125I insulin receptor binding characteristics on umbilical cord blood erythrocytes from normal and diabetic pregnancies

Umbilical cord blood erythrocyte insulin receptor characteristics of 13 normal and 14 diabetic pregnancies were evaluated to elucidate the effect of maternal diabetes on fetal insulin binding. Specific insulin binding to erythrocytes was similar in the two populations. However, in comparison to infants of nondiabetic women, infants of diabetic mothers exhibited a fourfold decrease in receptor affinity and a fourfold increased number of receptor sites in spite of significant hyperinsulinemia. The in utero infant of a diabetic mother therefore functions with a comparatively low affinity/high capacity insulin binding system that allows it to maintain normal insulin sensitivity in the presence of hyperinsulinemia. This altered, but balanced, mechanism may play an important role in glycemic homeostasis in utero and in the development of neonatal hypoglycemia.     

Human placental growth hormone causes severe insulin resistance in transgenic mice

OBJECTIVE: The insulin resistance of pregnancy is considered to be mediated by human placental lactogen, but the metabolic effects of human placental growth hormone have not been well defined. Our aim was to evaluate the effect of placental growth hormone on insulin sensitivity in vivo using transgenic mice that overexpress the human placental growth hormone gene. STUDY DESIGN: Glucose and insulin tolerance tests were performed on 5 transgenic mice that overexpressed the human placental growth hormone variant gene and 6 normal littermate controls. The body composition of the mice was assessed by dual-energy radiograph absorptiometry, and free fatty acid levels were measured as a marker of lipolysis. RESULTS: The human placental growth hormone levels in the transgenic mice were comparable to those attained in the third trimester of pregnancy. These mice were nearly twice as heavy as the control mice, and their body composition differed by a significant increase in bone density and a small decrease in percentage of body fat. Fasting insulin levels in the transgenic mice that overexpressed placental growth hormone were approximately 4-fold higher than the control mice (1.57 +/- 0.22 ng/mL vs 0.38 +/- 0.07 ng/mL; P <.001) and 7 times higher 30 minutes after glucose stimulation (4.17 +/- 0.54 ng/mL vs 0.62 +/- 0.10 ng/mL; P <.0001) with no significant difference in either fasting or postchallenge glucose levels. Insulin sensitivity was markedly decreased in the transgenic mice, as demonstrated by an insignificant decline in glucose levels after insulin injection compared with the control mice, which demonstrated more than a 65% reduction in glucose levels (P <.001). CONCLUSION: Human placental growth hormone causes insulin resistance as manifested by fasting and postprandial hyperinsulinemia and minimal glucose lowering in response to insulin injection. Human placental growth hormone is a highly likely candidate to mediate the insulin resistance of pregnancy.     

Significance of umbilical and uterine artery velocimetry in the well-controlled pregnant diabetic

The measurement of umbilical and uterine artery velocity waveforms was used to study pregnancies complicated by diabetes. Continuous wave Doppler velocimetry was used to identify the umbilical and uterine artery velocity waveforms. A systolic:end diastolic ratio (S:D ratio) was calculated to analyze the obtained velocity waveforms. We treated 33 tightly controlled and monitored diabetic gravidas. The mean blood sugar value for this population was 95 +/- 8 mg/dL, and the mean umbilical artery S:D ratio was 2.5 +/- 0.3. That group of patients was compared to a group on which we reported previously. Statistically significant differences were found between the well-controlled and poorly controlled populations in third-trimester S:D ratios, number of stillbirths and neonatal morbidity. Uterine artery velocimetry allowed the identification of a patient who developed preeclampsia. This study seems to have indicated that umbilical and uterine artery velocimetry may have an adjunctive role in the surveillance of pregnancies complicated by diabetes.     

Human placental lactogen (hPL) model for the normal pregnancy.

This study includes 75 females with normal pregnancies, and presents individual cases of longitudinal series of human placental lactogen (hPL). Samples for hPL levels are taken during the period from gestational week 26 and until labour. A modified Gompertz equation is defined, characterized as growth at a continuously decreasing exponential rate, which finally plateaus in gestational week 36. This modified Gompertz equation adequately fitted individual hPL series. The work describes that a final hPL forecast for the normal pregnancy could be obtained in gestational week 30 using knowledge on maternal height and age, combined with a single hPL sample. The present model was applied in six pathological pregnancies with intrauterine growth retardation, and in all cases measured hPL levels were below the model estimate.     

Expression of intercellular adhesion molecule-1 in umbilical and placental vascular tissue of gestational diabetic and normal pregnancies

Objective  

Expression of intercellular adhesion molecule-1 (ICAM-1), a marker of endothelial dysfunction leading to damaging vascular disorders, in umbilical and placental vascular tissue of gestational pregnancies was compared to non-diabetic controls.     

Human placental lactogen in pre-eclampsia

Summary. Serum placental lactogen (hPL) was measured in serial blood samples obtained from 663 pregnant women at weekly intervals from 36 to 40 weeks. The group included 231 women with pre-eclampsia. Levels of h PL were significantly elevated in primigravidae with this condition but not in multigravidae. In all groups h PL levels were significantly reduced in association with growth retardation, but the clinical value of this observation appeared to be greater in multigravidae than in primigravidae. It is suggested that in primigravidae with pre-eclampsia maternal hPL levels reflect both the pathology of the disease as well as the condition of the fetus.     

