Surfactant Secretion by Type II Pneumocytes is Inhibited by High Glucose Concentrations

Abstract

Delayed fetal lung maturation is observed in poorly controlled diabetic pregnancies. To investigate whether elevated glucose levels inhibit basal surfactant secretion and synthesis in type II cells and whether inhibitory effects on secretion can be reversed by secretagogues, type II cells isolated from 20-day fetal rat lung explants were initially cultured in [H3] choline containing media with glucose concentrations of 5.5, 10, 25, 50, and 100 mM, or in equiosmolar mannitol controls. Further incubation in nonradioactive media containing matched glucose levels with and without 1 x 10(-5) M terbutaline 1 x 10(-6) M and 1 x 10(-8) M 12-O-tetradecanoylphorbol 13-acetate (TPA) allowed assessment of incorporation of choline into phosphatidylcholine (PC) and its subsequent secretion. PC secretion was inhibited by culture in high glucose conditions, resulting in an approximately 30% reduction in secretion under 50 and 100 mM glucose conditions compared to culture at 5.5 or 10 mM glucose (p < .01); this decrease could not be explained by changes in osmolarity or in all viability after culture in high glucose. Insulin (1 unit/mL) had no significant impact on secretion (92 +/- 7% of control). Terbutaline-stimulated cells grown under 50 and 100 mM glucose conditions had significantly lower secretion rates than did terbutaline-stimulated cells cultured in 5.3 mM glucose (p < .05). Exposure to TPA resulted in significant increase in surfactant secretion by cells grown in both 5.5 and 100 mM glucose; however, the percentage increase (39.5 +/- 6.8% and 94.8 +/- 8.0% with 10(-8) M and 10(-6) MTPA, respectively) was significantly lower than in controls (87.8 +/- 8.0% and 152.1 +/- 18.8%, respectively) (p < .001). Choline incorporation into PG was also decreased by 100 mM glucose to 77 +/- 9% of control (p < .01). These data indicate that high glucose levels inhibit both surfactant synthesis and baseline and secretagogue-stimulated surfactant secretion by type II cells. This inhibitory effect on surfactant secretion may further exacerbate the decrease in surfactant synthesis and the pulmonary maturational delay seen in infants of diabetic pregnancies.

Care of the Infant of the Diabetic Mother

“…Late preterm (34-37 weeks) IDMs commonly have apparent surfactant deficiency respiratory distress syndrome despite their advanced gestational age. Fetal hyperglycemia and hyperinsulinism have been associated with pulmonary immaturity and decreased synthesis and secretion by type II pneumocytes of surfactant phospholipids and their associated proteins [62][63][64][65][66]. Earlier studies indicated that high glucose and insulin concentrations inhibit the production of surfactant by blocking key enzymes in the phosphatidylcholine pathway.…”

Roles of Ca 2+ and Protein Tyrosine Kinase in Insulin Action on Cell Volume via Na + and K + Channels and Na + /K + /2Cl − Cotransporter in Fetal Rat Alveolar Type II Pneumocyte

“…Insulin has been reported to affect various types of ion channels and transporters in various types of cells including epithelial cells (Engle, Langan & Sanders, 1983;Kaplan et al, 1984;Marunaka, 1988;Han et al, 1996;Gewolb & O'Brien, 1997). In lung epithelia, insulin has also been reported to have effects on the amiloride-sensitive Na + -permeable channels and the bumetanide-sensitive Na + /K + /2Cl − cotransporter .…”

Effect of Acute Glucose Depletion Following Glucose Excess on Surfactant Phospholipid Synthesis in Developing Fetal Lung

“…Both excessive or de cient substrate provision during fetal life can be associated with changes in fetal lung development. The infant of the poorly controlled diabetic mother has a higher incidence of respiratory distress syndrome [ 5,11] , and high insulin and glucose levels have both been found to inhibit fetal lung maturation in various experimental systems [5][6][7][8][9][10] . Maternal starvation also has been reported to result in decreased pulmonary surfactant content in fetal guinea pigs [ 26] .…”

“…We have previously demonstrated that high glucose and high insulin in vitro can result in delayed fetal lung maturation [ 9,10] , a pretranslational downregulation of the fetal lung insulin receptor [ 12,13] , and decreased glucose uptake by the fetal lung [ 13] . Although downregulation of the insulin receptor might be expected to result in the maintenance of intracellular glucose homeostasis under high glucose conditions, it may be counterproductive in the short run when conditions of excess substrate are followed abruptly by substrate depletion, as may occur in infants of diabetic mothers in the immediate postnatal period or in fetuses of the diabetic pregnancy during periodic hypoglycemia in the insulin-treated mother.…”

“…Both high glucose and insulin have been implicated as inhibitors of fetal lung maturation in vitro [5][6][7][8][9][10] , consistent with an increased incidence of respiratory distress syndrome in some infants of diabetic pregnancies [ 11] . We have demonstrated an inhibitory eÚ ect of high glucose and high insulin on insulin receptor number and binding ( but not receptor affinity) , on insulin receptor mRNA, and on glucose uptake in fetal rat lung explants [ 12,13] .…”