About 50% of individuals with diabetes type 1 or 2 experience peripheral neuropathy, characterized by weakness, numbness, and pain in the hands and feet. This condition is caused by high blood sugar levels damaging peripheral nerves.

Salk Institute researchers have discovered that altered amino acid metabolism also plays a role in diabetes-related peripheral neuropathy by observing that diabetic mice with low levels of serine and glycine were more prone to the condition.

Additionally, they were able to reduce neuropathy symptoms in diabetic mice by supplementing their diets with serine.

The study, which was published today in Nature, suggests that some “non-essential” amino acids play significant roles in the nervous system. The study also adds to the growing body of evidence supporting this idea. These findings may provide a new method for identifying individuals at high risk for peripheral neuropathy, as well as a potential treatment option.

“We were surprised that dialing up and down a non-essential amino acid had such a profound effect on metabolism and diabetic complications,” remarks senior author Christian Metallo. “It just goes to show that what we think of as dogma can change under different circumstances, such as in disease conditions.”

Proteins and specialized fat molecules known as sphingolipids, which are prevalent in the nervous system, are made up of amino acids.

The study found that low levels of the amino acid serine cause the body to use a different amino acid in the formation of sphingolipids, altering their structure. These altered sphingolipids then accumulate, which may contribute to damage to peripheral nerves.

This accumulation was observed in diabetic mice, but the same amino acid switch and sphingolipid changes also occur in a rare human genetic disorder characterized by peripheral sensory neuropathy, suggesting that this phenomenon is present across multiple species.

To further investigate the link between chronic serine deficiency and peripheral neuropathy, the research team fed mice either control or serine-free diets, in combination with low-fat or high-fat diets, for up to 12 months.

The researchers found that low serine levels in combination with a high-fat diet caused an acceleration of peripheral neuropathy in mice. In contrast, supplementing serine in diabetic mice slowed down the progression of peripheral neuropathy and resulted in better outcomes.

Additionally, they tested the compound myriocin, which stops the enzyme that replaces serine with another amino acid during the formation of sphingolipids. Myriocin treatment reduced peripheral neuropathy symptoms in mice fed a high-fat, serine-free diet. These results emphasize the importance of amino acid metabolism and sphingolipid production in maintaining a healthy peripheral nervous system.

Serine deficiency has also been linked to various neurodegenerative disorders, such as macular telangiectasia type 2, which causes vision loss. Metallo and his team had previously discovered a connection between altered serine and sphingolipid metabolism in patients with this condition. In mice, a lack of serine resulted in increased levels of atypical retinal sphingolipids and decreased vision. Serine is currently being evaluated in clinical trials for its safety and effectiveness in treating macular telangiectasia and Alzheimer’s disease.

Peripheral neuropathy is generally managed through dietary changes to lower blood sugar levels and by using pain relievers, physical therapy, and mobility aids, such as canes and wheelchairs. Foods that are naturally rich in serine include soybeans, nuts, eggs, chickpeas, lentils, meat, and fish. Serine supplements are also inexpensive and can be easily found over the counter.

But the researchers say it’s too soon to tell people with diabetes to start taking serine supplements to avoid neuropathy.

“You would likely need to take a lot to make a difference, and not everyone needs extra serine,” Metallo adds. “We need more time to understand serine physiology in humans and explore potential downsides to supplementation.”

To this purpose, Metallo and Handzlik are now working on a serine tolerance test that will be used to detect diabetes and will be comparable to the glucose tolerance test.

“We want to identify those at highest risk for peripheral neuropathy so we can treat only those who might benefit most,” adds first author Michal Handzlik.

Source: 10.1038/s41586-022-05637-6

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