New protein linked to gestational diabetes
For 40 years scientists have accepted there are four enzymes which kick-start the body's ability to get energy [calories] from food. But a protein just found, may be the actual predictor for whether expectant moms develop diabetes during pregnancy.
The discovery of the four catalysts of energy production called hexokinases, generated more research into how we metabolize carbohydrates, and how interfering with those enzymes through medications could help manage metabolic disorders such as diabetes.
But this biochemical foursome may not deserve all of the credit for carbohydrate metabolism. Scientists at Duke and Northwestern universities, have found the hexokinase team actually has a fifth player.
The work appears in the journal Nature Communications.
"This swims against the past 40 years of research and what we thought we knew. Hexokinases are critical to basically all of our energy production. Finding a fifth one opens the door to more study into how we metabolize sugar, as well as genetic links to metabolic disorders.
"We know that children born to women with hyperglycemia during pregnancy, may be more likely to be born large and subject to health impacts down the road, such as obesity and diabetes."
Tim Reddy PhD, senior author of the study, Assistant Professor of Biostatistics and Bioinformatics, Duke University.
The new protein is called HKDC1. Researchers report this enzyme may be a genetic predictor for whether an expectant mom develops hyperglycemia, or excess blood sugar, during pregnancy.
Hyperglycemia is a potentially harmful environment for a growing fetus and can contribute to obesity and diabetes later in the child's life. While at least 4 percent of pregnant women develop diabetes during pregnancy, as many as 400,000 women each year in the U.S. have gestational hyperglycemia, which equals about 10 percent of expectant mothers. Hyperglycemia during pregnancy may have many of the same harmful long-term health effects as full-blown gestational diabetes, according to a landmark study published in the New England Journal of Medicine in 2008.
Doctors have counseled expectant mothers on the risks of high blood sugar and the benefits of proper diet and exercise to lessen the risk. But there currently isn't a method to screen women for their risk of developing high blood sugar while pregnant. Often, mothers are diagnosed too late, after they have developed diabetes.
While all humans have this fifth hexokinase, it appears during pregnancy women with less of it are unable to metabolize glucose as well as others. Researchers hope these findings lead to a test indicating the potential for developing hyperglycemia amongst pregnant women.
"The discovery of this gene creates a path forward to better predicting a woman's risk," Reddy adds. "Knowing that there is this new hexokinase at play could also give us more information on how to inhibit or activate it, and anything we can to do disrupt the cycle would be an important advance to stem the epidemic of diabetes we see today."
Further investigation into the enzyme could create potential targets for new therapies for metabolic conditions, said William Lowe, M.D., a senior author of the study and professor of medicine at Northwestern University Feinberg School of Medicine.
"This study shows the benefit of large-scale genetic studies as they begin to shed light on new molecules that are important for metabolism. It's ancient history in the field of carbohydrate biochemistry that there were four members of the family.Something like 40 years goes by, and then here comes this cowboy, showing up late to the party."
Christopher Newgard, Ph.D., an author of the paper and Director of the Duke Molecular Physiology Institute.
Maternal ?glucose levels during pregnancy impact the developing fetus, affecting metabolic health both early and later on in life. Both genetic and environmental factors influence maternal metabolism, but little is known about the genetic mechanisms that alter ?glucose metabolism during pregnancy. Here, we report that haplotypes previously associated with gestational hyperglycaemia in the third trimester disrupt regulatory element activity and reduce expression of the nearby ?HKDC1 gene. We further find that experimentally reducing or increasing ?HKDC1 expression reduces or increases hexokinase activity, respectively, in multiple cellular models; in addition, purified ?HKDC1 protein has hexokinase activity in vitro. Together, these results suggest a novel mechanism of gestational ?glucose regulation in which the effects of genetic variants in multiple regulatory elements alter ?glucose homeostasis by coordinately reducing expression of the novel hexokinase ?HKDC1.
In addition to Reddy, Lowe and Newgard, study authors include Cong Guo; Anton E. Ludvik; Michelle E. Arlotto; M. Geoffrey Hayes; Loren L. Armstrong; Denise M. Scholtens; Christopher D. Brown; Thomas C. Becker; and Brian T. Layden.
This work was funded by grants from the National Institutes of Health (T32 DK007169; DK42583; R01 MH101822) and the Department of Veterans Affairs Career Development Grant 1IK2BX001587.
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