Effect of Late Gestation Fetal Hyperglucagonaemia on Placental Function, Fetal Protein Accretion and Growth

Research background: role of glucagon in IUGR

The hormone glucagon is best known as a regulator of glucose, but it also plays important roles in protein metabolism and overall energy expenditure. The hormone glucagon:

• Stimulates the liver to take up amino acids, decreasing their availability in the bloodstream
• Stimulates protein breakdown via amino acid oxidation
• Inhibits protein synthesis

Until now, relatively little has been known about the effects of glucagon prenatally, but some animal research suggests that it has some similar effects in protein metabolism. Previous studies indicate that fetal concentrations of glucagon increase in response to stress, such as in hypoxia at delivery, starvation of the mother, or IUGR. It was unknown whether this was simply a sign of fetal distress or whether the increased glucagon itself might have greater impacts on the fetus and placenta.

Investigators in the Perinatal Research Center at Children’s Hospital Colorado and the University of Colorado sought to examine how the fetus’ metabolism changed in response to more than 24 hours of elevated glucagon in the fetal blood. (This would reflect similar changes in physiology such as that found in placental insufficiency or a chronically stressed fetus.) They wanted to know if exposure to this increased glucagon would decrease the fetus’ nutrient supply or reduce placental function.

Hypotheses

• Infusions of increased glucagon in the fetus’ blood would decrease the concentration of amino acids in the fetal blood.
• The increased glucagon would not affect blood flow or nutrient uptake through the placenta or fetal growth.

Research methods: analysis of fetal sheep exposed to increased glucagon using maternal and fetal blood

Sheep in a late stage of gestation were used in the study. In the experimental groups included in the final analysis, extra glucagon was directly infused into the bloodstream of the fetuses of 12 pregnant sheep for eight to 10 days. A control group of 10 fetal sheep received saline only.

Using specialized catheters, they were able to take multiple blood samples from the uterine artery and vein and the umbilical artery and vein. This allowed them to perform detailed explorations of the physiology of the placenta, including fetal and maternal nutrient concentrations.

To detect protein/amino acid metabolism and nutrient uptake rates, the team infused a tracer of [1-13C] leucine and analyzed results via gas chromatography-mass spectrometry.

The team also collected data on flow rates in both the uterine and umbilical vessels.

They also assessed an important hormone for fetal growth: placental hormone chorionic somatomammotropin (CSH). They assessed both its secretion and the expression of the CSH gene and closely related genes.

Research results: impact on glucagon-exposed fetuses and placental function

Key findings include

• Final fetal weight was 13% lower in the fetuses who received extra glucagon.
• Fetuses who received extra glucagon had >28% lower concentration of 16 different amino acids in their blood.
• Protein synthesis was 49% lower in the fetuses exposed to extra glucagon.
• Amino acid incorporation (“protein accretion”) from the blood was 92% lower in the fetuses in the glucagon group.
• In the glucagon group, the uterine vessel uptake of 10 different amino acids was lowered by >48%.
• Glucagon exposure also lowered the umbilical uptake of seven different amino acids by >29%.
• Insulin concentrations were 57% lower in the fetuses exposed to extra glucagon.
• Uterine blood flow was 33% lower in the mothers who had a fetus receiving extra glucagon.
• The CSH gene was downregulated, reducing production of the hormone. The placenta of the glucagon-treated sheep released 80% less CSH into the mother’s circulation.

Research discussion

The researchers found decreased concentrations of amino acids in the blood vessels of the fetuses who had been exposed to increased glucagon. Fetal weight was also lower in the fetuses exposed to extra glucagon. This was consistent with other features, such as lower amino acid uptake rates and lower levels of insulin in this group. The mothers of these fetuses had lower uterine blood flow as well as lower uptake of amino acids through the uterine vessels. Umbilical vessel uptake of amino acids was also lower.

Together, these results suggest overall reduced transport of nutrients through the placenta. The results also were consistent with the lower genetic expression of CSH and corresponding lower amounts of this hormone, one known to be important for fetal growth.

Significance of findings

This study is the first to show that glucagon can downregulate maternal placental nutrient transport as well as uterine blood flow. This challenges the currently accepted model, in which signaling from the mother to the placenta is emphasized, with little attention given to the potential impact of signaling from the fetus to the placenta.

Research conclusion: fetal glucagon helps regulate fetal metabolism and placental function in IUGR

Elevated glucagon produced by the fetus is not only a response to IUGR but also an important regulator of fetal metabolism and placental function. The authors speculate that this may be an adaptive response, allowing the fetus to help reduce its growth. This may give it a greater chance of surviving when resources are scarce.