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Why sugary nerves aren’t so sweet

Oliver receives his certificate from David Willetts, Minister of State for Universities and Science

Oliver receives his certificate from David Willetts, Minister of State for Universities and Science

Why does excess sugar in the bloodstream cause nerve damage in diabetes? In his article commended for the 2013 Max Perutz Science Writing Award, Oliver Freeman, a PhD student at the University of Manchester, tells us how he’s trying to find out.

Strewn across my desk are big sheets of A3 paper. Like sprawling cobwebs, lines criss-cross all over them, splattered with a traffic light system. These are diagrams showing the pathways of metabolism. Built up over decades, they describe what happens to chemicals in your cells, and how cells make energy from them.

The traffic light system is for me. It tells me which chemicals go down (red), which do not change (yellow) and which go up (green). I am interested in diabetes, and more specifically the impact that it has on energy generation in the nervous system. The colours denote the differences between diabetic nerves and healthy nerves.

Sugary nerves may sound like a marketable new pick-n-mix sweet but if this happens in the body, it can cause disastrous consequences. We all know that diabetes results in high blood sugar. What is less well publicised however, are the effects that diabetes has on the rest of the body.

When sugar levels rise in diabetes it is because sugars cannot get into your muscles and so end up circulating the body instead. To enter your muscles sugars need insulin, which is not present in type 1 diabetes and doesn’t work properly in type 2. This means that there are vast amounts of sugar swirling around the body. This sugar soaks into specific organs and tissues of the body and causes damage. The most common part of the body impacted this way is the nervous system and nerve damage such as this is known as diabetic neuropathy.

Diabetic neuropathy is a nasty condition as it can cause sufferers to feel agonising pain in their hands and feet, or it can cause them to feel nothing at all. Perhaps you’re thinking the latter is preferable, but when you can’t feel anything in your feet, there’s a high chance of being oblivious to a cut. This cut may get infected and before you realise it, the foot is too infected to stay and needs to be amputated.

Normally, sugars are used as the primary source for energy generation in your cells. All my charts of metabolism spiral around sugars. Hypotheses about how excess sugar causes nerve damage are plentiful but experimental treatments targeted at these have yielded disappointing results in clinical trials. For this reason, what my work aims to do is to generate new hypotheses by going back to square one.

We have performed an untargeted, ‘shotgun’ approach to measure as many of the chemicals in the nerves as we can. What we measure is not biased by how people think neuropathy might develop, and so it allows us to start a clean slate. By measuring the chemicals in healthy nerves and diabetic nerves in a mass spectrometer, we can build up a picture of what is happening within them, and how they are generating their energy. My way of doing this is reading off the values for each chemical, finding it on the chart of metabolism, and highlighting it in a traffic light system.

To fire electrical signals up and down them all day, nerves need to generate a lot of energy. What my traffic lighted cobwebs tell me is happening is unsurprisingly, sugars increase a great deal in diabetic nerves. What is interesting is that despite this increase in sugars, there isn’t an increase in energy generation. Instead, a lot of this sugar is being converted to fat. Following the lines that lead from sugars to fats, you can see a lot of the chemicals in green.

What becomes of these fats is worrying. The typical way people think about metabolism is in terms of weight gain and loss. If you eat more calories than you need, the excess will be converted to fats which will be stored around the body. If you eat less calories than you need, these fats will then be broken down to generate energy.

Unfortunately, this doesn’t appear to be the case in the diabetic nerve. To the other side of these green highlighted fats is lots of red, showing the breakdown of fats to create energy is failing. What appears to be the case is that not only are the sugars not generating the energy needed, neither are the accumulating fats.

So why does any of this matter? Well, what this research has done is to create a number of new hypotheses to test. It has given us and others some new ideas as to why diabetic nerves might be failing. It has given us new ideas for treatments and it has given us new ways to test other new treatments. I hope that by correcting some of these reds and greens, perhaps we can make a real push towards better management of nerve damage.

Oliver Freeman

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