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Aims: Podiatrists constitute a key member of a multidisciplinary foot care team, but their services remain underutilized. We sought to gain insights into the daily practice of podiatrists focusing on screening for and monitoring of diabetic sensorimotor polyneuropathy (DSPN) as well as foot management., Methods: This cross-sectional survey included 125 podiatrists from 12 federal states across Germany who responded to an online questionnaire., Results: The majority of patients treated in podiatry practices were referred by general practitioners and diabetologists. Screening for or follow-up of DSPN was performed by 36% of the respondents at least once a year, by 28% only at initial examination, by 21% only at suspicion, and by 10% basically at each treatment visit. Instruments to assess vibration, touch/pressure, and temperature sensation were used by 81% to 94% of the podiatrists. Previously undiagnosed DSPN and foot ulcers were detected frequently/very frequently (≥6 cases/mo) by 24.0 and 18.4% of the podiatrists, respectively. Almost all podiatrists advised daily self-monitoring of feet and appropriate foot care and >50% gave advice on medical treatment., Conclusions: Podiatrists play an important role in the detection, monitoring, and management of both DSPN and diabetic foot ulcers, suggesting that the utilization of their services should be fostered., Competing Interests: Disclosure D.Z., R.L., Kh.R, K.R., and O.S. are advisory board members of the National Education Initiative (NAI) and received honoraria for speaking activities from Wörwag Pharma. D.Z. received research grants from Wörwag Pharma. R.La. is also an advisory board member of the NAI and received a grant for prevention activities for the German Diabetes Foundation., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.

Objective: Previous observational studies have suggested an association between gut microbiota and diabetic neuropathy (DN). However, confounding factors and reverse causality make the causal relationship between gut microbiota and DN uncertain. We aimed to investigate the interactive causal relationships between the abundance of gut microbiota and DN., Methods: We conducted a Mendelian randomization (MR) analysis to examine the causal relationship between gut microbiota and DN. Genomic data on gut microbiota at the genus level were obtained from the MiBioGen Consortium, including 18,340 individuals of European descent. Data on diabetic polyneuropathy (DPN) were obtained from the FinnGen Consortium, which included 1,048 cases and 374,434 controls, while data on diabetic autonomic neuropathy (DAN) were also obtained from the FinnGen Consortium, including 111 cases and 374,434 controls. Causal effects were primarily estimated using inverse variance weighted (IVW) analysis, supplemented with four validation methods, and additional sensitivity analyses to assess the pleiotropy, heterogeneity, and robustness of instrumental variables., Results: The IVW analysis indicated that Prevotella 9 had a protective effect on DPN (OR = 0.715, 95% CI: 0.521-0.982, P = 0.038), and Bacteroides also showed a protective effect (OR = 0.602, 95% CI: 0.364-0.996, P = 0.048). On the other hand, Ruminococcus 2 had a promoting effect on DPN (OR = 1.449, 95% CI: 1.008-2.083, P = 0.045). Blautia (OR = 0.161, 95% CI: 0.035-0.733, P = 0.018), Clostridium innocuum group (OR = 3.033, 95% CI: 1.379-6.672, P = 0.006), and Howardella (OR = 2.595, 95% CI: 1.074-6.269, P = 0.034) were causally associated with DAN in the IVW analysis, with no evidence of heterogeneity or pleiotropy. Sensitivity analyses showed no significant pleiotropy or heterogeneity., Conclusion: Our study identified a causal relationship between gut microbiota and the increased or decreased risk of diabetic neuropathy. These findings underscore the importance of adopting a comprehensive approach that combines gut microbiota modulation with other therapeutic interventions in the management of diabetic neuropathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Hao, Qi, Wu, Li, Yang, Zhang and Liu.)

Aims: We recently reported that genetic variability in the TKT gene encoding transketolase, a key enzyme in the pentose phosphate pathway, is associated with measures of diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. Here, we aimed to substantiate these findings in a population-based KORA F4 study., Materials and Methods: In this cross-sectional study, we assessed seven single nucleotide polymorphisms (SNPs) in the transketolase gene in 952 participants from the KORA F4 study with normal glucose tolerance (NGT; n = 394), prediabetes (n = 411), and type 2 diabetes (n = 147). DSPN was defined by the examination part of the Michigan Neuropathy Screening Instrument (MNSI) using the original MNSI > 2 cut-off and two alternative versions extended by touch/pressure perception (TPP) (MNSI > 3) and by TPP plus cold perception (MNSI > 4)., Results: After adjustment for sex, age, BMI, and HbA1c, in type 2 diabetes participants, four out of seven transketolase SNPs were associated with DSPN for all three MNSI versions (all p ≤ 0.004). The odds ratios of these associations increased with extending the MNSI score, for example, OR (95% CI) for SNP rs62255988 with MNSI > 2: 1.99 (1.16-3.41), MNSI > 3: 2.27 (1.26-4.09), and MNSI > 4: 4.78 (2.22-10.26); SNP rs9284890 with MNSI > 2: 2.43 (1.42-4.16), MNSI > 3: 3.46 (1.82-6.59), and MNSI > 4: 4.75 (2.15-10.51). In contrast, no associations were found between transketolase SNPs and the three MNSI versions in the NGT and prediabetes groups., Conclusions: The link of genetic variation in transketolase enzyme to diabetic polyneuropathy corroborated at the population level strengthens the concept suggesting an important role of pathways metabolising glycolytic intermediates in the evolution of diabetic polyneuropathy., (© 2024 The Author(s). Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Purpose: The aim of this systematic review is to evaluate the usefulness of sural nerve ultrasonography in diagnosing diabetes mellitus (DM) and diabetic polyneuropathy (DPN), the latter of which is a common long-term complication for diabetic patients that frequently involves the sural nerve., Methodology: A meta-analysis of the cross-sectional areas (CSAs) of sural nerves in healthy individuals and patients with diabetes mellitus based on a total of 32 ultrasonographic-based studies from 2015 to 2023 was performed. Sub-analyses were performed for factors such as geographical location and measurement site., Results: The meta-analysis showed that the mean CSA of the sural nerve was significantly larger in DM patients with DPN only compared to healthy individuals across all regions and when pooled together. An age-dependent increase in the CSA of healthy sural nerves is apparent when comparing the paediatric population with adults., Conclusion: Sural nerve ultrasonography can distinguish diabetic adults with DPN from healthy adults based on cross-sectional area measurement. Future studies are needed to clarify the relationships between other parameters, such as body metrics and age, with sural nerve CSAs. Cut-offs for DPN likely need to be specific for different geographical regions., (© 2024. The Author(s).)

