Canadians help in major advance in diabetes research

ABRIDGED NEWS RELEASES

MCGILL UNIVERSITY

IMPERIAL COLLEGE, LONDON

************************** Discovery is first gene known to affect how insulin works, not how it is produced

A breakthrough by an international team of researchers in Canada, France, the UK and Denmark has uncovered a new gene that could lead to better treatment of type 2 diabetes, as well as a better understanding of how this widespread disease develops.

Unlike most of the genes that have been shown to cause diabetes, the new gene, called Insulin Receptor Substrate 1 (IRS1), doesn't affect how insulin is created in the pancreas, but rather, how the body responds to insulin already in the bloodstream, say the researchers, whose work will be published in Nature Genetics Sept. 6.

"Most of the genes that we've identified as diabetes risk genes to date reduce the function of the pancreas, specifically of beta cells in the pancreas that make insulin," explained Dr. Robert Sladek of McGill University and the Génome Québec Innovation Centre in Montreal, a corresponding author of the paper. "IRS1 has to do with the function of the other tissues in the body. Rather than reduce production of insulin, this gene reduces the effect of insulin in muscles, liver and fat, a process called insulin resistance."

Insulin, a hormone produced in the pancreas, enables the body's cells to absorb glucose from food and turn it into energy. Different types of diabetes are caused by the body's inability to produce sufficient insulin, inability to use its own insulin properly, or a combination of both factors.

"IRS1 is the first inside the cell that gets activated by insulin," Sladek continued. "It basically tells the rest of the cell, 'hey, insulin is here, start taking in glucose from the blood!' If IRS1 doesn't work, the whole process is disrupted."

The research was conducted by an international team including Sladek, Dr. Constantin Polychronakos of McGill's Faculty of Medicine; Dr. Philippe Froguel of the CNRS and Lille 2 University in France and Imperial College London; Dr. Oluf Pedersen of the University of Copenhagen and Aarhus University in Denmark and their colleagues at many institutions across Europe and North America.

This study, which used genetic material drawn from more than 6,000 French participants divided into two separate groups, represents the final step in a series of collaborations between these researchers that has redrawn our understanding of diabetes genetics. In this instance, not only did the researchers pinpoint a new diabetes-linked gene, they found the genetic trigger, which leads to malfunction, in a totally unexpected place.

"It's a single-nucleotide polymorphism (SNP, pronounced 'snip'), a single letter change in your DNA," said Sladek. "What's interesting about this particular SNP is that it's not linked genetically to the IRS1 gene in any way; it's about half-a-million base-pairs away, in the middle of a genetic desert with no known genes nearby. In genetic terms, it's halfway from Montreal to Halifax. And yet we can see that it causes a 40-per-cent reduction in the IRS1 gene, and even more important, a 40-per-cent reduction in its activity. Which means that even if insulin is present, it won't work."

Sladek hopes this discovery may lead to new therapeutic lines of attack in the future.

"It's possible that in diabetic patients, the signal to turn this gene on and off might be impaired. But we might be able to use one of the other pathways to turn it on," he said.

************************** Scientists discover new genetic variation that contributes to diabetes

Scientists have identified a genetic variation in people with type 2 diabetes that affects how the body's muscle cells respond to the hormone insulin, in a new study published today in Nature Genetics. The researchers, from Imperial College London and other international institutions, say the findings highlight a new target for scientists developing treatments for diabetes.

Previous studies have identified several genetic variations in people with type 2 diabetes that affect how insulin is produced in the pancreas. Today's study shows for the first time a genetic variation that seems to impair the ability of the body's muscle cells to use insulin to help them make energy.

People with type 2 diabetes can have problems with the body not producing enough insulin and with cells in the muscles, liver and fat becoming resistant to it. Without sufficient insulin, or if cells cannot use insulin properly, cells are unable to take glucose from the blood and turn it into energy. Until now, scientists had not been able to identify the genetic factors contributing to insulin resistance in type 2 diabetes.

In the new research, scientists from international institutions including Imperial College London, McGill University, Canada, CNRS, France, and the University of Copenhagen, Denmark, looked for genetic markers in over 14,000 people and identified four variations associated with type 2 diabetes. One of these was located near a gene called IRS1, which makes a protein that tells the cell to start taking in glucose from the blood when it is activated by insulin. The researchers believe that the variant they have identified interrupts this process, impairing the cells' ability to make energy from glucose. The researchers hope that scientists will be able to target this process to produce new treatments for type 2 diabetes.

Professor Philippe Froguel, one of the corresponding authors of today's study from the Department of Genomic Medicine at Imperial College London, said: "We are very excited about these results - this is the first genetic evidence that a defect in the way insulin works in muscles can contribute to diabetes. Muscle tissue needs to make more energy using glucose than other tissues. We think developing a treatment for diabetes that improves the way insulin works in the muscle could really help people with type 2 diabetes.

"It is now clear that several drugs should be used together to control this disease. Our new study provides scientists developing treatments with a straightforward target for a new drug to treat type 2 diabetes," added Professor Froguel.

The researchers carried out a multistage association study to identify the new gene. First, they looked at genome-wide association data from 1,376 French individuals and identified 16,360 single-nucleotide polymorphisms (SNPs), or genetic variations, associated with type 2 diabetes. The researchers then studied these variations in 4,977 French individuals.

Next, the team selected the 28 most strongly associated SNPs and looked for them in 7,698 Danish individuals. Finally, the researchers identified four SNPs strongly associated with type 2 diabetes. The most significant of these variations was located near the insulin receptor substrate 1, or IRS1, gene.

To test their findings, the team analyzed biopsies of skeletal muscle from Danish twins, one of whom had type 2 diabetes. They found that the twin with diabetes had the variation near IRS1 and this variation resulted in insulin resistance in the muscle. They also noted that the variation affected the amount of protein produced by the gene IRS1, suggesting that the SNP controls the IRS1 gene.

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