Muscular problems in children with neonatal diabetes are neurological | University of Oxford

Muscular problems in children with neonatal diabetes are neurological

New research into muscular problems associated with a rare, inherited form of diabetes that affects infants early on in life could pave the way for improved treatments for the condition.

The Oxford University study found that muscle weakness and coordination problems sometimes seen in patients with neonatal diabetes are caused by problems in the brain rather than the muscles.

Neonatal diabetes affects one in 100,000 infants in the UK. It usually begins in the first six months of a child's life and can be accompanied by development defects affecting speech, movement, and cognitive function.

In 2004, Professor Frances Ashcroft from Oxford University and Professor Andrew Hattersley at the Peninsula Medical School discovered that neonatal diabetes was caused by a genetic defect which produces an overactive protein known as a potassium channel.

The overactive potassium channel prevents the release of insulin from cells in the pancreas, and the lack of insulin, which controls blood sugar level, results in diabetes.

As a result of this work, children with neonatal diabetes were not only able to be diagnosed more accurately, but it was also possible to switch them from daily insulin injections to sulfonylurea tablets. Sulfonylurea drugs, which had already been in use for type 2 diabetes for over 50 years, target the potassium channels and stimulate insulin release.

‘As well as having problems secreting insulin, around one in five children with neonatal diabetes tend to develop more slowly than most and have problems walking and talking,’ explained Professor Ashcroft of Oxford’s Department of Physiology, Anatomy and Genetics.

‘Sulfonylurea revolutionised treatment for these children, allowing them to take a pill to control their diabetes rather than daily insulin injections. In many cases, the drugs also improve their neurological problems and a few children started to walk or talk shortly after switching medication.’

However, sulfonylurea drugs did not always restore muscle function to normal and in some patients they were ineffective.

To investigate the cause of the muscle problems, Professor Ashcroft and her colleagues at the University of Oxford developed two mouse models in which the genetic defect found in the patients was inserted into either the muscle cells or the nerve cells. The research, funded by the Wellcome Trust and the Royal Society, is published in the journal Science.

When the potassium channel was overactive in the muscles, the mice had no problems with moving. However, when the channel malfunctioned in the central nervous system – the brain and the nerves – the mice had impaired muscle strength, disturbed balance and movement, and showed hyperactivity.‘

'Our results suggest that the problems that children with neonatal diabetes have with muscle weakness and coordination occurs in their nerve cells, but not in their muscle cells,’ said first author of the study Rebecca Clark of the Department of Physiology, Anatomy and Genetics at Oxford. ‘This has implications for how we might improve treatments for this condition.’

Professor Ashcroft explained: 'For sulfonylureas to be able to shut down the defective potassium channels in the brain, they must first cross the blood-brain barrier. This means we need to use drugs that are able to enter the brain effectively.’

Professor Ashcroft and colleagues say that the findings should help them focus in on which areas of the brain are affected by the defective potassium channel, and that they can now use their mouse model to look at how the patients' genetic defect affects cognitive function.

The research was supported by the Wellcome Trust, the Medical Research Council, the Royal Society, the European Union, the Muscular Dystrophy Campaign and the Myasthenia Gravis Association.