- The mother's blood sugar levels during pregnancy can have a large effect on how likely the baby is to have congenital heart disease.
- If a pregnant woman has poorly controlled diabetes with rapidly fluctuating sugar levels, she may be at a higher risk of having a child with the condition.
- High glucose levels boosted a chemical process that made the heart cells divide rapidly, but did not allow them to mature well.
High glucose levels -- whether caused by diabetes or other factors -- keep heart cells from maturing normally. This might be the reason for mothers with fluctuating blood sugar levels to have babies with congenital heart disease.
A research team at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA led by Atsushi "Austin" Nakano found that when developing heart cells are exposed to high levels of glucose, the cells generate more building blocks of DNA than usual, which leads the cells to continue reproducing rather than mature.
‘High sugar levels in the mothers blood make the baby up to five times more likely to have congenital heart disease.’
"High blood sugar levels are not only unhealthy for adults; they're unhealthy for developing fetuses," Nakano said. "Understanding the mechanism by which high blood sugar levels cause disease in the fetus may eventually lead to new therapies."
Non-genetic reason Behind Congenital Heart Disease
Although genetics plays a large role in the development of congenital heart disease, the leading non-genetic risk factor for the disease is a mother having diabetes during pregnancy. Babies born to women with high levels of glucose in their blood during pregnancy are two to five times more likely to develop the disorder than other babies.
However, researchers have never been able to define the precise effect of glucose on the developing fetus.
To find out, Nakano et al. used stem cells and experiments in pregnant mice with diabetes. First, heart cells were grown from human stem cells, and exposed to high levels of glucose in a dish. This revealed a new mechanism for how high sugar levels affect heart formation.
Cells that were exposed to small amounts of glucose matured normally. But cardiomyocytes that had been mixed with high levels of glucose matured late or failed to mature altogether, and instead generated more immature cells.
The researchers discovered that, when exposed to extra glucose, the cardiomyocytes over-activated the pentose phosphate pathway -- a cellular process that, among other things, generates nucleotides, the building blocks of DNA. In cells with high glucose levels, the pentose phosphate pathway made more nucleotides than usual. The scientists showed that the excess of building blocks kept the cells from maturing.
"More nutrition is generally thought to be better for cells, but here we see the exact opposite," Nakano said. "By depleting glucose at the right point in development, we can limit the proliferation of the cells, which coaxes them to mature and makes the heart muscle stronger."
Nakano's group observed the same thing at work in pregnant mice with diabetes: The heart cells of fetuses divided quickly but matured slowly.
Targeting Pentose Phosphate Pathway
Nakano said the finding could lead to better methods of making cardiomyocytes from stem cells. Today, most protocols for generating cardiomyocytes in the lab lead to immature cells, but targeting the pentose phosphate pathway could help generate more mature cells for regenerating heart cells or for research purposes.
Congenital heart disease affects nearly 1 in 100 children born in the U.S., making it the most common birth defect. The severity of the symptoms it causes varies, ranging from a slightly weakened heart muscle and no symptoms to severe heart deformations that require surgery.
CHDs are termed critical because they cause inadequate oxygenation of blood. This is because the blood from the right and left sides of the heart get mixed up. This leads to cyanosis (bluish discoloration of skin and mucous membranes). Hence a broader or alternate way to categorize CHDs are defects that can be "Cyanotic" or "Acyanotic".
- Haruko Nakano, Itsunari Minami, Daniel Braas, Herman Pappoe, Xiuju Wu, Addelynn Sagadevan, Laurent Vergnes, Kai Fu, Marco Morselli, Christopher Dunham, Xueqin Ding, Adam Z Stieg, James K Gimzewski, Matteo Pellegrini, Peter M Clark, Karen Reue, Aldons J Lusis, Bernard Ribalet, Siavash K Kurdistani, Heather Christofk, Norio Nakatsuji, Atsushi Nakano. 'Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis.' eLife (2017). http://dx.doi.org/10.7554/eLife.29330.