Background: In patients with diabetic polyneuropathy (DPN), differences in postural control due to losing the lower limb somatosensory information were reported. However, it is still unclear by which mechanisms the dynamic postural instability is caused., Objectives: This study aimed to investigate postural control differences and neuromuscular adaptations resulting from foot somatosensory loss due to DPN., Methods: In this controlled cross-sectional study, fourteen DPN patients and fourteen healthy controls performed the Functional Reach Test (FRT) as a dynamic task. The postural control metrics were simultaneously measured using force plate, motion capture system, and surface electromyography (sEMG). The main metrics including reach length (FR), FR to height ratio (FR/H), displacement of CoM and CoP, moment arm (MA), and arch height ratio. Also, kinematic (range of motion of ankle, knee, and hip joints), and sEMG metrics (latencies and root mean square amplitudes of ankle and hallux muscles) were measured. To compare variables between groups, the independent sample T-test for (normally distributed) and the Mann-Whitney U test (non-normally distributed) were used., Results: The subjects' reach length (FR), FR to height ratio, absolute MA, and displacement of CoM were significantly shorter than controls, while displacement of CoP was not significant. Arch height ratio was found significantly lower in DPN patients. We observed that CoM was lagging CoP in patients (MA = + 0.89) while leading in controls (MA = -1.60). Although, the muscles of patients showed significantly earlier activation, root mean square sEMG amplitudes were found similar. Also, DPN patients showed significantly less hip flexion, knee extension, and ankle plantar flexion., Conclusions: This study presented that decreasing range of motion at lower limbs' joints and deterioration in foot function caused poor performance at motor execution during FRT in DPN patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To assess the role of serum neurofilament light chain (NfL) levels in individuals with diabetic polyneuropathy (DPN) compared with controls, as well as to highlight the different sonographic changes in DPN and determine if NfL correlates with sonographic, clinical, and functional parameters., Methods: Diabetic individuals with signs or symptoms consistent with peripheral nerve involvement were recruited. They were evaluated by examination, functional neuropathy severity scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was performed of the bilateral median, ulnar, tibial, fibular, sural, and vagus nerves, and cervical roots 5 and 6. Results were compared with age, sex, and body mass index matched healthy controls., Results: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with diabetes with a mean and standard deviation of 6.95 ± 2.95 pg/mL in the diabetic group and 2.83 ± 0.77 pg/mL in controls (P < .001). Nerve cross-sectional area and serum NfL levels correlated significantly with clinical and functional parameters and with each other (P < .05)., Conclusion: Individuals with DPN have significantly higher NfL levels than healthy controls, and NfL levels correlate with ultrasonographic parameters. These findings may be useful for the diagnosis, prognosis, and disease monitoring of those with DPN, though further exploration is needed., (© 2023 American Institute of Ultrasound in Medicine.)

This study aimed to determine the efficacy of assessing the severity of diabetic polyneuropathy (DPN) in patients with untreated diabetes. Seventy-two patients with untreated type 2 diabetes who were hospitalized for glycemic control were enrolled and divided into the following two groups: patients who had no prior diagnosis and patients who were unattended or had discontinued treatment. Electrophysiological criteria consistent with Baba's classification were used to diagnose and assess the severity of DPN. The patients were divided into three subgroups: no DPN (stage 0), mild DPN (stage 1), and moderate or more-severe DPN (stages 2-4). Intergroup comparisons were performed for the clinical characteristics and the results of the nerve conduction studies. Twenty-two (30%), 25 (35%), and 25 (35%) patients were categorized into the no DPN, mild DPN, and moderate or more-severe DPN subgroups, respectively. The number of patients who were unattended or had discontinued treatment in the moderate or more-severe DPN subgroup was significantly higher than that in the no DPN subgroup. The patients in the moderate or more-severe DPN subgroup had an increased risk of developing diabetic retinopathy and nephropathy, with odds ratios of 19.5 and 11.0 for advanced stages of retinopathy and nephropathy, respectively. Thus, the assessment of the severity of DPN could aid in the prediction of the risk of developing diabetic complications in patients with untreated diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Horinouchi, Deguchi, Mukai, Ijuin, Kawamoto and Nishio.)

