Slowing of Peripheral Nerve Conduction Velocity in Children and Adolescents With Type 1 Diabetes Is Predicted by Glucose Fluctuations Free

Diabetic peripheral neuropathy (DPN) is defined as symptoms and/or signs of peripheral nerve dysfunction in individuals with diabetes, after exclusion of other causes (1). Once DPN is present, quality of life (2), in combination with autonomic neuropathy life expectancy (3), is reduced. Screening is recommended starting at age 11 years, 2–5 years after the diagnosis of type 1 diabetes (4), by careful history and clinical examination. In younger children, this can be negative as a result of reduced reliability or asymptomatic stage of DPN (5). Therefore, pediatric studies often use DPN definitions according to the Toronto Expert Panel as subclinical (6), possibly clinical (7), probably clinical (8), or confirmed clinical (5). This explains the wide variation in its reported prevalence in children and adolescents, from 0 to 62% (5–8).

Because of the increasing incidence of type 1 diabetes worldwide (9), as well as the incompletely understood pathogenesis of and missing causal therapy for DPN, we conducted this study to learn more about the prevalence of and risk factors for DPN. We used nerve conduction velocity (NCV) as the most sensitive and objective screening tool for DPN (5) and looked for clinical signs and symptoms. Reduced NCV is not synonymous with DPN, but it shows a functional limitation in the meaning of preneuropathy. We examined risk factors for DPN, such as inadequate glycemic control, high glucose variability, longer duration of diabetes, increasing age and height (5,10,11), and existing comorbidities, including vitamin D deficiency (6), cardiovascular risk factors (11), and the influence of autoimmune comorbidities and/or diabetes autoantibodies. Given that height is known to correlate negatively with NCV (11,12), we performed association studies with height-adjusted NCV (dNCV) values, in addition to conducting a multivariate correlation analysis.

This prospective, cross-sectional study was conducted at the Children’s Hospital of Eastern Switzerland in St. Gallen, Switzerland, from March 2016 to June 2022. The study was approved by the local ethics committee (St. Gallen, Switzerland) and registered with the Swiss project database (2022-00216, EKOS 22/018). Written informed consent was obtained from the caregivers.

Children age ≥5 years as well as young adults diagnosed with type 1 diabetes at least 6 months prior were eligible for inclusion in the study group. Depending on the measured diabetes autoantibodies (GAD, zinc transporter 8, IA2, pancreatic cell antibody, and/or insulin antibody) at first diagnosis, clinical picture, C-peptide level, and if indicated genetic analyses, diabetes classification was made. Children with other chronic diseases, premature birth, or family history of any inherited neurologic disease were excluded.

Fifty-three children and young adults with diabetes were recruited for a nerve conduction study (NCS) at the time of their main annual examination, which involved comprehensive pediatric and neurologic examinations (including vibration perception threshold testing using a C128-Hz tuning fork), control of the metabolic laboratory parameters, and screening for associated autoimmune diseases (autoimmune thyroid gland disease and celiac disease).

In addition to the measured glycated hemoglobin (HbA_1c) in all individuals with diabetes, long-term glycemic control was assessed using the mean HbA_1c of the last one to five annual checkup HbA_1c levels, depending on diabetes duration. The glucose profile of individuals wearing a continuous glucose monitoring (CGM) device >70% was analyzed according to the following parameters: time in range (TIR; percentage of time glucose is within range 3.9–10.0 mmol/L), mean glucose, coefficient of variation for mean glucose (CV), and SD of mean glucose (glucose SD). Fitting to the time span HbA_1c reflects the average blood glucose, the glucose profile was analyzed over a period of 90 days before the NCS. Additionally, the same parameters were studied in the whole diabetes group with CGM and self-monitored blood glucose. Glucose profile calculations were performed using one of the following evaluation programs: Diabass (version 6; mediaspects GmbH, Balingen, Germany), Carelink (Medtronic Diabetes, Inc., Northridge, CA), Libre View (version 3.10; Abbott Diabetes Care, Ltd., Witney, U.K.), or Dexcom Clarity Clinic Portal (Dexcom International Switzerland, Horw, Switzerland). Several other DPN risk factors (dyslipidemia, high blood pressure, malnutrition, vitamin D insufficiency [<50 nmol/L], and renal or ophthalmologic diabetic disease) were assessed but not examined further because of their low prevalence.

The department of pediatric neurology continuously collects normative NCV data of children with mild unilateral traumatic nerve injuries. During the study period, 50 children were recruited according to the same exclusion criteria as those used for the study group.

