ABSTRACT
Background and Objective:
Data on the role of anti- and proinflammatory markers in diabetes and prediabetes and their associations with diabetic neuropathy are limited. Therefore, the aim of this study was to determine and compare the associations of inflammatory markers and nerve function with blood glucose levels among diabetic patients and prediabetic patients.
Methods:
This was a cross-sectional study consisting of 80 participants (40 diabetic patients and 40 prediabetic patients). The assessment involved a detailed history and neurological examination, including neuropathy symptom scoring (NSS) and the neuropathy deficit score (NDS), to grade neuropathy if present. Baseline investigations were performed, and HbA1c values were assessed in all the subjects. Serum TNFα and IL-10 levels were measured via enzyme-linked immunosorbent assay (ELISA). Nerve function was evaluated through a nerve conduction study. The data were subjected to an independent sample t test.
Results:
The results revealed a significant increase in the concentrations of IL-10 (P = 0.016) and TNFα (P < 0.001) in diabetic patients compared with prediabetic patients. Nerve conduction velocity in the sural nerve (right side, P = 0.019; left side, P = 0.001) and ulnar nerve (right side, P = 0.007; left side, P = 0.005) was also lower in both limbs of diabetic patients than in those of prediabetic patients. Latency was greater in diabetic patients than in prediabetic patients.
Conclusions:
The inflammatory markers TNF-α and IL-10 were significantly elevated in patients with diabetes compared with those with prediabetes, and these markers might contribute to neuropathy in patients with diabetes. However, no associations were found between inflammatory markers and nerve function.
Keywords: Diabetes mellitus, diabetic neuropathy, inflammatory cytokines, interleukins, nerve conduction studies, prediabetic, TNF-α
Introduction
Type two diabetes mellitus is a serious public health problem. It has been strongly linked to various inflammatory cytokines in terms of pathogenicity. Moreover, these cytokines are also considered to be involved in the progression and development of diabetic complications. Moreover, these complications and elevated levels of specific cytokines are also observed in individuals with impaired glucose tolerance and prediabetes.[1] TNFα and interleukin-10 play predominant roles in immune regulation in metabolic syndromes. Furthermore, TNFα expression is increased when more adipose cells are present. They are also involved in diabetic neuropathy pathogenesis.[2] Uncontrolled glycemia leads to various complications in diabetic patients. An approximately 1% reduction in HbA1c was linked with a 37% decrease in microvascular complications and a 14% reduction in myocardial infarction (MI).[3] The results of a 10-year follow-up study revealed that type 2 diabetic patients who maintain better blood glucose control experience benefits later, including lower rates of MI, neuropathy, and death.[4]
Prediabetes is considered to be associated with various complications of type two diabetes, including peripheral neuropathy.[5] Both the incidence of neuropathy in patients with prediabetes and the occurrence of prediabetes in people who were investigated for the causative factors of peripheral neuropathy are suggested to be very high.[5,6] In recent studies, neuropathy development has been reported to be high. The involvement of distal sensory nerves in the course of neuropathy is predominant. This involvement of sensory nerves also occurs in the early phase of the disease.[7] Further research must be carried out to clarify the pathogenicity and etiological factors involved in prediabetes-related neuropathy. The increased production of proinflammatory cytokines in response to immune reactions is counterbalanced by the production of anti-inflammatory markers.[8] This balance is extremely important for regulating immune responses. Furthermore, low-grade inflammation or deranged levels of pro- and anti-inflammatory markers in prediabetes and diabetes patients might be involved in the progression of complications.[9] There are limited data available on the role of anti-inflammatory and proinflammatory markers in diabetes and prediabetes and their associations with diabetic neuropathy. Therefore, in this study, we aimed to assess and compare the role of inflammatory markers such as tumor necrosis factor alpha and interleukin in prediabetic patients, type two diabetic patients and their associated neuropathy.[10]
Methods
This cross-sectional study was conducted in the physiology laboratory of Khyber Medical University from February to November 2022. Eighty patients were selected from different hospitals in Peshawar. The patients were divided into two groups of 40 patients each: Type two diabetic patients and prediabetic patients. Patients with either diabetes mellitus for at least 3 years or a prediabetic status confirmed through their HbA1c levels with both having normal haemoglobin levels were selected for participation. Patients who were taking neurotoxins and had a history of alcohol abuse or neuropathy associated with diseases other than diabetes, such as kidney, liver, and thyroid-related diseases, electrolyte imbalance and peripheral vascular diseases, were excluded. In addition to a thorough clinical examination, a neurological examination was performed by examining the tendon and tone reflexes via the Neuropathy Deficit Score (NDS). According to the NDS, a score of 3–5 was considered mild deficit, a score of 6–8 was considered moderate deficit, and a score of 9–10 was considered severe neuropathic deficit.[9] The neuropathy symptom score (NSS) was determined for nerve conduction. According to this system, a score of 3–4 was labelled mild symptoms, a score of 5–6 was moderate, and a score ranging between 7--10 was included in the category of severe symptoms. From each patient, 5 millilitres of blood samples were collected in EDTA tubes to assess the complete blood count (CBC) to exclude anaemia, infections and glycosylated haemoglobin (HbA1c) levels. The complete blood count of each patient was performed via a multiparameter automated haematology analyser (BC 3000 plus, Mindray) via flow cytometry. The hormone concentration (TNFα) was measured via enzyme-linked immune sorbent assay (ELISA) via a Human TNF alpha ELISA Kit for the quantitative detection of human TNFα, Ela Science (catalogue no: E-EL-H0109). Furthermore, interleukin-10 (IL-10) was measured via ELISA via a human IL-10 ELISA Kit for the quantitative detection of IL-10, Ela Science (catalogue no: E-EL-H0103).