Objective: To determine the prevalence of insomnia and the effectiveness of its treatment in patients with a painful form of diabetic polyneuropathy (DPN)., Material and Methods: Fifty patients with the painful form of DPN were randomly divided into 2 groups: the standard therapy group (ST) and the extended therapy group (ET). In the ST group, a single lesson on sleep hygiene was conducted, in the ET group there were 3-4 face-to-face individual sessions for the treatment of insomnia for two weeks. Both groups were interviewed at the time of hospitalization, after 3 and 6 months. The severity of polyneuropathy and the nature of neuropathic pain were assessed using the Neuropathic Neuropathy Impairment Score in the Lower Limbs (NIS-LL) and the Neuropathy Total Symptom Score - 9 (NTSS-9); the intensity of pain was assessed using a Visual Analog Scale (VAS). Sleep disorders were analyzed using the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI)., Results: Sleep disorders of varying severity were observed in 82% of patients in the initial survey. In both groups, improvement in sleep quality was noted during treatment, but significantly better results were in the ET group, the ISI score after 6 months was 7.15±2.08 for the ST group and 3.07±2.49 for the ET group ( p <0.0001). In the ST group, there was no significant decrease in the intensity of pain and the severity of polyneuropathy in dynamics. In the ET group, a significant decrease in NTSS-9 and VAS scores was found during the initial survey and after 6 months ( p <0.0001). The intensity of pain also significantly decreased in the ET group compared with the ST group ( p <0.0001) at the end of follow-up, which indicates the importance of sleep normalization in the treatment of neuropathic pain., Conclusion: Most patients with the painful form of DPN have insomnia. Treatment of insomnia has shown its effectiveness as part of a multimodal approach to the managing of neuropathic pain in DPN and improving the quality of life of patients.

Diabetic peripheral neuropathy (DPN) is found in around one third of people with diabetes, but remains inadequately diagnosed and treated. Its management includes three cornerstones: 1) causal treatment with lifestyle modification, intensive diabetes therapy aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, 2) pathogenesis-oriented pharmacotherapy, and 3) symptomatic pain relief. Since symptomatic analgesic monotherapy only relieves the pain without targeting the underlying neuropathy and both has limited efficacy and is associated with adverse events, there is an unmet need for additional approaches derived from the pathogenetic concepts of DPN. Preclinical studies have suggested that diabetic neuropathy can be prevented or improved through the use of various agents that interfere with the pathophysiology of the underlying condition. Some of these encouraging findings could be translated successfully into the clinical setting. Efficacy and excellent safety were demonstrated in several meta-analyses (α-lipoic acid) and randomized clinical trials (benfotiamine, actovegin, epalrestat) in the treatment of symptomatic DPN. The NATHAN 1 trial demonstrated an improvement of neuropathic signs (deficits, impairments) after four years in asymptomatic DPN. These compounds are currently authorized for treatment of DPN in several countries. Long-term pivotal clinical trials should further establish their value as mono- and combination therapies in DPN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dan Ziegler has been consultant for Biogen, Mitsubishi Tanabe, Wörwag, Pfizer, Allergan, Berlin-Chemie, Viatris, Novartis, Novaremed, Takeda, Mundipharma, Bayer, Grünenthal, Nevro, Procter & Gamble, Clexio, Pathways Public Health, Cannaxan, Stada, GSK; Speaker: Wörwag, Pfizer, Takeda, AstraZeneca, Viatris, Berlin-Chemie, Mundipharma, Sanofi, Eva; Research support: Wörwag, Mitsubishi Tanabe, Novartis]., (Copyright © 2023. Published by Elsevier B.V.)

Aims/hypothesis: Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes., Methods: Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres., Results: There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures., Conclusions/interpretation: Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes., (© 2023. The Author(s).)

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., Competing Interests: The authors declare there are no competing interests., (©2023 Jørgensen et al.)

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder that results from complex interactions of both environmental and genetic factors. Many single nucleotide polymorphisms (SNPs), including noncoding RNA genes, have been investigated for their association with susceptibility to T2DM and its complications, with little evidence available regarding Caucasians. The aim of the present study was to establish whether four miRNA SNPs (miR-27a rs895819 T>C, miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, and miR-499a rs3746444 A>G) are correlated with susceptibility to T2DM and/or diabetic polyneuropathy (DPN) in a Romanian population. A total of 167 adult T2DM patients and 324 age- and sex-matched healthy controls were included in our study. miRNA SNPs were detected by real-time PCR using a TaqMan genotyping assay. A significant association with T2DM was observed only for the miR-499a rs3746444 A>G SNP in all the tested models, and the frequencies of both the miR-499a rs3746444 AG and the GG genotypes were higher in the T2DM patients compared to the controls. No correlation was observed for the miR-27a rs895819 T>C, miR-146a rs2910164 G>C, or miR-196a2 rs11614913 C>T SNPs in any genetic model. When we assessed the association of these SNPs with DPN separately, we found a positive association for the miR-499a rs3746444 SNP in both codominant and dominant models (OR 6.47, 95% CI: 1.71-24.47; OR 2.30, 95% CI: 1.23-4.29, respectively). In conclusion, this study shows that miR-499a rs3746444 A>G may influence both T2DM and DPN susceptibility, with carriers of the GG genotype and the G allele being at an increased risk in the Romanian population.

