|Year : 2019 | Volume
| Issue : 1 | Page : 62-66
Study of peripheral neuropathy in patients with type 2 diabetes mellitus
Wafik M El-Sheikh, Ibrahim E Alahmar, Gelan M Mohamed, Mohamed A El-Sheikh
Department of Neuro-psychiatry, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||29-Jan-2016|
|Date of Acceptance||04-Apr-2016|
|Date of Web Publication||17-Apr-2019|
Mohamed A El-Sheikh
Department of Neuro-pscychiatry, Faculty of Medicine, Menoufia University, Menoufia
Source of Support: None, Conflict of Interest: None
To compare serum levels of tumor necrosis factor-alpha (TNF-α) in patients with peripheral neuropathy and patients without neuropathy in type 2 diabetes mellitus (T2DM) and study the relation between nerve conduction studies of motor and sensory nerves and the serum level of TNF-α in T2DM.
TNF-α presence in the serum of diabetic patients can be used as an indicator for the development of neuropathy with nerve conduction studies.
Patients and methods
This cross-sectional study was conducted in diagnosed T2DM patients. They were divided into two groups: group I (n = 40) with clinically detectable diabetic peripheral neuropathy (DPN) of shorter duration and group II (n = 40) with clinically detectable DPN of longer duration. They were compared with patients without clinical neuropathy (n = 40); clinical diagnosis was based on Neurologic Severity Score (NSS) and National Disability Services (NDS) for signs. Blood samples were collected for the estimation of serum TNF-α. Nerve conduction velocity was measured in the upper and lower limbs. Median, ulnar, common peroneal, and posterior tibial nerves were selected for motor nerve conduction study and median and sural nerves were selected for sensory nerve conduction study.
The serum level of TNF-α in type 2 diabetic patients with peripheral neuropathy is higher than those without neuropathy. The serum level of TNF-α shows statistically significant negative correlation with nerve conduction velocities which is higher in type 2 diabetic patients (5–10 years duration) with peripheral neuropathy.
A high level of TNF-α in the serum of T2DM patients with neuropathy shows possible contribution in the development of neuropathy. This cytokine might be used as a biomarker for DPN.
Keywords: nerve conduction velocity, peripheral neuropathy, tumor necrosis factor-alpha, type 2 diabetes mellitus
|How to cite this article:|
El-Sheikh WM, Alahmar IE, Mohamed GM, El-Sheikh MA. Study of peripheral neuropathy in patients with type 2 diabetes mellitus. Menoufia Med J 2019;32:62-6
|How to cite this URL:|
El-Sheikh WM, Alahmar IE, Mohamed GM, El-Sheikh MA. Study of peripheral neuropathy in patients with type 2 diabetes mellitus. Menoufia Med J [serial online] 2019 [cited 2019 Aug 23];32:62-6. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/62/256096
| Introduction|| |
Diabetic peripheral neuropathy (DPN) is the most commonly reported long-term diabetic complication, affecting up to 50% of type 2 diabetic mellitus (T2DM) patients . A number of neuropoietic cytokines including interleukin-1, interleukin-6, and tumor necrosis factor-alpha (TNF-α) exhibit pleiotropic effects on glia cells and neurons important for the homeostasis of the peripheral, central, and autonomic nervous systems. These cytokines are produced locally by residual and infiltrating macrophages, lymphocytes, mast cells, Schwann cells, fibroblasts, and sensory neurons. TNF-α is locally produced by Schwann cells and has a role in peripheral nerve regeneration and regulation of apoptosis . The metabolic changes induced by hyperglycemia lead to dysregulation of cytokine control. There are multiple metabolic pathways which are dysregulated in T2DM , and this dysregulation occurs after diagnosis of diabetes or may begin years or even decades before diagnosis of the disease ,. It develops on (or with) a background of long-standing hyperglycemia ,. During the pathologic process, TNF-α may initiate and promote the development of nerve dysfunction via various pathways. Macrophages, which are activated by high glucose , oxidative stress , and Acute Gastroenteritis (AGEs)  in a diabetic state, may infiltrate into nerve tissues  and locally produce much TNF-α, resulting in endothelial and nerve fiber damage. However, precise mechanisms of how TNF-α is responsible for the pathogenesis of diabetic polyneuropathy remain to be elucidated.
| Patients and Methods|| |
The study was a cross-sectional study conducted on 120 patients, having T2DM, suffering from neuropathy selected from Menoufia University Hospital clinic of diabetes from January 2015 to January 2016. The study was approved by the ethical Committee of the faculty of medicine Menoufia University and the patient gave an informed consent.
