Defective Gene Linked to High Blood Glucose Levels

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Title: Defective Gene Linked to High Blood Glucose Levels
URL: http://www.pslgroup.com/dg/220836.htm
Doctor's Guide
May 2, 2008

NEW YORK -- May 2, 2008 -- Canadian, French, and British researchers have identified a DNA sequence that controls the variability of blood glucose levels in people. This is a potentially significant discovery because high blood glucose levels in otherwise healthy people often are indications of heart disease and higher mortality rates. The article appears in the May 1 online issue of Science.

The study, conducted by researchers from Imperial College London, London, UK; the French National Research Institute, Lille, France; and McGill University, Montreal, Quebec, Canada, utilised data collected from a large genome study originally conducted for diabetes research that looked at more than 390,000 different locations -- or loci -- on the human genome. The study's first important diabetes results were published in 2007. Findings were confirmed by analysing the genetic makeup of an additional 8,000 individuals with blood glucose levels within the nondiabetic range, to verify that the same genetic mutations were visible in these individuals.

Researchers discovered that a single DNA mutation within 3 different genes explained, in part, why some individuals have high or low blood glucose levels. These genes are believed to actually 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 research showed that the mutated islet-specific glucose-6-phosphatase catalytic subunit-related protein (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.

"These sequences explain about 5% of the normal variation in blood glucose levels between otherwise healthy people," explained Robert Sladek, MD, Faculty of Medicine, McGill University, Department of Human Genetics, McGill University Health Centre Research Institute, and the McGill University and Genome Quebec Innovation Centre, all in Montreal, Quebec, Canada. "Five percent may not sound huge, but for complex traits, that's rather a lot. By contrast, hundreds of different genes influence height."

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.

In addition, the researchers believe that the mutation in the IGRP gene could cause an increase of around 5% 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.

SOURCES: Imperial College London and McGill University

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