Insulin-like growth factors I and II peptide and messenger RNA levels in macrosomic infants of diabetic pregnancies

Abstract

Objective: Fetal macrosomia is a common complication of maternal diabetes mellitus and is associated with substantial morbidity, but the precise cellular and molecular mechanisms that induce fetal macrosomia are not well understood. We hypothesized that the macrosomia or accelerated fetal growth seen in infants of diabetic mothers is due to a perturbation of a putative placental-fetal growth axis involving growth hormone and insulin-like growth factors. Insulin-like growth factors I and II (IGF-I and IGF-II) are ubiquitous peptides that share structural homology with insulin and have been implicated in processes that control fetal growth. Studies of IGF levels in pregnancies complicated by diabetes and macrosomia have shown conflicting results. We set out to resolve these inconsistencies using molecular techniques to measure the placental IGF-I and IGF-II messenger RNA levels in placentas and a specific radioimmunoassay to measure IGF-I and IGF-II peptide levels in cord serum of normal and diabetic pregnancies.

Methods: Placentas and cord blood were collected immediately after delivery at term from patients from each of three study groups: 1) nonmacrosomic infants of nondiabetic mothers (controls), 2) macrosomic infants of diabetic mothers, and 3) nonmacrosomic infants of diabetic mothers. Both IGF-I and IGF-II levels were measured in cord serum and placental tissue by a specific radioimmunoassay. Total RNA was extracted and analyzed by Northern gels hybridized to IGF-I or IGF-II riboprobes.

Results: Levels of IGF-I in cord serum from the macrosomic diabetic group (83 +/- 4.2 ng/mL) were significantly higher than levels from either the nonmacrosomic nondiabetic group (38 +/- 1.9 ng/mL) or the nonmacrosomic diabetic group (13 +/- 3.5 ng/mL). There was a direct linear correlation between cord serum IGF-I and infant birth weight, independent of diabetes (r2 = 0.61, P < .01). On the other hand, IGF-II cord serum levels were elevated in diabetic pregnancies (337 +/- 12.2 ng/mL) compared with nondiabetic women (172 +/- 19.8 ng/mL), but there was no correlation with birth weight (r2 = 0.035, P = .52). In contrast to cord blood levels, IGF-II peptide levels were significantly decreased in the placentas from mothers with diabetes compared with nondiabetic controls (116 +/- 3.2 versus 158 +/- 5.3 ng/mL, respectively). Levels of IGF-I peptide in placentas from both nondiabetic controls and diabetic mothers were below the sensitivity of the assay. Levels of IGF-I and IGF-II mRNA did not differ in placentas from diabetic mothers versus nondiabetic controls.

Conclusion: Cord serum IGF-II levels are elevated in diabetic pregnancies without a concomitant increase in placental IGF-II levels. This novel finding, combined with the finding that IGF-I levels are correlated with macrosomia independent of the diabetic state, contributes to our understanding of the possible mechanisms involved in fetal growth in pregnancies complicated by diabetes.