How Diabetes Damages Nerves: The Science Behind Diabetic Peripheral Neuropathy

By Jill Waldbieser

The rising rate of diabetes in the United States has long been a cause for concern. Not only does the disease have many harmful impacts on health, but there is also a lack of education and research about its relationship to chronic pain.

While not everyone with diabetes experiences pain, those who do make up a significant proportion. Up to half of all individuals who have diabetes will develop neuropathy, a complication involving damage to the nerves. The most common form for this population is diabetic peripheral neuropathy (DPN), which affects the peripheral nerves. The condition most often initially affects the nerves in the feet and legs, but it also can affect those in the hands and arms. Of those with DPN, 30% or more may experience pain as a result. Even taking into account only diagnosed cases of diabetes, that still leaves 4.5 million or more Americans affected by diabetic neuropathic pain.

“Unfortunately, most people are not aware that neuropathic pain can be a complication of DPN, which is perhaps why there are so many people who may not be diagnosed in daily practice,” says Rodica Pop-Busui, MD, PhD, a diabetologist, professor of internal medicine, metabolism, endocrinology, and diabetes, and vice chair of clinical research in the Department of Internal Medicine at the University of Michigan. She notes that, unfortunately, many people with diabetes don’t get screened for DPN until they either feel pain or experience more advanced loss of sensation or even foot ulcerations, at which point the condition has progressed significantly.

“Thus, early, sustained, and effective DPN screening is recommended for all people with diabetes and even prediabetes,” Pop-Busui says.

Chronic pain of any type is challenging to treat, and the pain due to DPN is particularly complex, because the exact physiological mechanisms causing it are still not entirely known.

Fortunately, there has been a recent push to better understand DPN and develop more treatments for the condition, says A. Gordon Smith, MD, FAAN, professor and chair of neurology at the Virginia Commonwealth University Department of Neurology.

This is a welcome development after decades of what he calls “an inadequate level of investment from the pharmaceutical industry,” though “understandable because it is such an intractable disease.” DPN research is ongoing, and Smith sees these clinical trials as important for more than just those living with DPN.

“There is value in recognizing early neuropathy, because it is a canary in a coal mine for other preventable and treatable complications of metabolic risk, including dementia and strokes,” he says. What is gleaned from these trials may be applicable to other forms of neuropathy, Smith explains: “So lessons from painful diabetic neuropathy are useful for more than twice the population.”

Here is what experts know about DPN so far, and what they hope to further learn about treating it.

How diabetes can break down nerves

“Neuropathy” is a broad term that refers to nerve damage, but when speaking about DPN, the specific form it takes is known as “peripheral polyneuropathy,” Smith says. In these cases, pain starts in the feet. As the disease progresses, the pain may move up the nerves to the knees, and more rarely, the hands.

“The underlying problem in diabetic neuropathy is damage to the tips of the longest nerves,” Smith says. Diabetes involves the body’s inability to regulate blood sugar. Over time, persistently high blood sugar levels can damage the small blood vessels that supply nutrients to nerve cells. Elevated blood sugar levels also cause direct metabolic injury to nerve cells. As a result, the nerve cells become damaged or die off.

Scientists have identified two ways that this can cause pain. The first is that the damaged nerves fire abnormally, sending pain signals to the brain. The second is that the abnormal signals from damaged peripheral nerve cells induce the brain to perceive pain in the affected area. “It’s a mix of abnormalities in how the peripheral nerves are firing and how the brain and spinal cord are interpreting and processing those signals,” Smith explains.

Variances in DPN pain

It’s still a mystery why some people with DPN experience pain and some don’t, or why their pain levels can vary so widely. The pain has been described as tingling, burning, and shooting, or likened to electric shocks or pins-and-needles sensations. Many people also report loss of sensation that may make it more difficult to notice injuries; the inability to sense temperature; or the feeling that they are wearing tight socks or are walking on stumps, Smith says.

Frequently, these symptoms are worse at night, which can interfere with sleep, Pop-Busui notes.

Some of the research that’s being done now is looking at phenotypes and sub-populations to determine markers for who may be at risk for DPN and why. “Pain is complex,” Pop-Busui says. “There are so many factors that contribute at a metabolic level. We’re making efforts to understand entirely metabolic pathways of pain.”

She recently completed a study that sought to determine key traits in individuals with DPN. This information, published in Diabetes Care in February 2024, may help clinicians treating individuals with diabetes better predict which patients might be more likely to also develop DPN.

Identifying risk and promoting understanding

Several factors appear to increase the risk of pain associated with DPN, including lifestyle factors, the severity of the nerve damage, and genetic predisposition (one analysis published in 2023 identified five genes that were expressed differently in individuals with neuropathic pain compared to control subjects). In some instances, effectively managing diabetes has been shown to slow the progression of DPN.

However, Smith says, “Once neuropathy is established, it’s very difficult to reverse.” Treatment options are also limited.

“There is real value in studying disease-modifying treatments as early as possible,” he says. “Treating early is almost always better than treating late.”

For those reasons, prevention is preferable. Pop-Busui notes that the standards of care developed by the American Diabetes Association recommend screening for DPN at least once a year in all people with diabetes, but not all clinicians or patients are aware of or follow that recommendation. Screenings involve examining the feet, discussing pain or loss of sensation, and conducting various physical tests to measure nerve response and sensation.

“People who have very subtle changes associated with nerve damage may initially ignore the problem,” Pop-Busui says, identifying the need for more education and awareness for both patients and clinicians. One awareness effort that she advocated for, the International Association for the Study of Pain’s Neuropathic Pain Special Interest Group (NeuPSIG), seeks to promote a greater understanding among clinicians of the mechanisms, assessment, treatment, and prevention of neuropathic pain.

Smith agrees that research and education are key—for instance, community education related to lifestyle factors that can help prevent or slow the onset of diabetes and DPN. Now that more attention is being paid to DPN on a larger, multidisciplinary scale, those affected by it may begin to see more solutions.

“Trials are ongoing,” Smith says. “The bottom line is we’re starting to see an investment [in this research], and that brings hope to patients.”