Effects of progressive resistance training in individuals with type 2 diabetic polyneuropathy: a randomised assessor-blinded controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the effects of progressive resistance training (PRT) on muscle strength, intraepidermal nerve fibre density (IENFD) and motor function in individuals with type 2 diabetic polyneuropathy (DPN) and to compare potential adaptations to those of individuals with type 2 diabetes without DPN and healthy controls. METHODS: This was an assessor-blinded trial conducted at the Neurology department, Aarhus University Hospital. Adults with type 2 diabetes, with and without DPN and healthy control participants were randomised to either supervised PRT or non-PRT for 12 weeks. Allocation was concealed by a central office unrelated to the study. The co-primary outcomes were muscle strength in terms of the peak torque of the knee and ankle extensors and flexors, and IENFD. Secondary outcome measures included the 6 min walk test (6MWT), five-time sit-to-stand test (FTSST) and postural stability index obtained by static posturography. RESULTS: A total of 109 individuals were enrolled in three groups (type 2 diabetes with DPN [n = 42], type 2 diabetes without DPN [n = 32] and healthy control [n = 35]). PRT resulted in muscle strength gains of the knee extensors and flexors in all three groups using comparative analysis (DPN group, PRT 10.3 ± 9.6 Nm vs non-PRT -0.4 ± 8.2 Nm; non-DPN group, PRT 7.5 ± 5.8 Nm vs non-PRT 0.6 ± 8.8 Nm; healthy control group, PRT 6.3 ± 9.0 Nm vs non-PRT -0.4 ± 8.4 Nm; p<0.05, respectively). Following PRT the DPN group improved the 6MWT (PRT 34.6 ± 40.9 m vs non-PRT 2.7 ± 19.6 m; p=0.001) and the FTSST (PRT -1.5 ± 2.2 s vs non-PRT 1.5 ± 4.6 s; p=0.02). There was no change in IENFD following PRT in any of the groups. CONCLUSIONS/INTERPRETATION: PRT improved muscle strength of the knee extensors and flexors and motor function in individuals with type 2 diabetic polyneuropathy at levels comparable with those seen in individuals with diabetes without DPN and healthy control individuals, while no effects were observed in IENFD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03252132 FUNDING: Research reported in this paper is part of the International Diabetic Neuropathy Consortium (IDNC) research programme, supported by a Novo Nordisk Foundation Challenge Program grant (grant no. NNF14OC0011633) and Aarhus University.

Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management.

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.

Falls in individuals with type 2 diabetes; a cross-sectional study on the impact of motor dysfunction, postural instability and diabetic polyneuropathy.

AIM: To estimate the incidence of falls in individuals with type 2 diabetes compared to healthy controls and to describe the characteristics of fallers with type 2 diabetes in relation to motor dysfunction, postural instability and diabetic polyneuropathy (DPN). METHODS: This is a cross-sectional study of individuals with type 2 diabetes with DPN (n = 54), without DPN (n = 38) and healthy controls (n = 39). Falls were recorded within the preceding year. DPN was defined by clinical scores and nerve conduction studies. Motor function was assessed by a 6-min walk test (6 MWT), five-time sit-to-stand test (FTSST) and isokinetic dynamometry at the non-dominant ankle and knee. An instability index (ST) was measured using static posturography. Univariate and bivariate descriptive statistics were used for group comparisons. RESULTS: Compared with healthy controls, individuals with diabetes had a higher incidence of falls 36%, (n = 33) versus 15%, (n = 6), p = 0.02. There were no differences in falls when comparing individuals with and without DPN. Fallers had an impaired 6 MWT versus non-fallers (450 ± 153 m vs. 523 ± 97 m respectively), a slower FTSST (11.9 ± 4.2 s vs. 10.3 ± 2.9 s respectively) and a higher ST (53 ± 29 vs. 41 ± 17 respectively), p < 0.02 for all. CONCLUSION: Individuals with type 2 diabetes reported a higher number of falls within the preceding year compared to healthy controls, irrespective of the presence of DPN. The main factors associated with falls were increased postural instability, lower walking capacity and slower sit-to-stand movements. The 6 MWT, FTSST and posturography should be considered in future screening programs in identification of individuals at risk for falls.

