Delay in Pulmonary Glycogen Degradation in Fetuses of Streptozotocin Diabetic Rats

Abstract

SummaryThe developmental profile of pulmonary glycogen was investigated in fetuses of rats made diabetic before conception with the injection of 40 mg/kg streptozotocin.Lungs of control litters showed increasing pulmonary glycogen concentration from day 16-20, followed by significant decline by term (= 22 days). In contrast, the diabetic litters, which had pulmonary glycogen concentration equal to controls until day 20, showed significantly higher glycogen values ( P < 0.01) on days 21and 22, consistent with a delay in glycogen degradation. This coincided with the fiding of decreased amounts of fetal pulmonary phosphatidylcholine and disaturated phosphatidylcholine on day 21 of the diabetic gestation (P < 0.05), but not before that time.Pulmonary glycogen phosphorylase A activity was significantly decreased in the diabetic litters on the final days of gestation, at the same time that the delay in glycogen breakdown became evident. Pulmonary glycogen synthase activity did not differ in the control and diabetic fetuses. SpeculationThe delay in pulmonary glycogen degradation seen in the fetus of the diabetic gestation is thus temporally related to the delay in lung maturation seen in this model and may be secondary to a decrease in the activity of the glycogenolytic enzyme phosphorylase A. Decreased availability of pulmonary glycogen stores for surfactant synthesis may be important in elucidating the mechanism of the delayed pulmonic maturation seen in fetuses of diabetic pregnancies.There is a growing body of evidence that implicates glucose, and its storage form glycogen, in the biosynthesis of surface active phospholipids in the developing fetus (11,36,42). Pulmonary glycogen content, which increases throughout most of gestation, falls rapidly near term, coincident with the appearance of lamellar bodies in alveolar type I1 cells and with an increase in choline incorporation into the surface active ~h o s~h o l i~i d fraction (27. 44). fhese maturational processes-the ialI & pu&onary glycogen; the rise in surfactant svnthesis, and the amearance of lamellar bodies-are all accelerated by the admini'siration of exogenous glucocorticoids (14,23,29,31,32). In a retrospective analysis, Robert et al. (3 1 ) showed that infants of diabetic pregnancies have a 5.6 times greater risk of developing the respiratory distress syndrome than those of nondiabetic gestations. It might therefore be expected that fetuses of diabetic pregnancies would have coincident aberrations in surfactant production and pulmonary glycogen metabolism. Indeed, increased pulmonary glycogen stores have been observed in fetal (39) and newborn (35) animals born to diabetic mothers; however, others report diminished glycogen content in the lungs of fetuses of experimental diabetic pregnancies (43).We used the streptozotocin diabetic rat as a means of studying fetal pulmonary glycogen metabolism throughout the diabetic gestation, in an effort to clarify the role of substrate availability with respect to the observed delay in lung maturation seen in the di...

Thyroid Hormone Opposes Some Glucocorticoid Effects on Glycogen Content and Lipid Synthesis in Developing Fetal Rat Lung

“…The rate of choline incorporation into phosphatidylcholine more than tripled between 19-20 days gestation and 1 day after birth. These profiles are similar to those previously reported for glycogen content (28,(30)(31)(32) and phosphatidylcholine synthesis (28,(33)(34)(35)(36) in the rat. Similar developmental profiles have been reported in other species (1,14).…”

Changes in Surfactant Phospholipids in Fetal Rat Lungs from Normal and Diabetic Pregnancies

“…This observation, as well as the transient nature of the abnormalities, helps to explain some of the discrepancies reviewed in detail elsewhere (3). It should be noted, however, that the pattern of abnormalities that we found in PC and DSPC is exactly the same as that reported by Gewolb et al (8). Their data were obtained in a study of whole fetal lungs taken from streptozotocin rat pregnancies at 19-22 days of gestation, in which the low phospholipid levels were demonstrable only on day 2 1 which corresponds to day 20.5 as designated herein.…”

“…Possible explanations for the discrepancies include variations in the animal species studied, the timing of gestation, the severity of maternal diabetes, and the biochemical approach used to quantitate fetal lung phospholipids. In the rat and rabbit, nevertheless, many observations converge to the conclusion that maternal diabetes delays morphologic (4-6) and biochemical (6)(7)(8) maturation of the fetal lung, making these species useful animal models when they are given pancreatic Pcell toxic agents, e.g. alloxan and STZ.…”

Dexamethasone Enhances Surfactant Protein Gene Expression in Streptozotocin-Induced Immature Rat Lungs

“…Uncontrolled diabetic pregnancy in humans is accompanied by fetal hyperglycemia and hyperinsulinemia. The STZ-DB model used here, exhibits fetal hyperglycemia with normal to low plasma insulin levels (38,42), suggesting that hyperglycemia has an important role in inhibiting SP mRNA levels in vivo. In this regard, high glucose (50-100 mM) but not insulin (1UImL) delayed fetal lung development in d 20 fetal rat lung explants as determined by reduced incorporation of 3~ into phosphatidylcholine and disaturated phosphatidylcholine (43).…”

“…Only females with blood glucose more than 250 mg/dL were used for the experiments. Conditions of mating and sacrifice have been previously described (38). Successful mating was confirmed by the presence of a copulatory plug or a vaginal smear positive for sperm on the morning after caging male and female rats together.…”