Single gene mutation found to cause insulin sensitivity

Oxford researchers have discovered the first single gene responsible for insulin sensitivity in humans.  Since the opposite condition of insulin resistance is a significant marker of type 2 diabetes, the discovery could potentially lead to new pathways for diabetes drugs and future treatments.

The scientists decided to look at the gene – PTEN – based on previous studies, which examined common variants across the human genome that might lead to an increased risk for diabetes.

“They’ve shown a link between the cell cycle and a risk for type 2 diabetes, which has started to suggest there might be a genetic overlap in terms of your predisposition for getting diabetes and cancer,” study author Dr. Anna Gloyn, of the Oxford Center for Diabetes, Endocrinology and Metabolism at Oxford, told,

Mutations in just one PTEN gene have been associated with an increased risk of cancers – such as breast, womb and thyroid cancer.  To go along with this established link, mouse models have shown that PTEN also plays a role in the pathways important for metabolism.

“This gene was a good candidate to pick because you could hypothesize that if there was a defect in this gene, it could impact not only cell growth, which would lead to cancer, but it could also affect their metabolic outcome,” Gloyn said.

The scientists, interested in learning more about the gene’s dual role, recruited people in the U.K. with a condition known as Cowden syndrome, which is caused by a faulty mutation in the PTEN gene.  People with Cowden syndrome have a higher risk for cancer and often develop polyps on their skin, mouth and bowels.

Cowden syndrome is rare; only one out of every 200,000 people have the condition.  An estimated 300 people have the condition in the U.K., which made it difficult for the researchers to study.  However, they were able to assemble 15 people with the condition, matching each participant with a healthy counterpart who served as their control test subject.

Both the participants and the control subjects were given glucose drinks to see how well their bodies could cope.  Those with Cowden syndrome showed increased insulin sensitivity.

“With very low amounts of this [insulin] hormone, they could clear the glucose from their system,” Gloyn said.  “… the cells in our pancreas are responsible for secreting insulin – which helps to clear glucose from our blood.  The people who have these mutations respond very quickly to lower levels of glucose.”

For those suffering from type 2 diabetes, the opposite is true.  The body’s insulin is less effective at clearing glucose – essentially sugar – from the blood.  Because it is more difficult for their bodies to metabolize glucose, people who suffer from diabetes are typically overweight or obese.  Drugs used to combat diabetes typically strive to boost insulin sensitivity.

However, while those with Cowden syndrome were better at clearing glucose, they also had higher levels of obesity than the control group – providing an interesting paradox for the researchers.

“You would think if we have insulin sensitive people they’d be thin, but that wasn’t the case,” Gloyn said.

Now that faulty PTEN has been identified as having this metabolic effect in humans, Gloyn said the discovery could lead to new treatments for diabetes – but further research is definitely needed.

“If you were going to design a PTEN inhibitor…there’d be a strong chance you’d have cancer like properties,” Gloyn said.  “It’s like a ying yang – you’d have an increased risk of cancer, but a decreased risk of diabetes.”

Gloyn said that because of this duality, it’s important to know exactly what the target effects will be when developing new drugs.