MRI of Skeletal Muscles in Participants with Type 2 Diabetes with or without Diabetic Polyneuropathy.

BackgroundDiabetic polyneuropathy (DPN) is associated with loss of muscle strength. MRI including diffusion-tensor imaging (DTI) may enable detection of muscle abnormalities related to type 2 diabetes mellitus (DM2) and DPN.PurposeTo assess skeletal muscle abnormalities in participants with DM2 with or without DPN by using MRI.Materials and MethodsThis prospective cross-sectional study included participants with DM2 and DPN (DPN positive), participants with DM2 without DPN (DPN negative), and healthy control (HC) participants enrolled between August 2017 and June 2018. Muscle strength at the knee and ankle was determined with isokinetic dynamometry. MRI of the lower extremities included the Dixon sequence, multicomponent T2 mapping, and DTI calculated fat fractions (FFs), T2 relaxation of muscle (T2water), fractional anisotropy (FA), and diffusivity (mean, axial, and radial). One-way analysis of variance and Tukey honestly significant difference were applied for comparison between groups, and multivariate regression models were used for association between MRI parameters, nerve conduction, strength, and body mass index (BMI).ResultsTwenty participants with DPN (mean age, 65 years ± 9 [standard deviation]; 70% men; mean BMI, 34 kg/m2 ± 5), 20 participants without DPN (mean age, 64 years ± 9; 55% men; mean BMI, 30 kg/m2 ± 6), and 20 HC participants (mean age, 61 years ± 10; 55% men; mean BMI, 27 kg/m2 ± 5) were enrolled in this study. Muscle strength adjusted for age, sex, and BMI was lower in participants with DPN than in DPN-negative and HC participants in the upper and lower leg (plantar flexors [PF], 62% vs 78% vs 89%; P < .001; knee extensors [KE], 73% vs 95% vs 93%; P < .001). FF was higher in leg muscle groups of participants with DPN than in DPN-negative and HC participants (PF, 20% vs 10% vs 8%; P < .001; KE, 13% vs 8% vs 6%; P < .001). T2water was prolonged in leg muscle groups of participants with DPN when compared with HC participants (PF, 33 msec vs 31 msec; P < .001; KE, 32 msec vs 31 msec; P = .002) and in the lower leg when compared with participants without DPN (PF, 33 msec vs 32 msec; P = .03). In multivariate regression models, strength was associated with FA (b = -0.0004), T2water (b = -0.03 msec), and FF (b = -0.1%) at thigh level (P < .001). Furthermore, FA (b = -0.007), T2water (b = -0.53 msec), and FF (b = -4.0%) were associated with nerve conduction at calf level (P < .001).ConclusionMRI of leg muscle groups revealed fat accumulation, differences in water composition, and structural changes in participants with type 2 diabetes mellitus and neuropathy. Abnormalities were most pronounced in the plantar flexors.© RSNA, 2020Online supplemental material is available for this article.See also the editorial by Sneag and Tan in this issue.

The impact of vestibular dysfunction on falls and postural instability in individuals with type 2 diabetes with and without diabetic polyneuropathy.

