6000 Danes are helping researchers to understand neuropathy

Imagine a burning-hot sock that feels far too tight on your foot or a similar hot glove constricting your hand and fingers. Not for a minute or two, but all the time and all day long.

This is the daily reality for millions of people with diabetic peripheral neuropathy. Up to half the people with type 1 or type 2 diabetes will develop neuropathy at some point, and it is chronic.

Nevertheless, researchers still know very little about neuropathy. They do not know what causes it, the optimal treatment for people who have it or which people have the greatest risk of developing it.

However, this will become a thing of the past if Troels Staehelin Jensen, Clinical Professor of Neurology, Department of Medicine, Aarhus University, has his way. A Challenge Programme grant from the Novo Nordisk Foundation has given him 6 years to focus on many of the unanswered questions about neuropathy.

“Neuropathy is not fatal, but it really reduces people’s quality of life, and they get depressed. Many just sit at home with their feet up. They cannot exercise, they can hardly walk, and walking can be also be dangerous because they lose the sensation in their feet and toes. Serious infections and eventually amputations can result if people constantly stub their toes on obstacles and get ulcers or if they cannot feel their shoes rubbing against their foot,” explains Troels Staehelin Jensen.

The research project is scheduled to end in 2022

Neuropathy affects the nerves

Neuropathy is sometimes called infection of the nerves. However, Troels Staehelin Jensen says that this is in fact a misleading term because the nerves do not actually have bacterial inflammation. Instead, the thousands of nerve fibres are dysfunctional because their metabolism is disordered and the nerve fibres gradually die.

In neuropathy, the longest nerves die first, especially the nerves in the toes, feet and hands.

When the nerves afflicted by neuropathy die, people feel a tingling, stinging or burning sensation in the feet and hands or experience complete sensory loss so that their feet appear dead.

People with more severe neuropathy may also lose muscle strength in their hands or feet. They thus have difficulty walking and fall frequently.

Many people with type 1 and type 2 diabetes develop neuropathy, but it can also result from other causes such as chemotherapy, kidney disease, vitamin deficiency, excessive alcohol consumption or exposure to other toxic substances.

The treatment of painful neuropathy is insufficient. Existing treatments mainly target reducing pain, treating ulcers and physiotherapy.

Lack of oxygen and inability to remove waste products damage nerve cells

Various theories have been proposed for why people with diabetes develop neuropathy. A predominant theory involves oxidative stress. The nerves may lack oxygen and sustain damage, making them unable to function normally.

One such function is transporting vital nutrients from the nerve cell to the nerve endings and taking waste products the other direction.

The nerve cells at the ends of the nerves die if they do not get the nutrients required, or waste metabolites from fat and glucose can accumulate, causing nerve damage, which causes waste products to accumulate further.

In the long term, waste products in the nerves are a death sentence for nerve cells.

“This may happen because not enough oxygen is transported to the nerves, and the conveyor belt from the nerve cell to the nerve ends malfunctions. This is not because the circulatory system is overloaded. Something completely different happens with the nerves, and a completely different kind of stress destroys the nerve cells when they are under pressure. Further, the longer the nerves are, the more difficulty the body has in transporting nutrients and oxygen to them and waste products from them. The nerves that extend from the spine to the toes are up to one metre long in adults, so these nerves are extremely vulnerable,” explains Troels Staehelin Jensen.

New nerve cells are sensitive to changes in weather

However, when nerves malfunction, they can be regenerated just like the sprouts on a beech tree in spring. The nerve fibres dying back interact with new nerve sprouts.

Troels Staehelin Jensen says that this can be both good and bad.

The body’s ability to regenerate nerve cells is good, but people with neuropathy generate especially sensitive new nerve fibres that cause the special types of pain associated with neuropathy.

The new nerve cells are very sensitive to both pressure and touch. They may even be sensitive to changes in atmospheric pressure: if the pressure drops, for example, many people with neuropathy experience more noticeable symptoms such as tingling, prickling or burning sensations in the feet or hands.

“Many people with neuropathy complain that, when the weather changes, they cannot sleep at night or do anything without experiencing pain. This indicates that these new nerve sprouts are very sensitive,” says Troels Staehelin Jensen.

6000 Danes with diabetes participated

Troels Staehelin Jensen’s research team is collaborating with colleagues at the University of Michigan and the University of Oxford to determine why neuropathy develops. They are striving to identify biomarkers that signal the development of neuropathy and pain before onset.

“After all, once people have neuropathy, there is no going back. They have to live with it for the rest of their lives. Recognizing the earliest signs of the disease is therefore important. We have focused a lot of energy on figuring that out,” says Troels Staehelin Jensen.

About 6000 people with diabetes are helping the researchers to better understand neuropathy. Many already have neuropathy, and others are about to develop it because of diabetes.

Everyone completed questionnaires about their health and lifestyle, and almost every conceivable physical and biochemical parameter was assessed, including blood pressure, body mass index, blood tests, DNA, electrical examination of nerves, skin biopsies and measuring nerve fibres in the cornea.

“First, we have determined how many people with diabetes have neuropathy: about one in five. However, that percentage is expected to increase the longer people have diabetes. Second, we conducted the first studies of who might have higher risk. Factors that are associated with increased risk of developing neuropathy and pain include obesity, especially abdominal fat or central obesity; we do not know why this central fat is particularly dangerous for developing neuropathy, but we will explore this further,” says Troels Staehelin Jensen.

