Protein Commonly Screened for In Pregnancy is Linked to Gestational Diabetes

New research shows that low levels of a protein commonly seen in screening tests for chromosomal disorders during the first trimester of pregnancy is associated with adipose tissue remodeling, glucose resistance, and gestational diabetes mellitus in pregnant women, according to a study published in Science Translational Medicine.

The study highlights a new role for pregnancy-associated plasma protein A, known as PAPPA, in gestational diabetes, with translational potential as both a diagnostic tool and therapeutic target, according to the study.

“We currently evaluate women for gestational diabetes at 24 to 28 weeks of pregnancy, so there’s only a short window of time when we can intervene clinically,” said Tiffany Moore Simas, MD, chair and professor of obstetrics and gynecology, in a press release. “If there was an opportunity to intervene earlier during pregnancy, we have a greater opportunity to improve outcomes.”

According to the study, gestational diabetes mellitus is one of the most common complications of pregnancy, and women with gestational diabetes are unable to use insulin effectively. As glucose builds up in the blood instead of being absorbed by the cells, causing hyperglycemia, it results in insulin being less effective at removing glucose from the blood, otherwise known as insulin resistance.

“Gestational diabetes is a huge health problem not just for mothers, but also for children, because we know these metabolic changes can be passed on to the next generation,” said Silvia Corvera, MD, endowed chair in Diabetes Research and professor of molecular medicine, in the release. “Children born from mothers with gestational diabetes are at higher risk for metabolic diseases and type 2 diabetes as they get older.”

Corvera and Moore Simas ran a series of RNA screens on adipose tissue from pregnant women after cesarean delivery so they could identify possible differences in gene expression. Further, they also ran RNA screens on adipose tissue from nonpregnant women undergoing bariatric surgery, as these samples were compared to elucidate differences between adipose tissue growth in response to pregnancy or overnutrition.

One of the findings was the elevated presence of insulin-like growth factor-binding protein 5 (IGFBP5) in fat from pregnant women, as IGFBP5 traps another protein, insulin-like growth factor-1 (IGF-1), which is necessary for cell proliferation and tissue growth. Corvera and Moore Simas thought that the high levels of IGFBP5 in adipose tissue may be connected to a well-known protein, PAPPA, because previous research has shown that pregnant women produce PAPPA, which is not normally found circulating in the blood, according to the researchers.

Corvera found that the PAPPA protein was cleaving IGFBP5, and this cleavage freed IGF-1 to act on cells of adipose tissue and make healthy adipose tissue during pregnancy. Since PAPPA levels are normally screened for in the first trimester of pregnancy, Moore Simas and her team reviewed the medical records of 6361 pregnant women to analyze levels of PAPPA in the first trimester and compare them with blood glucose levels later in pregnancy. She found that lower levels of PAPPA were correlated to increased insulin resistance and gestational diabetes later in pregnancy.

The results support the hypothesis that increased levels of PAPPA and IGFBP5 in pregnant women allow IGF-1 to work, so that healthy adipose tissue can be produced. However, lower levels of PAPPA, which correlate with excessive insulin resistance, do not promote healthy adipose tissue, leading to excessive insulin resistance, increased blood glucose levels, and gestational diabetes in pregnant women, according to the study.

By contrast, lower levels of PAPPA, which correlate with excessive insulin resistance, don’t promote healthy adipose tissue, leading to excessive insulin resistance, increased blood glucose levels, and gestational diabetes in pregnant women, according to the study.

“It’s as though the placenta is telling the adipose tissue what to do, through expression of PAPPA,” Corvera said in the press release.

The study authors hope to conduct future research to record PAPPA and glucose levels at various points in pregnancy to more accurately pinpoint how and when PAPPA is triggering physiological changes during pregnancy. Further, they hope to see whether PAPPA levels can be used to predict blood glucose levels, insulin resistance, and gestational diabetes before the presentation of clinical symptoms.

“Beyond the diagnostic and therapeutic potential of these findings, this is a new pathway involved with gestational diabetes that we’ve identified,” Moore Simas said in the press release. “There’s a lot more to understand about this novel mechanism and how it works.”

Corvera added that the PAPPA protein is vital for healthy adipose tissue to develop.

“Although very large amounts of PAPPA are made by the placenta during human pregnancy, it is possible that it may play a role outside pregnancy, as small amounts of PAPPA are also made in other tissues,” Corvera said in the press release. “In this way the PAPPA protein and the IGF-1 signaling pathway could play a role in the healthy development of adipose tissue outside of pregnancy and be relevant for other metabolic diseases. This is something we’re eager to explore.”

REFERENCE

Protein commonly screened for in pregnancy is linked to gestational diabetes. UMass Med News. Published November 25, 2020. Accessed April 22, 2021. https://www.umassmed.edu/news/news-archives/2020/11/protein-commonly-screened-for-in-pregnancy-is-linked-to-gestational-diabetes/