Delayed fetal pulmonary maturation in a rabbit model of the diabetic pregnancy.

Bose, Carl; Manne, D N; D’Ercole, A. Joseph; Lawson, Edward E.

doi:10.1172/jci109847

Cited by 31 publications

(19 citation statements)

References 39 publications

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“…This would also go along with the lack of macrosomia noted in this model (8, 16,30). Bose et al (4) also noted equivalent fetal insulin levels, a decreased fetal glucose/insulin ratio and a lack of tissue overgrowth in their alloxan rabbit model. The injection of the rats prior to impregnation negates the possibility of a direct toxic effect of streptozotocin on the fetal pancreas.…”

Section: Discussionmentioning

confidence: 84%

“…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 diabetic pregnancy (4,31,39,40). In addition, the activities of enzymes of glycogen synthesis and breakdown were measured in order to gain an understanding of control mechanisms of glycogen metabolism in the developing fetal lung and its relationship to phospholipid synthesis.…”

Section: Speculationmentioning

confidence: 99%

“…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 diabetic pregnancy (4,31,39,40). In addition, the activities of enzymes of glycogen synthesis and breakdown were measured in order to gain an understanding of control mechanisms of glycogen metabolism in the developing fetal lung and its relationship to phospholipid synthesis.…”

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Delay in Pulmonary Glycogen Degradation in Fetuses of Streptozotocin Diabetic Rats

et al. 1982

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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...

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Section: Discussionmentioning

confidence: 84%

Section: Speculationmentioning

confidence: 99%

mentioning

confidence: 99%

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Delay in Pulmonary Glycogen Degradation in Fetuses of Streptozotocin Diabetic Rats

et al. 1982

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“…For example, maternal diabetes may impair lung maturation (34,35), so that relative hypoxia may contribute to the delay in mitochondrial adenine nucleotide uptake in the newborns. Furthermore, hypoxia stimulates catecholamine secretion (36).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Hypoxia or Maternal Diabetes Delays Postnatal Development of Liver Mitochondria

Aprille

Nosek

1987

Pediatr Res

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ABSTRACT. The matrix adenine nucleotide pool size of rat liver mitochondria was low at birth (2.6-3.0 nmol ATP+ADP+AMP/mg mitochondrial protein). After parturition, the pool size was increased by 50-75% within 1 h, which was sufficient for full development of state 3 respiration rates. The adenine nucleotide pool size continued to increase to 100-150% of the value at birth by 2-3 h postnatal. The ATPIADP ratio in isolated mitochondria also increased postnatally, to about double the value at birth by 3 h. There were no matrix volume changes over this postnatal period, so the increased ATP+ADP+AMP pool size and the increased ATPIADP ratio together inferred an overall increase of about 5-fold in the matrix ATP concentration under aerobic conditions. The postnatal uptake of adenine nucleotides into mitochondria occurred at a slower rate in newborns that were hypoxic (11% Oz) and in newborns of diabetic mothers (diabetes induced on day 5 of gestation by streptozotocin injection). The normal increase in matrix ATP content is responsible for the rapid stimulation of pyruvate carboxylation (an ATP-requiring matrix reaction) and this in turn contributes to the rapid postnatal onset of gluconeogenesis. The results suggest that delayed adenine nucleotide uptake into liver mitochondria may retard initiation of gluconeogenesis in newborns experiencing hypoxia, as in respiratory distress or in newborns of diabetic mothers. We speculate that this mechanism contributes to the persistent hypoglycemia that is typical of these at-risk newborns. (Pediatr Res 21: 266-269,1987) Mitochondria isolated from full-term fetal rat liver are functionally well coupled, but the rate of oxidative phosphorylation (state 3 respiration) is very low (reviewed in Reference 1). Within 1 h after birth, the state 3 rate increases to adult values (2-4). This functional maturation depends on a rapid increase in the mitochondrial adenine nucleotide content (ATP+ADP+AMP) which occurs in the immediate postnatal period (2, 4-6) In addition to activating state 3 respiration the increased adenine nucleotide pool size may also stimulate metabolic pathways that have adenine nucleotide-dependent enzymes within the mitochondrial compartment (reviewed in Reference 1). One matrix enzyme subject to this kind of control is pyruvate carboxylase. In both the newborn rat and rabbit the sudden postnatal increase in the matrix ATP concentration enhances pyruvate carboxylation rates enabling the onset of gluconeogenesis and recovery from postnatal hypoglycemia (7-9). Thus, the accumulation of adenine nucleotides into the mitochondria appears to be important for metabolic adaptation to neonatal life (see Reference 1).Received May 13, 1986; accepted October 23, 1986. Correspondence and reprint requests Dr. June R. Aprille, Mitochondria1 Physiology Unit, Department of Biology, Tufts University, Medford, MA 02155.Supported by NIH Grants HD 16936 and NS 14936.There is considerable evidence that hormones and oxygenation are important controlling factors for the subcellular red...