The nerve conduction study (NCS) test was carried out with a four-channel EMG/NCS machine (5000q pro Canadian machine, Nr Sighn Company) by an expert physician. All the data were imported into Excel and analysed with SPSS version 22. Descriptive analysis was performed for all the variables. Comparisons between diabetic patients and prediabetic patients were performed via independent sample t tests, where P < 0.05 was considered significant. Verbal and written informed consent was obtained from all study participants. The study was approved by the Khyber Medical University-Advanced Studies and Research Board (KMU-AS and RB) with NO. DIR/KMU-AS and RB/CI/000701.
Results
Among the 80 patients, 34% were males, whereas 66% were females. The mean age of the type two diabetic group was 51.4 ± 11.1 years, whereas that of the prediabetic group was 43.6 ± 12.6 years. Blood results, including Hemoglobin concentration, Blood cell counts, Glycosylated Hb, TNF alpha and Interleukin 10 are shown in Table 1. Neuropathy symptom scoring (NSS) and neuropathy deficit scoring (NDS) were both significantly greater in diabetic subjects than in prediabetic subjects (P = 0.000). The HbA1c level in diabetic patients was 9.3 ± 1.5, whereas that in prediabetic patients was 5.9 ± 0.3, indicating a statistically significant difference (P < 0.001). A highly significant increase in the serum level of TNFα, a proinflammatory marker, and IL-10, an anti-inflammatory marker, was observed in diabetic patients compared with prediabetic patients (P = 0.000).
Table 1.
Comparison of biochemical parameters between type two diabetic and prediabetic patients
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Hemoglobin (gm/dl) | 12.6±1.3 | 12.9±1.2 | 0.361 |
| Red blood cell count (mill/count) | 4.6±0.5 | 4.8±0.8 | 0.369 |
| Total leukocyte count (cell/cmm) | 8.9±1.7 | 7.81±1.2 | 0.061 |
| Platelet count (cell/cmm) | 294.5±61.9 | 296.5±74.9 | 0.897 |
| Mean corpuscular volume (fl) | 80.9±5.6 | 81.78±2.1 | 0.369 |
| Mean corp. Hb (pg) | 26.8±2.4 | 26.4±2.3 | 0.425 |
| Mean corp. Hb Concentration (g/dl) | 26.42±2.3 | 32.84±2.6 | 0.702 |
| Packed cell volume (%) | 38.0±3.9 | 39.06±4.3 | 0.257 |
| Glycosylated Hb (%) | 9.3±1.5 | 5.9±0.3 | 0.000* |
| TNFα (pg/ml) | 31.6±27.2 | 12.0±7.6 | 0.000* |
| Interleukin 10 (pg/ml) | 5.03±8.4 | 1.6±1.7 | 0.016* |
*Significant
Comparison of sensory nerve conduction parameters in the upper limbs
Sensory nerve conduction velocities and proximal and distal latencies in diabetic patients were compared with those in prediabetic patients [Table 2]. The differences in the sensory nerve conduction velocities and sensory latencies of the median and ulnar nerve in the upper limb were not statistically significant except for the difference in the left ulnar sensory peak latency, which was 3.0 ± 0.7 in the diabetic group and 2.6 ± 0.6 in the prediabetic group, indicating a statistically significant difference (P = 0.01). In addition, no other sensory nerve conduction assessment revealed any electrodiagnostic abnormalities.
Table 2.
