The Effect of Prolonged Intrauterine Hyperinsulinemia on Iron Utilization in Fetal Sheep

Abstract

ABSTRACT. Newborn infants of poorly controlled insulindependent diabetic mothers demonstrate a redistribution of iron from serum and tissue stores into red blood cells. These changes may be due to increases in iron utilization during augmented Hb synthesis, which compensates for chronic intrauterine hypoxemia induced by prolonged fetal hyperinsulinemia. We tested this hypothesis by measuring plasma iron, total iron-binding capacity, percent iron-binding capacity saturation (total iron-binding capacity saturation), Hb concentration, total red cell Hb, and total red cell iron in the arterial blood of 11 chronically instrumented fetal sheep after 7-12 d of infusion with 15 U/day of insulin (n = 5) or placebo (n = 6). The insulin-infused fetal sheep had higher mean f SD plasma insulin concentrations (448 +. 507 versus 11 f 8 mU/L; p < 0.001) and lower arterial oxygen saturations (38 f 7 versus 54 2 9%; p < 0.02). The insulin-infused group had a lower mean plasma iron concentration (20.8 f 10.9 versus 42.1 f 14.7 pM/L;p < 0.02) and total iron-binding capacity saturation (36 2 20 versus 64 2 22%; p < 0.02) and a higher total red cell Hb (45.4 + 8.7 versus 32.6 2 8.8 g; p < 0.02) and total red cell iron content (154 f 29 versus 111 f 29 mg; p < 0.02) when

The Effect of In Utero Insulin Exposure on Tissue Iron Status in Fetal Rats

“…Our findings, when consid-* p < 0.05 compared to placebo. ered in conjunction with our previous observations of decreased plasma iron concentrations during hyperinsulinemia-induced erythropoiesis in fetal sheep (4), suggest that late gestation hyperinsulinism results in a reduction of plasma and tissue iron content in the fetus to provide iron needed for red cell mass expansion (5). These two models potentially explain the abnormal plasma iron status found in infants of poorly controlled diabetic mothers at birth (1-3) and raises the possibility that these infants may be at risk for reduced tissue iron content as well.…”

“…The resultant compensatory expansion of the red cell mass, which we have documented in fetal sheep (4,5) and which is characterized by polycythemia in infants of diabetic mothers (12), necessitates an increase in iron delivery to the bone marrow for Hb synthesis. This increased iron use is thought to result in the reduced plasma iron concentrations, which we have documented in fetal sheep and newborn infants of diabetic mothers (2-4).…”

“…Because we did not monitor arterial oxygen saturation or erythropoietic response in the fetuses, we can only surmise that events similar to those documented in fetal sheep (4,5) took place in the rat in response to insulin loading. We did not find higher insulin concentrations in the insulin-treated groups at the time of death.…”

“…The severity of these abnormalities is inversely related to the mother's glycemic control during pregnancy, and is directly related to the degree of macrosomia at birth and elevations of cord blood erythropoietin and Hb concentrations (3). Using chronically catheterized fetal sheep, we have previously shown that in utero hyperinsulinemia causes fetal hypoxia, compensatory expansion of the red cell mass, and low serum iron concentrations, most likely due to increased iron utilization for Hb synthesis (4,5).…”

Iron Deficiency Alters Auditory Recognition Memory in Newborn Infants of Diabetic Mothers

“…The degree of iron deficiency in the newborn IDM is also a function of poor maternal glycemic control and to the degree of fetal hypoxia and augmented erythropoiesis (5). Studies in fetal sheep demonstrate that fetal hyperglycemia with its attendant hyperinsulinemia results in an increased fetal metabolic rate (51,52) and increased oxygen demand with a compensatory increase in the red cell mass (53)(54)(55). The latter increases the utilization of iron and in severe cases causes depletion of tissue iron initially from liver, heart, and finally the brain as available fetal iron is shifted into the red cell mass (6,18).…”