet and streptozotocin. After diabetes confirmation, rats were mated, and after pregnancy was confirmed, they were allocated into three groups: control group (CG); high-fat group (HFG); and flaxseed oil group (FOG). At weaning, female offspring (n = 6/group) received standard chow diet and were euthanized at 100 days of life. The following blood pressure and the percentage of the aortic elastic fibre were analysed. RESULTS: HFG showed higher blood pressure, and the use of flaxseed oil avoided this condition in FOG (p < 0.001) and increased the percentage of the aortic elastic fibre (p < 0.022). CONCLUSIONS: Flaxseed oil reduced the damage caused by maternal hyperglycaemia, promoting normal blood pressure and elasticity of the aorta in female offspring.

Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis.

Neural tube defects are among the most common of the malformations associated with diabetic embryopathy. To study the molecular mechanisms by which neural tube defects occur during diabetic pregnancy, we have developed a new experimental system using pregnant diabetic mice. In this system, the rate of neural tube defects is about three times higher in embryos of diabetic mice than in embryos of nondiabetic mice. Most of the defects affected presumptive midbrain and hindbrain structures and included open defects (i.e., exencephaly) and gross maldevelopment. By semiquantitative reverse transcription-polymerase chain reaction and in situ hybridization, we found that expression of Pax-3, a gene required for neural tube closure in the area of the midbrain and hindbrain, is significantly reduced in the embryos of diabetic mice. The same regions of the neural tube where Pax-3 had been underexpressed were found subsequently to contain high concentrations of cells undergoing apoptosis. Reduced expression of Pax-3 appears to be responsible for this apoptosis because apoptotic cells were also found at sites of neural tube defects in embryos carrying null mutation of the Pax-3 gene. Finally, mouse strains that carry null mutations in Pax-3 develop neural tube defects that resemble the malformations that occur in embryos of diabetic mice. These results suggest that Pax-3 is an important developmental control gene, expression of which is disturbed in embryos of diabetic mice, and that as a consequence, apoptosis of the neural tube occurs. This pathway may be responsible for many of the neural tube defects resulting from diabetic pregnancy.

Hyperosmolar nonketotic diabetic syndrome following treatment of human immunodeficiency virus infection with didanosine.

OBJECTIVE: To determine whether didanosine (DDI), one of the drugs commonly used to treat infection with human immunodeficiency virus (HIV), contributes to the development of diabetes and hyperosmolar nonketotic diabetic syndrome (HNKDS). CASE SUMMARY: One female patient was treated with DDI for infection with HIV during pregnancy. Soon after starting DDI treatment, she developed diabetes, which progressed to HNKDS. CONCLUSIONS: Although not reported in the literature, hyperglycemia following treatment with DDI has been noted in 82 patients and is usually associated with pancreatitis. DDI should be recognized as one of the drugs known to potentially cause diabetes and HNKDS. With the increasing use of DDI and other drugs that cause hyperglycemia, such as pentamidine and dapsone, blood glucose should be monitored frequently in the HIV-infected patients.

Fetal lung lecithin metabolism in the glucose-intolerant Rhesus monkey pregnancy.

Fetal lung lecithin metabolism was examined in rhesus monkey gestations complicated by glucose intolerance secondary to maternal streptozotocin (STZ) administration. Fetuses of STZ-treated mothers were delivered at 85% to 89% of term and were compared to two control groups of fetuses from normal pregnancies--one group age-matched to the STZ pregnancies, and the other composed of fetuses delivered in the final 10% of gestation. In the glucose-intolerant pregnancies, two measures of fetal lung lecithin biosynthesis--the amniotic fluid lecithin-to-sphingomyelin (L/S) ratio and the rate of 14C-choline incorporation into lecithin in fetal lung slices--were significantly greater than in age-matched normal gestations and were similar to results in late-gestation controls. However, lung lecithin concentrations in the glucose-intolerant group were comparable to the age-matched controls, and both were significantly less than in the late-gestation controls. Since the gestational age, mode of delivery, and fetal acid-base status were the same in the age-matched groups, we conclude that these changes in fetal lung lecithin metabolism are due to the effects of maternal glucose intolerance.

Ketoacidosis in pregnancy associated with the parenteral administration of terbutaline and betamethasone. A case report.

Diabetic ketoacidosis occurred in a woman without a prior history of glucose intolerance. The condition was associated with the combined administration of terbutaline and betamethasone. The patient required insulin therapy for the remainder of her pregnancy but had no further insulin requirements postpartum.

The onset of maternal diabetes in swine induces alterations in the development of the fetal preadipocyte.

