New Genetic Clues Point to Serine Metabolism in Diabetic Nerve Damage

Diabetic peripheral neuropathy (DPN)—damage to nerves in the hands and feet—affects many people with diabetes and can cause pain, numbness, and loss of mobility. Despite decades of research, doctors still have no disease-modifying treatments that can stop or reverse it. Even when blood sugar is well controlled, some people develop neuropathy while others don't, suggesting that other biological factors beyond glucose are involved.

Current understanding focuses heavily on how high blood sugar damages nerves over time. But this doesn't explain everything. Scientists have long suspected that genetic differences between individuals play a role in who gets neuropathy and who doesn't. This new study takes a major step toward identifying those genetic factors and the biological pathways they affect.

Researchers performed a genome-wide association study (GWAS)—a method that scans DNA from thousands of people to find genetic variants linked to disease—using data from three large research programs: the VA Million Veteran Program, the UK Biobank, and the All of Us Research Program. They looked at people with and without diabetes to identify which genetic variants were specifically associated with neuropathy risk.

In people with type 2 diabetes, the team found seven genetic locations strongly linked to neuropathy. Importantly, two of these locations sit on genes called PHGDH and PSPH, which control how the body manufactures serine, a building block amino acid. Four of the seven findings were confirmed in a separate population, strengthening confidence in the results. Notably, no significant genetic links were found in people with type 1 diabetes or people without diabetes, suggesting that the genetic drivers of neuropathy may differ between these groups.

The discovery of serine-production genes in neuropathy suggests a new biological pathway worth exploring. Using a statistical method called Mendelian randomization, researchers tested whether differences in blood serine levels causally affect neuropathy risk. The results showed that higher genetically predicted serine levels were associated with lower DPN risk—meaning serine may actually protect against nerve damage.

This is an important clue, but it raises new questions: Why would serine be protective? Does it affect how nerves function? Does it influence inflammation or how cells use energy? Does it work differently in people with type 1 versus type 2 diabetes? These are the kinds of questions that follow-up research will need to answer.

Identifying genetic pathways is the beginning, not the end, of drug discovery. These findings point researchers toward biological mechanisms that could potentially be targeted with new therapies, but years of additional laboratory and clinical research lie ahead. The fact that these genetic clues emerged specifically in type 2 diabetes means that serine metabolism may not be the main driver of neuropathy in type 1 diabetes, highlighting the importance of understanding both forms of the disease separately.

For people living with diabetes today, this research does not change management or treatment decisions. However, it does expand our understanding of why neuropathy develops and opens new doors for future prevention and treatment strategies. Anyone concerned about nerve damage should continue working with their healthcare team on blood sugar management and regular foot care, which remain the most proven ways to reduce neuropathy risk.

Source: medRxiv : the preprint server for health sciences. Evidence type: PubMed indexed literature. Type1Cure is an information and intelligence hub, not a medical advice service. This article summarizes published research and does not provide diagnosis, treatment, or personal medical guidance. Always talk to your own care team before changing anything about your Type 1 diabetes management.