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From injections to pills - the research on neonatal diabetes

They govern everything we think and do, they give us the ability to feel pain and to secrete insulin: they are the ion channels that are present in every one of our cells and that control the electrical impulses in our nerve and muscle cells.
“For me, they are the very spark of life”, says Dame Frances Ashcroft, professor at the University of Oxford, who is also now to be an honorary doctor at Lund University.

In her research, professor Dame Frances Ashcroft examines how our blood sugar is controlled and what goes wrong in diabetes.

“Type 2 diabetes is a major problem, exacerbated by the obesity epidemic, and it is important that we get to grips with both of them soon”, she says.

The starting point for the research is a protein known as an ion channel, that most people may have never even heard of …

“Everything we see and do is regulated by electrical signals and I have always been interested in how the proteins that govern the signals actually work.”

Involved in insulin secretion

Frances Ashcroft is behind the important discovery that an ion channel in the insulin-producing cells is involved in the processes that control insulin secretion.

Insulin is produced by the beta cells in the pancreas and secreted when blood sugar rises after a meal. It stimulates the uptake of  glucose in muscle, fat and liver, so restoring the normal blood sugar level. When the beta-cells don't work properly, or the beta-cells have been destroyed, diabetes develops.

Her discovery is that a type of ion channel, which functions like a tiny pore in the cell membrane, is crucial to the process resulting in the secretion of insulin.

“When the pore is open, insulin is not secreted and when it is closed, insulin is secreted. What happens is that when your blood sugar level rises, the pores close, setting off a series of complex processes that result in insulin secretion”, she explains.

A rare inherited form of diabetes

The discovery has come to play a very important part for people suffering from a rare inherited form of diabetes, known asneonatal diabetes.

It was previously thought that people born with diabetes had type 1 diabetes, a form of the disease which often arises in children and young people and is caused by an autoimmune attack on the patient’s own cells. In cases of type 1 diabetes, there are eventually no, or very few, insulin-producing cells left and patients must take insulin for the rest of their lives, either through daily injections or using an insulin pump.

Now we know that neonatal diabetes is caused by a genetic mutation which means that the ion channels do not close. This results in no insulin being released even if the beta cells are full of insulin. It is as if the cells are simply switched off.

The mutations were discovered for the first time by Professor Andrew Hattersley at the University of Exeter in England,

“When that happened, he phoned in a very excited state to tell me and I will never forget that day!” says Frances Ashcroft.

Together, they went on to show how the mutations function – and that an existing drug (sulfonylurea, which was already administered to patients with type 2 diabetes) made it possible to close the ion channels.

“As the medicines could close the channels in people who were born with diabetes, perhaps they could switch from their insulin injections to sulfonylurea taken in pill form. To everyone’s delight, this worked!”

From discovery to the clinic

Few researchers are lucky enough to witness how a discovery they have made improves people’s lives so concretely, as Frances Ashcroft and Andrew Hattersley were able to do.

“From the discovery that the ion channel was controlled by glucose to our discovery of the first mutation, it took twenty years. From that point, it only took three–four years until the first patient was treated”, she explains.

The challenge today is to understand more about type 2 diabetes which is an enormous problem that has not yet been solved.”

When she is not doing research, she writes popular science books – about research.

“I would never have dared to do that if, as a doctoral student, I had not had a supervisor who did it. He was from the old school and although did not help me much with my project, he taught me a lot about life and was always there when I needed him. He also taught me that one can do other things besides science, like writing books.”

She wishes that she had been more self-confident in her youth.

“Life would have been a lot simpler if I had believed in myself from the start”.

Text: Sara Liedholm

Footnote: The text is based on filmed interviews with Dame Fances Ashcroft by Professor Denis Noble in the series "Voices from Oxford".

 

More about Dame Fances Ashcroft´s research, films and books:

https://www.dpag.ox.ac.uk/research/ashcroft-group

Frances Ashcroft
Dame Frances Ashcroft

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Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00