Diabetes induced during gestation has previously been demonstrated to increase adipose accretion in the fetal pig. The present experiment examined whether maternal diabetes alters the proliferation and differentiation of the fetal preadipocyte. Seven crossbred gilts were injected with alloxan (50 mg/kg) at d 75 of gestation to induce diabetes and seven additional gilts were injected with buffer (controls). All gilts underwent Caesarean section of d 105 of gestation. Cells obtained from adipose tissue of fetuses of diabetic swine (FDS) at d 105 of gestation demonstrated a greater (P < .05) proliferative response (57%) and higher (P < .05) rates of differentiation as determined by sn-glycerol-3-phosphate dehydrogenase (142% increase) and lipoprotein lipase (80% increase) activities than cells acquired from fetuses of control swine (FCS). Adipogenic activity of the sera from these two groups of fetuses did not differ when tested on adipose tissue from fetuses at 105 d of gestation. However, use of these sera on cells derived from normal fetuses at 75 d of gestation resulted in detection of an increase (P < .05) in adipogenic activity within the sera from FDS. This study suggests that maternal diabetes causes alterations in the preadipocyte fraction of cells within the developing adipose tissue that result in formation of more adipocytes and thus permits greater capacity for lipid accumulation in the growing fetus of the diabetic pig. These alterations in the preadipocyte result from the activity of factors that transitionally function during the latter half of gestation.

Localization of glycogen in the placenta and fetal and maternal livers of cadmium-exposed diabetic pregnant rats.

This study was designed to investigate the effects of Cd exposure on the glycogen localization in the placenta and in fetal and maternal livers in streptozotocin (STZ)-induced-diabetic pregnant rats. Ninety-nine virgin female Wistar rats (200-220 g) were mated with 33 males for at least 12 h. From the onset of pregnancy, the rats were divided into four experimental groups (control, Cd treated, STZ treated, and Cd+STZ treated). The Cd-treated group was injected subcutaneously daily with CdCl2 dissolved in isotonic NaCl, starting at the onset of pregnancy throughout the experiment. Diabetes was induced on d 13 of pregnancy by a single intraperitoneal injection of STZ in the STZ-treated group. In addition to the daily injection of Cd, a single intraperitoneal injection of STZ was also given on d 13 of pregnancy in the Cd+STZ-treated group. The rats received the last injection 24 h before being sacrificed and 10 randomly selected rats in each group were sacrificed on d 15 and d 20 of pregnancy. Blood samples were taken for determination of the serum glucose and insulin levels. Fetal and maternal livers of sacrificed rats in all groups were harvested on d 15 and d 20 of pregnancy, whereas placentas were harvested only on d 20 of pregnancy for histochemical examination. Although both Cd and STZ caused hyperglycemia and decreased insulin secretion, Cd-alone treatment increased the glycogen content only in the placental labyrinth, whereas STZ-alone treatment increased the glycogen content only in the maternal part of the placenta. Increased glycogen localization was observed in both the placental labyrinth and the maternal part of placenta when Cd and STZ were given together. Fetal and maternal livers of control and other treatment groups were not different regarding the glycogen content on d 15 or d 20 of pregnancy. It was concluded that Cd exposure during pregnancy might produce a glycogen localization in the placenta of diabetic rats. However, the function and the mechanisms of increased glycogen contents in the placenta of Cd-exposed pregnant diabetic rats remain unclear and further studies are needed.

Effects of cadmium exposure on morphological aspects of pancreas, weights of fetus and placenta in streptozotocin-induced diabetic pregnant rats.