Comparison of sensory nerve conduction parameters in the upper limb
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Right median sensory onset latency (ms) | 2.7±1.0 | 2.5±0.7 | 0.362 |
| Right median sensory peak latency (ms) | 3.3±1.2 | 3.2±0.9 | 0.363 |
| Right median sensory nerve conduction velocity (m/s) | 37.3±14.6 | 41.6±13.2 | 0.162 |
| Right ulnar sensory onset latency (ms) | 2.2±0.5 | 2.1±0.6 | 0.654 |
| Right ulnar sensory peak latency (ms) | 2.8±0.6 | 2.7±0.6 | 0.408 |
| Right ulnar sensory nerve conduction velocity (m/s) | 46.3±9.4 | 49.4±9.9 | 0.165 |
| Left median sensory onset latency (ms) | 2.7±0.9 | 2.5±0.9 | 0.216 |
| Left median sensory peak latency (ms) | 3.3±1.0 | 3.0±1.0 | 0.235 |
| Left median sensory nerve conduction velocity (m/s) | 39.9±11.8 | 40.4±13.5 | 0.864 |
| Left ulnar sensory onset latency (ms) | 2.3±0.3 | 2.1±0.4 | 0.541 |
| Left ulnar sensory peak latency (ms) | 3.0±0.7 | 2.6±0.6 | 0.014* |
| Left ulnar sensory nerve conduction velocity (m/s) | 46.9±4.8 | 48.2±8.9 | 0.415 |
*Significant
Comparison of motor nerve conduction parameters in the upper limbs
Median and ulnar motor nerve conduction in both the right and left upper limbs was evaluated in the diabetic and prediabetic groups. Abnormalities in nerve conduction studies of both right and left ulnar motor proximal latencies and nerve conduction velocities were considerably lower in the participants with diabetes than in those with prediabetes, with P values shown in Table 3.
Table 3.
Comparison of motor nerve conduction in the upper limbs
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Right median motor distal latency (ms) | 4.2±1.3 | 3.6±0.9 | 0.171 |
| Right median motor proximal latency (ms) | 9.2±2.0 | 9.0±6.5 | 0.862 |
| Right median motor nerve conduction velocity (m/s) | 42.4±9.3 | 46.8±10.4 | 0.511 |
| Right ulnar motor distal latency (ms) | 2.9±0.5 | 2.7±0.5 | 0.105 |
| Right ulnar motor proximal latency (ms) | 7.6±1.2 | 7.0±1.0 | 0.009* |
| Right ulnar motor nerve conduction velocity (m/s) | 49.0±7.8 | 54.0±8.2 | 0.007* |
| Left median motor distal latency (ms) | 4.2±1.2 | 4.0±1.4 | 0.535 |
| Left median motor proximal latency (ms) | 9.0±1.9 | 8.47±1.9 | 0.207 |
| Left median motor nerve conduction velocity (m/s) | 52.7±66.0 | 45.7±9.3 | 0.506 |
| Left ulnar motor distal latency (ms) | 3.3±1.0 | 2.8±0.5 | 0.112 |
| Left ulnar motor proximal latency (ms) | 7.7±2.0 | 9.0±3.1 | 0.041* |
| Left ulnar motor nerve conduction velocity (m/s) | 46.2±11.8 | 53.2±9.7 | 0.005* |
*Significant
Comparison of F-wave latency in the upper limbs
The F-wave latency in the upper limbs was not significantly different between the diabetic and prediabetic groups (P > 0.05), except for the left ulnar nerve F-wave latency, with a mean of 21.4 ± 0.6 in the diabetic group and 21.0 ± 0.8 in the prediabetic group [Table 4].
Table 4.
Comparison of F-wave latency in the upper limbs of patients
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Diabetics | Prediabetics | ||
| Right ulnar F-wave latency (ms) | 21.3±0.5 | 21.2±1.1 | 0.709 |
| Left median F-wave latency (ms) | 21.2±0.3 | 21.3±0.8 | 0.289 |
| Left ulnar F-wave latency (ms) | 21.4±0.6 | 21.0±0.8 | 0.010* |
| Right median F-wave latency (ms) | 21.5±0.4 | 21.3±1.0 | 0.924 |
*Significant
Comparison of sensory nerve conduction parameters between the two groups in the lower limbs
An electrodiagnostic study of sensory nerves in the lower limbs revealed that the onset and peak latencies of the sural nerve were similar in diabetic and prediabetic patients. However, the mean right and left sural nerve conduction velocities were considerably lower in diabetic patients than in prediabetic patients (P < 0.05), as shown in Table 5.
Table 5.
