Maternal Hyperglycemia Directly and Rapidly Induces Cardiac Septal Overgrowth in Fetal Rats

Abstract

Cardiac septal overgrowth complicates 10–40% of births from diabetic mothers, but perplexingly hyperglycemia markers during pregnancy are not reliably predictive. We thus tested whether fetal exposure to hyperglycemia is sufficient to induce fetal cardiac septal overgrowth even in the absence of systemic maternal diabetes. To isolate the effects of hyperglycemia, we infused glucose into the blood supply of the left but not right uterine horn in nondiabetic pregnant rats starting on gestational day 19. After 24 h infusion, right-sided fetuses and dams remained euglycemic while left-sided fetuses were moderately hyperglycemic. Echocardiograms in utero demonstrated a thickened cardiac septum among left-sided (glucose-exposed, 0.592 ± 0.016 mm) compared to right-sided (control, 0.482 ± 0.016 mm) fetuses. Myocardial proliferation was increased 1.5 ± 0.2-fold among left-sided compared to right-sided fetuses. Transcriptional markers of glucose-derived anabolism were not different between sides. However, left-sided fetuses exhibited higher serum insulin and greater JNK phosphorylation compared to controls. These results show that hyperglycemic exposure is sufficient to rapidly induce septal overgrowth even in the absence of the myriad other factors of maternal diabetes. This suggests that even transient spikes in glucose may incite cardiac overgrowth, perhaps explaining the poor clinical correlation of septal hypertrophy with chronic hyperglycemia.

Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis

“…Our results indicate that the fetuses of T2DM dams have hypertrophic hearts, supporting the clinical observations of babies of women with pregestational T2DM 15, 16, 45, 46 . It has been shown that transient hyperglycemic exposure is sufficient to induce septal overgrowth 47 . Thus, chronic mild hyperglycemia in T2DM is the major cause for fetal cardiac hypertrophy.…”

High glucose alters fetal rat islet transcriptome and induces progeny islet dysfunction

“…On gestation day (GD) 20, a vascular catheter draining into the left uterine artery was placed in timed pregnant CD Sprague Dawley rats (Charles River, Wilmington, MA, USA) to infuse glucose directly into the left uterine artery (Yao et al 2010, Gordon et al 2015. Maternal tail vein blood glucose levels were measured prior to anesthesia (n = 13 GD 20 dams).…”

“…Journal of Endocrinology be used as a single data (Vieleisis & Oh 1983, Roest et al 2004, Gordon et al 2015. All results were represented as mean ± s.e.m., while fold changes of RT-qPCR results were represented as log2FC in comparison to RNA-seq results.…”

“…We hypothesize that maternal hyperglycemia alters the offspring pancreatic islet transcriptome, consequently conferring increased offspring susceptibility to developing pancreatic islet dysfunction. To create the fetal hyperglycemic environment, we employed a model capable of inducing localized fetal hyperglycemia in rats (Yao et al 2010, Gordon et al 2015. While maintaining maternal euglycemia, this model targets glucose delivery to fetuses residing in the left uterine horn, allowing the use of fetuses in the right uterine horn as genetically similar controls as they remain normoglycemic (Yao et al 2010, Gordon et al 2015.…”

“…To create the fetal hyperglycemic environment, we employed a model capable of inducing localized fetal hyperglycemia in rats (Yao et al 2010, Gordon et al 2015. While maintaining maternal euglycemia, this model targets glucose delivery to fetuses residing in the left uterine horn, allowing the use of fetuses in the right uterine horn as genetically similar controls as they remain normoglycemic (Yao et al 2010, Gordon et al 2015. Using an RNA sequencing approach, we identified early transcriptome alterations induced by late gestation hyperglycemia in fetal islets.…”