This study was designed to evaluate the effects of Cd exposure on morphological aspects of beta-cell and weights of fetus and placenta in streptozotocin (STZ)-induced diabetic pregnant rats. Ninety-nine virgin female Wistar rats (200-220 g) were mated with 33 males for at least 12 h. From the onset of pregnancy, the rats were divided into four experimental groups (control, Cd treated, STZ treated, and Cd+STZ treated). The Cd-treated group was injected subcutaneously daily with CdCl2 dissolved in isotonic NaCl, starting at the onset of pregnancy throughout the experiment. Diabetes was induced on the 13th d of pregnancy by a single intraperitoneal injection of STZ in STZ-treated group. In addition to the daily injection of Cd, a single intraperitoneal injection of STZ was also given on the 13th d of pregnancy in the Cd+STZ-treated group. The rats received the last injection 24 h before being sacrificed and 10 randomly selected rats in each group were sacrificed on the 15th and 20th d of pregnancy. Blood samples were taken for the determination of the serum glucose and insulin levels. Maternal pancreases, fetuses, and placentas of sacrificed rats in all groups were harvested (fetal pancreas was also harvested only on the 20th d of pregnancy) for morphological and immunohistochemical examinations. Cd exposure alone caused a degeneration, necrosis, and weak degranulation, but Cd exposure with STZ caused a severe degeneration, necrosis, and degranulation in the beta-cells of the pancreatic islets. No morphological or immunohistochemical differences were found in beta-cells of fetal pancreatic islets of control or other treatment groups. Cd exposure alone also decreased the fetal and placental weights. The administration of STZ alone, on the other hand, increased the placental weight. Cd, STZ, and Cd+STZ administration increased the glucose and decreased the insulin level. The increase in glucose and decrease in insulin levels were higher when Cd and STZ were given together. All of these changes were more severe on the 20th d than those on the 15th d of the pregnancy. It is concluded that Cd exposure during pregnancy may reduce the birth and placental weights and produce necrosis, degeneration, and degranulation in beta-cells of pancreatic islets, causing an increase in the serum glucose level. These changes might be severe in diabetic pregnant mothers.

Impaired intestinal active calcium absorption and reduction of serum 1alpha, 25(OH)2D3 in streptozotocin-induced diabetic pregnant rats with hypocalcemia in their fetuses.

PURPOSE: The effects of maternal diabetes mellitus on fetal hypocalcemia were studied in streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Experiments were performed using Wistar rats rendered diabetic with streptozotocin. Treatment with insulin was started in six diabetic pregnant rats after diabetes induction. On day 21 of gestation, cesarean section was performed and serum ionized calcium, parathyroid hormone and 1alpha, 25-dihydroxyvitamin D3 were measured and the active intestinal calcium absorption was measured in mother rats using the everted gut sac technique. RESULTS: In untreated diabetic pregnant rats, serum 1alpha, 25-dihydroxyvitamin D3 and the active intestinal calcium absorption were significantly decreased, and the placental calcium transfer was disturbed compared with the control and insulin-treated groups. Furthermore, serum ionized calcium levels were markedly reduced in fetuses from untreated diabetic pregnant rats. However, these abnormalities of calcium metabolism in untreated diabetic rats could be corrected by treatment with insulin. CONCLUSIONS: These data indicate that diabetes mellitus in pregnant rats a contribute to negative calcium homeostasis which is probably related to the development of fetal hypocalcemia.

-Glucose, insulin and C-peptide kinetics during tocolysis with oral fenoterol-. / Glukose-, Insulin- und C-Peptid-Kinetik unter Tokolyse mit oralem Fenoterol.

OBJECTIVE: The effect of oral fenoterol therapy (40 mg/day) on the kinetics of glucose, insulin and C-peptide during an oral glucose tolerance test (oGTT; 100 g glucose) was investigated in the third trimester. METHODS: 54 patients without tocolytic therapy (25 with a pathologic oGTT) were compared with 36 patients who received tocolytic therapy (18 patients with a pathologic oGTT). RESULTS: The patients with a normal or pathologic oGTT and with or without tocolytic therapy showed no significant differences in respect of the concentrations of glucose, insulin and C-peptide. During tocolytic therapy, an early increase in insulin was observed as well as slightly elevated C-peptide concentrations and a decreased C-peptide/insulin quotient.

[The effect of vitamin E on antioxidant tissue activity in pregnant rats with streptozocin-induced diabetes]. / Wplyw witaminy E na aktywnosc tkankowych enzymów antyoksydacyjnych u ciezarnych szczurów z cukrzyca streptozotocynowa.

