Studies in mice by a Salk Institute research team have shown how altered amino acid metabolism can represent a contributing factor to diabetes-associated peripheral neuropathy. Their experiments found that diabetic (db/db) mice with low levels of two related amino acids, serine and glycine, were at higher risk for peripheral neuropathy. The symptoms of neuropathy in these mice could also be alleviated by supplementing the animals’ diets with serine. The study adds to growing evidence that some “non-essential” amino acids (NEAA) play important roles in the nervous system. The results may also point to a new way to identify people 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,” said Christian Metallo, PhD, a professor in Salk’s Molecular and Cell Biology Laboratory. “It just goes to show that what we think of as dogma can change under different circumstances, such as in disease conditions.” However, the researchers do also say that it would be premature to advise people with diabetes to take serine supplements to prevent neuropathy. “You would likely need to take a lot to make a difference, and not everyone needs extra serine,” Metallo added “We need more time to understand serine physiology in humans and explore potential downsides to supplementation.”
Metallo led the study with Michal Handzlik, PhD, a postdoctoral researcher in his lab, who is first author of the team’s published paper Nature, which is titled “Insulin-regulated serine and lipid metabolism drive peripheral neuropathy.” In their report they concluded, “These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.”
Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves, the authors explained. “Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes.” Serine and glycine are closely related NEAAs, levels of which have been found to be reduced in patients with metabolic syndrome, but the mechanistic drivers and downstream consequences of this aren’t understood, the team continued. “Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy.”
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.
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 Metallo and his team observed this accumulation in their diabetic mouse models, the same amino acid switch and sphingolipid changes also occur in a rare human genetic disease marked by peripheral sensory neuropathy, indicating that the phenomenon is consistent across many species.
To determine whether long-term, chronic serine deficiency drives peripheral neuropathy, Metallo’s 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. “Collectively, these data suggest that supplementation of serine can slow the progression of diabetic peripheral neuropathy,” they wrote.
The researchers also tested the compound myriocin, which inhibits the enzyme that switches out serine for another amino acid as sphingolipids are assembled. They found that myriocin treatment reduced peripheral neuropathy symptoms in mice fed a high-fat, serine-free diet. “Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism,” the researchers stated. These findings underscore the importance of amino acid metabolism and sphingolipid production in the maintenance of a healthy peripheral nervous system. “Our results highlight physiologically relevant molecular links between serine and glycine homeostasis, sphingolipid metabolism, and diabetic co-morbidities,” they further stated. “Normalizing circulating serine levels via dietary supplementation delays the onset and progression of sensory neuropathy in db/db mice.”
Serine deficiency has been associated with various neurodegenerative disorders. Metallo and collaborators previously found a link between altered serine and sphingolipid metabolism in patients with macular telangiectasia type 2, a condition that causes vision loss. In mice, reduced serine led to increased levels of atypical retinal sphingolipids and reduced vision. Serine is currently being tested in clinical trials for its safety and efficacy in treating macular telangiectasia and Alzheimer’s disease. “… supplementation of serine and B vitamins improves peripheral neuropathy in some preclinical models and are the focus of clinical trials for various neurodegenerative disorders,” the researchers added.
Peripheral neuropathy is typically managed with dietary changes—to reduce blood sugar levels—as well as using pain relievers, physical therapy, and mobility aids, such as canes and wheelchairs. Foods naturally rich in serine include soybeans, nuts, eggs, chickpeas, lentils, meat, and fish, and serine supplements are inexpensive and available over the counter. The researchers are not, however, advocating that diabetes patients should take serine supplements to prevent neuropathy.
Metallo and Handzlik are developing a serine tolerance test (STT), similar to a glucose tolerance test that is used to diagnose diabetes. “We want to identify those at highest risk for peripheral neuropathy so we can treat only those who might benefit most,” Handzlik said. The authors further suggested, “Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal … A STT, analogous to an oral glucose tolerance test (OGTT), could identify patients that exhibit elevated, postprandial serine disposal and who might be particularly susceptible to sensory neuropathy.”