Abstract
Aims/hypothesisThe individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein.MethodsSchwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months.ResultsIn neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519).Conclusions/interpretationThis study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers.Graphical abstract
Highlights
More than 50% of individuals with diabetes mellitus develop neuropathy, the major form of which is diabetic peripheral neuropathy (DPN)
Myelin-specific circulating mRNA (cmRNA) Using human iPSC Schwann cells, we observed that high glucose alone was able to reduce the intracellular mRNA levels of peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), proteolipid protein 1 (PLP1) and myelin basic protein (MBP) as well as MPZ protein expression significantly
PLP1 cmRNA could be detected in 79% of participants (96 of 122) and showed no association with DPN, whereas PMP22 cmRNA was detectable in only 58%
Summary
More than 50% of individuals with diabetes mellitus develop neuropathy, the major form of which is diabetic peripheral neuropathy (DPN). When it comes to the structural integrity of nerve fibres, only indirect assumptions can be made Clinical approaches such as neuronal conduction velocity (NCV) testing or magnetic resonance neurography (MRN) can help to differentiate between axonal and demyelinating damage in experimental settings, but are time consuming and costly [4, 5]. These diagnostic tests have very little predictive value on the progression of DPN, especially with regard to hypoalgesia, defined by the loss of sensorimotor function, which is a result of slow-developing NCV deficits in individuals suffering from DPN [6, 7]
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