Harmful blood glucose levels linked to defective gene

May 01, 2008

A genetic mutation that can raise the amount of glucose in a person's blood to harmful levels is identified today in a study in the journal Science.

High levels of blood glucose increase the risk of cardiovascular disease and early death, even in healthy people who do not have diabetes and whose blood glucose levels are at the higher end of the range considered 'normal' by doctors. One in five people in the UK has a high blood glucose level.

The study, by researchers from Imperial College London, the French National Research Institute and McGill University in Canada, reveals an association between high levels of blood glucose and a mutation in a gene known as G6PC2 or IGRP.

The research shows that the mutated IGRP gene blocks the action of a sensor called glucokinase. By stopping glucokinase from doing its job, the gene prevents the body from keeping tight control over its levels of blood glucose. Glucokinase works by signalling to cells known as beta cells which then secrete insulin to keep blood glucose levels under control.

The researchers hope their findings could enable a therapy to be developed to stop the defective IGRP gene from blocking the glucokinase sensor. This would restore control of glucose levels in the blood and help prevent these levels from becoming too high.

The researchers believe that the mutation in the IGRP gene could cause an increase of around five percent in the level of glucose in the blood. This small percentage increase would be enough to raise a person's risk of health problems because levels of blood glucose are so tightly controlled.

Epidemiological studies have shown that 80 percent of the risk of cardiovascular disease is related to a blood glucose level just above the average. High blood glucose levels are linked to obesity, poor nutrition and lack of exercise.

Professor Philippe Froguel, leading author of the research from the French National Research Institute and the Department of Genomic Medicine at Imperial College London, said: "Having a high level of blood glucose is a bit like having high cholesterol or high blood pressure in that the higher the level, the greater your risk of serious health problems. Our study helps unravel the genetic reasons why some people have higher levels of glucose in their blood than others.

"At present, doctors advise people with high blood glucose levels to lose weight and exercise. We hope that ultimately our research will mean we can develop new treatments to stop people from developing high blood glucose levels, which would enable them to live longer and healthier lives," added Professor Froguel.

The scientists reached their conclusions after comparing the genetic makeup of 654 non diabetic people with differing levels of blood glucose, from the low to the high end of the 'normal' range. The researchers looked at mutations in the building blocks, called nucleotides, which make up DNA.

There are mutations, known as single-nucleotide polymorphisms, in around one in every 600 nucleotides. The scientists examined over 392,000 of these mutations to find the ones specific to high blood glucose levels. The researchers confirmed their findings by analysing the genetic makeup of a further 8000 individuals with blood glucose levels within the non diabetic range, to verify that the same genetic mutations were visible in these individuals.

Today's study follows on from a study published in February 2007 by the same team, where they identified the most important genes associated with a risk of developing type-2 diabetes.
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The research was funded by Genome Canada, Genome Quebec, the French National Agency for Research, the Medical Research Council and the National Academia of Finland.

Imperial College London

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