Comparison of sensory nerve conduction parameters in the lower limbs
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Right sensory sural onset latency (ms) | 2.4±1.18 | 2.4±0.7 | 0.986 |
| Right sural sensory peak latency (ms) | 3.1±1.3 | 3.1±0.8 | 0.886 |
| Right sural sensory nerve conduction velocity (m/s) | 35.4±17.2 | 43.2±10.9 | 0.019* |
| Left sural sensory onset latency (ms) | 2.0±1.3 | 2.4±0.7 | 0.172 |
| Left sural sensory peak latency (ms) | 2.7±1.7 | 3.3±0.8 | 0.391 |
| Left sural sensory nerve conduction velocity (m/s) | 31.3±20.2 | 44.8±8.2 | 0.000* |
*Significant
Comparison of motor nerve conduction parameters in the lower limb
Motor nerve conduction parameters were assessed for peroneal and tibial nerves in the lower limbs. The left peroneal latencies were significantly decreased (P < 0.05), with a mean of (4.8 ± 1.1) in the diabetic group compared with (4.0 ± 0.8) in the prediabetic group. The other parameters that were significantly lower in diabetic patients than in prediabetic patients were left peroneal motor fibular head latency, right tibial motor ankle latency, right tibial motor popliteal fossa latency, right tibial motor NCV, left tibial motor ankle latency, and left tibial motor fibular head latency, with P values less than 0.05 [Table 6].
Table 6.
Comparison of motor nerve conduction parameters in the lower limbs
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Right peroneal motor ankle latency (ms) | 4.4±1.8 | 4.0±0.7 | 0.231 |
| Right peroneal motor fibular head latency (ms) | 12.2±3.5 | 11.0±1.8 | 0.086 |
| Right peroneal motor NCV (m/s) | 40.8±10.1 | 40.7±5.6 | 0.927 |
| Right tibial motor ankle latency (ms) | 4.9±1.4 | 4.2±0.8 | 0.006* |
| Right tibial motor popliteal fossa latency (ms) | 15.0±5.4 | 12.2±2.2 | 0.003* |
| Right tibial motor NCV (m/s) | 34.7±11.4 | 39.0±6.8 | 0.043* |
| Left peroneal motor ankle latency (ms) | 4.8±1.1 | 4.0±0.8 | 0.000* |
| Left peroneal motor fibular head latency (ms) | 12.9±2.1 | 11.3±1.9 | 0.001* |
| Left peroneal motor NCV (m/s) | 39.6±7.0 | 42.4±6.2 | 0.062 |
| Left tibial motor ankle latency (ms) | 5.3±1.4 | 3.9±0.7 | 0.000* |
| Left tibial motor fibular head latency (ms) | 15.0±3.0 | 11.4±2.3 | 0.000* |
| Left tibial motor NCV (m/s) | 37.2±9.1 | 39.7±5.5 | 0.131 |
*Significant
F-wave latencies for both the peroneal and tibial nerves were evaluated, revealing nonsignificant differences among the groups, as shown in Table 7.
Table 7.
Comparison of F waves in the lower limbs of patients in both groups
| Parameters | Mean±SD | P | |
|---|---|---|---|
|
| |||
| Type two diabetics | Prediabetics | ||
| Right peroneal F-wave latency (ms) | 21.1±0.4 | 21.6±2.2 | 0.252 |
| Left peroneal F-wave latency (ms) | 21.4±0.6 | 21.5±2.2 | 0.649 |
Discussion
The results of this study revealed that the level of TNFα, which is a proinflammatory marker, is considerably greater in diabetic patients than in prediabetic patients [Table 1]. This finding is in accordance with other studies in which TNFα was found to be significantly elevated among type two diabetic patients, suggesting that it is one of the factors responsible for the pathogenesis of diabetes mellitus.[10] Furthermore, the levels of TNFα and other proinflammatory markers are elevated in individuals with type two diabetes regardless of neuropathy.[11,12]
In our study, TNFα levels were also increased in prediabetic individuals but not to the same extent as they were in type two diabetic patients. This finding is supported by another study that suggested that elevated levels of inflammatory markers are related to insulin resistance rather than defects in insulin secretion in prediabetic individuals.[13] As low-grade inflammation is associated with insulin resistance, the elevated levels of TNFα may be attributed to its association with insulin resistance and type two diabetes mellitus. We did not find any correlation between inflammatory markers and nerve function; however, a significant increase in both IL-10 and TNFα was detected in diabetic patients compared with prediabetic patients. Uncontrolled hyperglycaemia in type two diabetes patients can be aggravated by chronic diabetic complications involving micro- and microvasculature.[14] Prediabetes, due to genetic predispositions, is more common in first-degree relatives of diabetic patients.[15] Furthermore, if prediabetic individuals do not modify their lifestyle or diet, they are also prone to developing complications related to hyperglycemia.[16]
Multiple studies suggest that it might occur due to altered metabolism, abnormal immune responses, elevated glucose levels, and predisposing genetic factors.[17]
This study also revealed that IL-10 levels were significantly greater in diabetic subjects than in prediabetic subjects. This finding is similar to that of a study that suggested that the levels of IL-10 and other anti-inflammatory markers are increased in response to elevated TNFα levels.[18]
This finding is in accordance with another study reporting that IL-10 levels are elevated compared with normal levels in response to immune responses that promote insulin resistance. In such cases, IL-10 is considered to increase insulin sensitivity.[19] This may be because immune responses are involved in inducing type two diabetes. This, however, is also in accordance with other studies that reported that IL-10 levels are increased in response to increased levels of proinflammatory markers, primarily TNFα and IL-6.[20] The increase in anti-inflammatory marker levels may be due to the compensatory effects of these cytokines in response to increased proinflammatory marker levels.