Oral contraceptives and insulin receptor binding in normal women and those with previous gestational diabetes

The effect of a low-dose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel) on glucose tolerance, plasma insulin response to a glucose challenge, and insulin receptor binding to monocytes and erythrocytes was investigated in seven women with previous gestational diabetes and seven nondiabetic control subjects. Investigations were performed in the luteal phase before the hormonal intake and after hormonal treatment for 2 and 6 months. Before treatment, women with previous gestational diabetes had significantly impaired glucose tolerance (p less than 0.05) when compared with the healthy controls, but no differences in insulin receptor binding were observed. Glucose tolerance and the insulin response to oral glucose remained unchanged in both groups during the treatment period. In the control subjects a significant decrease (p less than 0.05) in insulin receptor binding to monocytes was observed after hormonal intake for 6 months whereas the insulin receptor binding remained unchanged in the women with previous gestational diabetes. No correlation was found between the receptor binding data obtained from monocytes and erythrocytes in either group of women. The study demonstrates that in lean nondiabetic women and women with previous gestational diabetes of normal weight without first-degree history of diabetes there is no apparent direct association between glucose tolerance, plasma insulin levels, and insulin binding to erythrocytes and monocytes during intake of low-dose oral contraceptives.     

Mobilization of placental glycogen in diabetic rats

Since glycogen accumulates in the placenta in diabetes and does not appear to be susceptible, in general, to the effect of fasting, the capacity of catecholamines to elicit glycogenolysis was investigated in non-diabetic and diabetic rats. Injection of epinephrine or isoproterenol caused a decrease in placental glycogen within 20 min in non-diabetic, 20 day pregnant rats, in association with the rise in serum glucose and lactate. Incubation with isoproterenol induced glycogenolysis in placental slices from non-diabetic and diabetic rats, nearly commensurate with lactate production. This effect of isoproterenol was concentration dependent and of similar magnitude in non-diabetic and diabetic rat placentas. Glucagon was ineffective in inducing placental glycogenolysis in vivo or in vitro. Protracted stimulation of the catecholamine receptor by the administration of cholera toxin effected a pronounced decrease in placental glycogen, percentagewise higher in diabetic than non-diabetic rats. These results show that placental glycogen is amenable to mobilization by hormonal stimuli effecting phosphorylase activation.     

The effect of insulin on oestradiol and progesterone release by normal and diabetic placentae in vitro

In an attempt to define better the metabolic differences between normal, insulin-dependent and non-insulin-dependent diabetes, we have compared the effect of insulin on the secretion of oestradiol and progesterone in term placental explant culture. Placentae from non-diabetic and from diabetic, non-insulin-dependent diabetic patients demonstrated a similar response to incubation with insulin. This response consisted of a dose-dependent increase in both oestradiol and progesterone in the incubation media after 24 h. In contrast, the placentae of insulin-dependent diabetics showed a decrease in oestradiol and no change in progesterone secretion following exposure to insulin. These differences in response to insulin may underlie other metabolic differences between the placentae in the different groups.     

Glucocorticoids inhibit placental cytokines from cultured normal and preeclamptic placental explants

Glucocorticoids are used in pregnancy to enhance fetal lung maturity as well as to ameliorate antepartum and postpartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, but it is not clear if glucocorticoids can modulate placental cytokine production. The aim of this study is to examine the effect of glucocorticoids at equivalent doses used for fetal lung maturity on placental tissue production of cytokines (IL-10, IL-6 and TNF-alpha). Placental biopsies were taken from the decidual surface of term placentas of normal pregnancy (n = 5) and preeclampsia (n = 5). Villous explants were cultured with increasing concentrations of glucocorticoids (betamethasone and methyl-prednisolone, 0.0025 microM, 0.25 microM and 25 microM). The dose effect of glucocorticoids on cytokines (TNF-alpha, IL-6 and IL-10) production was examined using ELISA. There was a stepwise reduction of TNF-alpha (23.6-97.5% reduction) and IL-6 (13.7-71% reduction) with increasing doses of betamethasone and methyl-prednisolone from placentas of women with preeclampsia and normal pregnancy. However, IL-10 was not altered in conditioned medium by increasing doses of glucocorticoids. Our data suggest that the ratio of pro-inflammatory to anti-inflammatory cytokine (Th1/Th2) is potentially altered by exogenous glucocorticoids. These changes have a favourable effect on the ratio in preeclampsia with a reduction in the potentially vascular active pro-inflammatory cytokines but without altering or decreasing the necessary anti-inflammatory cytokine IL-10 production in placental tissue.     

Angiogenesis and placental growth in normal and compromised pregnancies

Research on the subject of pre-eclampsia has revolved around placental growth and angiogenesis, as both are central to the aetiology of the disease. Vascular angiogenic growth factor (VEGF) is elevated in pre-eclampsia and correlates with the severity of disease. Its actions in vitro mimic the actions of plasma from women with pre-eclampsia. This chapter examines the available evidence that implicates VEGF in the maternal systemic effects seen in pre-eclampsia, and discusses how an understanding of this growth factor could lead to diagnostic and therapeutic options. Oxygenation status is the unifying concept that surrounds the discussion of placental growth and angiogenesis. The concept that 'hypoxia' is too simplistic a notion to describe pre-eclampsia is discussed. Maldevelopment of the angiogenic process can be assessed by Doppler ultrasound. The future may see a role for magnetic resonance imaging in the identification of poorly perfused placenta.     

Fetal circulation in normal pregnancy and in placental insufficiency

The fetal circulation is different from the adult circulation. One of the quite common conditions that are challenging to the developing fetus is placental hypoxia. Regardless of its cause, placental vascular insufficiency is commonly assumed to be an important factor in the development of intrauterine growth retardation. Several mechanisms are involved in the fetal adaptation to the decompensation during hypoxemia. Doppler Ultrasound technologies can help to evaluate of the fetal wellbeing.