The Possibility of Using Lipid Biomarkers to Predict Diabetic Neuropathy, with Gregory Weiss, MD

Gregory Weiss, MD

Diabetes affects close to 40 million Americans with as many as half of those going on to develop nerve damage and painful diabetic neuropathy. Neuropathy can lead to severe disability and dramatic reductions in quality of life.

Once neuropathy sets in, it is often irreversible due to permanent damage to nerve fibers. Historically it has been difficult to predict which diabetics will develop neuropathy and which will not. In fact, glucose control has been shown to prevent neuropathy only marginally down the road.¹

Although the determinants of neuropathy in type 2 diabetics remain elusive, emerging evidence suggest that obesity and dyslipidemia may be important risk factors.¹ A Danish study demonstrated an association between low high-density lipoprotein (HDL) levels and neuropathy.² Unfortunately data surrounding lipid biomarkers in neuropathy have been limited by the collection of only basic lipid panels on most patients. However, recent advances in mass spectrometry now allow us to examine a greater array of lipids, now termed the lipidome, from routine bio-samples.¹

“We have the potential to test for these lipid biomarkers in patients with type 2 diabetes to identify those with the highest risk of developing peripheral neuropathy and facilitate more focused management of those patients,” wrote study investigators, who were led by Eva Feldman, MD, PhD, of the University of Michigan.

Feldman and colleagues found a link between developing neuropathy and a critical metabolic pathway called Beta-oxidation which converts lipids into energy used by the nerves.¹ When this pathway is blocked, energy starved nerves become damaged, and neuropathy ensues. Even more exciting, the lipid profiles associated with Beta-oxidation inhibition can be recognized as early as 10 years before neuropathy occurs.¹

The serum lipidomics signature found in this study may be a key prognostic test in the coming future. The authors found, specifically, that decreased serum medium-chain acylcarnitines and increased free fatty acids were associated with development of peripheral neuropathy ten years later.¹ They also found that patients who developed neuropathy also had lower phosphatidylcholines and higher lysophosphatidylcholines when compared to those who did not develop neuropathy. These findings give us specific targets, not only for prognosis, but quite possibly targets for treatment.

“As we learn more about the relationship between serum lipid species and neuropathy, it will open up the possibility of targeted therapeutic treatment, both with drugs and lifestyle interventions,” Feldman and colleagues note.

“Our findings support the concept that unsaturated healthy fats are a better source of energy for nerves that highly saturated fats. We strongly recommend a Mediterranean-type diet to maintain a healthy nervous system,” the team continued.

The authors found some common themes here. Obesity and poor diet in general may lead to both hyperglycemia and altered lipid profiles. Now with these data we see that the type of lipid may be a crucial determinant of outcome. Identifying specific lipid signatures that can be tested for early in the course of diabetes, or even in prediabetes offers clinicians the opportunity for earlier intervention. Perhaps if we are able to encourage better diet and more exercise at first discovery of this lipidomic pattern neuropathy could be avoided altogether.

These findings offer us a chance to look at diabetes, altered lipid metabolism, and nerve damage from a higher altitude. The mainstay of lipid management continues to be HMG-CoA Reductase inhibitors or statins which act through cholesterol pathways which, based on this new data, may not prove effective in preventing neuropathy.¹ The authors suggest a need for therapeutics that optimize fatty acid metabolism and enhance mitochondrial Beta oxidation.¹ This brings new hope for diabetic patients facing the pain and disability of peripheral neuropathy.

References:

1. Afshinnia, F., Reynolds, E. L., Feldman, E. L., et al. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes. Annals of Clinical and Translational Neurology. Volume 9, Issue 9 p. 1392-1404
2. Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes Care. 2018;41(5):1068-1075.