From gene discovery to revolutionising clinical care
27 January 2021
6 mins to read
Monogenic diabetes, diabetes caused by a single gene, was not understood or recognised when the Exeter diabetes lab was set up in 1995. Patients knew diabetes ran in their family, yet they were typically treated as either type 1 or type 2 – meaning large numbers were not getting the best treatment.
Meanwhile, genetic research was just emerging. "We needed to be at the forefront of gene discovery, and we started with a clean sheet” said Professor Andrew Hattersley. “Professor Sian Ellard set up a cutting-edge genetics lab from scratch. With the help of NHS consultants around the UK we collected blood samples for DNA from families with diabetes in multiple generations. It was hard work, but that was our precious resource for finding genes that cause diabetes."
The team faced huge challenges, yet made incredible progress. They helped discover new genes causing different subtypes of monogenic diabetes, identified families in these new genetic subtypes, determined the best treatments for them and shared this information worldwide.
Pioneering gene discovery to improve outcomes
Finding a single genetic mutation amid six billion pieces of genetic code is akin to finding a single spelling mistake in a whole library of books.
Geneticist Dr Elisa de Franco, who started her career as a PhD student at Exeter 10 years ago, said: “When I began, looking for new genes was almost a guessing game – we were testing one gene at a time.
"Over the years, progress in whole DNA sequencing has removed that guesswork. We can now filter through genes to see what’s really happening. Some genes that cause diabetes have been a total surprise – we had no idea they were involved in insulin production."
"Over the years, progress in whole DNA sequencing has removed that guesswork. We can now filter through genes to see what’s really happening. Some genes that cause diabetes have been a total surprise – we had no idea they were involved in insulin production."
Dr Elisa de Franco
Diabetes UK RD Lawrence Research Fellow
Finding such genes means identifying a new diabetes subtype – but that’s just the beginning. A wide range of scientists and clinicians then work together to discover the gene’s function, and how best to treat the condition.
Exeter has now identified more than 21 genes that can cause diabetes. The strength of this collaboration swiftly moves gene discovery into diagnostic testing. Today, the Exeter team provides testing for more than 200 countries.
From discovery to revolutionising treatment
An early success of this precision diabetes approach led to a revelation with huge impact. In 2006, the team discovered that neonatal diabetes could be caused by a problem in the potassium channel in half of affected babies. They identified that this would respond to treatment by a simple tablet – meaning an end to a lifetime of insulin injections, and much better blood glucose control.
Professor Andrew Hattersley said: “It was actually very dangerous to stop insulin treatment and give these patients a tablet – but we had to take that risk, and the families were keen. Remarkably, not only could they stop taking insulin injections, but their blood sugar control was outstanding. Their lives were completely transformed.”
As a result, every patient that develops diabetes in the first six months of life should be offered a genetic test, and half of them can stop insulin treatment.
Sharing knowledge to improve precision diabetes care
From the outset, communication with clinicians was crucial. They needed to be alert to signs that their patients may not have types 1 or type 2 diabetes, and that meant an ambitious clinical education programme.
Diabetes nurse Professor Maggie Shepherd had continued to update families from who she’d first collected samples, and their clinicians. "It was really exciting to get the right diagnosis and to ensure the families and their clinicians were aware of the potential impact of that result, which often meant changing and improving treatment for the whole family."
Today, the team shares new findings directly with its network of families and clinicians worldwide, which changes understanding and care. "For me as a nurse, it’s hugely important to be able to make a difference for our patients by ensuring they have the correct diagnosis and treatment."
Part of the process of increasing awareness of monogenic diabetes amongst nurses and clinicians is a two day course on genetic diabetes, which attracts clinicians from across the world. A nationwide network of genetic diabetes nurses upskill at Exeter three times a year. Between them, they have shared their knowledge to 11,000 healthcare professionals across the UK, leading to increased recognition of monogenic diabetes.
Professor Shepherd said: "Awareness of monogenic diabetes is now so much greater. If you are identified with a genetic form of diabetes anywhere in the world, the diagnostic test you have and the treatment you receive could be as a direct result of research at Exeter."
"Awareness of monogenic diabetes is now so much greater. If you are identified with a genetic form of diabetes anywhere in the world, the diagnostic test you have and the treatment you receive could be as a direct result of research at Exeter."
Professor Maggie Shepherd
Honorary Clinical Professor, Lead Research Nurse
A future of precision diabetes for all
Exeter’s work has led to a global shift towards genetic testing in diabetes, yet the team has sights set on even greater impact. Even more genetic subtypes remain to be found, and they are expanding work outside of white European populations, where most studies have been done.
In one exciting new avenue, scientists can now use blood samples from pregnant women to test whether a baby in the womb has inherited particular types of genetic diabetes. This can directly aid the management of that pregnancy and ensure appropriate treatment, improving the lives of both mother and baby.
Wellcome Trust Fellow Dr Kashyap Patel, and a consultant in diabetes and endocrinology, said: "Our incredible progress in genetics has led to some of the best examples of precision diabetes in the world, yet there’s much we still need to learn".
"As genetic sequencing becomes cheaper and more prevalent, we’re full steam ahead in laying the groundwork for clinicians to be able to tell their patients right from the diagnosis of diabetes what type of diabetes then have, the likely clinical features, and the best treatment options will be for them. That’s incredibly exciting".
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