The Effects of Chronic Fetal Hyperglycemia on Substrate Uptake by the Ovine Fetus and Conceptus

Abstract

ABSTRACT. Hyperglycemia in fetal sheep has been shown to increase the fetal metabolic rate. Fetal venous glucose infusion was performed in eight late gestation, chronically catheterized fetal lambs to assess any changes in substrate uptake by the ovine uterus and conceptus. Fetal glucose infusion (1 1.9 f 0.6 mg glucose. kg-'. min-') caused a stable increase in fetal plasma glucose concentration approximately 3-fold above baseline. The fetal glucose entry rate increased from 6.6 f 0.7 to 9.3 f 0.6 mg.kg-'. min-' by day 3 of infusion (p < 0.01) despite a net umbilical glucose excretion during the period of fetal hyperglycemia. Due to a concomitant increase in fetal oxygen consumption, no change in fetal glucose/02 quotient was observed. A significant relationship was noted (p < 0.02) between the fetal glucose entry rate and the rate of fetal oxygen consumption. Fetal glucose infusion caused a decrease in uterine glucose uptake as well. No changes were observed in calculated net placental glucose uptake although the relative fetal contribution increased from net placental exit to fetus to a placental uptake amounting to 20.8 f 5.8% of the total placental glucose uptake ( p < 0.01). Although no changes in fetal lactate concentration occurred, both maternal and fetal lactate entry rates increased, the magnitude of increase being significantly related to fetal glucose concentration. Both maternal and fetal insulin concentrations rose during the period of fetal hyperglycemia and were related to the respective increases of maternal or fetal substrate uptakes but not to fetal oxygen consumption. These studies suggest that glucose induces significant stimulation of fetal oxidative metabolism and that fuel needs during this period are met by accelerated fetal glucose entry as well as accelerated placental production of lactate. Superimposed hypoxemia during these circumstances might be expected to have a greater effect on fetal oxygenation and pH than during normoxemic circumstances. (Pediatr Res 19: 659-666, 1985) Abbreviations f, umbilical blood flow (ml. kg-'. min-') F, uterine blood flow (ml -min-') glu, glucose concentration (mgldl) lac, lactate concentration (mM) ala, alanine concentration (mM) Common abnormalities in human infants of diabetic mothers include gross fetal macrosomia and visceromegaly with attendant postnatal hyperinsulinemia and hypoglycemia (1, 2). Autopsied infants of diabetic mothers have shown evidence of significant pancreatic islet hyperplasia (3,4) to support the hypothesis that excesses in maternal-fetal ducose transfer are responsible for fetal pancreatic islet stimulation and subsequent signs of fetal insulin excess. However, some features shared by fetuses of severely diabetic mothers such as an increased late stillborn rate and a poor ability to tolerate labor have not been adequately explained by the mechanism of excessive substrate transfer. Previous information obtained from chronically catheterized fetal sheep has suggested that fetal glucose infusion is associated with stimulation...

Maternal diabetes alters the development of ductus venosus shunting in the fetus

“…The DV shunts oxygenated UV blood to the fetal heart and brain, bypassing the liver , and increased shunting serves as a protective mechanism . In fetal lamb and humans with gestational diabetes, hyperglycemia leads to accelerated metabolism and oxygen consumption, causing chronic fetal hypoxemia . However, the UV blood distribution and DV flow pattern in pregestational diabetic pregnancies have not been reported previously.…”

Sources and Disposition of Fetal Glucose: Studies in the Fetal Lamb

“…32 Thus, glucose kinetics appear to be similar whether or not insulin is allowed to increase or not. Similarly, Philipps et al 16 have demonstrated that 3 days of glucose infusion at a rate of 12.5 mg/kg/min to the fetal sheep results in statistically indistinguishable glucose concentrations whether or not insulin concentration increases. 16 In these studies, the increase in insulin was prevented by the prior fetal injection of streptozotocin, a known beta-cell toxin.…”

“…Similarly, Philipps et al 16 have demonstrated that 3 days of glucose infusion at a rate of 12.5 mg/kg/min to the fetal sheep results in statistically indistinguishable glucose concentrations whether or not insulin concentration increases. 16 In these studies, the increase in insulin was prevented by the prior fetal injection of streptozotocin, a known beta-cell toxin. Since glucose concentration reached a plateau while glucose infusion was ongoing, the rate of glucose utilization must have equaled total glucose uptake (umbilical glucose uptake plus the exogenous glucose infusion rate).…”

“…This rate of glucose utilization did not appear to be influenced to any appreciable extent by the ability to increase insulin secretion, since there was a marked disparity in the insulin levels between animals that had received streptozotocin versus controls, whereas glucose concentrations were equivalent. 16 Thus, it would appear from several independent sources that substrate availability and concentration appear to be the major determinants of fetal glucose utilization, at least in the fetal sheep.…”

Effect of hyperinsulinemia on amino acid utilization in the ovine fetus

“…These observations define a relatively high sensitivity of the effect of plasma insulin concentration, independent of changes in plasma glucose and amino acid concentrations, on amino acid utilization in the late-gestation ovine fetus. Normal dietary variations in maternal and fetal glucose concentrations, as well as experimental manipulations of fetal glucose concentrations, produce a similar magni-tude of change in fetal insulin concentrations (11,26). Thus it is reasonable to conclude that physiological increases in insulin concentration in late-gestation fetal sheep have the capacity to promote acute increases in fetal amino acid and nitrogen utilization.…”