Increased N-glycosylation and reduced transferrin-binding capacity of transferrin receptor isolated from placentae of diabetic women.

Infants of diabetic mothers are frequently born iron deficient because their fetal iron demand exceeds placental iron transport capacity. Although transferrin receptor (TfR) expression is increased, binding to diferric transferrin is decreased proportionately to the severity of maternal disease. It is hypothesized that TfR isolated from diabetic placentae has altered N-glycosylation since proper glycosylation of N-linked oligosaccharides is important for normal TfR binding kinetics to diferric transferrin. TfR was obtained from syncytiotrophoblastic membranes of six diabetic and six non-diabetic human placentae. Competitive binding to 125I-transferrin demonstrated a higher Kd in the diabetic TfR (P = 0.04), directly correlated to cord serum C-peptide concentration (r = 0.81, P < 0.001). The molecular weight of the monomeric form of TfR prior to treatment with glycopeptidase F (PNG-F) was greater in the diabetic group (P < 0.001) was directly related to the Kd (r = 0.77, P = 0.002). Treatment with PNG-F eliminated the molecular weight difference between the two groups. Increased glycosylation of the N-linked oligosaccharides of TfR isolated from diabetic placentae may alter the three-dimensional structure or charge of the receptor, thus reducing its binding affinity for transferrin.

Liver and brain iron deficiency in newborn infants with bilateral renal agenesis (Potter's syndrome).

Significant changes in fetal iron status potentially occur in pregnancies in which reduced fetal nutrient delivery is severe enough to result in intrauterine growth retardation (IUGR), particularly if chronic fetal hypoxia is also present and increases fetal iron demand for hemoglobin synthesis. Neonates rarely die following IUGR secondary to maternal preeclampsia, but bilateral renal agenesis, which is also characterized by reduced maternal-fetal blood flow, late gestation placental failure, and IUGR, is uniformly fatal. We measured neonatal liver iron concentration, as an assessment of fetal storage iron status, and heart and brain iron concentrations, as assessments of nonheme tissue iron status, in 11 infants who died in the neonatal period of bilateral renal agenesis, and compared them with values for gestational age-matched control infants whose gestation was not complicated by fetal growth retardation or hypoxia. Stainable nonheme iron in the hepatocytes was significantly reduced in all and completely absent in 8 of the 11 cases of renal agenesis (P < .001 compared with control). The mean +/- SEM liver iron concentration of the bilateral renal agenesis group (999 +/- 218 micrograms/g dry tissue weight) was 26% of the control value (3894 +/- 548 micrograms/g dry tissue weight; P < .001). Brain iron concentration was also lower in the group with bilateral renal agenesis (109 +/- 17 vs. 161 +/- 19; P = .015) and was correlated with liver iron concentration (r = .47; P = .03). Heart iron concentrations were similar in the two groups. Nine of the subjects with bilateral renal agenesis had placental weights below the fifth percentile for gestational age. The bilateral renal agenesis group had a lower mean birth weight (P < .001) and had a higher prevalence of fetal growth retardation (55% vs. 0%; P < .001). We conclude that infants with bilateral renal agenesis are at risk for severe iron deficiency of storage and nonstorage tissues. Liveborn infants with nonfatal fetal conditions characterized by significant restriction of maternal-fetal blood flow may also be at significant risk for postnatal iron deficiency.

Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers.

Infants of diabetic mothers frequently have polycythemia, elevated serum erythropoietin concentrations, and decreased serum iron and ferritin concentrations, likely representing a redistribution of fetal iron into erythrocytes to support augmented fetal hemoglobin synthesis. We hypothesized that fetal liver, heart, and brain iron concentrations are also reduced in these infants. After obtaining autopsy tissue from infants who had died before 7 days of age, we measured liver, heart, and brain iron concentrations using atomic absorption spectrophotometry. Seven infants of diabetic mothers and seven gestational age-matched control infants were studied. All infants of diabetic mothers had pancreatic islet cell hyperplasia, indicating fetal hyperglycemia and hyperinsulinemia. Liver iron concentrations in the infants of diabetic mothers were 6.6% of control values (489.0 +/- 154.4 vs 7379.7 +/- 1473.8 micrograms/gm dry tissue weight (mean +/- SEM); p less than 0.001), heart iron concentrations were 43.9% of control values (124.7 +/- 20.5 vs 284.1 +/- 34.8 micrograms/gm dry tissue weight; p less than 0.002), and brain iron concentrations were 60.6% of control values (106.1 +/- 13.7 vs 175.2 +/- 10.7 micrograms/gm dry tissue weight; p less than 0.003). Heart and brain iron concentrations were directly correlated with liver iron concentrations (r = 0.80 for both; p less than 0.001) and indicated that hepatic iron was greater than 75% depleted before heart and brain iron reduction. We conclude that severely affected infants of diabetic mothers have reduced liver, heart, and brain iron concentrations. The role of tissue iron deficiency in the genesis of the abnormal clinical findings in these infants deserves further consideration.

Placental transferrin receptor in diabetic pregnancies with increased fetal iron demand.

Augmented fetal hemoglobin synthesis during diabetic pregnancy increases fetal iron demand. To study the effect of increased fetal iron demand on placental transferrin receptor (TR), we utilized a monoclonal antibody to localize placental TR immunoreactivity and 125I-labeled transferrin to study TR binding characteristics in 10 placentas from poorly controlled diabetic mothers with increased fetal iron demand and 10 placentas from nondiabetic mothers. The infants born to the diabetics had higher cord serum C-peptide, erythropoietin, and hemoglobin concentrations, indicating fetal hyperinsulinemia and hypoxia, with augmented erythropoiesis and iron demand. TR immunoreactivity was localized to the syncytiotrophoblast in both groups, was greater in the diabetic group, and was inversely correlated with fetal storage iron (r = -0.75; P < 0.001). Scatchard analysis of 125I transferrin binding data confirmed greater receptor number (Bmax 17.9 +/- 2.2 vs. 12.6 +/- 1.3 pM/mg protein, P = 0.05), but reduced binding affinity [dissociation constant (Kd) 7.6 +/- 0.9 vs. 5.4 +/- 0.4 nM/l, P = 0.03] in the diabetic group. The TR staining intensity, Bmax, and Kd were each correlated with cord C-peptide, suggesting either a primary or secondary role for fetal hyperinsulinemia in TR expression. This study provides in vivo evidence that fetal factors, such as iron demand or hyperinsulinemia, influence regulation of placental TR in humans. The increase in placental syncytiotrophoblastic TR expression associated with reduced cord serum ferritin concentration suggests that the fetus utilizes both increased placental iron transport and mobilization of fetal iron stores to support augmented fetal erythropoiesis.