UNLABELLED: The aim of our study was to establish if moderate doses of nonenzymatic antioxidant, vitamin E, could play a role in the antioxidant defence system in pregnant diabetic rats and their offspring. Two models of experimental diabetes were used: the 1st group consisted of 30 female Wistar rats which were given a single dose of streptozotocin (40 mg/kg) and were mated 7 days later, whereas in the 2nd group diabetes was induced on the 7th day of pregnancy (using the same dose of streptozotocin). In each part of the experiment diabetic animals were divided into two equal groups: vitamin E supplemented and fed with standard diet only. Our controls consisted of 20 normal rats. On the 1 day after delivery rats were decapitated and homogenates of maternal liver and uterus as well as neonatal lungs and liver were prepared. Then the following parameters were measured: malondialdehyde (MDA) concentrations in the homogenates and blood serum (colorimetric assay), glutathione (GSH) levels (colorimetric test), the activity of CuZn superoxide dismutase (SOD) (spectrophotometric method) and glutathione peroxidase (GPx) (immunoenzyme technique). Statistical analysis was performed using Mann-Whitney U test. The neonates of diabetic rats were smaller than healthy ones and serum glucose concentration was markedly higher in diabetic animals, especially in model I. MDA levels increased significantly, whereas GSH content and SOD as well as GPx activities were markedly diminished in diabetic pregnant rats and their offspring in comparison with the control group. In animals supplemented with tocopherol MDA concentrations declined significantly, GSH content and SOD activities were markedly elevated in almost all types of tissues studied, whereas glutathione peroxidase remained suppressed. CONCLUSIONS: By monitoring the activity of chosen scavenging enzymes in homogenates and body fluids we can accumulate information on ongoing biological oxidative stress. Our results suggest that diabetic pregnant rats and their neonates are exposed to an increased oxidative stress, but vitamin E supplementation could at least in part reduce its detrimental effects.

[Maternal diabetic ketosic decompensation which occurred during corticotherapy for fetal lung maturation. A report of three cases]. / Décompensation cétosique d'un diabète maternel au décours d'une corticothérapie de maturation pulmonaire fœtale. À propos de trois cas.

Three cases of ketosis decompensation occurring immediately in type I diabetic after corticotherapy for lung foetal maturation (LFM) are reported. Few of observations have been published. Increasing doses of insulin is mandatory under close monitoring of blood glucose levels, in particular according to the protocol proposed by Kaushal et al.: infusion of insulin adapted to the results of glucose levels, as a supplementation to the usual doses in each patient. Diabetes does not lead to hesitate prescribing a corticotherapy for LFM, but requires a strict control of needs in insulin to avoid a ketosis decompensation.

The PI3K/Akt and MAPK-ERK1/2 pathways are altered in STZ induced diabetic rat placentas.

Diabetic pregnancy is associated with complications such as early and late embryonic death, fetal growth disorders, placental abnormalities, and embryonal-placental metabolic disorders. Excessive apoptosis and/or changes of proliferation mechanisms are seen as a major event in the pathogenesis of diabetes-induced embryonic death, placental weight and structural anomalies. Akt and ERK1/2 proteins are important for placental and fetal development associated with cellular proliferation and differentiation mechanisms. The mechanism underlying the placental growth regulatory effects of hyperglycemia have not been elucidated. Moreover, it is still not determined how Akt and ERK1/2 proteins related proliferation and apoptosis mechanisms are influenced by Streptozotocin (STZ) induced diabetic rat placental development. The aim of this study was to investigate the expression levels and spatio-temporal immunolocalizations of Akt, p-Akt, ERK1/2 and p-ERK1/2 proteins in normal and STZ-treated diabetic rat placental development. In order to compose the diabetic group, pregnant females were injected with a single dose of 40 mg/kg STZ intraperitonally seven days before their sacrifice at 12th, 14th, 16th, 18th and 20th day of their gestation. We found that maternal diabetic environment led to a decrease in ERK1/2 and Akt phosphorylation during rat placental development. It could be said that MAPK-ERK1/2 and PI3K/Akt cell signaling pathways are affected from hyperglycemic conditions in rat placentas. In conclusion, hyperglycemia-induced placental and embryonal developmental abnormalities could be associated with reduction of Akt and ERK1/2 phosphorylation.

Altered ureteric branching morphogenesis and nephron endowment in offspring of diabetic and insulin-treated pregnancy.

There is strong evidence from human and animal models that exposure to maternal hyperglycemia during in utero development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified ex vivo using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7 ± 23.3 vs. STZ 153.2 ± 24.6, mean ± SEM, p<0.01) and ureteric tree length (control 33.1 ± 2.6 mm vs. STZ 17.6 ± 2.7 mm, p = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2 ± 64.9 vs. STZ 822.4 ± 74.0, p<0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.

Alternations of phospholipid profile in placenta of streptozotocin-induced diabetic rat.

Phospholipids have important roles in many biological processes, but their role in fetal malformation in pregnancy in diabetes is unclear. Metabolic fingerprinting of placental phospholipids in pregnant streptozotocin-induced type 1 diabetic rats was performed using Fourier transform-ion cyclotron resonance mass spectrometry. Some of the fetuses from the pregnant diabetic rats exhibited ventricular septal defects. Alterations of phospholipid compositions in the diabetic rat placenta were detected. We suggest that these changes in phospholipids in the diabetic placenta might be involved in development of fetal malformation in a type 1 diabetic pregnancy.