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Therapeutic footwear becomes the first treatment line in the prevention of diabetic foot ulcer and future complications of diabetes. Previous studies and the International Working Group on the Diabetic Foot have described therapeutic footwear as a protective factor to reduce the risk of re-ulceration. In this study, we aimed to analyze the efficacy of a rigid rocker sole to reduce the recurrence rate of plantar ulcers in patients with diabetic foot. Between June 2016 and December 2017, we conducted a randomized controlled trial in a specialized diabetic foot unit. Fifty-one patients with diabetic neuropathy who had a recently healed plantar ulcer were randomized consecutively into the following two groups: therapeutic footwear with semi-rigid sole (control) or therapeutic footwear with a rigid rocker sole (experimental). All patients included in the study were followed up for 6 months (one visit each 30 ± 2 days) or until the development of a recurrence event. Primary outcome measure was recurrence of ulcers in the plantar aspect of the foot. A total of 51 patients were randomized to the control and experimental groups. The median follow-up time was 26 [IQR-4.4-26.1] weeks for both groups. On an intention-to-treat basis, 16 (64%) and 6 (23%) patients in the control and experimental groups had ulcer recurrence, respectively. Among the group with >60% adherence to therapeutic footwear, multivariate analysis showed that the rigid rocker sole improved ulcer recurrence-free survival time in diabetes patients with polyneuropathy and DFU history (P = 0.019; 95% confidence interval, 0.086-0.807; hazard ratio, 0.263). We recommend the use of therapeutic footwear with a rigid rocker sole in patients with diabetes with polyneuropathy and history of diabetic foot ulcer to reduce the risk of plantar ulcer recurrence. ClinicalTrials.gov NCT02995863.

We assessed the effect of different doses of vitamin D supplementation on microcirculation, signs and symptoms of peripheral neuropathy and inflammatory markers in patients with type 2 diabetes (T2DM). Sixty-seven patients with T2DM and peripheral neuropathy (34 females) were randomized into two treatment groups: Cholecalciferol 5000 IU and 40,000 IU once/week orally for 24 weeks. Severity of neuropathy (NSS, NDS scores, visual analogue scale), cutaneous microcirculation (MC) parameters and inflammatory markers (ILs, CRP, TNFα) were assessed before and after treatment. Vitamin D deficiency/insufficiency was detected in 78% of the 62 completed subjects. Following treatment with cholecalciferol 40,000 IU/week, a significant decrease in neuropathy severity (NSS, p = 0.001; NDS, p = 0.001; VAS, p = 0.001) and improvement of cutaneous MC were observed (p < 0.05). Also, we found a decrease in IL-6 level (2.5 pg/mL vs. 0.6 pg/mL, p < 0.001) and an increase in IL-10 level (2.5 pg/mL vs. 4.5 pg/mL, p < 0.001) after 24 weeks of vitamin D supplementation in this group. No changes were detected in the cholecalciferol 5000 IU/week group. High-dose cholecalciferol supplementation of 40,000 IU/week for 24 weeks was associated with improvement in clinical manifestation, cutaneous microcirculation and inflammatory markers in patients with T2DM and peripheral neuropathy.

The need for strategies to prevent complications from diabetic neuropathy (DPN) is well recognized. However, foot-ankle exercise programs show weak to moderate evidence, and barriers to their implementation persist, including broad and facilitated access to exercise programs, which guarantee for equity. In this paper, we report for the first time the effectiveness of a web-based foot-ankle exercise program aiming to improve DPN-related outcomes, gait biomechanics and functional outcomes. Sixty-two participants with DPN were randomly allocated into the control group (CG; n  = 31), which received the usual care, or the intervention group (IG; n  = 31), which received the usual care plus a 12-week foot-ankle exercise program using a web-based software (the SOPeD software). The primary outcomes, DPN symptoms and severity, were assessed using the Brazilian version of the Michigan Neuropathy Screening Instrument and the Decision Support System for Classification of Diabetic Polyneuropathy, respectively. Secondary outcomes included tactile sensitivity (monofilaments) and vibration perception (tuning fork), functional outcomes, such as foot pain and function (Foot Health Status Questionnaire), foot muscle strength and plantar pressure during gait (emed plate), and foot-ankle kinematics and kinetics during gait. Outcomes were assessed at baseline, 12 and 24 weeks by an assessor blinded to group allocation. DPN symptoms and severity remained unchanged after the web-based foot-ankle program. However, IG showed improvements compared to CG, with greater functional reach at 12 weeks, better foot function, reduced foot pain and greater plantarflexion degree during push-off at 24 weeks. Regarding plantar loading during gait, the forefoot pressure reduced in the IG at 12 weeks compared to baseline, but at 24 weeks, forefoot load increased in the IG compared to CG. The 12-week web-based foot-ankle exercise program was feasible, acceptable, demonstrating safety with minimal adverse events, such as delayed onset muscle soreness and foot muscle cramping. While DPN-related outcomes were unaffected by the 12-week SOPeD program, modest improvements in foot pain and function, functional reach, and changes in plantar pressure and plantarflexion degree during gait were noted, mostly at 24 weeks. Trial registration: ClinicalTrials.gov, NCT04011267. Registered on 8 July 2019.

