Investigators at the National Institute of Biological Sciences in Beijing and China Agricultural University have identified mixed lineage kinase domain-like protein (MLKL) as an important player in diabetic neuropathy.

They published their results in the Proceedings of the National Academy of Sciences on March 28, 2022.

Diabetic neuropathy, or nerve damage, is the most common of the many possible complications of diabetes, with an estimated one-third to one-half of diabetes patients having some form of neuropathy. Most often, it is sensory neuropathy, affecting the legs and feet.

Sensory neuropathy can lead to unpleasant sensations. But the opposite situation is also a problem – the inability to feel pain, in particular the pain that results from vascular and consequent tissue damage in the foot.

Along with an inability of wounds to heal because of insufficient blood flow to the affected area, this impaired pain signaling contributes to the need for amputations in diabetic patients.

In the U.S., tens of thousands of such amputations are performed annually. And although the risk of amputation has decreased for individual patients, the prevalence of diabetes is rising, so the overall number of amputations is increasing.

Considering those statistics, very little is known about neuropathy – including whether it is at its root due to damage to neurons themselves, or to the myelin sheath that insulates them.

"Diabetic neuropathy is generally considered to be an axonal neuropathy rather than a demyelinating disease per se," the authors wrote in their paper. But "there are reports from human diabetic neuropathy patients showing segmental demyelination without prominent axonal degeneration, suggesting that demyelination could happen without axonal damage. Therefore, understanding the demyelination process during diabetic neuropathy should facilitate the development of mechanism-based therapies for preventing diabetes associated complications or treating ongoing myelin degradation."

In the work now published in PNAS, the team followed up on earlier work showing that MLKL played a role in both demyelination and necroptosis, a form of cell death that sits somewhere between programmed death via apoptosis, and injury-induced necrosis.

In injured neurons, MLKL was phosphorylated and started to break down the myelin sheath, and that mice lacking MLKL were protected from this breakdown.

In their present paper, the team reported that MLKL played a role in diabetes-induced destruction of the myelin sheath, as well.

The investigators induced diabetes 1 wild-type mice, as well as several strains that had mutations in the gene for MLKL.

The team first showed that diabetes led to the decompaction of myelin around the peripheral nerves, which compromised their insulation and slowed the speed with which the affected neurons were able to signal.

Those effects were blunted in animals with mutations in MLKL that prevented its activation. So did treatment with the MLKL inhibitor TC-013249.

In biopsy samples from diabetes patients, the team also found higher levels of MLKL as compared to healthy controls.

The authors acknowledged that their interventions "did not fully restore the ultrastructure or the function of myelin, suggesting the existence of other contributors to diabetes-induced demyelination." Nevertheless, they argued, their work provides "proof of principle that MLKL is a valuable therapeutic target for the treatment of diabetic neuropathy."

MLKL could also be developed as a biomarker. Amputations can become necessary because neuropathy has been asymptomatic, allowing issues such as diabetic foot ulcers to progress more or less silently. MLKL is activated by phosphorylation on a specific amino acid, serine 441 (S441).

"Developing diabetic neuropathy-specific biomarkers will help clinicians to identify actionable changes in the disease progressions of their patients, especially if such biomarkers are present in easily assayable sample materials," the authors wrote. "Thus, antibodies that recognize the human equivalent of S441 phosphorylation in MLKL could potentially be used to detect this biochemical marker for diabetic neuropathy."