This study was carried out on three groups of patients: group I: 40 diabetic patients with clinically detectable motor or mixed sensorimotor peripheral neuropathy of shorter duration (<5 years), group II: 40 diabetic patients with clinically detectable motor or mixed sensorimotor peripheral neuropathy of longer duration (5–10 years), and group III (control group): 40 diabetic patients without clinical neuropathy.
Each participant in this study was subjected to a written informed consent and those diagnosed with T2DM with motor or mixed sensorimotor neuropathy were included in this study. However, the participants who have acute diabetic complications (e.g. Diabetic ketoacidosis (DKA)), acute or chronic illnesses other than diabetes (RF: refractory anaemia, liver cell failure) or local causes that affect nerves were excluded. Also, control participants were subjected to a written informed consent, history of T2DM, and no history of other chronic illnesses.
Each of the studied groups was subjected to history taking, clinical examination, and laboratory investigations including serum glucose, serum level of TNF-α, and nerve conduction studies were measured in both upper and lower limbs. Median, ulnar, common peroneal, and posterior tibial nerves were selected for motor nerve conduction studies and median and sural nerves were selected for sensory nerve conduction studies.
Data were analyzed using the Statistical Program for Social Science, version 18.0, for Windows (SPSS, Chicago, Illinois, USA). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage. A one-way analysis of variance was used to compare between more than two means. χ2 test of significance was used in order to compare proportions between two qualitative parameters. Pearson's correlation coefficient (r) test was used for correlating data. Linear regression: it is used to test and estimate the dependence of a quantitative variable based on its relationship to one or more independent variables. A P value of less than 0.05 was considered significant; a P value less than 0.001 was considered as highly significant; and a P value of more than 0.05 was considered insignificant.
| Results|| |
After assessment of patients of T2DM in a diabetic clinic 80 patients were selected for this study and were divided into two groups based on the duration of disease. They were compared with a group of patients without clinical neuropathy. The mean and SD of various baseline, anthropometric parameters are shown in [Table 1].
|Table 1: Demographic and clinical characteristics of type 2 diabetic patients with and without peripheral neuropathy|
Click here to view
Group I neuropathy (<5 year duration of T2DM) shows a significant increase in serum TNF-α when compared with diabetic patients without neuropathy [Table 2].
|Table 2: Serum glucose and tumor necrosis factor-alpha in type 2 diabetic patients with and without peripheral neuropathy|
Click here to view
Group II neuropathy (5–10 year duration of T2DM) shows a significant increase in fasting and postprandial blood sugar, serum TNF-α when compared with T2DM without clinical neuropathy [Table 2].
Nerve conduction velocity in group I peripheral neuropathy was compared with group I peripheral neuropathy in T2DM patients [Table 3].
|Table 3: Comparison between motor nerve conduction velocities in patients with and without peripheral neuropathy|
Click here to view
Motor Nerve Conduction Velocity (MNCV) in ulnar, common peroneal on the right side, and MNCV of posterior tibial nerve on the left side are significantly decreased (P < 0.05), while the difference of all other nerve velocities are not significant [Table 4].
|Table 4: Comparison between sensory nerve conduction velocity in patients with and without peripheral neuropathy|
Click here to view
TNF-α shows a positive correlation with duration and age in neuropathy patients in both groups, shorter and longer duration. This correlation is significant for the duration in both groups and age in group I neuropathy [Table 5].
|Table 5: Correlation between serum level of tumor necrosis factor with clinical data of type 2 diabetes mellitus and nerve conduction studies|
Click here to view
Correlation of biomarker TNF-α with nerve conduction velocity in patients of neuropathy in T2DM (only left side was correlated as both sides have similar results) shows a significant negative correlation with median MNCV, ulnar MNCV, and sural Sensory Nerve Conduction Velocity (SNCV) in shorter duration (group I) and a significant correlation with median MNCV and ulnar MNCV in longer duration (group II neuropathy) as well. All other nerves also show negative correlation but not up to a significant level [Table 5].
| Discussion|| |
In the present study, the glycemic status of T2DM patients with neuropathy with different durations are compared with that of patients without neuropathy. The mean fasting blood glucose and postprandial glucose are similar in patients of group I neuropathy (<5 years duration) and without neuropathy. In another place group II neuropathy (patients with longer duration) shows a significant increase in fasting serum glucose and postprandial serum glucose in comparison to patients without neuropathy.
