Patricia Porte

Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus.

Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (11.9 +/- 0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial O2 content difference by 24 h of infusion (P less than 0.01). Calculated fetal O2 consumption increased from 8.1 +/- 0.4 ml/kg per min in the control period to a maximum value of 10.6 +/- 0.3 ml/kg per min by third infusion day (P less than 0.01), which is an increase of approximately 30%. The degree of stimulation of fetal O2 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal O2 consumption was accompanied by a significant increase in fetal O2 extraction with no change in either fetal O2 delivery or fetal blood O2 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial PCO2 was linearly related (P less than 0.001) to the magnitude of increase in fetal O2 consumption. These studies suggest that chronic fetal hyperglycemia induces a state of accelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

Eosinophils, but Not Eosinophil Peroxidase or Major Basic Protein, Are Important for Host Protection in Experimental Brugia pahangi Infection

ABSTRACT The attenuation of eosinophilia by the administration of monoclonal antibodies to CCR3 consistently correlates with impairment in worm elimination following primary intraperitoneal Brugia pahangi infections in mice. Host protection was unimpaired in mice deficient in eosinophil peroxidase (EPO) or major basic protein 1 (MBP-1), suggesting that eosinophils are essential in host protection but that neither EPO nor MBP-1 alone is.

The effects of chronic fetal hyperglycemia on substrate uptake by the ovine fetus and conceptus

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 (11.9 ± 0.6 mg glucose kg−1 min−1) caused a stable increase in fetal plasma glucose concentration approximately 3-fold above baseline. The fetal glucose entry rate increased from 6.6 ± 0.7 to 9.3 ± 0.6 mg kg−1 min−1 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/O2 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 ± 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.I 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.

Inhibition of glucose-induced insulin secretion by indomethacin and sodium salicylate in the fetal lamb☆☆☆

The modulation of fetal insulin secretion by prostaglandins was studied with the aid of the prostaglandin synthesis inhibitors indomethacin and sodium salicylate in 10 chronically catheterized fetal lambs. Glucose-induced fetal insulin secretion was inhibited within 60 minutes by preinjection of either indomethacin or sodium salicylate in the fetal lambs. In the sodium salicylate experiments a significant (p less than 0.01) dose-related response (degree of insulin suppression) was noted between doses of 100 to 350 mg/kg of fetal weight. In a selected group of sodium salicylate injections prostaglandin levels were found to fall to 58% of control by 2 hours after injection. Five neonatal lambs exposed to a similar regimen were noted to have an exaggerated insulin response to glucose infusion when compared to fetal lambs. However, indomethacin or sodium salicylate pretreatment resulted in no suppression of glucose-induced insulin release. This finding may be of importance in explaining the observation of an increased incidence of fetal growth retardation after long-term exposure to salicylates in humans and in animal models.

Effects of Fetal Insulin Secretory Deficiency on Metabolism in Fetal Lamb

Fetal insulin secretion may be of importance in determining both fetal metabolic rate and glucose homeostasis in the resting state. To investigate this question, streptozocin (STZ) was injected into 10 late-gestation fetal lambs, and the effects of STZ on fetal pancreatic insulin storage and secretion, fetal metabolic rate, and umbilical glucose uptake were then studied. Fetal STZ injection caused a relative fetal hyperglycemia by 24 h after injection. Fetal hyperglycemia reached a maximum by 72 h and persisted for at least 10 days after injection. Neonates delivered after fetal injection were frankly diabetic. Fetal STZ injection was associated with complete suppression of both glucose- and tolbutamide-stimulated insulin release, although no changes in peripheral insulin concentration were observed when compared with controls. Fetal pancreatic insulin content was only 13% of that expected on the basis of gestational age. In a subgroup of 7 STZ-treated fetal lambs, fetal hyperglycemia was related to decrements in umbilical venoarterial difference of glucose, umbilical glucose uptake, and glucose-O2 quotient. No changes in maternal glucose homeostasis or in fetal O2 consumption were noted. The data suggest that deficient fetal insulin storage and secretion are associated with a decrement in exogenous fetal glucose entry but not in fetal metabolic rate. Whether the observed fetal changes relate to enhanced endogenous fetal glucoseproduction with a passive decrease in maternofetal glucose transfer or are simply due to a decrease in overall fetal glucose utilization is not known. It is speculated that a quantitative decrease in pancreatic insulin secretion is responsible for the observed changes.

Regulation of cerebral glucose metabolism in normal and polycythemic newborn lambs

In contrast to previous investigations, a recent study of polycythemic lambs suggested that cerebral glucose delivery (concentration × blood flow), not arterial glucose concentration, determined cerebral glucose uptake. In the present study, the independent effects of arterial glucose concentration and delivery on cerebral glucose uptake were examined in two groups of chronically catheterized newborn lambs (control and polycythemic). Arterial glucose concentration was varied by an infusion of insulin. CBF was reduced in one group of lambs (polycythemic) by increasing the hematocrit. At all arterial glucose concentrations, the cerebral glucose delivery of the polycythemic group was 59.6% of the control group. At arterial glucose concentrations of > 1.6 mmol/L, cerebral glucose uptake was constant and similar in both groups. At arterial glucose concentrations of ≤1.6 mmol/L, cerebral glucose uptake was unchanged in the control group, but was significantly decreased in the polycythemic group. In contrast, the cerebral glucose uptake was similar in both groups over a broad range of cerebral glucose delivery values. At cerebral glucose delivery values ≤83 μmol/min/100 g, there was a significant decrease in cerebral glucose uptake in both groups. During periods of low cerebral glucose delivery and uptake, cerebral oxygen uptake fell in the control group but remained unchanged in the polycythemic group. Maintenance of cerebral oxygen uptake in the polycythemic group was associated with an increased extraction and uptake of lactate and β-hydroxybutyrate. We conclude that cerebral glucose delivery, not arterial glucose concentration alone, determines cerebral glucose uptake.

Intrauterine growth retardation after long-term maternal salicylate administration in the rabbit☆

The effects of chronic maternal salicylism on fetal growth were studied in chronically catheterized pregnant rabbits. Graded intravenous infusions of sodium salicylate were given continuously between days 22 and 29 of gestation. Maternal plasma salicylate concentrations (mean +/- SD) of 12.0 +/- 1.6 mg/dl (low-dose group) or 24.1 +/- 5.3 mg/dl (high-dose group) were achieved. Control rabbits were infused with saline solution. Pups were delivered by hysterotomy on day 29. Fetal/maternal salicylate concentration ratios were near unity for both infusion groups. There were significant dose-related reductions (mean +/- SD) in fetal weight (control, 39.7 +/- 6.7 gm; low-dose group, 34.4 +/- 6.4 gm; high-dose group, 22.2 +/- 7.1 gm; p less than 0.001) and in crown-rump length (control, 9.7 +/- 0.45 cm; low-dose group, 9.1 +/- 0.68 cm; high-dose group, 7.7 +/- 0.86 cm; p less than 0.001). There was a significant reduction in fetal brain weight only in the high-dose group, and brain weight/fetal weight ratios were increased, suggesting relative sparing of brain growth. Liver weight was significantly reduced in both low- and high-dose groups. In contrast to results in previous animal studies, standardized intravenous maternal salicylate administration in rabbits induced a reproducible and dose-dependent asymmetrical fetal growth retardation.