Research Profile - Using a bigger net

Most researchers try to narrow the field of suspects when sleuthing sources of disease. Two CIHR-funded researchers are trying the opposite approach in their investigation of a common pregnancy condition that appears to leave newborns predisposed to obesity and diabetes.

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In 2010, Drs. Luigi Bouchard and Diane Brisson published findings in Diabetes Care that linked exposure to gestational diabetes to epigenetic changes in the leptin gene, which is instrumental in how the body consumes and expends energy.

"To my knowledge, we were the first to publish the leptin story, finding out about epigenetic differences in newborns exposed to gestational diabetes. But we suspect there are many other genes affected by the exposure," says Dr. Bouchard of the Université de Sherbrooke.

The two researchers are now using a bigger net as they attempt to snare all the genes affected by gestational diabetes. Their goal is to measure epigenetic changes – modifications to strands of DNA caused by a process called methylation – that occur after exposure to this condition.

"We are looking at all the genes in the genome," says Dr. Bouchard. "At the end of the experiment, we could have up to few hundreds of genes that are affected. We expect to find new genes along with those that were already associated with traits related to obesity and diabetes development."

Gaining a better understanding of the epigenetic impacts of gestational diabetes is important given that 6-18% of Canadian women develop the condition when they become pregnant – with overweight women the most likely candidates for contracting it.

"There is a lot of variation in the prevalence of gestational diabetes among various populations," says Dr. Brisson of the Université de Montréal and Chicoutimi Hospital. "It's higher among women in Aboriginal populations. But with the increase in obesity prevalence worldwide we can expect gestational diabetes to increase in other populations in the coming years."

The researchers' findings suggest that any level of hyperglycemia (high blood sugar levels caused by lack of insulin) during pregnancy affects the epigenome of the baby and how it develops prenatally.

"New research data we presented at the 2011 Canadian Obesity Network annual meeting indicates that you don't necessarily have to pass the threshold characterizing gestational diabetes to have an impact on the baby's genome," says Dr. Bouchard. "It's a good contribution to this field because now organizations such as the International Association of Diabetes and Pregnancy Study Groups are suggesting revisions to the criteria for a gestational diabetes diagnosis to lower the thresholds."

While the researchers are currently working on a one-year project funded by the Canadian Institutes of Health Research (CIHR), they have been gathering placenta samples for about five years with funding from Fonds de recherche en Santé du Québec (FRSQ). Their long-range plan is to track the progress of the newborns every five years to monitor the stability of the gestational diabetes-related changes at the epigenetic level.

The goal, says Dr. Bouchard, is to better understand the molecular mechanisms involved in how a mother's gestational diabetes affects the health of the baby growing in her womb. Ultimately, the aim is to help find ways to break the cycle that sees overweight or obese mothers develop diabetes during pregnancy and pass along a predisposition to becoming obese and developing diabetes to their children.

Says Dr. Bouchard: "The missing part is: what explains this link? What we are expecting to show is that epigenetics is part of the process involved in this link. Of course, there will be other processes, but we think epigenetics is an important part of it."

Dr. Ravi Retnakaran, a clinician/scientist at Mount Sinai Hospital in Toronto who specializes in endocrinology, says Drs. Bouchard and Brisson's research provides insight into what happens when a fetus is exposed to gestational diabetes.

"Further work by Drs. Bouchard and Brisson and others is going to help delineate the genes that are being affected, which then has two important applications: it potentially gives us a way of identifying those offspring who are at risk and may gives us ways to consider rational therapies," says Dr. Retnakaran.

"We want to show that a detrimental fetal environment like gestational diabetes has impacts on a newborn at the epigenetic level. We believe that some of those differences will be constant in the development of the child and will be associated with an increased risk of obesity and diabetes throughout their lives."
-- Dr. Luigi Bouchard