Diabetic peripheral neuropathy is one of the most common complications of type two diabetes and can lead to disabilities in diabetic and prediabetic patients. The results of the present study indicate that NSS and NDS, which are performed for the grading of neuropathy and its symptoms, are significantly lower among prediabetic patients than among type two diabetic patients. These findings are similar to the results of a study suggesting that the NSS and NDS scoring systems are considerably greater among type two diabetic patients with symptoms of neuropathy.[21] This finding is also supported by a clinical study showing that diabetes and its metabolic syndrome have higher scores when assessed by the NDS and NSS grading systems.[22] This might be because neuropathy and its associated symptoms are related to uncontrolled hyperglycemia.
A nerve conduction study (NCS) was carried out to assess nerve function, which appeared to decline among diabetic subjects; however, mostly normal results were observed in the prediabetic group. The main differences in the mean values among the groups were observed in the left ulnar sensory latency, right and left ulnar motor latency, nerve conduction velocity, right and left sural sensory nerve conduction velocity, left peroneal latency, right tibial latency and conduction velocity [Table 5 and 6]. This finding is in accordance with the literature suggesting a decline in nerve function in diabetes.[23]
Additionally, our research receives validation from a decade-long observational study that examines the advancement of diabetic neuropathy. A previous study revealed a gradual decrease in nerve conduction velocities over time when diabetic individuals were compared with those without these conditions.[24] These metabolic abnormalities in the nerves of diabetic patients are due to the direct exposure of nerve tissue or its vasculature to high concentrations of glucose. However, the majority of previous studies revealed normal nerve function in prediabetic individuals.[25] This difference might be due to different age groups, genders and ethnicities, as discussed in studies suggesting the relationship of nerve function with age. The mean age of individuals in the prediabetes group was relatively high, as observed in our study. Research has shown that the reduction in nerve function among type two diabetic patients is also due to hyperglycaemia, polyol pathways and abnormal protein metabolism, which lead to a decrease in nerve conduction velocity in type two diabetic patients.[26]
Furthermore, in our study, F wave latencies were not significantly different in either the upper or lower limbs, except for the left ulnar nerve F latency, which was slightly lower in diabetic patients than in prediabetic patients [Table 4]. This is in contrast to a study that reported that F wave latency is greatly reduced in patients with type two diabetes and diabetic neuropathy.[27] F waves are dependent on age, sex, and anthropometric parameters, and differences in recording procedures can account for the variability in F wave measurements.[28] This is further explained by a study that revealed increased F wave latencies among chronic diabetic patients, which may be due to the use of improper techniques.[29]
As far as the study limitations are concerned, we were only able to perform sampling once due to financial restraints. This study considered individuals from a specific area of the country with a limited sample size of 80 individuals; therefore, the results lack generalizability. As NCS is a painful procedure, interpretation of its parameters cannot be carried out multiple times. Larger-scale multicentric studies should be carried out in the future to focus on additional parameters of neuropathy in diabetic patients, especially prediabetic patients.
Conclusion
This study revealed that the levels of inflammatory markers such as TNFα and IL-10 are elevated in patients with type two diabetes and prediabetes. The study also suggested that these markers are not strongly correlated with neuropathy in individuals with type two diabetes and prediabetes. As this is a single-centre study, further studies are needed to provide a more precise interpretation of the present results. Moreover, multicentre studies including a larger percentage of the population are needed to verify the current results.
Ethics approval and consent to participate
The study was approved by the Khyber Medical University-Advanced Studies and Research Board (KMU-AS and RB) with NO. DIR/KMU-AS and RB/CI/000701.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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