Approximately half of people with type 1 or type 2 diabetes experience peripheral neuropathy (weakness, numbness, and pain) primarily in the hands and feet. The condition occurs when high levels of sugar circulating in the blood damage peripheral nerves.
Now, working with mice, Salk Institute researchers have identified another factor contributing to diabetes-associated peripheral neuropathy: altered non-essential amino acid (NEAA) metabolism.
Amino acids are the building blocks that make up proteins and specialized fat molecules called sphingolipids, which are abundant in the nervous system. Low levels of the amino acid serine force the body to incorporate a different amino acid in sphingolipids, which changes their structure. These atypical sphingolipids then accumulate, which may contribute to peripheral nerve damage. While the team observed this accumulation in diabetic mice, the same amino acid switch and sphingolipid changes occur in a rare human genetic disease marked by peripheral sensory neuropathy, indicating that the phenomenon is consistent across many species.
Mammals obtain serine from the diet, de novo synthesis from glucose and via glycine and one-carbon metabolism, with the liver and kidney serving as major sites for postprandial NEAA metabolism. Circadian and postprandial variations in amino acids and glucose make the diagnosis of metabolic defects challenging.
Non-essential amino acids play important roles in the nervous system
Christian Metallo, a professor in Salk’s Molecular and Cell Biology Laboratory and his team found that diabetic mice with low levels of two related amino acids, serine and glycine, are at higher risk for peripheral neuropathy. What’s more, the researchers were able to alleviate neuropathy symptoms in diabetic mice by supplementing their diets with serine.
To determine whether long-term, chronic serine deficiency drives peripheral neuropathy, the team fed mice either control or serine-free diets in combination with either low-fat or high-fat diets for up to 12 months.
The researchers were surprised to find that low serine, in combination with a high-fat diet, accelerated the onset of peripheral neuropathy in the mice. In contrast, serine supplementation in diabetic mice slowed the progression of peripheral neuropathy, and the mice fared better.
The researchers also tested the compound myriocin, which inhibits the enzyme that switches out serine for another amino acid as sphingolipids are assembled. Myriocin treatment reduced peripheral neuropathy symptoms in mice fed a high-fat, serine-free diet.
These findings underscore the importance of amino acid metabolism and sphingolipid production in the maintenance of a healthy peripheral nervous system.
More time is needed to understand serine physiology in humans and explore potential downsides to supplementation. It would be great to identify those at highest risk for peripheral neuropathy so we can treat only those who might benefit most.
Michal K. Handzlik, Jivani M. Gengatharan, Katie E. Frizzi, Grace H. McGregor, Cameron Martino, Gibraan Rahman, Antonio Gonzalez, Ana M. Moreno, Courtney R. Green, Lucie S. Guernsey, Terry Lin, Patrick Tseng, Yoichiro Ideguchi, Regis J. Fallon, Amandine Chaix, Satchidananda Panda, Prashant Mali, Martina Wallace, Rob Knight, Marin L. Gantner, Nigel A. Calcutt, Christian M. Metallo. Insulin-regulated serine and lipid metabolism drive peripheral neuropathy. Nature, January 25, 2023; DOI: 10.1038/s41586-022-05637-6