Aims/hypothesis Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. Methods This study included adults (aged 20–86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. Results Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: −0.26 ± 0.64 vs −0.17 ± 0.62, p =0.44; GSRS: −0.35 ± 0.62 vs −0.32 ± 0.59, p =0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: −0.47 ± 0.78 vs −0.33 ± 0.75, p =0.34; GSRS: −0.46 ± 0.90 vs −0.35 ± 0.79, p =0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs −19 min, p =0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p >0.05). The tVNS was well-tolerated. Conclusions/interpretation Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. Trial registration ClinicalTrials.gov NCT04143269 Funding The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045) Graphical Abstract

Aims/hypothesisThe aim of this study was to test the effectiveness of a structured strength and balance training intervention in improving health-related quality of life (HRQoL) and functional status in individuals with diabetic peripheral neuropathy (DPN).MethodsThe study was a single-blind parallel-group randomised controlled trial comparing 2 months of once-weekly home-based strength and balance training against standard medical therapy. Participants were patients with physician-diagnosed type 2 diabetes and neuropathy recruited from five public sector institutions in Singapore between July 2014 and October 2017. Participants were block-randomised to intervention or control arms. Outcomes were assessed at baseline, 2 months and 6 months by a trained assessor blinded to group assignment. Primary outcomes were change in physical component summary (PCS) score of SF-36v2 (a 36-item generic HRQoL instrument that has been validated for use in Singapore) and EQ-5D-5L index score (derived from a five-item generic HRQoL instrument [EQ-5D-5L]) over 6 months. Secondary outcomes were change in functional status (timed up-and-go [TUG], five times sit-to-stand [FTSTS], functional reach, static balance, ankle muscle strength and knee range of motion) and balance confidence over 6 months. Mean differences in scores between groups were compared using mixed models.ResultsOf the 143 participants randomised (intervention, n = 70; control, n = 73), 67 participants were included in each arm for the final intention-to-treat analysis. The two groups were similar, except in terms of sex. There were no significant differences between groups on the primary outcomes of PCS score (mean difference [MD] 1.56 [95% CI −1.75, 4.87]; p = 0.355) and EQ-5D-5L index score (MD 0.02 [95% CI −0.01, 0.06]; p = 0.175). There were significant improvements in TUG test performance (MD −1.14 [95% CI −2.18, −0.1] s; p = 0.032), FTSTS test performance (MD −1.31 [95% CI −2.12, −0.51] s; p = 0.001), ankle muscle strength (MD 4.18 [95% CI 0.4, 7.92] N; p = 0.031), knee range of motion (MD 6.82 [95% CI 2.87, 10.78]°; p = 0.001) and balance confidence score (MD 6.17 [95% CI 1.89, 10.44]; p = 0.005). No adverse events due to study participation or study intervention were reported.Conclusions/interpretationShort-term structured strength and balance training did not influence HRQoL but produced sustained improvements in functional status and balance confidence at 6 months. More intensive interventions may be needed to influence HRQoL in these individuals. However, this intervention may be a useful treatment option for individuals with DPN to reduce the risk of falls and injuries.Trial registrationClinicalTrials.gov NCT02115932FundingThis work was supported by the National Medical Research Council, Singapore.

Elevated Triglycerides Correlate With Progression of Diabetic Neuropathy Timothy D. Wiggin 1 , Kelli A. Sullivan 1 , Rodica Pop-Busui 2 , Antonino Amato 3 , Anders A.F. Sima 4 and Eva L. Feldman 1 1 Department of Neurology, University of Michigan, Ann Arbor, Michigan; 2 Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan; 3 Sigma-Tau Research, Sigma-Tau Pharmaceuticals, Gaithersburg, Maryland; 4 Departments of Pathology and Neurology, Wayne State University, Detroit, Michigan. Corresponding author: Eva L. Feldman, efeldman{at}umich.edu . T.D.W. and K.A.S. are both first authors and contributed equally to this article. Abstract OBJECTIVE To evaluate mechanisms underlying diabetic neuropathy progression using indexes of sural nerve morphometry obtained from two identical randomized, placebo-controlled clinical trials. RESEARCH DESIGN AND METHODS Sural nerve myelinated fiber density (MFD), nerve conduction velocities (NCVs), vibration perception thresholds, clinical symptom scores, and a visual analog scale for pain were analyzed in participants with diabetic neuropathy. A loss of ≥500 fibers/mm 2 in sural nerve MFD over 52 weeks was defined as progressing diabetic neuropathy, and a MFD loss of ≤100 fibers/mm 2 during the same time interval as nonprogressing diabetic neuropathy. The progressing and nonprogressing cohorts were matched for baseline characteristics using an O'Brien rank-sum and baseline MFD. RESULTS At 52 weeks, the progressing cohort demonstrated a 25% decrease ( P < 0.0001) from baseline in MFD, while the nonprogressing cohort remained unchanged. MFD was not affected by active drug treatment ( P = 0.87), diabetes duration ( P = 0.48), age ( P = 0.11), or BMI ( P = 0.30). Among all variables tested, elevated triglycerides and decreased peroneal motor NCV at baseline significantly correlated with loss of MFD at 52 weeks ( P = 0.04). CONCLUSIONS In this cohort of participants with mild to moderate diabetic neuropathy, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control, or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of diabetic neuropathy. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received December 19, 2008. Accepted April 6, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

