Monogenic diabetes results from the inheritance of a mutation or mutations in a single gene. It may be dominantly or recessively inherited or may be a de novo mutation and hence a spontaneous case. In children, almost all monogenic diabetes result from mutations in genes that regulate beta-cell function although diabetes can rarely occur from mutations resulting in very severe insulin resistance
The majority of patients with genetically proven monogenic diabetes are initially incorrectly diagnosed as Type 1 or Type 2 diabetes. It is important to correctly diagnose monogenic diabetes as it can predict the clinical course of the patient, explain other associated clinical features and most importantly guide the most appropriate treatment. In addition, making a diagnosis will have implications for other family members, often correcting the diagnosis and treatment as well as allowing appropriate genetic counselling
Advances in molecular genetics have led to the identification of the genes associated with many clinically identified subgroups of diabetes. The identification of genes has explained clinical heterogeneity in conditions defined on the basis of when they were diagnosed e.g. neonatal diabetes and Maturity Onset Diabetes of the Young (MODY). Now molecular genetics is being used as a diagnostic test which can help define the diagnosis and treatment of children with diabetes. As these tests are expensive, genetic testing should be limited to those who are likely to be positive.
The research team was awarded a Queen's Anniversary Prize which recognised the world-class work of the Peninsula Medical School in combating diabetes. Scientists have identified new forms of diabetes, developed new treatments and then trained frontline medical staff to use them. Their work has meant that hundreds of patients, many of them children or babies, no longer require insulin injections and can transfer to tablets. This has made it much easier for patients to control their blood sugar levels and dramatically improved their quality of life.
The scientists' research focuses on 'monogenic' diabetes. This is much less common than Type 1 and Type 2 diabetes, but nevertheless affects around 50,000 people in the UK alone. Monogenic diabetes itself comprises many different subtypes, all resulting from changes in a single gene.
Professor Andrew Hattersley, who leads the research team, said: 'It is only in recent years that we have begun to identify and unravel monogenic diabetes. It means that many patients have been misdiagnosed and treated as if they were suffering from the more common forms of the condition. We have patients who have been injecting insulin for 20 years or more who can now treat their diabetes with tablets.'
As the genetic subtypes of diabetes were unknown until the 1990s, integrating this new genetic knowledge into clinical care is a major educational problem. Most healthcare professionals have had little or no training in genetics. Maggie Shepherd and Sian Ellard, who work with Professor Hattersley, have therefore launched a variety of educational initiatives. These include a website for patients and healthcare professionals, www.diabetesgenes.org, and educational programmes for doctors and nurses. Most importantly, with funding from the Department of Health, they have set up a training programme in genetics for specialist diabetes nurses throughout the UK.
Diabetes patient Tracey Davies, from Yeovil, is one patient who has benefited from this work. She was able to transfer to tablets after 17 years of injections.
Said Mrs Davies: 'It's made an amazing difference. For years I had to inject insulin before every meal I was a walking pin cushion! When I was first diagnosed no-one knew about monogenic diabetes so the research done at Exeter has really made a difference to people like me.'
A major future challenge is to define the genetic susceptibility to Type 2 diabetes, the commonest form of diabetes, and to use this information to improve both treatment and prevention. This will only be achieved if studies can be performed with a sufficient sample size to ensure enough power to enable the multiple genetic components to be defined. The Exeter scientists have collaborated with colleagues in Oxford, Imperial College, Queen Elizabeth College, London, Cambridge and Newcastle to establish a unique collection of DNA from patients with diabetes and have played a central role in collaborations within the UK and internationally.
This trailblazing work is important because it points to the next phase of medicine. Rather than trying to define what is best for a group of patients with a condition such as diabetes it becomes important to subdivide this group so that doctors can make a more individualised choice on medicines that are best for this specific patient.
The lab provides genetic testing to patients throughout the world and has received samples from over 60 countries. In the last 15 years the team in Exeter have published over 350 papers and secured a total of over £21 million in grants for research.
The citation that accompanied Professor Hattersley's appointment as a Fellow of the Royal Society, stated: "His clinical observations and physiological studies in patients with diabetes resulting from mutations in single genes have resulted in key insights into insulin secretion, foetal development, and patients' clinical care. Importantly his work led him to revolutionise treatment for most patients with genetic subtypes of diabetes by replacing insulin injections with sulphonylurea tablets."