"High blood sugar levels are not only unhealthy for adults; they're unhealthy for developing fetuses," says scientist Atsushi “Austin” Nakano from the University of California - Los Angeles. Nakano and his colleagues recently discovered why mothers with diabetes are two to five times more likely to have a baby born with congenital heart disease. Their new study, published in the journal eLife, shows why high glucose levels are to blame.
Credit: UCLA Broad Stem Cell Research Center/eLife
Congenital heart defects are the the most common birth defects in the country, and maternal diabetes is the leading non-genetic risk factor for developing these defects. The new UCLA study shows that a pregnant mother’s high glucose levels, whether as a result of diabetes or something else, prevents normal maturation of heart cells.
Researchers are hoping that by understanding the details of this relationship, they can develop new therapies to treat or even prevent congenital heart disease in the context of maternal diabetes.
When a developing fetus is exposed to high levels of glucose from the mother, production of above-average levels of DNA nucleotides is triggered. Nucleotides, known by the letters A, G, T, and C in the context of DNA, are the building blocks that make up strands of DNA. High levels of glucose activates a particular cellular process called the “pentose phosphate pathway” that produces nucleotides. In response, immature cells continue to proliferate instead of maturing.
Nakano and his team studied this phenomenon by experimenting with human embryonic stem cells grown into heart muscle cells, called cardiomyocytes, which they then exposed to “varying levels of glucose.” Small amounts of glucose did not disrupt normal maturation of cardiomyocytes. But high levels of glucose exposure lead to late maturation or even no maturation at all, with the immature cardiomyocytes instead producing more immature cells.
The findings from this experiment highlight the role of glucose in the development of congenital heart defects, a role that can be targeted.
"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 explained.
The real-world applications of this study include improving techniques of transforming stem cells into cardiomyocytes, and the potential to target the pentose phosphate pathway as a way to promote cardiomyocyte maturation. Nakano and his team are on their way to exploring these applications.