In the DPN group, there was a positive correlation between DPN and neutrophil (r = 0.091, P = .032), lymphocyte (r = −0.150, P < .001), TG (r = 0.106, P = .013) according to Pearson correlation analysis. The multivariate logistic regression models included age, sex, BMI, SBP, DBP, the levels of FPG, Fins, IR, TG, TC, HDL-C, LDL-C, HbA1c, Cr, UA, NLR, neutrophil, lymphocyte, WBC, 2hPG, alcohol consumption, and current smoking status among the DPN group and DM group. Results in multivariate logistic regression analysis showed that DPN was independently related to NLR (P = .002, OR = 4.960, 95% CI = 1.843–13.349), urinary albumin (P = .016, OR = 1.007, 95% CI = 1.001–1.012), TG (P = .025, OR = 1.166, 95% CI = 1.019–1.334), and smoking (P = .009, OR = 2.155, 95% CI = 1.214–3.828) (Table 2).
T2DM and its complications have been proved to be an inflammatory disease and immune system dysfunction.[24,25] Research has shown that chronic inflammation contributes to the occurrence and development of DPN in diabetic patients.[8,9,26,27] Nuclear factor κB (NF-κB) can be induced by stimuli such as hyperglycemia and oxidative stress. The activation of NF-κB will stimulate the inflammatory response by increasing the expression of ICAM-1, proinflammatory cytokines, and chemokines. The overexpression of ICAM-1 results in the gathering of inflammatory cells that releases large quantities of cytokines to recruit more inflammatory cells. Myeloperoxidase and reactive oxygen species are released during the activation of increased neutrophils, which may lead to enhanced oxidative stress and persistent inflammation. These cascades in inflammatory responses will eventually lead to an increase in neutrophils. On the other hand, T2DM and its complications may be associated with lymphopenia. Many clinical and experimental studies witnessed the similar lymphopenia in people with diabetes with microvascular, macrovascular, and other complications.[14–16,31,32] This may be attributed to the increased oxidative DNA damage and apoptosis in peripheral blood lymphocytes.
NLR represents a combination of 2 major components of chronic inflammatory condition (high neutrophil and low lymphocyte). A high neutrophil value is a marker of the ongoing destructive nonspecific inflammatory process. A low lymphocyte value indicates relatively inadequate immune regulation as well as a quiescent immunity pathway. Hence, elevated NLR can reveal the functional status of the immune system in the process of chronic inflammation. In addition, compared with other leukocyte parameters (e.g., neutrophil, lymphocyte, and total leucocyte count), the stability of NLR is less influenced by physiological, pathological, and physical factors.[36,37]
On the other hand, it has been demonstrated that NLR is an independent risk factor for a DPN-related pathophysiological process named diabetic microangiopathy,[14–16] which affects the nutrition supply of neuronal and Schwann cells, causes nerve degeneration, and eventually leads to toperipheral neuropathy.
In our study, neutrophil is significantly higher in the DPN group than in the T2DM group while lymphocyte is significantly lower. Also, neutrophil is positively correlated with DPN while lymphocyte is negatively correlated with DPN. Those results indicated the different inflammatory degree between DPN and T2DM participants. NLR values were remarkably higher in the DPN group compared with those from the DM group (2.58 ± 0.50 vs 2.18 ± 0.61, P < .001). Logistic regression analysis showed that NLR (P = .002, OR = 4.960, 95% CI = 1.843–13.349) was an independent risk factor for DPN. Furthermore, multivariate logistic regression analysis in our study showed that NLR was an independent risk factor for DPN. Combining the results of multivariate logistic regression analysis and independent sample t test, we speculate that elevated NLR may predict a higher incidence of peripheral neuropathy in T2DM patients to some extent. The results suggest that NLR might not only contribute to the development of DPN but also serve as an auxiliary index in the early diagnosis of DPN. Since NLR is an inflammatory marker, it can be hypothesized that an appropriate control of chronic inflammation state in diabetic patients can preclude or alleviate DPN. Moreover, NLR may be an effective monitoring indicator for anti-inflammatory therapy.
Pearson correlation analysis showed that TG is positively correlated with DPN and multivariate logistic regression analysis showed that triglyceride, urine microalbumin, smoking, and 2hPG are risk factors for DPN as well. The study of Irina G Obrosova first proved the key roles of hypertriglyceridemia and increased fatty acid concentrations in contributing to prediabetic neuropathy through oxidative–nitrosative stress. A high-fat diet will not only raise the production of superoxide and peroxynitrite in the vast nervorum but also lead to peripheral nerve dysfunction associated with prediabetes.