In the present study, we measured the serum level of TNF-α in T2DM patients with peripheral neuropathy and compared with the level in patients of T2DM without neuropathy. The mean value of serum TNF-α level is found significantly increased in diabetic neuropathy patients of both less than 5 years duration and 5–10 years duration when compared with patients without neuropathy. Even TNF-α shows a consistent and significant increase with duration as the longer duration group is compared with the shorter duration of T2DM neuropathy patients. This result is consistent with previous studies who observed that this peptide contributes to the development of diabetic complications ,. The result in the present study is also consistent with the result of Huseynova et al. , who showed a significant increase in the level of TNF-α in various stages of compensation in T2DM patients. The high level of TNF-α in the serum of T2DM neuropathy patients in this study is also supported by the results of Navarro and Mora  and Skundrik and Lisak ., where the role of neuropoitic cytokines in DPN was disclosed.
In the present study, the level of TNF-α in different groups of neuropathy is correlated with nerve conduction velocity which shows a significant negative correlation with motor NCV in median and ulnar nerves and sensory NCV in the sural nerve. This result is supported by a previous study where significant correlation of TNF-α with sensory nerve conduction velocity was shown . This finding also coincides with the result reported by Summer et al.  and Drory et al.  where it was shown that nerve function may be affected by this cytokine level.
| Conclusion|| |
TNF-α was found to be increased in serum when compared with the patients without neuropathy. The serum level of TNF-α was found to be markedly raised in neuropathy patients and the trend continued when the duration of disease increased. We conclude that these cytokines TNF-α might be independently associated with peripheral neuropathy in T2DM and could be used as a biomarker for DPN.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Boulton AJ, Malik RA, Arezo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care 2003; 27
Armati PJ, Pollard JD. Immunology of the Schwann cell. Baillieres Clin Neurol 1996; 5
Mather KJ, Funahashi T, Matsuzawa Y, Edelstein S, Bray GA, Kahn S, et al
. Adiponectin, change in adiponectin, and progression to diabetes in the diabetes prevention program. Diabetes 2008; 57
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286
Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med 2006; 119:S10–S16.
Goldfine A, Patti ME, O'Shea S, Kolberg J, Gerwien R, McKenna M. Protein biomarkers in fasting serum samples correlate with diabetes risk factors (abstract). Diabetes 2008; 57
Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ III, O'Brien PC. Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 1999; 22
Dyck PJ, Davies JL, Clark VM, Litchy WJ, Dyck PJ, Klein CJ, et al
. Modeling chronic glycemic exposure variables as correlates and predictors of microvascular complications of diabetes. Diabetes Care 2006; 29
Morohoshi M, Fujisawa K, Uchimura I, Numano F. Glucose-dependent interleukin-6 and tumor necrosis factor production by human peripheral blood monocytes in vitro
. Diabetes 1996; 45
Mendez C, Garcia I, Maier RV. Oxidants augment endotoxin-induced activation of alveolar macrophages. Shock 1996; 6
Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 1988; 240
Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymaticglycation in the pathogenesis of diabetic neuropathy: a critical review for the end of the 20th
century. Diabetes Rev 1999; 7
Vlassara H. Chronic diabetic complications and tissue glycosylation. Relevant concern for diabetes-prone black population. Diabetes Care 1990; 13
King GL, Brownlee M. The cellular and molecular mechanisms of diabetic complications. Endocrinol Metab Clin North Am 1996; 25
Huseynova GR, Azizova GI, Efendiyev AM. Quantitative changes in serum IL-8, TNF- a and TGF-b1 levels depending on compensation stage in type 2 diabetic patients. Int J Diabetes Metab 2009; 17
Navarro JF, Mora C. Diabetes, inflammation, proinflammatory cytokines, and diabetic nephropathy. Sci World J 2006; 6
Skundrik DS, Lisak RP. Role of neuropoitic cytokines in development and progression of diabetic polyneuropathy: from glucose metabolism to neurodegeneration. Exp Diabetol 2003; 4
Matsuda M, Kawasaki F, Inoue H, Kanda Y, Yamada K, Harada Y, et al
. Possible contribution of adipocytokines on diabetic neuropathy. Diabetes Res Clin Pract 2004; 66 (Suppl 1)
Summer CJ, Sheth S, Griggin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003; 60
Drory VE, Lev D, Groozman GB, Gutmann M, Klausner JM. Neurotoxicity of isolated limb perfusion with tumor necrosis factor. J Neurol Sci 1998; 158
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]