Oxford University researchers have discovered, for the first time, a single gene responsible for increasing insulin sensitivity in humans. The research, published today in the New England Journal of Medicine is a milestone achievement in the journey towards understanding the group of metabolic diseases which stem from insulin resistance, including type II diabetes, metabolic syndrome or syndrome X and polycystic ovarian syndrome.
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 to treat conditions related to insulin resistance.
Insulin resistance occurs when the cells in the body become unresponsive to the message which the hormone insulin is trying to convey, namely to take a molecule of glucose into the cell where it can be burned for energy. To compensate, the pancreas will generally increase the production of insulin, until the cells ‘listen’, however, insulin affects other tissues in the body, and the abnormally high levels of insulin cause many problems in both men and women.
Insulin resistance is a major feature in polycystic ovarian syndrome and, if left untreated, frequently progresses into type II diabetes. More than half of women with PCOS will be diagnosed with diabetes or pre-diabetes before the age of 40. Unchecked insulin resistance causes a cascade of hormonal and metabolic dysfunction, which results in some very unpleasant symptoms, such as increased facial and body hair, loss of hair on the head, abdominal adiposity or beer belly, and a greatly increased risk of other serious diseases. Women with PCOS are four to seven times more likely to have a heart attack than women in the general population.
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.
Dr Anna Gloyn of the Oxford Centre for Diabetes, Endocrinology and Metabolism at the University of Oxford, who led the research project says
“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. 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.”
says first author Dr Aparna Pal of the University of Oxford.
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 which contains detailed data on over 5,000 healthy men and women aged 30 and living in Oxfordshire. All participants have undergone a detailed examination at a screening visit, donated DNA and given informed consent. The information is used to further research into the causes of diseases such as diabetes, obesity and cardiovascular disease.
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 concluded: ”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.”
“While there are promising research avenues to pursue here, in the meantime the best way to avoid diabetes remains exercising more and eating less.”
The Wellcome Trust, who funded the study, 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.
Aparna Pal, Thomas M. Barber, Martijn Van de Bunt, Simon A. Rudge, Qifeng Zhang, Katherine L. Lachlan, Nicola S. Cooper, Helen Linden, Jonathan C. Levy, Michael J.O. Wakelam, Lisa Walker, Fredrik Karpe, Anna L. Gloyn.PTENMutations as a Cause of Constitutive Insulin Sensitivity and Obesity. New England Journal of Medicine, 2012; 367 (11): 1002 DOI: 10.1056/NEJMoa1113966