Aims: We assessed the health data of 11,047 people with diabetes in the UK Biobank to rank 329 risk factors for diabetic polyneuropathy (DPN) and DPN with chronic neuropathic pain without a priori assumption., Methods: The Integrated Disease Explanation and Risk Scoring (IDEARS) platform applies machine learning algorithms to multimodal data to determine individual disease risk, and rank risk factor importance using mean SHapley Additive exPlanations (SHAP) score., Results: IDEARS models showed discriminative performances with AUC > 0.64. Lower socioeconomic status, being overweight, poor overall health, cystatin C, HbA1C, and immune activation marker, C-reactive protein (CRP), predict DPN risk. Neutrophils and monocytes were higher in males and lymphocytes lower in females with diabetes that develop DPN. Neutrophil-to-Lymphocyte Ratio (NLR) was increased and IGF-1 levels decreased in people with type 2 diabetes that later develop DPN. CRP was significantly elevated in those with DPN and chronic neuropathic pain compared to DPN without pain., Conclusions: Lifestyle factors and blood biomarkers predict the later development of DPN and may relate to DPN pathomechanisms. Our results are consistent with DPN as a disease involving systemic inflammation. We advocate for the use of these biomarkers clinically to predict future DPN risk and improve early diagnosis., Competing Interests: Declaration of Competing Interest PJA, JFK and JAO declare that they have no known financial interests or personal relationships that could have appeared to influence the work reported in this paper. BG is a director of Pacific Analytics PTY LTD & SMRTR PTY LTD, Australia; a founding member of the International Cerebral Palsy Genetics Consortium, and a member of the Australian Genomics Health Alliance, MA is a director of Allwright Analytics PTY LTD., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Diabetic polyneuropathy (DPN) is the most common type of diabetic neuropathy, rendering a slowly progressive, symmetrical, and length-dependent dying-back axonopathy with preferential sensory involvement. Although the pathogenesis of DPN is complex, this review emphasizes the concept that hyperglycemia and metabolic stressors directly target sensory neurons in the dorsal root ganglia (DRG), leading to distal axonal degeneration. In this context, we discuss the role for DRG-targeting gene delivery, specifically oligonucleotide therapeutics for DPN. Molecules including insulin, GLP-1, PTEN, HSP27, RAGE, CWC22, and DUSP1 that impact neurotrophic signal transduction (for example, phosphatidylinositol-3 kinase/phosphorylated protein kinase B [PI3/pAkt] signaling) and other cellular networks may promote regeneration. Regenerative strategies may be essential in maintaining axon integrity during ongoing degeneration in diabetes mellitus (DM). We discuss specific new findings that relate to sensory neuron function in DM associated with abnormal dynamics of nuclear bodies such as Cajal bodies and nuclear speckles in which mRNA transcription and post-transcriptional processing occur. Manipulating noncoding RNAs such as microRNA and long-noncoding RNA (specifically MALAT1 ) that regulate gene expression through post-transcriptional modification are interesting avenues to consider in supporting neurons during DM. Finally, we present therapeutic possibilities around the use of a novel DNA/RNA heteroduplex oligonucleotide that provides more efficient gene knockdown in DRG than the single-stranded antisense oligonucleotide.

Objective: The purpose of the present double-blind, placebo-controlled, randomized clinical trial was to evaluate the efficacy and safety of Cytoflavin in patients with diabetic polyneuropathy (DPN)., Material and Methods: Investigational therapy was administered in two steps: intravenous infusions of experimental drug/placebo for 10 days followed by oral administration for 75 days. In 10 clinical centers, 216 patients aged 45-74 years with a diagnosis of type 2 diabetes mellitus, symptomatic distal sensorimotor DPN, confirmed no earlier than 1 year before screening, on stable therapy (no change of drugs and doses) by oral hypoglycemic drugs, intermediate-acting, long-acting or extra-long-acting insulin, and/or GLP-1 receptor agonists., Results: By the end of treatment, the change of the Total Symptom Score (TSS) in the experimental group was -2.65 points, in the placebo group -1.73 points ( p <0.001). Improvement of symptoms in the experimental group was achieved regardless of the degree of compensation for type 2 diabetes (both in those with Hb1Ac <8.0% and in those with Hb1Ac ≥8.0%), but demonstrated better results in patients with less severe baseline symptoms (TSS <7.5). Improvement in the components of the TSS scale «paresthesia» and «numbness» occurred as early as on day 11 of therapy; by the end of treatment, a significant decrease in the «burning» component was also demonstrated. The experimental drug had a positive safety profile., Conclusion: Cytoflavin, intravenous solution and enteric-coated tablets (SPTF Polysan Ltd.) is indicated for the symptomatic treatment of DPN.

