Role of lipids and fatty acids in macrosomic offspring of diabetic pregnancy

Diabetic pregnancy frequently results in macrosomia or fetal obesity. It seems that the anomalies in carbohydrate and lipid metabolism in macrosomic infants of diabetic mothers are due to maternal hyperglycemia, which leads to fetal hyperinsulinemia. We have developed a rat model of macrosomic offspring and assessed the onset of obesity in these animals. The macrosomic offspring born to diabetic mothers are prone to the development of glucose intolerance and obesity as a function of age. It seems that in utero programing during diabetic pregnancy creates a “metabolic memory” which is responsible for the development of obesity in macrosomic offspring. We have demonstrated that the metabolism of lipids, and altered anti-oxidant status and immune system are implicated in the etiopathology of obesity in these animals. We have reported beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) in obese animals, born to diabetic dams.     

Role of adenosine in diabetic retinopathy

In diabetic retinopathy (DR), abnormalities in vascular and neuronal function are closely related to the local production of inflammatory mediators whose potential source is microglia. Adenosine and its receptors have been shown to possess anti-inflammatory properties that have only recently been studied in DR. Here, we review recent studies that determined the roles of adenosine and its associated proteins, including equilibrative nucleoside transporters, adenosine receptors, and underlying signaling pathways in retinal complications associated with diabetes.     

Fetomaternal adrenomedullin levels in diabetic pregnancy.

We investigated whether maternal and fetoplacental adrenomedullin, a newly discovered hypotensive peptide involved in the insulin regulatory system, is modified in diabetic pregnancy. We studied its correlation with pregnancy complications associated with this disease. Thirty-six pregnant women with diabetes (13 with type I and 23 with gestational diabetes mellitus) and in 40 uncomplicated pregnancies were included. 10 out of 36 diabetic pregnancies were complicated by gestational hypertension. In each woman, adrenomedullin concentration in maternal and fetal plasma and in amniotic fluid was assessed by specific radioimmunoassay. We found that overall mean amniotic fluid adrenomedullin concentration was higher (p < 0.05) in diabetic (14.7 +/- 1.6 fmol/ml) than in uncomplicated pregnancies (10.8 +/- 0.9 fmol/ml), whereas no differences were present in maternal and fetal plasma adrenomedullin levels between diabetic and uncomplicated pregnant women. High levels of amniotic fluid adrenomedullin were found in both type I and gestational diabetes mellitus pregnancies (13.7 +/- 1.4 and 15.6 +/- 2.2 fmol/ml, respectively). Diabetic pregnancies complicated by gestational hypertension showed lower (p < 0.05) amniotic fluid adrenomedullin concentrations than normotensive diabetic patients. These findings suggest that placental adrenomedullin production is upregulated in diabetic pregnancy, and it may be important to prevent excessive vasoconstriction of placental vessels.     

Early growth retardation in diabetic pregnancy.

Thirty-five insulin-dependent diabetic women with reliable menstrual histories were examined by ultrasonic scanning in the 7th-14th weeks of pregnancy. Judged from crown-to-rump length the fetuses were on average 5.4 days smaller than those in a local normal series. Ten of the fetuses were nine days or more smaller than normal and had a lower mean birth weight than the others, though the mean gestational age was similar. Maternal diabetes was not more severe in this group, but only two of the mothers had attended a special hospital for control of their disease as compared with 19 of the remainder. Although babies of diabetic mothers are often overweight, there appears to be a subgroup of cases in which fetal growth is retarded early in pregnancy, leading to low birth weight and possibly a higher incidence of congenital malformations.     

Conservative management of pregnancy in diabetic women.

In 1979 the obstetric management of pregnancies in diabetic women in Cardiff was changed from elective delivery at 37-38 weeks to delivery at term. This change was facilitated by home monitoring of blood glucose concentrations and improved techniques for assessing fetal wellbeing. There were 35 pregnancies in insulin dependent diabetics in 1972-8 and 45 in 1979-82. The quality of diabetic control during pregnancy was equally good in both periods. The average gestation at final admission to hospital increased from 30 to 37 weeks. Amniocentesis to assess fetal pulmonary maturity was necessary in 26 patients (74%) in the first period of study and in only four (9%) in the second. Gestational age at delivery increased from 37.4 to 39.4 weeks after the change in policy. The proportion of mothers entering spontaneous term labour and delivering vaginally increased from 14.3% to 37.8%. The mean birth weight of live born, singleton infants increased from 3090 g to 3650 g, the feeding pattern improved, and respiratory problems were less common. Morbidity was reduced and perinatal mortality was not increased with conservative management of pregnancy in diabetic women.     