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“…By contrast, inducing primary hyperinsulinemia in fetal rabbit or monkey in utero (6)(7)(8) failed to delay lung maturation. Furthermore, delayed lung maturation was observed in P-cytotoxic agent-induced animal models of diabetic pregnancy in which fetuses were devoid of reactional hyperinsulinism (9)(10)(11)(12)(13). Both the latter approaches suggest that the delay in lung maturation could be a direct consequence of chronic hyperglycemia, not involving hyperinsulinemia.…”

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confidence: 99%

Lung Maturation in the Hyperinsulinemic Rat Fetus

et al. 1987

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ABSTRACT. Hyperinsulinemic rat fetuses were obtained either by repeated in utero injections of long-acting insulin (resulting in fetal hypoglycemia) or by chronically infusing intravenous glucose to the mother (resulting in fetal hyperglycemia). Fetuses were examined at term. In insulininjected fetuses (n = IS), surfactant (S) fraction phosphatidylcholine (PC) and disaturated phosphatidylcholine (DSPC) were significantly decreased (3.6 f 0.1 nmol Pi/ mg tissue; p < 0.001 and 2.8 f 0.1 nmol/mg; p < 0.025, respectively) as compared with their saline-injected controls (4.8 f 0.2 and 3.3 f 0.1 nmol/mg, respectively, n-= 19). However, residual (R) fraction was unchanged, and there was no difference in whole-lung phospholipids (combined S and R fractions). These results are consistent with morphological data showing a lower lamellar body area per type I1 cell profile in insulin-injected fetuses as compared with their controls 11.41 f 0.13 pmZ (n = 72) versus 1.99 f 0.14 pm2 (n = 129) p < 0.011. Glycogen content was slightly higher in insulin-injected fetuses (18.5 f 1.0 pg/mg, n = 17) than in their controls (15.1 f 0.8 pg/mg, n = 18; p < 0.05). In the second model, changes in S fraction PC and DSPC were similar to those observed after insulininjections: 4.3 f 0.25 and 3.4 2 0.2 nmol Pi/mg in fetuses of glucose-infused rats (n = 10) versus 5.7 f 0.45 and 4.3 2 0.3 nmol Pi/mg, respectively, in controls (n = 10, p < 0.05). In addition, PG was also decreased (0.24 2 0.03 versus 0.40 f 0.04 nmol Pi/mg, n = 10; p < 0.01), and in contrast with insulin injections, reductions of DSPC and PG were detectable in whole lung. However, glycogen content was unchanged by glucose infusion (13.7 f 1.0 pg/ mg, n = 15 versus 14.0 f 1.1 pg/mg, n = 20 in controls).In both models, the phospholipid composition of material recovered by lung lavage was unchanged. Supported by lNSERM Grant PRC-135002 "Reproduction et Dtveloppement." 4The incidence of respiratory distress syndrome is increased in infants of diabetic mothers (1). This appears to result from a delayed maturation of the pulmonary surfactant system (2).A prominent feature of the fetus of diabetic mother is the association of hyperglycemia and reactional hyperinsulinemia (3). In vitro. an excess of insulin has been reueatedlv shown to dhay fetal ling maturation (reviewed in Ref, 2j. In vivb, however, the implication of hyperinsulinism in the mechanisms delaying lung maturation remains up to now an unsolved question. The maturational response of fetal lamb lungs to cortisol (4) was inhibited by chronic hyperglycemia and secondary hyperinsulinemia. Inducing hyperinsulinemia by litter-size reduction decreased amniotic fluid surfactant in fetal rabbits (5). By contrast, inducing primary hyperinsulinemia in fetal rabbit or monkey in utero (6)(7)(8) failed to delay lung maturation. Furthermore, delayed lung maturation was observed in P-cytotoxic agent-induced animal models of diabetic pregnancy in which fetuses were devoid of reactional hyperinsulinism (9-13). Both the latter approaches sug...

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Delayed fetal pulmonary maturation in a rabbit model of the diabetic pregnancy.

Cited by 31 publications

References 39 publications

Delay in Pulmonary Glycogen Degradation in Fetuses of Streptozotocin Diabetic Rats

Delay in Pulmonary Glycogen Degradation in Fetuses of Streptozotocin Diabetic Rats

Neonatal Hypoxia or Maternal Diabetes Delays Postnatal Development of Liver Mitochondria

Lung Maturation in the Hyperinsulinemic Rat Fetus

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