LC-MS Lipidomics Flags Diabetic Nerve Damage

Nerve damage in the hands and feet, known as distal symmetrical polyneuropathy (DSPN), is a common complication for people with type 1 diabetes. Yet doctors still do not have a reliable test that can catch it early or predict how it will progress. Part of the problem seems to come down to the body's chemistry, with long-term high blood sugar and unhealthy fat levels in the blood appear to play a role in both triggering and worsening this kind of nerve damage. To hunt for possible warning signs of this nerve damage, researchers took blood samples and used untargeted serum liquid chromatography-mass spectrometry (LC-MS) lipidomics to separate and identify the many different fat molecules circulating in the blood, casting a wide net rather than looking for anything specific ahead of time. A paper based on this research was published in the journal Diabetes, Obesity, and Metabolism.¹

Why is Diabetic Nerve Damage (DSPN) Hard to Diagnose and Treat, and What Might Be Driving It?

Diabetes affects more than 800 million people around the world, and that number is expected to keep climbing.²The nerve damage in the hands and feet associated with DSPN polyneuropathy, is a long-term complication that affects up to half of all people with diabetes.³In its early stages, this nerve damage tends to affect the smallest nerve fibers first, the kind involved in sensation, causing symptoms like pain, tingling, or numbness starting in the toes. Over time, it tends to creep further up the legs and can eventually reach the trunk of the body. Left unchecked, it is a major driver of foot ulcers, falls, and lower-limb amputations in people with diabetes.^3,4 

Diagnosing this kind of nerve damage in people with diabetes is tricky. Symptoms can be subtle and easy to miss, they often look like other types of nerve problems, patients do not always get screened as recommended, and by the time it is caught, the damage has often progressed too far to reverse. All of this means diagnosis frequently comes later than it should.⁵As with other diabetes-related complications, these delays in diagnosis mean the nerve damage often becomes permanent and raises the risk of eventually needing an amputation.³ Currently, there is no real cure for this nerve damage beyond the general strategies used to manage diabetes overall, largely because scientists still don't fully understand what's driving it in the first place.⁶Research suggests that certain metabolic problems, like high blood pressure, high blood sugar, and unhealthy fat levels, may contribute to this nerve damage by over-activating the body's inflammatory response, which can end up harming nerve cells.⁷

Can Specific Blood Fat Molecules Serve as Reliable Biomarkers for Detecting DSPN?

The initial study group for the study included 153 people with type 1 diabetes, split between those who had developed nerve damage and those who hadn't, plus 50 people without diabetes for comparison. To confirm their findings held up, the team then checked their results against a separate group of 99 people with type 1 diabetes whose nerve damage status was already known. Using statistical modeling, they narrowed down which fat molecules seemed most meaningfully linked to the condition, then double-checked those results with additional statistical tests to make sure the differences they were seeing were real and not just due to other factors.¹

In the first group of participants, researchers detected 543 different fat molecules in the blood, and out of those, 14 stood out as being linked to nerve damage. Digging deeper, six of those fat molecules showed a particularly clear, consistent pattern, with levels shifting across three groups: people without diabetes, people with diabetes but no nerve damage, and people with diabetes who had developed nerve damage. When the researchers checked their results against the second, independent group of participants, three of those six molecules held up, showing the same trend.¹

The team then built a prediction model that combined those six fat molecules with a few other pieces of health information already known to be important, including a standard blood sugar measure, blood pressure, and age. This combined model was good at telling apart those with and without nerve damage, correctly distinguishing them roughly 8 times out of 10 in both groups of participants. Adding the fat molecules into the mix did not dramatically boost accuracy on its own in either group individually, but when the team combined the statistical evidence from both groups together, the improvement became more convincing.¹

Separately, the researchers also found 22 fat molecules that differed depending on whether someone's nerve damage came with pain or not, suggesting these two forms of nerve damage might have somewhat different underlying biology.¹

The researchers report that a key strength of their study is “the serum lipidome profiling of two independent, well-phenotyped type 1 diabetes cohorts from multiple Steno Diabetes Centers, which ensures strong representation of real-world clinical practice and enhances the generalizability of the findings across clinical settings. The study is further strengthened using a standardized questionnaire with strict diagnostic criteria to differentiate between painful and painless DSPN in type 1 diabetes individuals. To identify a diagnostic lipidomic signature and assess its diagnostic accuracy, we used supervised machine learning methodologies, which increase the generalizability of the findings.”¹

However, this study has a few key limitations. It only looked at participants at one point in time, so it can't prove these fat molecules truly cause nerve damage, only that they are linked. The comparison groups also weren't perfectly matched by sex, age, blood sugar, or diabetes duration, though the researchers statistically adjusted for some of these differences. Group sizes were based on who was available during the study, rather than planned. Finally, other unmeasured factors, like diabetes duration, kidney function, insulin sensitivity, and cholesterol medications, may have influenced the results. The researchers say larger, more carefully designed studies are needed to confirm the findings.¹

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References

1. Muk, T.; Okdahl, T.; Kokla, M. et al. Serum Lipidomics Profiling Identify Novel Biomarkers of Distal Symmetrical Polyneuropathy in Type 1 Diabetes. Diabetes Obes Metab. 2026. DOI: 10.1111/dom.71257
2. Zhou, B.; Rayner, A. W.; Gregg, E. W. et al. Worldwide Trends in Diabetes Prevalence and Treatment From 1990 to 2022: A Pooled Analysis of 1108 Population-Representative Studies With 141 Million Participants. Lancet 2024, 404(10467), 2077–2093. DOI: 10.1016/S0140-6736(24)02317-1/ATTACHMENT/6BEF1425-5487-46DF-B2FD-4BC21216DCDF/MMC1.PDF
3. Pop-Busui, R.; Boulton, A. J.; Feldman, E. L. et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 2017, 40 (1), 136-154. DOI: 10.2337/dc16-2042
4. Pfannkuche, A.; Alhajjar, A.; Ming, A. et al. Prevalence and Risk Factors of Diabetic Peripheral Neuropathy in a Diabetics Cohort: Register Initiative “Diabetes and Nerves.” Endocr. Metab. Sci. 2020, 1, 100053. DOI: 10.1016/j.endmts.2020.100053
5. Brock, C.; Andersen, H.; Alibegovic, A. C. et al. Barriers and New Opportunities in Developing Effective Therapies for Diabetic Neuropathy: International Expert Consensus Recommendations. Diabetes Res Clin Pract. 2025, 221, 112010. DOI: 10.1016/j.diabres.2025.112010
6. Mizukami, H.; Osonoi, S. Collateral Glucose-Utilizing Pathways in Diabetic Polyneuropathy. Int. J. Mol. Sci. 2021, 22 (1), 94. DOI: 10.3390/ijms22010094
7. Feldman, E. L.; Nave, K. A.; Jensen, T. S. et al. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron. 2017, 93 (6), 1296-1313. DOI: 10.1016/j.neuron.2017.02.005