Residual B-cell function and glycaemic control in diabetic pregnancy

Serum C-peptide immunoreactivity (CPR), mean blood glucose and blood glycosylated haemoglobin Hb A1c were measured in 23 insulin-dependent diabetic women at 11-12, 23-24, 33-34 and 37-38 gestational weeks in order to elucidate changes in residual B-cell function during pregnancy and their influence on the glycaemic control. CPR values generally increased at the 23-33 gestational weeks, with a significant difference between the mean of the peak values and the mean of the values at the first admission. When the subjects were divided into two groups on the basis of the residual B-cell function at the first admission, the glycaemic control during pregnancy was significantly better in those with higher residual B-cell activity. The overall prevalence of marked residual B-cell activity was higher than previously reported in non-pregnant insulin-dependent diabetic subjects. The results indicate clinically important enhancement in residual B-cell function during pregnancy. The mechanism of this improvement is poorly known although the more strict management of diabetes during gestation may be an important factor.     

Self-monitoring of blood glucose in diabetic pregnancy.

Admission to hospital is usually recommended to achieve the best possible diabetic control during pregnancy. We have used blood glucose monitoring at home to find out if patients can achieve equally good control outside hospital. Twenty-five consecutive diabetic patients were studied, of whom 20 had taken insulin before pregnancy. Six of their 14 previous pregnancies had ended in perinatal death. The 25 women performed 4247 blood glucose measurements during their pregnancies. Overall the mean blood glucose concentration was 7.1 mmol/l (128 mg/100 ml); before meals the mean was 6.5 mmol/l (117 mg/100 ml). Mean concentrations were lower in the third trimester, but at no stage was control in hospital significantly better than at home. The mean hospital stay before delivery was 22 days, and all patients had live babies. Monitoring blood glucose concentrations at home produces greater understanding and motivation among patients, improves control early in pregnancy, and shortens time spent in hospital.     

Changes of oxidative stress parameters in diabetic pregnancy

BACKGROUND: The molecular aetiology of disturbed embryogenesis and other unfavourable outcomes in offspring of diabetic mothers is not fully understood. Experimental studies have suggested an involvement of radical oxygen species (ROS) in the teratological process. THE AIM OF OUR STUDY: To investigate if maternal diabetes in humans is capable of inducing alterations in vascular oxidative stress parameters and whether such changes are associated with disturbances in foetal development. METHODS: Seventy patients with pre-gestational diabetes (PGDM) were chosen for the study: 29 (41.4%) belonged to class B according to White, 15 (21.4%) to class C, 8 (11.4%) to class D, 3 (4.3%) to class F, 3 to class R and 12 (17.1%) to class F/R. In 20 (28.6%) patients from this group an unfavourable outcome was noted. All patients were subjected to intensive insulin therapy. Glycaemia was estimated by daily self-monitoring, and diurnal glucose profiles and glycated haemoglobin (HbA1c) concentrations were measured monthly. Oxidative stress was evaluated as changed superoxide dismutase, catalase and glutathione peroxidase activities as well as of malondialdehyde (MDA) and peroxides concentrations in maternal erythrocytes and blood serum. RESULTS: Prior to conception, the mean glycaemia in the group that had a planned pregnancy was 6.6mmol/l and HBA1c was 9.35%. Throughout the course of pregnancy, these parameters were maintained at a level of 6.7 mmol/l and 7.85%, respectively. The activity of all antioxidative enzymes was lower before than during pregnancy, and so was the concentration of MDA. The MDA concentrations were higher in patients with elevated glycaemia and with an unfavourable outcome. The investigated ROS, the glycaemia level, as well as the concentration of HBA1c did not show any significant differences between pregnancies with and without vascular complications. Patients with a favourable perinatal outcome presented a higher activity of antioxidant enzymes, than those with unfavourable outcome, throughout the whole course of pregnancy. The appearance of unfavourable perinatal outcomes in relation to parameters of oxidative stress was assessed by logistic regression. Both SOD and GPX activities, as well as peroxides' concentration, showed significant correlations (p < 0.005) with foetal complications. However, after mean glucose levels in the studied group were included into these analyses, this relationship was only evident with SOD and GPX activity (p < 0.0016). CONCLUSION: Oxidative stress is one of several important factors contributing to unfavourable outcome of human diabetic pregnancy.     