Aim: This study aimed to determine the association between vestibular dysfunction, falls, and postural instability in individuals with type 2 diabetes (T2D) compared to healthy control individuals and to examine the impact of diabetic polyneuropathy (DPN). Methods: This cross-sectional study included individuals with T2D with DPN (n = 43), without DPN (n = 32), and healthy controls (n = 32). Cervical and ocular vestibular evoked myogenic potentials (VEMP) were recorded, and latencies and amplitudes were determined. DPN was diagnosed based on nerve conduction studies and clinical scores. Postural instability was examined using a static posturographic balance system and calculated as an instability index (ST). Falls were recorded retrospectively during the past year. Group comparisons were conducted by using univariate and bivariate statistics. Results: Individuals with T2D experienced more falls than healthy controls (T2D with DPN n = 12[38%], T2D without DPN n = 15[35%], controls n = 5[16%], p = 0.04). Individuals with T2D had decreased postural stability, T2D with DPN, ST (median of 52[iqi = 33; 77]), T2D without DPN, ST (median of 31[iqi = 24; 39]), controls ST (median of 26[iqi = 19; 33], p = 0.01), when comparing all three groups. Individuals with T2D had a greater number of no-responses in oVEMP compared to controls (T2D with DPN, n = 15[46.9%] T2D without DPN n = 25[58.1%], controls n = 9[28.1%], p = 0.04). No difference was found in cVEMP and oVEMP amplitudes in any of the groups. Irrespectively of DPN, fallers with T2D had decreased oVEMP and cVEMP latencies on the right ears, when comparing to non-fallers, respectively, n10 (fallers [median of 16, iqi=15;19 ms.] vs. non-fallers [median of 25 iqi=16;35 ms]); p13 (fallers [median of 16, iqi=15;17 ms.] vs. non-fallers [median of 15, iqi=8;16 ms.], p < 0.05). Conclusion: Falls and postural instability were more frequent in individuals with T2D compared to healthy controls. Fallers with T2D had vestibular end-organ impairments based on the oVEMP and cVEMP latencies on the right but not the left ears, irrespective of DPN. Individuals with T2D had more frequent no-response of the oVEMP, indicating impaired vestibular nerve function.

The Impact of Diabetic Neuropathy on Activities of Daily Living, Postural Balance and Risk of Falls - A Systematic Review.

OBJECTIVE: The objective of this review is to discuss a compilation of the currently available literature regarding the impact of diabetic neuropathy (DN) on activities of daily living (ADL), postural stability, and risk of falls. METHODS: A systematic electronic search strategy was conducted on PubMed/MEDLINE database, Cochrane Library, and Embase in March 2020. This narrative review included clinical cross-sectional studies assessing ADL, postural balance, and falls in adults with DN. All studies underwent a quality assessment based on the Newcastle Ottawa scale developed to assess cross-sectional studies. RESULTS: Forty-two studies were identified. A total of 37 studies evaluated postural stability in DN, 10 studies assessed fall accidents, and three studies assessed ADL in individuals with DN. Seven studies assessed both postural stability and fall accidents, and one study assessed postural stability and ADL. Each of the studied outcome variables was assessed separately. Based on a quality assessment, eight studies were excluded resulting in an evaluation of 34 studies. CONCLUSIONS: Diabetic neuropathy has a negative impact on postural balance and gait kinematics combined with an increased fall risk. Because of the few number of studies available, we were unable to evaluate the impact of DN on ADL. Our findings are in concordance with previous reviews, supporting the evidence for DN as a critical measure negatively impacting postural stability and fall risk in individuals with diabetes. Further clinical investigative studies are needed.

Normative reference values for the dorsal sural nerve derived from a large multicenter cohort.

