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

Abstract

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...

Intrafetal glucose infusion alters glucocorticoid signaling and reduces surfactant protein mRNA expression in the lung of the late-gestation sheep fetus

“…It has been suggested that a link between hyperinsulinemia and RDS may involve a reduction in glycerol-3-phosphate and dihydroxyacetone phosphate production, which impairs surfactant phospholipid synthesis in the lung (54). A further potential mechanism regulating changes in the fetal lung following exposure to hyperglycemia and hyperinsulinemia involves ␤-receptor binding, which plays a vital role in surfactant release and reabsorption of fetal lung liquid (62,64). Interestingly, although the latter study demonstrated a negative impact of hyperglycemia and hyperinsulinemia, similar to that experienced in this study, regarding ␤-receptor binding in the lung, there was a greater effect in males than females (62).…”

“…A further potential mechanism regulating changes in the fetal lung following exposure to hyperglycemia and hyperinsulinemia involves ␤-receptor binding, which plays a vital role in surfactant release and reabsorption of fetal lung liquid (62,64). Interestingly, although the latter study demonstrated a negative impact of hyperglycemia and hyperinsulinemia, similar to that experienced in this study, regarding ␤-receptor binding in the lung, there was a greater effect in males than females (62). This represents a potential mechanism for male infants to suffer disadvantage in respiratory morbidity following exposure to uncontrolled diabetes during pregnancy.…”

“…With the exception of one study examining factors, including glycogen regulation, surfactant lipid content (65), ␤-cell receptor binding (62), and surface-active material flux in tracheal fluid (60,63) in the lung of the fetal sheep following exposure to hyperglycemia and hyperinsulinemia (analogous to the conditions experienced by a fetus in an uncontrolled diabetic pregnancy), no studies have evaluated the effect on regulation of SFTP expression in a large animal model with a developmental lung pattern similar to that of humans. Furthermore, no molecular mechanism has been identified to explain the historical link between uncontrolled diabetes in pregnancy and RDS in infants of diabetic mothers.…”