Stained tissue with changes in blood vessels in adipose tissue between non-pregnant and pregnant women. Photo credit: R. Rojas-Rodriguez et al., Scientific Translational Medicine (2020)

Laboratory examinations and analyzes of epidemiological data by Dr. Silvia Corvera and Dr. Tiffany Moore Simas, MPH, MEd, and colleagues show that low protein levels, which are common in screening tests for chromosomal disorders during the first trimester of pregnancy, are linked to adipose tissue remodeling, glucose resistance, and gestational diabetes in pregnant women. The study, published in Science Translational Medicine, describes a new role of pregnancy-associated plasma protein A, known as PAPPA, in gestational diabetes with translational potential as a diagnostic tool and therapeutic target.

“We currently screen women for gestational diabetes between the 24th and 28th week of gestation. So there is only a short window of time in which we can intervene clinically,” said Dr. Moore Simas, Chair and Professor of Obstetrics and Gynecology. “If there was an opportunity to intervene earlier in pregnancy, we have a greater chance of improving results.”

Dr. Corvera, Endowed Chair of Diabetes Research and Professor of Molecular Medicine, added, “Gestational diabetes is a major health concern not only for mothers but also for children, as we know these metabolic changes can be passed on to the next generation of children who are mothers with Gestational diabetes who are born have a higher risk of metabolic diseases and type 2 diabetes with age. “

Gestational diabetes mellitus is one of the most common complications of pregnancy, affecting up to 5 to 9 percent of all pregnancies in the United States. Women with gestational diabetes cannot use insulin effectively. Glucose builds up in the blood instead of being absorbed by the cells, which leads to hyperglycemia. Unlike type 1 diabetes, which is caused when the body doesn’t make enough insulin, gestational diabetes makes insulin less effective at removing glucose from the blood, known as insulin resistance.

The exact causes of gestational diabetes are not clear. However, about half of women with gestational diabetes develop type 2 diabetes within three to five years, which indicates an underlying or increased susceptibility. In addition, exposure to hyperglycemia correlates with other metabolic disorders, obesity, and cardiometabolic disorders in offspring.

During pregnancy, a woman’s physiology changes to accommodate the nutritional needs of the mother and child, including a decrease in insulin sensitivity, which allows for improved availability of glucose to the fetus. Likewise, healthy expansion and accumulation of adipose tissue is a normal physiological change necessary to maintain proper nutrient levels for the mother and fetus. Healthy adipose tissue is also important for metabolism and glucose homeostasis. It keeps fat away from other organs like the heart and liver, where it can build up and cause disease.

What causes gestational diabetes and possible role for PAPP-A. Photo credit: Silvia Corvera

Moore Simas, a practicing gynecologist, has often seen these physiological changes firsthand. “One of the things that you notice when you have a caesarean section is that the appearance of adipose tissue varies a lot from person to person,” said Moore Simas. “These are observable differences in the internal adipose tissue around the organs that did not seem to necessarily match the mother’s weight.”

Moore Simas mentioned these observations to Corvera, who studies the molecular mechanisms of adipose tissue and diabetes. The two then began working together to try to uncover the underlying molecular changes associated with adipose tissue during pregnancy.

To determine the factors that contribute to differences between healthy and unhealthy adipose tissue in pregnant women, Corvera performed a series of RNA screenings on adipose tissue from pregnant women after caesarean section to identify possible differences in gene expression. She also performed RNA screenings for adipose tissue from non-pregnant women who were undergoing bariatric surgery. These samples were compared to clarify differences in adipose tissue growth in response to pregnancy or overeating.

“This was an opportunity to study how adipose tissue differs between pregnant and obese women,” Corvera said. “Were there differences that could help us understand how healthy adipose tissue compares to unhealthy tissue?”

Among the findings was the increased presence of insulin-like growth factor binding protein 5 (IGFBP5) in fat from pregnant women. IGFBP5 captures another protein, insulin-like growth factor-1 (IGF-1), which is necessary for cell proliferation and tissue growth. Corvera and Moore Simas believed that the high IGFBP5 levels in adipose tissue could be related to a well-known protein, PAPPA. It has been known for years that pregnant women produce PAPPA, which does not normally circulate in the blood. This protein produced by the placenta continues to rise until the end of pregnancy and disappears once the placenta is shed. Although low levels of PAPPA have been used to check for Down syndrome and other chromosomal disorders, its precise biological function is not well understood.

Corvera worked in both human cells and mouse knock-out models that did not express PAPPA and found that the PAPPA protein cleaved IGFBP5. This cleavage allowed IGF-1 to act freely on cells of the adipose tissue and to produce healthy adipose tissue during pregnancy. IGF-1 is active throughout life, but is most active during puberty. It is usually sequestered unless it binds to an insulin growth factor binding protein. Once bound, it works in conjunction with growth hormones in the development of new tissue. This is one of the reasons its levels rise during the growth spurts associated with puberty.

Protein, commonly studied during pregnancy, has been linked to gestational diabetes

Sprouts from adipose tissue explants obtained either from non-pregnant women or from pregnant women with normal blood sugar. Photo credit: R. Rojas-Rodriguez et al., Scientific Translational Medicine (2020)

PAPPA levels are usually assessed in the first trimester of pregnancy because of their correlation with chromosomal disorders. The availability of these biological samples enabled Moore Simas and her team to review the medical records of 6,361 pregnant women to analyze PAPPA levels in the first trimester and compare them to blood sugar levels later in pregnancy. She found that lower PAPPA levels later in pregnancy correlated with increased insulin resistance and gestational diabetes.

These results support the hypothesis that elevated PAPPA and IGFBP5 levels in pregnant women enable IGF-1 to act, so that healthy adipose tissue can be produced. In contrast, lower levels of PAPPA, which correlate with excessive insulin resistance, do not promote healthy adipose tissue, leading to excessive insulin resistance, elevated blood sugar levels, and gestational diabetes in pregnant women.

“It’s like the placenta is telling adipose tissue what to do by expressing PAPPA,” Corvera said.

The next step for Moore Simas and Corvera is to record PAPPA and glucose levels at different points in pregnancy to more accurately determine how and when PAPPA induces physiological changes during pregnancy. You’ll also want to see if PAPPA levels can be used to predict blood sugar levels, insulin resistance, and gestational diabetes before clinical symptoms appear.

“Beyond the diagnostic and therapeutic potential of these results, this is a new gestational diabetes-related avenue that we have identified,” said Moore Simas. “There is much more to understand about this novel mechanism and how it works.”

Corvera said, “During pregnancy, the PAPPA protein is important for the development of healthy adipose tissue. Although very large amounts of PAPPA are made by the placenta in humans during pregnancy, it is possible that it could be produced in small amounts outside of pregnancy Role played by PAPPA are made in other tissues as well. In this way, the PAPPA protein and IGF-1 signaling pathway could play a role in the healthy development of adipose tissue outside of pregnancy and be relevant to other metabolic disorders. This is something we are eager to explore. ”

Exercise during pregnancy improves the health of obese mothers by restoring their tissues

More information:
R. Rojas-Rodriguez et al., “PAPPA-Mediated Adipose Tissue Reshaping Mitigates Insulin Resistance and Protects Against Gestational Diabetes in Mice and Humans”, Science Translational Medicine (2020).… scitranslmed.aay4145 Provided by the University of Massachusetts Medical School

Quote: Protein commonly screened during pregnancy is linked to gestational diabetes (2020, November 26th), which was released on November 26, 2020 from pregnancy-linked.html was obtained

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