EU-funded study offers hope of better treatments for neonatal diabetes
Muscle weakness experienced by many neonatal diabetes patients is caused by problems in the central nervous system and not the muscles, new EU-funded research reveals. The study, published in the journal Science, could lead to new and better treatments for the condition. EU support for the work came from the BIOSIM ('Biosimulation - a new tool in drug development') project, which is funded under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6), and the EDICT ('European drug initiative on channels and transporters') project, which is funded under the Health Theme of the Seventh Framework Programme (FP7). Neonatal diabetes is an inherited condition that usually appears in the first six months of life. In addition to difficulties controlling blood sugar levels, many patients also have weak and flaccid muscles and balance problems as well as defects affecting speech and cognitive development. For many years, patients faced a lifetime of insulin injections to treat their condition. That all changed in 2004 when the genetic defect behind neonatal diabetes was identified. It turns out that neonatal diabetes patients have a genetic mutation which results in the production of an overactive version of a protein that forms KATP (ATP-sensitive potassium) channels in cell membranes. Among other things, KATP channels control the release of insulin from the beta cells of the pancreas; when the KATP becomes overactive, it blocks the release of insulin. This results in diabetes. This discovery allowed patients to stop their insulin injections and switch to sulphonylurea tablets; these close KATP channels that are open, thereby stimulating the release of insulin. '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 Frances Ashcroft of the University of Oxford in the UK. 'Sulphonylurea 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.' Sulphonylurea has worked well in most patients. However, some patients continue to suffer from muscle problems and there are also concerns that the drugs could damage the heart. In this latest study, scientists sought to get to the bottom of the muscle weakness issue. To do so, they created two groups of genetically modified mice. In one group, the mutated KATP gene was inserted into the muscle cells, while in the second group, it was inserted into the nerve cells. The muscle function of these mice was then compared with that of healthy, normal mice. The mice with the mutation in their muscles performed as well as the healthy mice and their motor control and balance appeared to be unaffected. In contrast, the mice with the mutation in the nerve cells performed poorly in all muscle function tests. They also suffered from poor balance. Interestingly, the mice with the mutation in their nerve cells also displayed signs of hyperactivity. Although hyperactivity is not listed as a characteristic feature of neonatal diabetes, there are numerous reports of pronounced hyperactivity in children with the condition. 'Our results with mice raise the possibility that this is caused by KATP channel overactivity and might therefore be included as a feature of [neonatal diabetes],' the scientists write. '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,' commented Rebecca Clark of the University of Oxford. 'This has implications for how we might improve treatments for this condition.' Currently, most neonatal diabetes patients are treated with a sulphonylurea drug that targets KATP channels in both muscle and nerve cells. 'These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits,' the researchers note. Furthermore, the drugs need to be able to get into the brain. Efforts should therefore focus on finding drugs that are able to cross the blood-brain barrier easily, the researchers recommend. Looking to the future, the team now plans to investigate precisely which areas of the brain are affected by the overactive KATP channel and study how the genetic defect causes the cognitive defects often associated with neonatal diabetes.
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