The Association between Genomic DNA Methylation and Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes Mellitus

Abstract

Aim DNA methylation is thought to be involved in regulating the expression of key genes and inducing diabetic peripheral neuropathy (DPN). However, clinically, the level of whole-genome DNA methylation and its relationship with DPN remains unclear. Methods 186 patients with type 2 diabetes mellitus (T2DM) admitted to the Second Affiliated Hospital of Soochow University since Jul. 2016 to Oct. 2017 were enrolled in the study, including 100 patients in the DPN group and 86 patients in the non-DPN group, diagnosed with Toronto Clinical Scoring System (TCSS). Clinical and biochemical characteristics between the two groups were compared, and the correlations with TCSS scores were analyzed. Furthermore, the levels of genomic DNA methylation of leukocytes, measured with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), were also analyzed between the two groups. Results Age, duration, triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), creatinine, uric acid (UA), blood urea nitrogen (BUN), and C-reactive protein (CRP) were significantly higher in the DPN group. Estimated glomerular filtration rate (eGFR) and the level of genomic DNA methylation were much lower in the DPN group. Spearman correlation analysis showed that TCSS was positively correlated with age, duration, UA, and CRP and was negatively correlated with body mass index (BMI), eGFR, and the level of genomic DNA methylation. Interestingly, multiple stepwise regression analysis showed that only duration, genomic DNA methylation, and eGFR had impacts on TCSS. The results also showed that the levels of genomic DNA methylation did not change significantly whether or not there was renal injury. Another multiple stepwise regression analysis showed that TCSS and BMI were the influencing factors of genomic DNA methylation. Finally, we found that genomic DNA methylation levels were decreased significantly in the DPN group compared with the non-DPN group when the duration is ≥5 years or BMI ≥ 25 kg/m2. Conclusion Low level of genomic DNA methylation is a relative specific risk factor of diabetic peripheral neuropathy in patients with type 2 diabetes.

Study on Risk Factors of Peripheral Neuropathy in Type 2 Diabetes Mellitus and Establishment of Prediction Model

“…The higher LDL-C, the greater the risk of DPN in T2DM patients [ 13 ]. The blood viscosity of patients with diabetes increases because of the abnormal blood lipid levels, which impedes blood flow, results in the formation of a micro thrombus, and substantially affecting blood circulation [ 5 ]. An insufficient blood supply in the nervous system leads to an energy metabolism disorder, which substantially impairs the transmission of signals in the nervous system [ 14 ].…”

“…Hyperuricemia is significantly associated with an increased risk of DPN, and hyperuricemia is associated with an increased risk of peripheral blood disorders [ 30 ]. A positive correlation has been observed between TCSS scores and UA levels [ 5 ]. However, further studies are needed to determine whether UA is involved in the pathogenesis of peripheral neuropathy in patients with T2DM.…”

“…From September 2018 to July 2019, follow-up of the population was performed to diagnose DPN using the TCSS. Many studies have confirmed that the consistency between the screening of DPN with TCSS score ≥6 points is good [ 3 , 4 ], and the sensitivity and specificity of the TCSS are greater than 70% when the scores are ≥6 [ 5 ]. Therefore, patients with a TCSS score ≥6 points were diagnosed with DPN in the follow-up survey.…”

Role of C-Reactive Protein in Diabetic Inflammation

“…Nevertheless, in male and female patients, symptomatic peripheral diabetic neuropathy and inflammation are related to endothelial dysfunction and elevated CRP serum levels [ 135 ]. It is assumed that in patients with T2DM peripheral neuropathy, increased CRP levels are positively correlated with inflammation grade [ 133 ]. Furthermore, according to data from a large cohort study where participants were monitored for one year, hs-CRP levels above 2.5 mg/L could predict neuropathy complications in T2DM [ 136 ].…”

Genetic and Epigenomic Modifiers of Diabetic Neuropathy

“…Genome-wide methylation analysis of samples collected 16–17 years apart from the same diabetic patients revealed a persistency of DNA methylation over time at key genomic loci associated with diabetic complications [ 80 ]. Hyperglycemia is changing DNA methylation status inducing alterations in gene expression related to PDN and significantly reduced methylation of whole genomic DNA in white blood cells represents a potential biomarker for PDN [ 81 ]. Additionally, new evidence has pointed out that different DNA methylation patterns in genes related to nerve regeneration and functionality have an important role in the development of cardiovascular autonomic neuropathy (CAN) in patients with DM type 1 [ 82 ].…”