NCV measurements were performed in the diabetes and control groups. After adaptation to the constant maintained room temperature, a motor NCS of the peroneal, tibial, and median nerves and a sensory NCS of the median nerve were conducted on the right side, unless this was not possible (e.g., because of injury), according to the clinical standards of Broser and Lütschg (13).

When considering an NCS in the pediatric population, it should be noted that NCV of all peripheral nerves increases until age ∼10 years (13). In addition, numerous changes during puberty are known to affect glycemic control and comorbidity (11). Therefore, in order to perform a group comparison between the diabetes and control groups, the study population was divided into three age-groups: 5.0 to <10.0 years (prepuberty), 10.0 to <16.0 years (puberty), and 16.0 to <24.0 years (postpuberty).

Furthermore, it is important to note that the NCV of the peroneal nerve is negatively correlated with body height (12). To account for this confounder, two methodologic approaches were adopted. First, a partial regression was performed (14) by calculating dNCV, relating the NCV of a child with diabetes to the regression line given by Hyllienmark (12) according to the following formula: dNCV = measured NCV − NCV of healthy children of the same height. This mentioned regression line could be confirmed by the data of our control group (Supplementary Fig. 1). Second, a multiple linear regression model was fitted (two-way ANOVA).

To estimate the required sample size, the study by Walter-Höliner et al. (15) was considered, because it analyzed the development of DPN in children by NCS. With a significance criterion of α = 0.05 and 0.80 power, the minimum sample size needed to detect small differences between the diabetes and control groups according to Velleman and Welsch (14) was N = 45. Data were entered into Excel for storage, and additional analyses were performed in the statistical computation program R (16). The two-sample Wilcoxon test (Mann-Whitney U test) was used to compare the diabetes and control groups (17). Pearson correlation tests were performed to examine the associations between dNCV and glycemic control parameters. The significance level α was set to 0.05. A total of eight statistical tests were performed, and to control for multiple comparisons, the false discovery rate was corrected using the Benjamini-Hochberg procedure (18).

All data are available from the corresponding author.

The characteristics of the 53 and 50 participants in the diabetes and control groups, respectively, and the subgroups are shown in Table 1 and Supplementary Tables 1, 2, and 3.

In the age- and height-matched subgroup of children age 10–16 years, a significant reduction in NCV was found in the diabetes group in comparison with the control group for all four investigated nerves (Fig. 1). This was most pronounced in the peroneal nerve and existed in all diabetes subgroups (Fig. 1, Supplementary Fig. 2, and Supplementary Table 4).

Given the strong and robust effect on the peroneal nerve, the study focused on this nerve, performing regression analyses of the entire diabetes group with peroneal dNCV.

The slowing of the dNCV showed a significant negative correlation with the mean glucose of the preceding 3 months (n = 33; R = −0.42; P = 0.016), the concomitantly measured HbA_1c (n = 53; R = −0.22; P = 0.022) (Fig. 2A), and the mean HbA_1c (n = 48; R = −0.37; P = 0.01), but dNCV was not significantly associated with TIR (n = 33) (Fig. 2B). Glucose variability, expressed as CV and glucose SD, demonstrated the most significant negative correlation (n = 33) (Fig. 2C and D). Glucose SD was also highly significantly associated with dNCV in the entire diabetes group (n = 53; R = −0.32; P = 0.0013 with CGM use and/or self-monitored blood glucose). To investigate this finding further, a multiple regression model was adopted with the variables NCV, glucose SD, and height. In this model, height and glucose SD explain 60% of the total variability of peroneal NCV (n = 48; R² = 0.580; F_{(3, 44)} = 20.29; P < 0.001) (Supplementary Table 5). The overall association between NCV and glucose SD was negative, and the strength of this negative association was less pronounced in taller versus shorter patients (Supplementary Fig. 3).

There was no obvious correlation between dNCV and disease onset or overall duration (Fig. 3A and B). However, during the first 5 years after diabetes diagnosis, disease duration was negatively associated with dNCV (R = −0.41; P = 0.0041), reaching a steady state thereafter.

No association was found between dNCV and diabetes autoantibodies or coexisting autoimmune diseases (Supplementary Fig. 4).