Multivariate logistic regression analysis also showed that urine microalbumin, smoking, and 2hPG are risk factors for DPN. A meta-analysis by Carole Clai has provided evidence that smoking is closely linked with the incidence of DPN. Smoking has direct toxic effects, and it is associated with oxidative stress, systemic inflammation, and endothelial dysfunction, increasing the risk of nerve damage through these pathways. Urine microalbumin is not only a significant sign of early renal impairment but also a sign of changes in the vascular system. Therefore, the presence of urine microalbumin can be an important predictor of microvascular and macrovascular complications of diabetes. 2hPG has been proved to be an important risk factor for peripheral neuropathy in subjects with diabetes and prediabetes.[42,43] Hyperglycemia creates a proinflammatory microenvironment, accelerating inflammatory processes and the release of inflammatory biomarkers contributing to DPN.
Previous studies have suggested that the Michigan Neurological Disease Screening Scale (MNSI), Diabetic Neuropathy Symptom (DNS) score, are good screening tools for diabetic neuropathy, and the Toronto Clinical Scoring System (CSS) can detect diabetic peripheral sensorimotor polyneuropathy (DSP) presence and severity.[45–47] However, those diagnosis methods of DPN are easily affected by subjective feelings of patients while NLR is an objective, economic indicator which can be more effective in predicting DPN. Furthermore, these methods ignore the screening of asymptomatic neuropathy. In addition, high cost and time consuming also restrict the application of these traditional methods in extensive clinical screening for DPN. On the contrary, NLR can easily be calculated by the ratio of neutrophils to lymphocytes in peripheral blood. Moreover, the calculation of NLR is outstanding due to its high stability, high repeatability, and a relatively low cost.
There are limitations in our study. First, the relationship between the values of NLR and degrees of the severity of DPN was not explored. Further study in which participants are divided into different groups according to their severity of DPN is needed. Second, our sample is small and it is restricted to regions and race which may cause bias in those statistic results, so larger-scale research is demanded to further evaluate the application of NLR in DPN prediction.
The authors thank the Zhujiang Hospital of Southern Medical University, Guangdong, China and the Chinese People's Liberation Army General Hospital, Beijing, China for providing the data.
. Davies M, Brophy S, Williams R, et al. The prevalence, severity, and impact of painful diabetic peripheral neuropathy
in type 2 diabetes. Diabetes Care 2006;29:1518–22.
. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956–62.
. Chéliout-Héraut F, Zrek N, Khemliche H, et al. Exploration of small fibers for testing diabetic neuropathies. Joint Bone Spine 2005;72:412–5.
. Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60:108–11.
. Cameron NE, Eaton SE, Cotter MA, et al. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001;44:1973–88.
. Malik RA, Tesfaye S, Thompson SD, et al. Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia 1993;36:454–9.
. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–350.
. Vincent AM, Callaghan BC, Smith AL, et al. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 2011;7:573–83.
. Kampoli AM, Tousoulis D, Briasoulis A, et al. Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus
. Curr Pharm Des 2011;17:4147–58.
. Cho H, Hur HW, Kim SW, et al. Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment. Cancer Immunol Immunother 2009;58:15–23.
. Walsh SR, Cook EJ, Goulder F, et al. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91:181–4.
. Uthamalingam S, Patvardhan EA, Subramanian S, et al. Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. Am J Cardiol 2011;107:433–8.
. Bhat T, Teli S, Rijal J, et al. Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther 2013;11:55–9.
. Öztürk ZA, Kuyumcu ME, Yesil Y, et al. Is there a link between neutrophil-lymphocyte ratio and microvascular complications in geriatric diabetic patients? J Endocrinol Invest 2013;36:593–9.
. Huang W, Huang J, Liu Q, et al. Neutrophil-lymphocyte ratio is a reliable predictive marker for early-stage diabetic nephropathy. Clin Endocrinol (Oxf) 2015;82:229–33.
. Ulu SM, Dogan M, Ahsen A, et al. Neutrophil-to-lymphocyte ratio
as a quick and reliable predictive marker to diagnose the severity of diabetic retinopathy. Diabetes Technol Ther 2013;15:942–7.
. Luo P, Li R, Yu S, et al. The relationship between neutrophil-to-lymphocyte ratio
and intracerebral hemorrhage in type 2 diabetes mellitus
. J Stroke Cerebrovasc Dis 2017;26:930–7.
. Yuan ZY, Gao SG, Mu JW, et al. Prognostic value of preoperative neutrophil-lymphocyte ratio is superior to platelet-lymphocyte ratio for survival in patients who underwent complete resection of thymic carcinoma. J Thorac Dis 2016;8:1487.
