Chronic Hyperglycemia Reduces Surface Active Material Flux in Tracheal Fluid of Fetal Lambs

Warburton, David

doi:10.1172/jci110799

Cited by 22 publications

(9 citation statements)

References 24 publications

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“…In situations where glucose delivery to the lung remains high near term, metabolic maturation of the fetal lung may be compromised. This is supported by the observation that fetal hyperglycemia is implicated as a major etiologic factor in the pathogenesis of the respiratory distress syndrome (leading to decreased surfactant availability) in the infants of diabetic mothers (24,25). Further, in vitro studies have described a much greater lung utilization of glucose in fetal animals than in newborn and older animals (26).…”

Section: Discussionmentioning

confidence: 86%

Substrate Utilization by the Fetal Sheep Lung during the Last Trimester

Simmons

Charlton

1988

Pediatr Res

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ABSTRACT. I n vivo substrate utilization has not been described for the maturing fetal lung. We, therefore, studied pulmonary delivery and use of major fetal substrates in six chronically catheterized fetal lambs over 119-141 days gestation. Oxygen, glucose, lactate, and a-amino nitrogen concentrations were measured in the pulmonary artery and pulmonary vein whereas lung blood flow was determined using labeled microspheres. We found that lung oxygen availability and use increased near term. 606Using the chronically catheterized fetal sheep model (6), we determined the availability of major fetal substrates to the developing lung and lung substrate utilization during the third trimester. Pulmonary delivery and uptake of oxygen, glucose, lactate, and a-amino nitrogen were followed over the last weeks of gestation, allowing us to define the changing pattern of pulmonary substrate availability and use that accompanies advancing gestation. METHODSSurgical preparation and recovery. Six mixed Western, breeddated, pregnant sheep of 1 15-125 days gestation were surgically prepared with indwelling catheters, using methods described previously (6). Six fetal lambs were catheterized, five singletons and one from a set of twins. Surgery was performed after the animals had fasted 24 h. Spinal anesthesia was induced with 2.0 ml of 1 % tetracaine hydrochloride and analgesia was provided with intravenous pentobarbital (65 mg/ml) as needed. Polyvinyl catheters (0.050 inch inner diameter and 0.090 inch outer diameter) were placed in the maternal femoral artery and vein. The uterus was then exposed through a midline abdominal incision and opened. Local anesthesia with 1% xylocaine was used for all fetal incisions; pentobarbital (5-10 mg/kg) and succinyl choline (1 mg/kg) were given as needed for fetal sedation and to minimize fetal movement. Catheters (0.030 inch inner diameter and 0.048 inch outer diameter) were inserted either into the fetal femoral artery and vein of one hindlimb (four animals) or into the carotid artery and jugular vein (two animals). The fetal chest was then exposed and a thoracic incision was made on the left side, from sternum to spine. The pleural space was entered through the fourth intercostal space and the lungs were gently retracted. The pericardium was opened and a 20-gauge Teflon catheter, fitted on a piece of polyvinyl tubing (7), was then placed into the main pulmonary artery. A catheter (0.01 1 inch inner diameter and 0.030 inch outer diameter) was inserted into a distal pulmonary vein and threaded up into a major vein draining the upper lobe of the left fetal lung. The fetal chest was then closed. A multipore amniotic fluid catheter was anchored in the uterus and the uterus was also sutured closed. All catheters were exteriorized through a stab wound in the maternal flank, where they were protected by a mesh pocket. At surgery, penicillin (1 million units) and kanamycin (200 mg) were given to the ewe intravenously and were also instilled into the amniotic cavity.After surgery the ewes were fed ad...

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Section: Discussionmentioning

confidence: 86%

Substrate Utilization by the Fetal Sheep Lung during the Last Trimester

Simmons

Charlton

1988

Pediatr Res

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“…Warburton (10,11) has reported that both primary hyperinsulinemia with concomitant hypoglycemia, and chronic hyperglycemia with secondary hyperinsulinemia reduce SAM flux into tracheal fluid of fetal lambs. Before 128 d gestation, SAM flux into tracheal fluid in the current experiment was similar to Warburton's previously reported data.…”

Section: Discussionmentioning

confidence: 99%

“…However, the insulin-treated fetal lambs in this study became hypoglycemic relative to controls. In a subsequent study, Warburton (11) reported that chronic hyperglycemia with secondary hyperinsulinemia also reduces SAM flux into tracheal fluid of fetal lambs. In the human fetus, maternal diabetes mellitus leads to fetal hyperglycemia and hyperinsulinemia.…”

Section: Introductionmentioning

confidence: 93%

Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol.

