The opposite condition – insulin resistance – is a common feature of type 2 diabetes, so finding this cause of insulin sensitivity could offer new opportunities for pursuing novel treatments for diabetes.
Although mutations in the PTEN gene cause a rare condition with increased risk of cancer, the biological pathways the gene is involved in could offer promising targets for new drugs.
The Oxford University researchers, along with colleagues at the Babraham Institute in Cambridge and the Churchill Hospital in Oxford, report their findings in the New England Journal of Medicine. The study was funded by the Wellcome Trust, the Medical Research Council, the National Institute for Health Research Oxford Biomedical Research Centre, and and the Biotechnology and Biological Sciences Research Council.
‘Insulin resistance is a major feature of type 2 diabetes,’ says Dr Anna Gloyn of the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford, who led the work. ‘The insulin-producing cells in the pancreas may be working hard and pumping out lots of insulin, but the body’s cells no longer respond.
‘Finding a genetic cause of the opposite – insulin sensitivity – gives us a new window on the biological processes involved. Such understanding could be important in developing new drugs that restore insulin sensitivity in type 2 diabetes.’
The PTEN gene encodes for an enzyme that is part of the insulin signalling pathway in the body. It is known to have a role in controlling the body’s metabolism, and to play a part in cell growth. The Oxford team was interested in learning more about this dual role.
There is an inherited genetic condition called Cowden syndrome caused by faults in the PTEN gene. It is very rare and is thought to affect perhaps one in 200,000 people, with around 300 people with the condition in the UK. PTEN‘s role in cell growth sees people with Cowden syndrome develop many benign polyps in their skin, mouth and bowel, and have a higher risk than the general population of developing breast cancer, thyroid cancer and womb cancer.
‘PTEN is a gene that is heavily involved in processes for both cell growth and metabolism,’ says first author Dr Aparna Pal of the University of Oxford. ‘Given PTEN‘s dual role, we were interested in understanding the metabolic profile of people with Cowden syndrome. It was possible that mutations in PTEN could improve metabolism.’
The team carried out glucose tolerance tests with 15 people with Cowden syndrome and 15 matched controls. Those with Cowden syndrome had significantly higher insulin sensitivity. In collaboration with their colleagues at the Babraham Institute, the team showed that this was caused by increased activity in the insulin signalling pathway.
The researchers also noticed that the body mass index of those with Cowden syndrome appeared greater than the controls. They carried out a comparison with a much larger control group of over 2,000 individuals from the Oxford Biobank, a data and tissue resource for research established by Professor Fredrik Karpe.
This confirmed that those with Cowden syndrome had higher levels of obesity as a group than the controls. The extra body weight appeared to be caused by extra fat, and there were no differences in where the fat was stored compared to controls.
‘This was a surprise. Normally insulin sensitivity goes with being lean,’ says Professor Karpe.
Dr Gloyn concludes: ‘We now know that mutations that inactivate the PTEN gene result in increased cancer risk and obesity, but also increase insulin sensitivity which is very likely to protect against type 2 diabetes.
‘The study shows how intimately the biological pathways governing cell growth and metabolism are linked. We need to thoroughly understand these pathways to identify which genes to target in the development of new drugs.’
She adds: ‘While there are promising research avenues to pursue here, in the meantime the best way to avoid diabetes remains exercising more and eating less.’
Notes to editors
Approximately 2.9 million people are affected by diabetes in the UK, and there may be around a further 850,000 people with undiagnosed diabetes. Left untreated, diabetes can cause many different health problems including heart disease, stroke, nerve damage and blindness. Even a mildly raised glucose level can have damaging effects in the long-term.
Type 2 diabetes is by far the most common form of the disease. In the UK, about 90% of all adults with diabetes have type 2 diabetes. It occurs when the body does not produce enough insulin to control the level of glucose in the blood, and when the body is unable to use the insulin that is produced effectively. It is this second feature of type 2 diabetes that tends to be known as ‘insulin resistance’. Insulin resistance is often connected with obesity.
The paper ‘PTEN mutations cause constitutive insulin sensitivity and obesity in humans‘ is to be published in the New England Journal of Medicine with an embargo of 22:00 UK time / 17:00 US Eastern time on Wednesday 12 September 2012.
About the Medical Research Council
For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
About NIHR Oxford Biomedical Research Centre
The NIHR Oxford Biomedical Research Centre is funded by the National Institute for Health Research, and is a partnership between the Oxford University Hospitals Trust and the University of Oxford. The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world class facilities (both NHS and university), and conducting leading edge research focused on the needs of patients.
About the National Institute for Health Research (NIHR)
The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government’s strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website ( www.nihr.ac.uk). The views expressed in this news release are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
About the Babraham Institute
The Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The institute received £22.4M investment from BBSRC in 2010-11. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. www.babraham.ac.uk
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