. Lou M, Luo P, Tang R, et al. Relationship between neutrophil-lymphocyte ratio and insulin resistance in newly diagnosed type 2 diabetes mellitus
patients. BMC Endocr Disord 2015;15:9.
. Alberti KG, Zimmet PZ. Definition, diagnosis, and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–53.
. Thorne SL, Malarcher A, Maurice E, Caraballo R. Centers for Disease Control and Prevention (CDC). Cigarette smoking among adults—United States, 2007. MMWR Morb Mortal Wkly Rep 2008;57:1221–6.
. Sasaki S, Yanagibori R, Amano K. Self-administered diet history questionnaire developed for health education: a relative validation of the test-version by comparison with 3-day diet record in women. J Epidemiol 1998;8:203–15.
. Callaghan BC, Cheng HT, Stables CL, et al. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012;11:521–34.
. Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998;41:1241–8.
. Navarro JF, Mora C. Role of inflammation in diabetic complications. Nephrol Dial Transplant 2005;20:2601–4.
. Uceyler N, Rogausch JP, Toyka KV, et al. Differential expression of cytokines in painful and painless neuropathies. Neurology 2007;69:42–9.
. Doupis J, Lyons TE, Wu S, et al. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab 2009;94:2157–63.
. Mohamed AK, Bierhaus A, Schiekofer S, et al. The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors 1999;10:157–67.
. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066–71.
. Kawamura N, Dyck PJ, Schmeichel AM, et al. Inflammatory mediators in diabetic and non-diabetic lumbosacral radiculoplexus neuropathy. Acta Neuropathol 2008;115:231–9.
. Wang R, Zhang J, Li Y, et al. Neutrophil–lymphocyte ratio is associated with arterial stiffness in diabetic retinopathy in type 2 diabetes. J Diabetes Complications 2015;29:245–9.
. Ulu S, Bucak A, Ulu MS, et al. Neutrophil–lymphocyte ratio as a new predictive and prognostic factor at the hearing loss of diabetic patients. Eur Arch Otorhinolaryngol 2014;271:2681–6.
. Shiny A, Bibin YS, Shanthirani CS, et al. Association of neutrophil-lymphocyte ratio with glucose intolerance: an indicator of systemic inflammation in patients with type 2 diabetes. Diabetes Technol Ther 2014;16:524–30.
. Azab B, Daoud J, Naeem FB, et al. Neutrophil-to-lymphocyte ratio
as a predictor of worsening renal function in diabetic patients (3-year follow-up study). Ren Fail 2012;34:571–6.
. Luo P, Huang Y, Xu T, et al. Relationship between hyperuricemia and neutrophil-to-lymphocyte ratio
in type 2 diabetes mellitus
. Int J Clin Exp Pathol 2016;9:10833–8.
. Núñez J, Núñez E, Bodí V, et al. Usefulness of the neutrophil to lymphocyte ratio in predicting long-term mortality in ST segment elevation myocardial infarction. Am J Cardiol 2008;101:747–52.
. Gibson PH, Croal BL, Cuthbertson BH, et al. Preoperative neutrophil-lymphocyte ratio and outcome from coronary artery bypass grafting. Am Heart J 2007;154:995–1002.
. Lupachyk S, Watcho P, Hasanova N, et al. Triglyceride, nonesterified fatty acids, and prediabetic neuropathy: role for oxidative–nitrosative stress. Free Radic Biol Med 2012;52:1255–63.
. Vincent AM, Hayes JM, McLean LL, et al. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes 2009;58:2376–85.
. Clair C, Cohen MJ, Eichler F, et al. The effect of cigarette smoking on diabetic peripheral neuropathy
: a systematic review and meta-analysis. J Gen Intern Med 2015;30:1193–203.
. Chuengsamarn S, Rattanamongkolgul S, Jirawatnotai S. Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. J Diabetes Complications 2014;28:124–9.
. Lu B, Hu J, Wen J, et al. Determination of peripheral neuropathy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes—ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SHDREAMS). PLoS One 2013;8:e61053.
. Bongaerts BW, Rathmann W, Kowall B, et al. Postchallenge hyperglycemia is positively associated with diabetic polyneuropathy: the KORA F4 study. Diabetes Care 2012;35:1891–3.
. Nguyen DV, Shaw LC, Grant MB. Inflammation in the pathogenesis of microvascular complications in diabetes. Front Endocrinol (Lausanne) 2012;3:170.
. Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 2002;25:2048–52.
. Feldman EL, Stevens MJ, Thomas PK, et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281–9.
. Meijer JW, Smit AJ, Sonderen EV, et al. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score. Diabet Med 2002;19:962–5.
. Perkins BA, Olaleye D, Zinman B, et al. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250–6.