Cancer drug has a surprise effect on diabetes

A random conversation in the corridor between scientists from different research groups was the start of a creative partnership that resulted in a cancer drug curing diabetes in mice, and providing hope for people with type 1 diabetes.

The scientists were diabetes researcher Associate Professor Charmaine Simeonovic, and Professor Christopher Parish, a cancer research and immunologist. The cure was a cancer drug called Muparfostat, which prevents the destruction of insulin-producing cells and halts the progression of type 1 diabetes in non-obese diabetic mice.

Type 1 diabetes is an autoimmune disease, which destroys insulin-producing cells in the pancreas. This means the body can no longer regulate blood-sugar levels. Affecting more than 130 000 people in Australia, it is unclear what causes the disease, although both genetic and environmental triggers play a role.

Currently there is no cure for type 1 diabetes. To manage the disease, patients require daily insulin injections. While managing blood-sugar levels keeps these patients reasonably healthy, eventually most will end up with serious secondary complications. These can include kidney disease, heart disease, blindness, nerve disease and even amputation of limbs.

“At the time of diagnosis there can be up to 20 per cent of insulin-producing cells still remaining. So if we can protect those cells and allow them to continue to function and produce insulin then these long term complications won’t happen,” says Associate Professor Simeonovic.

An insight into protecting insulin-producing cells came when Simeonovic’s team discovered they contained high levels of a complex sugar called heparan sulfate.

Heparan sulfate is not normally present inside cells—it is found mainly on the surface of cells. To find it at high levels inside the pancreatic insulin-producing beta cells was quite unexpected.

“We found that heparan sulfate is necessary for beta cells to remain healthy. If they lose the heparan sulfate they die,” says Associate Professor Simeonovic.

“We then found that in type 1 diabetes, cells of the immune system produce an enzyme called heparanase that degrades heparan sulfate and this leads to death of the pancreatic beta cells,” she says.

Based on this discovery the team’s goal was clear, they had to find a way to shut down the heparanase enzyme.

They didn’t have to look far, as Professor Parish had developed Muparfostat many years ago as a cancer therapy and heparanase inhibitor.

And the results were astonishing.

“We found Muparfostat reduced diabetes in non obese diabetic mice by 50 per cent.

“The drug is both a heparanase inhibitor and heparan sulfate analogue. It was therefore possible that it not only prevented the degradation of heparan sulfate but also entered insulin-producing cells and replenished the lost heparan sulfate.

“Heparanase isn’t the only damaging process in the disease. But we think it is important and no one else has looked at this aspect before,” says Associate Professor Simeonovic.

A drug development company, Beta Therapeutics, has now been set up to develop similar drugs that can treat patients early in the disease. The drugs may also help pre-diabetic individuals, people who are autoantibody positive and haven’t yet developed clinical diabetes.

Associate Professor Simeonovic hopes that the research will also help those with type 2 diabetes, which occurs because of insulin resistance, rather than autoimmune destruction of insulin-producing cells.

In this type of diabetes, it seems the beta cells produce less heparan sulfate, rather than heparanase destroying the heparan sulfate, says Associate Professor Simeonovic.

“Potentially type 2 diabetes could also be treated with heparan sulfate replacing drugs,” she says.

Published in The John Curtin School of Medical Research – Research Highlights 2017.

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