Our study shows a significantly reduced NCV in all four investigated nerves in the age- and height-matched diabetes subgroup aged 10–16 years (Fig. 1). The peroneal nerve was the most severely and significantly affected in all diabetes subgroups across the age range of 5 to 23 years, similar to the findings of most other studies (19), likely because of its vulnerable anatomic course. The slowing of NCV was not associated with clinical symptoms, but as a possible sign of DPN, a reduced vibration perception threshold was found in 57% of individuals with diabetes. Our data align with previous findings that symptoms of neuropathy are rare in children and adolescents (19), despite its pathogenesis having already developed (20).

Because it is well known that the peroneal nerve negatively correlates with body height, peroneal dNCV was used for further analysis. Using this dNCV evaluation, the data were in line with other studies (6,21), indicating that neither age at disease onset nor overall disease duration correlated with dNCV (Fig. 3).

In fact, diabetes duration predicts the decrease in NCV, following a nonlinear pattern; after an initial improvement over the first 2 years (22), parallel to recovery from diabetes onset, there is further deterioration of NCV (15,22), which we also found in our dNCV data of various intervals after diabetes onset during the first 5 years of the disease. We interpret this dNCV slowing, which was glycemic control independent (Fig. 3), as ceased diabetes remission. Additional studies will examine whether this decrease is associated with the gradual end of C-peptide secretion and whether C-peptide will have a beneficial effect on NCV (23).

Glycemic control is the dominant factor in nerve function after 5 years of diabetes, according to our data (Figs. 2 and 3) (24,25). Of note, glucose variability, expressed by CV and glucose SD, correlated more significantly with dNCV than did mean glucose or HbA_1c (Fig. 2). This finding was verified by a multiple regression model, analyzing the associations of height, peroneal NCV (without height correction), and glucose SD, and confirmed the association between peroneal NCV and glucose SD (Supplementary Table 5). Interestingly, this association was more pronounced in shorter patients (Supplementary Fig. 3). This might hint that the nerve is primarily affected in the perinodal area, in proximity to the nodes of Ranvier, which are equally numerous in tall and short individuals. Conduction slowing there would thus affect the NCV of shorter nerves relatively more than longer nerves (13). Although TIR is recommended for assessing glycemic control, it was not significantly associated with dNCV (Fig. 2), probably because it reflects glucose fluctuations less accurately.

In conclusion, more attention should be paid to glucose variability in the care of individuals with diabetes, because the particularly robust correlation with glucose SD supports the finding that glucose variability is an independent risk factor for DPN (11).

Acknowledgments. The authors thank the team of the neurophysiologic department for their support in conducting the NCS measurements, the secretary of the neuropediatric team for organizing the measurements, and the diabetes team at the Children’s Hospital of Eastern Switzerland for their support. Finally, the authors thank all the children who participated in the study.

Funding. This study was supported by funds from the Canton of St. Gallen to the Children’s Hospital of Eastern Switzerland for the purpose of research promotion.

Duality of Interest. S.S.O., D.L.A., T.G., K.H., M.E., and A.S. received travel grants for international meetings (European Society of Pediatric Endocrinology) and/or education programs offered by Sandoz, Novo Nordisk, Merck, or Pfizer from the Department of Paediatric Endocrinology and Diabetology, Children’s Hospital of Eastern Switzerland, according to Swiss law. D.L.A. received cantonal research funding granted to the Hospital of Eastern Switzerland. K.H. received an honorarium for a presentation at the Leptin Forum Berlin 2022. P.J.B. received research funding from the ultrasound division of Canon Medical Systems. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.S.O. conducted the study, analysis and interpretation of results, and wrote the first draft of the manuscript. D.L.A. conducted the study, analysis, and interpretation of results, with E.P.W. assisting in analysis and interpretation of results. T.G. and K.H. were involved in the conception and design of the study. M.E., A.S., and all authors edited, reviewed, and approved the final version of the manuscript. J.L. and P.J.B. were also involved in the conception and design of the study, and P.J.B. also conducted the study, analysis, and interpretation of results. S.S.O. and P.J.B. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Data of this study have been reported in part at the Annual Meeting of the Swiss Society of Pediatric Endocrinology and Diabetology, St. Gallen, Switzerland, 20 January 2022; 60th Annual Meeting of the European Society for Paediatric Endocrinology, Rome, Italy, 15–19 September 2022; Annual Meeting of the Swiss Society of Endocrinology and Diabetology, Bern, Switzerland, 17–18 November 2022; Annual Meeting of the Swiss Society of Neuropediatrics, St. Gallen, Switzerland, 12–13 December 2022; and 15th Congress of the European Paediatric Neurology Society, Prague, Czech Republic, 20–24 June 2023.