Unhealthy lifestyles increase the risk of neuropathy

The researchers have found that lifestyle factors such as lack of exercise and unhealthy diet are associated with the risk of developing neuropathy.

Researchers already knew some of these factors, but the research by Troels Staehelin Jensen’s group has clarified this further.

“We started this research project in 2015, but the results are only starting to arrive now because gathering data from so many participants takes a long time. We will have many more results in the next couple of years,” explains Troels Staehelin.

In addition to the studies mentioned, the researchers have also performed neurological and electrical studies that may help to determine how nerves emit pain signals.

Exercise can increase the number of nerves

The researchers also tested intervention among people with severe neuropathy.

For example, people with neuropathy who cannot feel anything in their feet have difficulty walking in the dark because then they can neither see nor feel their way forward.

These people often fall and risk all sorts of injuries. However, Troels Staehelin Jensen’s research shows that appropriate exercise training can help people with neuropathy.

“We have created an exercise training programme for some people with neuropathy and have confirmed that really effective training can help these people get a little better and improve their motor function. We will now take skin biopsies and see whether the improvement in function because of exercise is also reflected in an increase in the numbers of new nerve fibres. This will be really interesting, because then this might reduce the symptoms without medication,” explains Troels Staehelin Jensen.

Examining the genetic basis of neuropathy

The results of the current research, which is in full swing, will be published over the next couple of years and will also add knowledge on other interesting aspects of neuropathy.

The research team at the University of Oxford is focusing on the genetic basis of developing neuropathy.

Although many people with type 2 diabetes develop neuropathy, many do not, and genetics may be a reason.

“The University of Oxford group specializes in this, and we think that the people who develop neuropathy have a certain genetic predisposition that makes them more susceptible. If we can find the basis of this genetic predisposition, we can use the information diagnostically to advise people with type 2 diabetes whether they have a high risk of developing this very unpleasant complication,” says Troels Staehelin Jensen.

Fat metabolites may damage nerves

Another important research goal is to investigate the metabolism of people who develop neuropathy, and the research group at the University of Michigan is focusing on this.

So far, the research results have shown that obesity and unhealthy diets play a role, and the researchers therefore assume that one or several metabolites produced in metabolizing fat cause some people with diabetes to develop neuropathy.

The researchers at the University of Michigan are currently conducting experiments on mice, investigating whether some fat metabolites can damage the nerve pathways and contribute to developing neuropathy. These results will be available in November 2019.

“In addition, we are analysing blood tests from people with mild and severe neuropathy to see whether these groups differ in fat metabolites. Although this will not entirely solve the enigma of neuropathy, it will contribute to understanding the factors that increase and reduce the risk of developing neuropathy. Our findings may help people by offering various therapies that will relieve some of their symptoms,” says Troels Staehelin Jensen.

Results may help to develop medicine for neuropathy

The ideal scenario for the researchers is that they discover exactly what determines whether people develop neuropathy.

If the cause is a harmful metabolite or a certain genetic predisposition, this may help enable early diagnosis and possibly treatment. For example, if a specific fat metabolite can be identified, the pharmaceutical industry might be able to develop medicine that targets this fat metabolite so that it does not accumulate or otherwise cause harm.

However, this is not within the scope of the current research project.

“We are not going to develop any kind of medicine now, but we will clarify certain factors that are important for neuropathy in diabetes, but as always in research when clarifying new things, other questions arise. We really want to determine the initial symptoms and how much or little a person with diabetes needs to be examined to diagnose neuropathy ,” says Troels Staehelin Jensen.

Is the brain also harmed?

The researchers are now wondering whether the nerve cell damage in neuropathy also affects other nerve cells, such as those in the brain. People with diabetes who have a high risk of developing neuropathy may also have damaged brain cells.

People with diabetes have an increased risk of developing Alzheimer’s disease and other types of dementia, depression and stroke, and perhaps the mechanisms are similar to those in neuropathy.

However, Troels Staehelin Jensen emphasizes that the current research project is limited to asking the questions about peripheral neuropathy. The new questions about possible brain cell damge in diabetes will have to be explored in another project.

“I would really like to investigate how diabetes affects the development of major noncommunicable diseases such as stroke, depression and cognitive failure. I hope that we can examine this in the future,” says Troels Staehelin Jensen.

Initiating a major prevention project

A separate goal of this major research project is to focus on neuropathy as a serious complication of diabetes.

According to Troels Staehelin Jensen, neuropathy has been overlooked, and no one has really taken an interest in it either professionally or among the general public. Instead, the focus has been on other complications of diabetes, such as eye diseases, kidney diseases and heart diseases.

Neuropathy is a chronic disease and early diagnosis is therefore important, preferably before onset, so that treatment can be started early and, if possible, onset can be prevented.

“I hope and think that we can get Danish podiatrists involved much more than we do today. They are already in contact with people with diabetes and are very highly skilled. There is great potential in getting them involved in collaboration with doctors, researchers and nurses so that we can initiate a major nationwide prevention project. This is what I want to do with the rest of this grant,” says Troels Staehelin Jensen.

“Painful and non-painful diabetic polyneuropathy: clinical characteristics and diagnostic issues” has been published in Journal of Diabetes Investigation. In 2014, the Novo Nordisk Foundation awarded a Challenge Programme grant of DKK 60 million to Troels Staehelin Jensen for the project International Diabetic Neuropathy Consortium (www.idnc.au.dk).