Objective: To study the effect of the combined drug Cytoflavin on the mechanisms of nonspecific inflammation in the treatment of diabetic polyneuropathy (DPN) with an assessment of the dynamics of the TNF-α index., Material and Methods: An open comparative prospective observation of patients with a history of DPN for more than 5 years and a high level of TNF-α was carried out. All patients underwent basic oral combined hypoglycemic therapy, the main group used the combined drug Cytoflavin 10 ml (per 200 ml 0.9% NaCl) for 10 days, followed by the transition to the enteral form of the drug, 2 tablets 2 times a day for 1 months The main indication for the appointment of Cytoflavin was the presence of comorbid pathology in the form of cerebrovascular disease in all studied patients. The severity of clinical symptoms of DPN, the quality of life (QOL) of patients, as well as the dynamics of the level of TNF-α as an indicator reflecting the process of inflammation were assessed., Results: As a result of the treatment in the study group, there was an improvement in QoL, a decrease in the severity of sensory complaints and a decrease in the level of TNF-α, which may indicate a possible anti-inflammatory mechanism of the combined drug Cytoflavin., Conclusion: Cytoflavin can inhibit inflammation and reduce the severity of sensitive disorders in patients with DPN.

The aim of this study was to assess vitamin D status in patients with type 2 diabetes and diabetic foot ulcers (DFU). A total of 242 participants with type 2 diabetes, mean age 59.1 ± 10 years, mean body mass index 31.4 ± 6.3 kg/m 2 , and estimated glomerular filtration rate ≥45 mL/min/1.73m 2 , were divided into 2 groups: 73 with DFU (35 with and 38 without active infection) and 169 without DFU (106 with diabetic peripheral neuropathy, 63 without complications). Neuropathy was assessed by 10 g monofilament, Rydel-Seiffer 128 Hz tuning fork, and temperature discrimination. Serum 25(OH)D (25-hydroxy vitamin D) was assessed by ECLIA (electro-chemiluminescence immunoassay) method. Median 25(OH)D level was 12.6 ng/mL (IQR [interquartile range] 9.3-17.6 ng/mL) in the studied cohort. The DFU group presented with lower 25(OH)D level as compared with diabetic patients without foot ulcers (non-DFU group): 11.6 ng/mL (IQR 8.5-15.8 ng/mL) versus 13.5 ng/mL (IQR 9.6-18.6 ng/mL), P = .001; the diabetic peripheral neuropathy subgroup demonstrated lower 25(OH)D level in comparison with participants without complications: 12.5 ng/mL (IQR 9-17.2 ng/mL) versus 15.9 ng/mL (IQR 10.4-20.8 ng/mL), P = .031. This remained significantly different even after correction for age and duration of diabetes. There was no difference in 25(OH)D level between the subgroups according to the presence of active infection. In conclusion, vitamin D deficiency may play a role in the development of diabetes complications.

Aims: We sought to obtain detailed information on the procedures and appraisal of screening for and diagnosing diabetic sensorimotor polyneuropathy (DSPN) in clinical practice., Methods: This cross-sectional survey included 574 physicians from 13 federal states across Germany who responded to a tripartite questionnaire., Results: The vast majority of the respondents reported to screen for DSPN at least once a year (87 %), while 65 % reported to examine the feet of DSPN patients at least twice a year. However, only 28 % and 20 % of the respondents used questionnaires and scores to assess the severity of neuropathic symptoms and signs, respectively. The rates of participants reporting that they do not use a standardized testing procedure were 58 % for pressure sensation, 62 % for pain sensation, and 54 % for thermal sensation. The rates of respondents reporting that they do not deploy a standardized assessment were 41 % for vibration sensation, 73 % for pressure sensation, 77 % for pain sensation, and 66 % for thermal sensation. Half of the physicians oriented themselves towards clinical guidelines when diagnosing DSPN., Conclusions: Despite relatively high screening rates, the willingness to implement both standardized testing procedures and assessment and to follow guidelines is low among physicians when screening for and clinically diagnosing DSPN., Competing Interests: Conflict of Interest DZ, RL, KhR, KR, and OS are advisory board members of the National Education Initiative and received honoraria for speaking activities from Wörwag Pharma. DZ and AS received research grants from Wörwag Pharma. RLa received a grant for prevention activities for the German Diabetes Foundation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Small fibre neuropathy (SFN) is an initial pathology of diabetic polyneuropathy (DPN). Serum lipopolysaccharide binding protein levels are positively correlated with the pain threshold in the foot, suggesting that the abundance of gut Gram-negative bacilli, which are a source of lipopolysaccharides, may be involved in the development of DPN. Furthermore, the abundance of the gut and oral microbiota is assumed to be involved in the pathogenesis of diabetes. Nevertheless, the association between SFN and the microbiota has not been clarified. A total of 1056 individuals were recruited in the 2018 Iwaki Health Promotion Project. Pain sensation was evaluated based on the pain threshold from intraepidermal electrical stimulation (PINT). Patients with PINT scores <0.15 mA were categorized into the low-PINT group (n = 718); otherwise, they were categorized into the high-PINT group (n = 283). Furthermore, each group was divided into the subjects with or without glucose tolerance based on HbA1c levels, fasting blood glucose levels and diabetic history. Principal coordinate analysis and α- and β-diversity of the microbiota were evaluated. The correlation between clinical and microbiota data was examined. Oral microbiota diversity showed no structural differences according to PINT scores, whereas principal coordinate analysis and α- and β-diversity revealed significant structural differences in gut microbiota (p < 0.01, p < 0.05 and p < 0.05, respectively), even after the participants with glucose intolerance were excluded (p < 0.01, p < 0.05 and p < 0.05, respectively). The relative abundance of the genus Bacteroides was significantly lower in high-PINT participants compared with low-PINT participants (10 ± 6.7% vs. 11.3 ± 7.0%, p < 0.01), even after the exclusion of subjects with diabetes and impaired fasting glucose (10.0 ± 6.5% vs. 11.2 ± 6.9%, p < 0.05). In univariate linear regression analyses, PINT was significantly correlated with metabolic syndrome parameters, eGFR, uric acid level and the abundance of Bacteroides. The correlation between Bacteroides and PINT scores remained significant after adjustment for multiple factors (β = -0.07181, p < 0.05). Changes of bacterial diversity and a low abundance of gut Bacteroides were correlated with elevated PINT scores in the Japanese population. This correlation may represent a new therapeutic option for SFN., (Copyright © 2022. Published by Elsevier Inc.)

