Gene sequence discovery explains blood sugar variability

Study examines risk potential in non-diabetes patients

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MONTREAL—A group of Canadian, French and British researchers have identified a DNA sequence that controls blood sugar variability, a potentially significant discovery because high blood glucose levels in non-diabetic people often are indicators of heart disease and higher mortality rates.

The research was conducted by Dr. Phillippe Froguel and colleagues at Imperial College London and le Centre national de la recherche scientifique (CNRS) in Lille, France, in collaboration with Dr. Robert Sladek, Dr. Constantin Polychronakos and their teams at McGill University and the McGill University Health Centre (MUHC) in Montreal. Dr. Ghislain Rocheleau, a post-doctoral fellow in Sladek's lab, was the study's co-first author.

In the study, researchers looked at the genetic code of healthy, non-diabetic individuals whose blood glucose levels were in the normal range.

"As you know, high levels of blood sugar can result in diabetes, but what we were really interested in learning was how blood sugar is regulated in people who don't have diabetes," Sladek says. "It turns out that with things like cardiovascular disease, stroke and heart attack, the risk can be increased by small increases in blood sugar, even in people whose blood sugar is in a normal range."

Working with data collected from a large genome study originally conducted for diabetes research that looked at over 390,000 different loci on the human genome, the researchers discovered that a single DNA mutation within three different genes explained, in part, why some individuals have high or low blood glucose levels.

"We found one region of the genome which contains a gene code called G6PC2, which influences blood sugar levels in these people," Sladek says. "We knew a little bit about what G6PC2 did, so we also looked at a couple of other genes that had similar functions. Lo and behold, we found that those genes as well influenced blood sugar levels in normal people."

The sequences explained about 5 percent of the normal variation in blood glucose levels between otherwise healthy people, Sladek explains.

"Five percent may not sound huge, but for complex traits, that's rather a lot. By contrast, hundreds of different genes influence height," he says.

The researchers believe that these genes affect the threshold level of glucose in the bloodstream, which triggers the secretion of insulin. The higher the threshold, the higher the blood glucose level will rise before insulin starts to regulate it, the study concluded.

"What is also interesting is that this particular gene, even though it influences blood sugar levels, does not cause people to get diabetes," Sladek adds. "The gene is interesting from that standpoint because it suggests that simply having a gene that increases blood sugar levels isn't sufficient enough to cause diabetes, and other things have to happen in diabetic patients to get the disease."

High blood glucose levels are also closely linked with increased risk for cardiovascular disease, and these findings hold out of the hope of discovering new management techniques and treatments, Sladek adds.

"What we'd like to know now, more, is how these work in the beta cells, the cells that make insulin in the body and are responsible for regulating blood sugar in the body," he says. "We'd also like to know whether the genes we found can influence the risk of one developing heart disease, as well. Obviously, the next step would be to get some collaborators on the heart disease side, and see whether some of these other genes might also play a role."

These findings provide important insights into the genetic mechanisms behind glucose metabolism, say the researchers, which they predict will lead to greater understanding of the genetic roots of metabolic disorders in general.

"In theory, any medical test which has a genetic component can use this approach," Sladek says. "That brings us to the idea of 'personalized medicine.' Eventually, we might be able to customize treatment to an individual's unique genetic structure."

The study, A Polymorphism Within the G6PC2 Gene Is Associated with Fasting Plasma Glucose Levels, was published May 1 in the online version of the journal Science.

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