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New type 2 diabetes gene makes cells resistant to insulin

21 September 2009
Appeared in BioNews 526

An international team of researchers has identified a novel gene variant in people with type 2 diabetes (T2D) that affects how muscle cells respond to insulin. The work - published in the journal Nature Genetics - was conducted by teams including those of Drs Robert Sladek and Constantin Polychronakos of McGill's Faculty of Medicine, Canada; Professor Philippe Froguel of the CNRS and Lille University in France and Imperial College London; and Dr Oluf Pedersen of the University of Copenhagen and Aarhus University in Denmark. The finding advances understanding of the disease whilst offering a novel target for treatment.

Insulin, a hormone produced in the pancreas, enables cells to take up glucose from the bloodstream, allowing them to store or use the energy it contains. All forms of diabetes stem from an inability to use glucose effectively.

The large-scale study involved the screening of some 14,000 people in different countries, whittling down thousands of T2D-associated gene variants to identify the one with the largest single influence on disease-state. A final experiment studied DNA and gene activity in muscle cells taken from Danish twins, one of whom had T2D. The variant, associated with a gene called IRS1, was only found in the twin with T2D.

‘IRS1 is the first [gene] inside the cell that gets activated by insulin', Dr Sladek says. ‘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 variant form of IRS1 causes a forty per cent reduction in the IRS1 gene-product and an equal reduction in its activity. This means that even if insulin is present, it has little influence on the muscle cell.

'We are very excited about these results', said Professor Froguel. ‘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'.

Lifestyle changes have caused the prevalence of T2D to double in the past twenty years, whilst its increased appearance in children has been linked to simultaneous rises in childhood obesity.

Also last week, researchers at the Karolinska Institute in Stockholm, Sweden, reported that cells exposed to excess fat will respond by shutting down genes necessary for proper response to insulin, potentially contributing to the onset of T2D. Such findings will shed light on the role of both genetic and environmental factors in susceptibility to common diseases.

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