Background and Purpose: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL-N), whereas the impact of upper limb neuropathy (UL-N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL-N and its functional and psychosocial consequences in type 2 diabetes., Methods: Individuals with type 2 diabetes (n = 141) and an age- and sex-matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status., Results: The prevalence of UL-N was 30.5% in patients with diabetes and that of LL-N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL-N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL-N had reduced estimates of psychosocial health including health-related QoL compared to control subjects and patients without UL-N. UL-N correlated with the severity of LL-N, but not with duration of diabetes, glycemia, age, or sex., Conclusions: This study points to a substantial prevalence of UL-N in type 2 diabetes. The sensory phenotype of patients with UL-N was similar to LL-N and was characterized by loss of sensory function. Our study demonstrated an association of UL-N with impaired manual dexterity and reduced health-related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Specialized cutaneous Schwann cells (SCs), termed nociceptive SCs, were recently discovered. Their function is not fully understood, but they are believed not only to support peripheral axons in mouse skin by forming a mesh-like neural-glio networking structure in subepidermal area, but also contributing to transduction of mechanical sensation and neuropathic pain. Diabetic neuropathy (DPN) is one of the most common complication of diabetes, however, the mechanisms behind painful and painless DPN remain unclear. Using a mouse model of DPN, we want to investigate if there are quantitative differences in nociceptive SC density between the condition of hyperglycemia-induced sensory abnormalities and control condition and at which stage in the disease the damage occurs. Here, we developed a set of counting rules for nociceptive SCs based on immunofluorescent staining, and applied the method to quantify the density of nociceptive SCs in control mice (n = 10), mice with nociceptive hypersensitivity at early diabetic stage (n = 5), and mice with sensory hyposensitivity at late diabetic stage (n = 5) in the Streptozotocin (STZ) model of type 1 diabetes. Nociceptive SCs were identified as S100 + /Sox10 + /DAPI + cells abutting to peripheral nerves, with the somas located within 25 µm depth in the subepidermal area and outside glands and large fiber bundles. Hypersensitive diabetic mice had decreased nociceptive SC density, despite having normal epidermal nerve fiber density, compared with age-matched control mice (P = 0.023). In contrast, there was a reduction in intraepidermal nerve fiber density but no difference in nociceptive SC density between hyposensitive diabetic mice and the age-matched control mice. This study provides a detailed description of how to identify and quantify nociceptive SC and demonstrates that nociceptive SC density declines before nerve fiber deterioration, which supports previous observations that nociceptive SCs are critical for maintenance of cutaneous sensory nerves., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite the worldwide prevalence and severe complications of type 2 diabetes mellitus (T2DM), the pathophysiological mechanisms underlying the development of diabetic polyneuropathy (DPN) are poorly understood. Beyond strict control of glucose levels, clinical trials for reversing DPN have largely failed. Therefore, understanding the pathophysiological and molecular mechanisms underlying DPN is crucial. Accordingly, this study explored biochemical and neuropathological deficits in a rat model of T2DM induced through high-fat diet (HFD) feeding along with two low-dose streptozotocin (STZ) injections; the deficits were explored through serum lipid, neurobehavioral, neurophysiology, neuropathology, and immunohistochemistry examinations. Our HFD/STZ protocol induced (1) mechanical hyperalgesia and depression-like behaviors, (2) loss of intraepidermal nerve fibers (IENFs) and reduced axonal diameters in sural nerves, and (3) decreased compound muscle action potential. In addition to hyperglycemia, which was correlated with the degree of mechanical hyperalgesia and loss of IENFs, we observed that hypertriglyceridemia was the most dominant deficit in the lipid profiles of the diabetic rats. In particular, SEPT9, the fourth component of the cytoskeleton, increased in the satellite glial cells (SGCs) of the dorsal root ganglia (DRG) in the T2DM-like rats. The number of SEPT9(+) SGCs/DRG was correlated with serum glucose levels and mechanical thresholds. Our findings indicate the putative molecular mechanism underlying DPN, which presumably involves the interaction of SGCs and DRG neurons; nevertheless, further functional research is warranted to clarify the role of SEPT9 in DPN.

Aims/introduction: This study examined the association between the severity of diabetic polyneuropathy (DPN) based on the Baba classification, and sarcopenia and its related factors., Materials and Methods: The participants were 261 patients with type 2 diabetes mellitus. DPN was classified as stages 0-4 according to the Baba classification. Sarcopenia was diagnosed based on measurements of the skeletal mass index, grip strength and walking speed, using the Asia Working Group for Sarcopenia 2019 diagnostic criteria., Results: The median age of the participants was 67 years, the proportion of men was 58.6%, the median estimated duration of diabetes was 10 years and the median values for glycated hemoglobin were 10.3%. With regard to DPN, the prevalence of Baba classification stages 0-2 was 90.8% (n = 237), and that of stage 3 or 4 was 9.2% (n = 24). The prevalence of sarcopenia was 19.9%. A trend toward an increase in the frequency of slow walking speed was seen as the stage of DPN progressed. The frequencies of sarcopenia and slow walking speed were higher in the group with the Baba classification stages 3 and 4 than in the group with stages 0-2. On multiple logistic regression analyses, however, DPN was not significantly related to sarcopenia and walking speed., Conclusions: Although severe DPN might be related to sarcopenia, the frequency of severe DPN is low in the clinical setting, indicating that its contribution to sarcopenia is modest., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Diabetic sensorimotor polyneuropathy (DSPN) affects around one third of people with diabetes and accounts for considerable morbidity, increased risk of mortality, reduced quality of life, and increased health care costs resulting particularly from neuropathic pain and foot ulcers. Painful DSPN is encountered in 13-26% of diabetes patients, while up to 50% of patients with DSPN may be asymptomatic. Unfortunately, DSPN still remains inadequately diagnosed and treated. Herein we provide international expert consensus recommendations and algorithms for screening, diagnosis, and treatment of DSPN in clinical practice derived from a Delphi process. Typical neuropathic symptoms include pain, paresthesias, and numbness particularly in the feet and calves. Clinical diagnosis of DSPN is based on neuropathic symptoms and signs (deficits). Management of DSPN includes three cornerstones: (1) lifestyle modification, optimal diabetes treatment aimed at near-normoglycemia, and multifactorial cardiovascular risk intervention, (2) pathogenetically oriented pharmacotherapy (e.g. α-lipoic acid and benfotiamine), and (3) symptomatic treatment of neuropathic pain including analgesic pharmacotherapy (antidepressants, anticonvulsants, opioids, capsaicin 8% patch and combinations, if required) and non-pharmacological options. Considering the individual risk profile, pain management should not only aim at pain relief, but also allow for improvement in quality of sleep, functionality, and general quality of life., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetic neuropathy (DN) encompasses a group of clinical or subclinical manifestations involving a dysfunction in the peripheral nervous system. The cause of the dysfunction is the development of microvascular complications related to diabetes, a disease that affects about 381 million people worldwide. Approximately 50% of patients currently diagnosed with diabetes are expected to manifest DN in the next 10 years. The diagnosis can be made clinically by establishing a good patient history and delving into the symptoms to rule out other etiologies. Treatment of DN focuses on glycemic control and the use of medications to reduce pain, including NSAIDs, antidepressants and antiepileptic drugs. The pathogenesis is of multifactorial origin, associated with various metabolic, vascular, inflammatory and neurodegenerative disorders. The three fundamental cellular alterations participating in the development of DN are chronic inflammation, endothelial dysfunction and oxidative stress. Since the combination of all three is capable of giving rise to nerve ischemia and direct axonal injury, these factors play a key role in the development of polyneuropathy. However, neuronal and microvascular changes do not occur in the same way in all patients with DN, some of whom have no detectable blood abnormalities., (Copyright © 2022. Published by Elsevier Inc.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuropathic pain is the most prevalent form of chronic pain caused by a disease of the nervous system, such as diabetic polyneuropathy. ɑ-Lipoic acid (ALA) is an antioxidant that has been widely studied for the treatment of pain symptoms in diverse conditions. Therefore, this study aimed to investigate the efficacy of ALA in the treatment of different types of pain through a systematic review and meta-analysis of randomized clinical trials. The study protocol was registered in the International Prospective Registry of Systematic Reviews (CRD42021261971). A search of the databases resulted in 1154 articles, 16 of which were included in the review (9 studies with diabetic polyneuropathy and 7 studies with other painful conditions). Most of the included studies had a low risk of bias. ALA showed efficacy for the treatment of headache, carpal tunnel syndrome and burning mouth syndrome. Meta-analysis was conducted only with the studies using diabetic polyneuropathy. Compared to placebo, ALA treatment decreased the total symptom score (TSS). The subgroup meta-analysis indicated a decrease of stabbing pain, burning, paraesthesia, and numbness in ALA-treated patients compared to placebo. In addition, both routes of administration, intravenous and oral, demonstrated the efficacy to reduce TSS. Therefore, ALA should be used to treat diabetic polyneuropathy pain symptoms. However, the standardization of treatment time and the dose may advance for the approval of ALA for clinical use in diabetic polyneuroneuropathy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Diabetic peripheral neuropathy (DPN) is one of the most common chronic microvascular complications in type 2 diabetes mellitus (T2DM). Hence, the present study aimed to investigate the association between Serum Uric Acid (SUA) levels and diabetic peripheral polyneuropathy in patients with type 2 diabetes., Methods: We performed this case-control study during 2019-2020 on individuals with diabetes referring to the Razi clinic of Rasht, in the north of Iran. Polyneuropathy in patients was assessed based on the Neuropathy Disability Score (NDS), Diabetic neuropathy symptom score (DNS) scoring system, and electromyography (EMG)/nerve conduction velocity (NCV). The inclusion criterion for the control group was normal EMG/NCV. Then, the patients were assessed for SUA level and also laboratory results., Results: In total, 230 patients with type 2 diabetes were examined. The mean SUA level in the DPN group was significantly higher compared to the control group (6.72 ± 1.75 vs. 4.57 ± 1.49 mg/dL). With increasing the SUA, the odds of developing neuropathy increased by 2.2 times (OR = 2.2). The risk factors for diabetic polyneuropathy included gender (male) (OR = 0.347), SBP (OR = 1.1), retinopathy (OR = 3.29), and microalbuminuria (OR = 4.44). The chance of developing polyneuropathy in patients with retinopathy was 3.3 times higher than in the control group, it was 4.4 times in microalbuminuria patients., Conclusion: Elevated SUA level increased the chance of developing peripheral polyneuropathy in a person with type 2 diabetes. SUA levels higher than 5.25 mg / dL expose a person with type 2 diabetes to developing peripheral polyneuropathy., (© 2022. The Author(s).)