Abstract Objective To evaluate the clinical effect of perineural platelet-rich plasma (PRP) injection for pain and numbness alleviation in diabetic peripheral neuropathy (DPN). Study Design A randomized prospective clinical trial. Setting Pain clinic and Rheumatology and Rehabilitation Departments, Assiut University Hospital. Methods Sixty adult patients with type II DM accompanied by DPN of at least six months’ duration were assessed by modified Toronto Clinical Neuropathy Score (mTCNS) and randomly allocated into two groups. Group I underwent ultrasound-guided perineural PRP injection and medical treatment, and Group II received medical treatment only. Patients were followed up at months 1, 3, and 6 with regard to pain and numbness visual analog scale (VAS) and mTCNS scores. Results Significant improvement was recorded in pain and numbness VAS scale scores in group I vs group II (P ≤ 0.001 during the whole study period for both parameters); at the same time, mTCNS improved in group I in comparison with group II with P = 0.01, 0.001, and <0.001 at months 1, 3, and 6, respectively. Conclusions Perineural PRP injection is an effective therapy for alleviation of diabetic neuropathy pain and numbness and enhancement of peripheral nerve function.

Diabetic polyneuropathy (DPN) is a notable microvascular complication of DM, affecting 16%-66% globally. DPN often leads to proprioceptive deficits in the lower limbs (LL), leading to impaired functional performance. However, evidence supporting proprioceptive rehabilitation programs (PRP) for DPN remains scarce. This pilot study aims to evaluate the effectiveness of a novel 12-week PRP on LL static and dynamic proprioception and shed light on the potential benefits of PRP for DPN population. Randomized Controlled Trail was conducted among 30 DPN patients (age 53.25±7.72 years, BMI 24.01±1.41 and DM duration 9.48±6.45 years), randomly allocated to intervention (n = 15) or control (n = 15) groups. The intervention group received PRP 3 times/week for 12 weeks. The control group received no exercise. Both groups received regular diabetic care. Static and dynamic proprioception of both LL were assessed at baseline, 6 weeks and 12 weeks. Position-reposition test was used to assess ankle joint position sense by obtaining difference between target and reproduced angles. Error in detecting knee angle and speed were obtained by performing Lower Limb Matching and Sense of Movement tests respectively to assess dynamic proprioception. Two-way ANOVA and paired comparisons revealed, no significant improvement in proprioceptive deficits at 6 weeks (p>0.05), but significant improvement was achieved at 12-weeks (p<0.05) in the intervention group. Mean errors in Pposition re-position(R:p<0.001, L;p<0.001) and Lower limb matching (R:p<0.001, L;p<0.001) tests reduced by 5° and 10° respectively, indicating a70% improvement in the intervention group. Error of detecting speed reduced only on right side by 0.041ms-1 accounting for a 42% improvement. No improvements were observed in the control group. Novel 12-week PRP may yield a significant reduction in LL proprioceptive deficits among DPN patients. Future RCTs with larger samples should compare the effectiveness of this PRP compared with conventional rehabilitation programs.

Aim: To investigate the efficacy of Superoxide Dismutase, Alpha Lipoic Acid, Acetyl L-Carnitine, and Vitamin B12 (B12) in one tablet in Diabetic Neuropathy (DN). Patients–methods: In this prospective, double-blind, placebo-controlled study, 85 patients with Diabetes Mellitus Type 2 (DMT2) were randomly assigned, either to receive the combination of four elements (active group, n = 43), or placebo (n = 42) for 12 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured the vibration perception threshold (BIO), and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Pain (PS) and quality of life (QL) questionnaires were administered. Results: At follow-up, BIO, MNSIQ, QL, PAIN, and SNCV, SNAP, and B12 levels had significantly improved inactive group (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.027, p = 0.031, and p < 0.001 respectively), whereas the inplacebo group MCR (mean circular resultant) and PAIN deteriorated (p < 0.001, p < 0.001). The changes in MNSIQ, QL, SNCV, BIO, and PAIN differed significantly between groups (p < 0.001, p < 0.001, p = 0.031, p < 0.001, and p < 0.001 respectively). Conclusions: The combination of the four elements in one tablet for 12 months in patients with DMT2 improved all indices of peripheral neuropathy, including SNAP and SNCV, pain, and Quality of Life perception, except CARTs and MNSIE.

Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP. This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period. All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group. There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.