Warburton¹

1983

J. Clin. Invest.

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A B S T R A C T I tested the hypothesis that chronic hyperglycemia with secondary hyperinsulinemia inhibits the stimulation of fetal lung maturation by cortisol. Glucose was infused (16±2 mg/kg per min, mean±SE) from 112 through 130 d gestation into five chronically catheterised twin fetal lambs from which tracheal fluid could be collected. In addition, cortisol was infused (420 pg/h) from 128 through 130 d gestation into both the five glucose-treated twins and the five twin controls. Serum glucose (48±2 mg/dl) and insulin levels (45±3 sU/ml) were significantly higher in the glucose-treated fetuses than serum glucose (23±2 mg/dl, P < 0.001) and insulin (15±3 MU/ml, P < 0.001) in the controls. Serum cortisol levels were <2 ug/dl before 128 d gestation and rose to >6 ig/dl, P < 0.001 during cortisol infusion in both the glucosetreated and control fetuses. Cortisol treatment of control fetuses was associated with a 4.8-fold increase in surface active material (SAM) flux into tracheal fluid, and a 7.7-fold increase in total phospholipid content, a 9.5-fold increase in mixed lecithin content, a 10.5-fold increase in disaturated phosphatidylcholine content, and a 5.6-fold increase in phosphatidylglycerol content of the tracheal fluid (all P < 0.001). In the glucose-treated fetuses there were no significant changes in the tracheal fluid SAM flux and phospholipid content following cortisol administration. In lung wash from the control fetuses treated with cortisol there was 8.9-fold more SAM, and on thin-layer chromatography there was 5.6-fold more total phospholipids, 3.9-fold more mixed lecithin, 6.2-fold more disaturated phosphatidylcholine, and 2.5-fold more phosphatidylglycerol when compared with lung wash from the glucose-treated fetuses treated with cortisol Received for publication 4 February 1983 and in revised form 11 April 1983. (all P < 0.001). Lung volumes at maximal inflation pressure during air pressure-volume studies were 1.8-fold greater in the cortisol-treated control fetuses than in the glucose-treated fetuses, P < 0.025. Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol. A similar mechanism may operate in utero to increase the incidence of respiratory distress syndrome in infants of diabetic mothers with poor maternal glucose homeostasis. Moreover, on the basis of these data, prenatal treatment of infants of diabetic mothers with corticosteroids might not be expected to enhance fetal lung maturation. INTRODUCTIONThe incidence of respiratory distress syndrome (RDS)' is reported by Robert et al. (1) to be increased 5.6-fold in infants of diabetic mothers (IDM), even when suitable corrections are made for gestational age. However, RDS may be less prevalent when maternal diabetes mellitus is mild and well controlled (2, 3). The IDM experiences hyperinsulinemia both in utero and in the postnatal period (4), particularly when glucose homeostasis is poor (4, 5).Stubbs and Stubbs (6) Mason et al. (20). The recovery rates for lipid e...

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“…Ewes were operated on at 110 days gestation under epidural anesthesia with 0.5% Pontocaine as described previously (3,5).…”

Section: Methodsmentioning

confidence: 99%

Chronic Glucose Infusion Inhibits Development of β-Receptor Binding in Fetal Lamb Lung

et al. 1988

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ABSTRACT. We used chronic fetal glucose infusion to test the hypothesis that chronic fetal hyperglycemia and hyperinsulinemia inhibit the development of @-receptor binding capapcity (Bmax) in fetal lamb lung. Glucose was infused (14 f 4 mg/kg/h, mean f SD) into eight twin and four singleton fetuses from 112 days gestation until death between 118-145 days gestation. The other eight twins and eleven additional singleton fetuses served as controls. Serum glucose levels were elevated 2-fold and serum insulin levels were elevated 3-fold in the glucose-infused fetuses. In the control fetuses @-receptor Bmax increased 2.5-folld between 130 days gestation and term. However, this increase was attenuated to 1.5-fold in the glucose infused fetuses, p < 0.01. The 50% inhibition of Bmax was similar in both male and female fetuses, except that the Bmax fell to 30% lower levels in males, p < 0.01. Chronic glucose infusion also resulted in an 80% reduction in lung lavage saturated phosphatidylcholine content, and an 85% reduction in tracheal fluid saturated phosphatidylcholine contemt,p < 0.001. Lung lavage and tracheal fluid saturated phosphatidylcholine content correlated significantly with beta receptor Bmax (r = 0.9, r = 0.85). We conclude that chronic glucose infusion inhibits the development of 8-receptor binding in fetal lamb lung, and that this effect is greater in males than females. Such a mechanism could be a factor in the predisposition of infants of diabetic mothers to develop respiratory distress and could contribute to a male disadvantage in respiratory morbidity. (Pediatr Res 24: 171-174,1988) Abbreviations Bmax, maximal binding capacity IDM, infant of diabetic mother RDS, respiratory distress syndrome SPC, saturated phosphatidylcholine DHA, dihydroalprenololWe have shown that fetal hyperinsulinemia occuring with either hyperglycemia (3) or hypoglycemia (4) is capable of inhibiting surface active material flux into the tracheal fluid of chronically catheterized fetal lambs. In human diabetic pregnancy, chronic fetal hyperglycemia with secondary hyperinsulinimia is more likely to occur. Surface active material flux into the tracheal fluid of fetal lambs has been used by several groups as a marker of in utero surfactant production (3-6). Recently we have found t h a t c h r o n i c fetal hyperglycemia a n d hyperinsulinemia also reduces the SPC content of lung lavage, and impairs lung stability to air inflation and deflation in fetal lambs (7), data that are compatible with decreased availability of surfactant in the fetal airways.Beta-receptor binding capacity has been shown to increase during the latter part of gestation in several species and this increase can be modulated by several hormones (8). We have recently shown that surface active material flux into the tracheal fluid of fetal lambs is significantly correlated with the increase in pulmonary P-receptor binding capacity (9), and that the fetal lamb lung responds to P-agonist stimulation with increased SPC in lung lavage and improved lung stability (1...

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Chronic Hyperglycemia Reduces Surface Active Material Flux in Tracheal Fluid of Fetal Lambs

Cited by 22 publications

References 24 publications

Substrate Utilization by the Fetal Sheep Lung during the Last Trimester

Substrate Utilization by the Fetal Sheep Lung during the Last Trimester

Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol.

Chronic Glucose Infusion Inhibits Development of β-Receptor Binding in Fetal Lamb Lung

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