Highlights in this article:
Amino acids serine and glycine are consistently reduced in patients with metabolic syndromes, but what are the drivers, and what metabolic pathway signaling are used to develop metabolic types are unclear. Dr. Metallo’s research team at Salk Institute found that serine deficiency and dyslipidemia are novel risk factors for peripheral neuropathy that may be exploited therapeutically.
Background:
Peripheral neuropathy is a condition that affects the nerves outside the brain and spinal cord. The peripheral nerves are responsible for transmitting messages from the brain and spinal cord to the rest of the body. When these nerves are damaged, it can lead to a variety of symptoms like numbness, tingling, and pain in the affected area. The causes of peripheral neuropathy can be varied, and they include diabetes, alcoholism, autoimmune disorders, infections, and certain medications. The symptoms can also be different depending on the type of neuropathy, and they can range from mild to severe.
There is currently no cure for peripheral neuropathy, but there are treatments available to manage the symptoms and slow down the progression of the condition. Treatment options will depend on the underlying cause of the neuropathy and may include medication, physical therapy, and lifestyle changes.
Discovery:
In this study, Dr. Metallo’s group investigated how a deficiency in the amino acid serine can lead to diabetic peripheral neuropathy, a common complication experienced by some patients with type 2 diabetes. They found that chronic, systemic serine deficiency can alter lipid homeostasis and contribute to the development of neuropathy. To mitigate neuropathy symptoms in obese diabetic mice, they modulated dyslipidemia with myriocin or 1-deoxysphingolipid biosynthesis with serine supplementation. Additionally, reduced circulating serine and glycine in diabetic mice may be driven by increased flux through gluconeogenesis, one-carbon metabolism, renal retention, and/or disposal of acyl glycines, which are influenced by dyslipidemia.
They propose that a serine tolerance test (STT) could identify patients who exhibit elevated, postprandial serine disposal and who might be particularly susceptible to sensory neuropathy. Normalizing circulating serine levels via dietary supplementation delays the onset and progression of sensory neuropathy in mice. Further research is needed to understand the mechanisms underlying the suppression of hepatic fatty acid synthesis and gene expression in the liver due to serine and glycine deprivation. Additionally, the research group developed a dietary model of serine-associated sensory neuropathy that could aid in understanding how neurotoxic dyslipidemia can be managed. Together, the study highlights the importance of serine and glycine homeostasis, sphingolipid metabolism, and their links to diabetic co-morbidities. Systemic serine deficiency emerges as a modifier of age- and diabetes-associated neuropathies.
For more information:
Nature 2023 1/25
https://www.nature.com/articles/s41586-022-05637-6
Insulin-regulated serine and lipid metabolism drive peripheral neuropathy
Dr. Metallo’s website: