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Insulin inhibits beta-adrenergic responses in fetal rabbit lung in explant culture
D J Davis1, J M Hickman, C A Lefebvre
1Department of Pediatrics, Emory University, Atlanta, Georgia 30322.
Insights
Maternal diabetes increases infant respiratory risks. Excess insulin may impair fetal lung beta-adrenergic responses, specifically reducing cyclic adenosine monophosphate (cAMP) generation, potentially explaining these respiratory issues.
Area of Science:
- Neonatal physiology
- Endocrinology
- Pulmonary medicine
Background:
- Infants born to diabetic mothers face higher risks of neonatal respiratory problems, including respiratory distress syndrome.
- Beta-adrenergic responses are crucial for fetal lung maturation, regulating surfactant production and fluid clearance.
Purpose of the Study:
- To investigate whether excess insulin interferes with the beta-adrenergic response cascade in fetal rabbit lungs.
- To determine insulin's effect on key components of the beta-adrenergic signaling pathway in lung explants.
Main Methods:
- Fetal rabbit lung explants were cultured for 48 hours with hormone supplementation.
- Assessed beta-adrenergic receptor concentration, G-proteins (Gs, Gi), and beta-agonist stimulated cyclic adenosine monophosphate (cAMP) generation.
- Measured cAMP-dependent phosphodiesterase activity and choline incorporation into phosphatidylcholine.
Main Results:
- Insulin did not alter beta-adrenergic receptor concentration in fetal lung explants.
- Insulin significantly reduced the capacity of isoproterenol to stimulate cAMP generation.
- While dexamethasone increased cAMP stimulation, concurrent insulin treatment lowered absolute cAMP levels.
Conclusions:
- Insulin's inhibitory effect on cAMP generation in fetal lungs may contribute to respiratory complications in infants of diabetic mothers.
- This finding suggests a potential mechanism linking maternal diabetes to neonatal respiratory distress.
Abstract:
Infants of diabetic mothers are at increased risk of a number of problems at birth. Among these problems are increased risks of respiratory distress syndrome and transient tachypnea of the newborn. Because surfactant synthesis, surfactant secretion, and lung fluid resorption are all mediated in part by beta-adrenergic responses, we asked if excess insulin interferes with the beta-adrenergic response cascade in fetal lung. Lungs from fetal rabbits (26 day) were grown in explant culture in hormone-supplemented culture medium. The explants were harvested after 48 h exposure to hormones and processed for determination of beta-adrenergic receptor concentration, guanine nucleotide regulatory proteins (Gs, Gi), beta-agonist stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation, cAMP-dependent phosphodiesterase activity, and choline incorporation into phosphatidylcholine. Although insulin did not change the concentration of beta-adrenergic receptors, it decreased the ability of isoproterenol to stimulate cAMP generation. Increase in stimulation over basal was similar in explants treated with dexamethasone and dexamethasone plus insulin, but absolute levels of isoproterenol-stimulated cAMP were less in the explants treated with dexamethasone plus insulin. We speculate that insulin inhibition of cAMP generation may be important in the pathogenesis of the respiratory problems of infants of diabetic mothers.