Diagnostics & Imaging Week Contributing Writer

LONDON — Blood glucose levels that are at the high end of normal are due to a genetic variation in an enzyme that plays a role in glucose metabolism, a new study has shown.

The finding is important because, on a population level, people with high-but-normal blood glucose levels are at an increased risk of developing cardiovascular disease. Ultimately, the discovery could also lead to new drugs for the treatment of type II diabetes.

Philippe Froguel, professor of genomic medicine at Imperial College London, said, "The level of blood glucose is crucially important for health. That level is controlled mainly by insulin secretion, but we currently don't know exactly how that works. Our finding opens new avenues that may eventually allow us to exert better control over blood glucose levels and maybe prevent the development of Type II diabetes."

A report of the study by Froguel, together with colleagues from the French National Research Institute and McGill University in Canada, appears in the May 1 issue of Science, in a paper titled "A Polymorphism Within the G6PC2 Gene Is Associated with Fasting Plasma Glucose Levels".

Last year, the same team published a study that identified the most important genes associated with a risk of developing Type II diabetes.

Froguel and his colleagues continued, however, to be intrigued by the association of high-but-normal blood glucose levels and increased risk of cardiovascular disease.

Someone who has a fasting blood glucose level of 1.25 g/l is said to be diabetic. Most people have a fasting blood glucose level of about 1 g/l. People who have a fasting blood glucose of 1.1 g/l, at the higher end of the normal range, are at about one-third increased risk of death over a 12-year period. The majority of such deaths result from cardiovascular disease. The relationship between higher fasting blood glucose levels and mortality appears to be approximately linear: there is no threshold effect.

Froguel's group therefore decided to revisit the data obtained from their earlier study, to examine whether they could identify genes that modulated blood sugar levels.

The genome-wide association study that resulted revealed an association between high levels of blood glucose and a mutation in a gene known as glucose-6-phosphatase (G6PC2), also known as IGRP.

Said Froguel, "There is a complex system of glucose sensing to allow the body to recognise when blood glucose rises after you eat. The main glucose sensor of the beta cell made by the first diabetes gene to be identified, by myself, in 1992 is called glucokinase. Glucokinase adds phosphate groups to glucose and ultimately triggers the release of insulin from the pancreas to lower blood glucose levels. G6PC2, in contrast, normally dephosphorylates glucose-6-phosphate and thus raises blood glucose levels. However, we found that the mutated G6PC2 gene blocks the action of glucokinase, and the result is less-tight control over levels of blood glucose."

A study by a different group, published last year, showed that mice lacking functional copies of the G6PC2 gene maintained lower blood glucose levels and had normal insulin responses.

Those researchers had focused on the G6PC2 gene for their knock-out study because the protein it encodes is the target of antibodies produced by the body during Type I diabetes, Froguel explained. "But we can now conclude that if we had a drug that could antagonise G6PC2, it might be a good treatment for type II diabetes," he said.

Froguel's group is now trying to understand exactly how the genetic variant in the G6PC2 gene affects the function of the protein it encodes. "We would also like to find out if it is possible to modulate the activity of the gene, with a drug, for example," he said. "In addition, we are expanding our work on normal people and following birth cohorts to examine how the levels of different biomarkers vary at different ages. We would like to be able to have a way of detecting type II diabetes earlier, as about half the people who have type II diabetes diagnosed by their doctors already have kidney disease, atherosclerosis or are beginning to go blind."

One important message from the Science paper, Froguel concluded, is that it is just as vital to work on normal people as on those with an established disease.

"Working on normal people can help you find out information that is useful for those with diseases like diabetes. That is important because all healthy people get sick one day."