Of the 37 million patients in the U.S. with Type 2 diabetes, about half of them suffer from peripheral neuropathy, according to National Institutes of Health estimates. The condition causes numbness, pain and weakness in the hands and feet. Treatments exist, but they aren’t particularly effective.
While clinicians and scientists have long known that high levels of glucose circulating in the bloodstream can lead to the nerve damage that causes neuropathy, it appears that altered levels of amino acids are playing a role, too. A new study published Jan. 25 in Nature by researchers from the Salk Institute showed that low levels of the amino acid serine put diabetic mice at risk for developing peripheral neuropathy. The scientists are now using their findings to develop a test that can indicate whether a patient could benefit from serine supplementation, which alleviated neuropathy symptoms in mice with diabetes.
Serine is a nonessential amino acid, meaning the body produces it on its own and doesn’t need to get it from external food sources the way it does essential amino acids. The term “nonessential” is not a reflection on how important they are to functioning; the molecules are used for energy metabolism and are involved in the synthesis of peptides, like glutathione. They’re also the building blocks of sphingolipids, fat molecules found heavily in the nervous system that are thought to be involved in tissue development, cell adhesion and more.
Prior to the Salk study. it was established that people with metabolic syndrome—a collection of conditions including high blood sugar, high blood pressure, excess body fat around the waist and high cholesterol, which together can increase the risk of Type 2 diabetes—had lower-than-normal levels of non-essential amino acids, specifically serine. Despite knowing that serine levels were reduced in patients with metabolic syndrome, the consequences weren’t clear.
But the researchers had some clues. Earlier studies by other teams linked low serine levels with abnormal sphingolipid formation in patients with the rare inherited condition hereditary sensory and autonomic neuropathy type 1, which is characterized by loss of sensation to temperature, pressure and pain. And studies on plasma from Type 2 diabetes patients found an association between neuropathy and reduced serine levels.
To put the puzzle together, the Salk scientists set out to establish a direct link between serine, neuropathy and diabetes. They started by characterizing serine levels in tissues from mice with and without the condition, finding that diabetic mice had about 30% less serine in the liver and kidneys than did wildtype controls. This suggested that diabetes drove down serine levels in organs involved in maintaining glucose and fat homeostasis, according to the researchers.
Next, over the course of a year, they gave mice without diabetes either a control or serine-free diet combined with high- or low-fat feed. They found that the mice who ate the low-serine, high-fat diet developed peripheral neuropathy, which was measured by testing their pain responses to heat and nerve fiber density in the skin of their paws. The lower nerve density was apparent by Month 12, while the impaired heat responses set in by month three.
To check whether altered sphingolipids were to blame, the scientists then dosed mice who were on a low-serine, high-fat diet for six months with the compound myriocin. In the context of low serine levels, the enzyme responsible for assembling sphingolipids substitutes serine for other amino acids—a shake-up that could lead to neuropathy, the researchers hypothesized. Myriocin inhibits the enzyme that swaps out the amino acids and should thus slow or prevent neuropathy from developing in mice at risk of developing it.
The researchers were right: A dose of myriocin every other day for six months mitigated the development of neuropathy in the mice fed the low-serine, high-fat diet for six months. This confirmed the role of the enzyme and aberrant sphingolipid production in neuropathy development.
The scientists then wondered whether supplementing serine could slow or reverse neuropathy in diabetic mice. They gave mice with diabetes a serine-enriched diet beginning when they were six months old, then measured their pain response to heat and tactile sensation when they were 6, 10 and 14 years old. While their weight didn’t change and they had slightly higher glucose levels compared to diabetic mice who were fed a regular diet, the mice that received the serine supplements developed neuropathy at a slower rate. They also had less abnormal sphingolipid development in their paws and liver.
“Collectively, these data suggest that supplementation of serine can slow the progression of diabetic peripheral neuropathy,” the scientists wrote in the study.
While it’s tempting to jump to trying serine supplementation in humans with neuropathy, the reality is more complicated. The researchers noted in a press release that people would likely need to take high doses of it to make a difference, and not everyone needs more.
Instead, they plan to develop a serine tolerance test akin to the oral glucose tolerance test that’s used to diagnose diabetes. This will help clinicians understand which patients might benefit from serine supplements.