Lung Maturation in the Hyperinsulinemic Rat Fetus

Abstract

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...

Regulation of lung sufactant protein gene expression

“…As the fetus of the diabetic mother is frequently found to be hyperinsulinemic, elevated levels of insulin may have negative effects on fetal lung maturation and surfactant levels contributing to the increased incidence of RDS in such infants. Fetal rats under hyperinsulinemic conditions were found to have delayed lung maturation as assessed by lamellar body and surfactant phospholipid contents (122). Indeed the amniotic fluid levels of SP-A are reduced in diabetes (123) and insulin treatment of fetal human lung explants (124)(125)(126) and H441 cells (127) results in reduced SP-A, SP-B and SP-C mRNA expression.…”

Cambios histomorfológicos en pulmón de rata recién nacida inducidos por ingesta materna de azúcar.

“…Con respecto a la evaluación morfológica pulmonar de los recién nacidos del grupo experimental, mostraron colapso alveolar, engrosamiento de pared alveolar y aumento en celularidad. Con relación a lo anterior, estudios experimentales indican que la hiperinsulinemia materna provoca retraso en la maduración pulmonar fetal 22 , deficiencia en la síntesis y secreción de surfactante 23 . Cabe mencionar que, en modelo experimental y en humanos el consumo de sacarosa produce resistencia a la insulina 24 , hiperinsulinemia e hiperlipidemia 25 .…”

Chronic in Utero Beta-Blockade Alters Fetal Lung Development

“…Other elements of surfactant production may have developed adversely under the influence of propranolol. Tissue SPC may also be a rela tively insensitive marker of pulmonary sur factant [23]. The incorporation period used may have been too short to demonstrate a small but significant difference in synthesis between groups.…”