Localized fetomaternal hyperglycemia: spatial and kinetic definition by positron emission tomography.

Jianrong Yao,Andrew W Norris,Chunlin Wang,Laura L B Ponto,Jeffrey L Segar,Diana Dang,John J Sunderland,Susan A Walsh,Alexander B Sawatzke,Shanming Hu,Gian Paolo Fadini

doi:10.1371/journal.pone.0012027

Abstract

BackgroundComplex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat.Methodology and Principal FindingsWe hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [18F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.9±0.1 and 2.8±0.3 fold under fasted and hyperinsulinemic conditions (p<10−11 n = 32-35 and p<10−12 n = 27–45) respectively. By contrast, centrally administered [3H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (103 mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained.Conclusions and SignificanceThis approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.

Highlights

The fetus normally is maintained in a protected environment, sheltered by maternal and placental homeostasis and detoxification mechanisms
Uterine artery catheter Blood flow to each uterine horn is primarily provided by its uterine artery, reaching flow rates of 1-2 mL/min near the end of gestation [24], [26]
An infusion catheter was advanced from the left femoral artery such that the tip lay just upstream of the left uterine artery takeoff (Fig. 1a)

Summary

Introduction

The fetus normally is maintained in a protected environment, sheltered by maternal and placental homeostasis and detoxification mechanisms When these protections fail or are breached, significant health consequences to the fetus can occur, inducing malformations [1], neonatal maladies [2], and/or disease susceptibilities that may not manifest for decades [3]. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat

Methods

Results

Discussion

Conclusion