Molecular Mechanisms of Maternal Diabetes Effects on Fetal and Neonatal Surfactant

Abstract

Respiratory distress is a significant contributor to newborn morbidity and mortality. An association between infants of diabetic mothers (IDMs) and respiratory distress syndrome (RDS) has been well recognized for decades. As obesity and diabetes prevalence have increased over the past several decades, more women are overweight and diabetic in the first trimester, and many more pregnant women are diagnosed with gestational diabetes. Glycemic control during pregnancy can be challenging due to the maternal need for higher caloric intake and higher insulin resistance. Surfactant is a complex molecule at the alveolar air-liquid interface that reduces surface tension. Impaired surfactant synthesis is the primary etiology of RDS. In vitro cell line studies, in vivo animal studies with diabetic rat offspring, and clinical studies suggest hyperglycemia and hyperinsulinemia can disrupt surfactant lipid and protein synthesis, causing delayed maturation in surfactant in IDMs. A better understanding of the molecular mechanisms responsible for surfactant dysfunction in IDMs may improve clinical strategies to prevent diabetes-related complications and improve neonatal outcomes.

Keywords: hyperglycemia; infants of a diabetic mother; lung development; respiratory distress syndrome; surfactant lipids; surfactant protein.

Figure 1

Comparison of alveolus between healthy lungs and infant of a diabetic mother (IDM) lung. Changes in IDM type II alveolar epithelial cell level magnified on the right. Fetal hyperglycemia and hyperinsulinemia secondary to maternal hyperglycemia affect surfactant production via different mechanisms. Hyperglycemia and hyperinsulinism are illustrated in the capillary. (1) Decreased level of surfactant proteins (SP-A, -B, -C, and -D) [42,43,44,45,46]. (2) Decreased level of SP-B causes abnormal tubular myelin formation. (3) Excess glucose inhibits phosphorylase A activity [47]. (4) Glucose decreases insulin receptor tyrosine kinase (TK) activity level [48]. (5) Glycogen storage is decreased due to decreased glycogen phosphorylase A activity. (6) Alterations in surfactant phospholipid synthesis affected by inadequate glucose resulting in decreased phosphatidyl glycerol (PG) and increased phosphatidyl inositol (PI) [38,39,40]. (7) These changes contribute to increased respiratory distress syndrome secondary to surfactant deficiency in IDMs.

Figure 2

Metabolic changes associated with maternal diabetes effects on surfactant compositions, receptors, and enzymes summarized. Abbreviations: PG (phosphatidyl glycerol), PI (phosphatidyl inositol), PC (phosphatidyl choline), DSPC (desaturated phosphatidyl choline), SP (surfactant protein), IGF-1R (insulin-like growth factor 1 receptor), and TK (tyrosine kinase) [38,39,40,42,43,44,45,46,47,48,50,51,52,53,54].