OBJECTIVES: Dorsal sural nerve conduction studies (NCS) may increase the sensitivity for the diagnosis of polyneuropathy, but clinical use is limited by a lack of reliable normative reference values in all age-groups. The aim of our study was to develop reference values for the dorsal sural nerve, based on a large multicenter cohort of healthy subjects. METHODS: Bilateral antidromic NCS were performed using standard surface electrodes in 229 healthy subjects (aged 21-80 years; median: 54 years). We assessed the normality of data distribution for amplitudes and conduction velocity (CV) and for their logarithmic (ln) transformation. The effects of age and height were determined using linear regression analysis. RESULTS: Sensory potentials were present in all subjects. Logarithmically transformed data were normally distributed. Age2 and height were most significantly associated with amplitude, and age and height with CV, respectively. There was no significant side-difference. Mean amplitudes (right and left) were 4.8 and 4.9 µV and mean CV 46.7 and 46.9 m/s. Reference limits were e (3.712515 - 0.0000956 * age2 - 0.0115883 * height ±â€¯1.96 * 0.51137) for amplitude and e (4.354374 - 0.0021081 * age - 0.0023354 * height ±â€¯1.96 * 0.11161) for CV. CONCLUSIONS: Dorsal sural nerve NCS are robust and have well defined normative limits. SIGNIFICANCE: The findings provide a basis for more sensitive NCS in clinical practice and future studies of the diagnostic accuracy of NCS in polyneuropathy.

Falls and fractures associated with type 2 diabetic polyneuropathy: A cross-sectional nationwide questionnaire study.

AIMS/INTRODUCTION: To examine the prevalence of falls and fractures, and the association with symptoms of diabetic polyneuropathy (DPN) in patients with recently diagnosed type 2 diabetes. MATERIALS AND METHODS: A detailed questionnaire on neuropathy symptoms and falls was sent to 6,726 patients enrolled in the Danish Center for Strategic Research in Type 2 Diabetes cohort (median age 65 years, diabetes duration 4.6 years). Complete data on fractures and patient characteristics were ascertained from population-based health registries. We defined possible DPN as a score ≥4 on the Michigan Neuropathy Screening Instruments questionnaire. Using Poisson regression analyses, we estimated the adjusted prevalence ratio (aPR) of falls and fractures, comparing patients with and without DPN. RESULTS: In total, 5,359 patients (80%) answered the questions on the Michigan Neuropathy Screening Instruments questionnaire and falls. Within the year preceding the questionnaire response, 17% (n = 933) reported at least one fall and 1.4% (n = 76) suffered from a fracture. The prevalence ratio of falls was substantially increased in patients with possible DPN compared with those without (aPR 2.33, 95% confidence interval [CI] 2.06-2.63). The prevalence ratio increased with the number of falls from aPR 1.51 (95% CI 1.22-1.89) for one fall to aPR 5.89 (95% CI 3.84-9.05) for four or more falls within the preceding year. Possible DPN was associated with a slightly although non-significantly increased risk of fractures (aPR 1.32, 95% CI 0.75-2.33). CONCLUSIONS: Patients with recently diagnosed type 2 diabetes and symptoms of DPN had a highly increased risk of falling. These results emphasize the need for preventive interventions to reduce fall risk among patients with type 2 diabetes and possible DPN.

Diabetic polyneuropathy and pain, prevalence, and patient characteristics: a cross-sectional questionnaire study of 5,514 patients with recently diagnosed type 2 diabetes.

Most studies of diabetic polyneuropathy (DPN) and painful DPN are conducted in persons with longstanding diabetes. This cross-sectional study aimed to estimate the prevalence of DPN and painful DPN, important risk factors, and the association with mental health in recently diagnosed type 2 diabetes. A total of 5514 (82%) patients (median diabetes duration 4.6 years) enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort responded to a detailed questionnaire on neuropathy and pain. A score ≥4 on the MNSI questionnaire determined possible DPN, whereas pain presence in both feet together with a score ≥3 on the DN4 questionnaire determined possible painful DPN. The prevalence of possible DPN and possible painful DPN was 18% and 10%, respectively. Female sex, age, diabetes duration, body mass index, and smoking were associated with possible DPN, whereas only smoking showed a clear association with possible painful DPN (odds ratio 1.52 [95% confidence interval: 1.20-1.93]). Possible DPN and painful DPN were independently and additively associated with lower quality of life, poorer sleep, and symptoms of depression and anxiety. Possible DPN itself had greater impact on mental health than neuropathic pain. This large study emphasizes the importance of careful screening for DPN and pain early in the course of type 2 diabetes.