Role of HLA-G and other immune mechanisms in pregnancy

Pregnancy loss (abortion) and pre-eclampsia represent the most common disorders in pregnant women. Besides infection, there are anatomical, endocrinological, genetic and immunological factors that can induce pregnancy disorders. Because the exact mechanisms of physiological pregnancy maintenance are still not clearly understood, the search for genes and proteins fulfilling this role is still in progress. One of the immune molecules that plays a beneficial role in pregnancy is the nonclassical HLA-G molecule. The molecule is mainly expressed on trophoblast cells in the foetal placenta and induces the immune tolerance of the foetus via its interaction with inhibitory receptors on maternal NK cells and CD8⁺ T lymphocytes. In relation to pregnancy disorders, associations between HLA-G polymorphism, HLA-G level and HLA-G function were described. Thus, the HLA-G molecule can be used as a new diagnostic marker and, potentially, for the future therapy of pregnancy disorders.     

Role of three isoforms of phospholipase A2 in capacitative calcium influx in human T-cells.

The present study was conducted on human Jurkat T-cell lines in order to elucidate the role of phospholipase A2 in capacitative calcium entry. We have employed thapsigargin (TG) that induces increases in [Ca2+]i by emptying the calcium pool of endoplasmic reticulum, followed by capacitative calcium entry. We designed a Ca2+ free/Ca2+ reintroduction (CFCR) protocol for the experiments, conducted in Ca2+-free medium. By employing CFCR protocol, we observed that addition of exogenous arachidonic acid (AA) stimulated TG-induced capacitative calcium influx. The liberation of endogenous AA and its autocrine action seems to be implicated during TG-induced capacitative calcium influx: TG potentiates the induction of constitutively expressed mRNA of four PLA2 isoforms (type 1B, IV, V, VI), the inhibitors of the three PLA2 isotypes (type 1B, V, VI) inhibit TG-induced release of [3H]AA into the extracellular medium, and finally, these PLA2 inhibitors do curtail TG-stimulated capacitative calcium entry in these cells. These results suggest that stimulation of three isoforms of PLA2 by thapsigargin liberates free AA that, in turn, induces capacitative calcium influx in human T-cells.     

Eicosanoid production and transfer in the placenta of the diabetic pregnancy

The metabolism of arachidonic acid (AA) and the transfer of its metabolites was determined in in vitro perfused placental tissue from normal pregnancies and those complicated by maternal insulin-dependent diabetes mellitus (IDDM). 14C-labelled AA was recirculated in the fetal circulation for 60 min while 3H-AA was recirculated in the maternal circulation. Placental effluent was subjected to high performance liquid chromatography (HPLC) and analysis of dual-label scintillation counts. Placentae from IDDM pregnancies converted 3-6 times more radiolabelled AA to eicosanoids than did normal placentae. In addition, the transfer of eicosanoids into the opposing circulation was doubled in placentae from IDDM pregnancies compared to normal placentae. The predominant direction of eicosanoid transfer in both groups of placentae was in the fetal-to-maternal direction. The relative amounts of eicosanoids produced was also altered in placentae from IDDM pregnancies. Increased amounts of thromboxane (Tx) B2 and hydroxyeicosatetraenoic acids (HETEs) were present in both circulations of placentae from IDDM pregnancies. Levels of 6-keto prostaglandin F1a (6KPGF1a) were significantly reduced in both circulations in placentae from IDDM pregnancies. Thus, the ratio of TxA2 to PGI2 and the ratio of HETEs to PGI2 were both significantly increased in placentae from IDDM pregnancies. These results suggest an imbalance in eicosanoid production which may be relevant to abnormal placental structure and function in IDDM pregnancies.