Background: The effect of diabetic polyneuropathy (DPN) and autonomic neuropathy (AN) on bone turnover in type 2 diabetes mellitus (DM) is uncertain due to the lack of data. In this study, we tried to determine the effect of DPN and AN on bone metabolism. Materials and Methods: The study included patients with type 2 DM (aged 18-80 years) and age-matched healthy individuals who presented to the Departments of Metabolism and Diabetes, Geriatrics, and General Internal Medicine, Cerrahpaşa Medical School, Istanbul University. The patients were examined to find out whether they had AN, and neuropathy scores were recorded by exploring peripheral neuropathy. Bone mineral density was measured by dual-energy X-ray (DXA). Demographic characteristics, the presence of microvascular complications, and biochemical data were obtained from patients' files. Serum cross-linked C-telopeptide (Ctx), osteocalcin, and bone-specific alkaline phosphatase (B-ALP) were analyzed. Results: The study comprised a total of 64 patients: 23 had type 2 DM and osteoporosis (OP) (duration of diabetes 10.1 ± 7 years; mean age 63 ± 9.1 years; female/male 18/5; Group 1), 41 had type 2 DM and non-OP (duration of diabetes 10.3 ± 7.6 years; mean age 58 ± 7.4 years; female/male 30/11; Group 2), and 26 healthy volunteers made up the control group (mean age 62 ± 11.9 years; female/male 14/12; Group 3). The bone turnover parameters were lower in type 2 DM individuals. The levels of osteocalcin (13.3 ± 5.2 ng/mL) and B-ALP (44.7 ± 10.9 IU/L) in patients with type 2 DM were lower than those of healthy subjects: osteocalcin (20.6 ± 10 ng/mL) and B-ALP (111 ± 31.4 IU/L; P  = 0.001 and P  = 0.000, respectively). Ctx levels (193.5 ± 49.3; 207.6 ± 40 ng/mL) were recorded to be similar ( P  = 0.2). AN was also noted as a risk factor for OP. For patients without AN, the likelihood of developing OP (odds ratio) was 0.7. The corresponding ratio for patients with AN was 9.3. Conclusions: Among the independent variables, the neuropathy score was determined to have an impact on bone turnover. AN was identified to be a significant risk factor for OP.

Background: Diabetic polyneuropathy (DPN) is the most prevalent consequence of diabetes mellitus, and it has a significant impact on the patient's health. This study aims to evaluate effects of antigravity treadmill training on gait and balance in patients with DPN. Methods: The study included 45 males with type 2 diabetes who were randomly assigned to one of two groups: the experimental group (n=23) or the control group (n=22). For a period of 12 weeks, the experimental group received antigravity treadmill training (75% weight bearing, 30 min per session, three times per week) combined with traditional physical therapy. During the same time period, the control group received only traditional physical therapy. The Biodex Balance System was used to assess postural stability indices, while the GAITRite Walkway System was used to assess spatiotemporal gait parameters. All measurements were obtained before and at the end of the study after 12 weeks of treatment. Results: The mean values of all measured variables improved significantly in both groups (P<0.05), with the experimental group showing significantly greater improvements than the control group. The post-treatment gait parameters ( i.e. , step length, step time, double support time, velocity, and cadence) were 61.3 cm, 0.49 sec, 0.25 sec, 83.09 cm/sec, and 99.78 steps/min as well as 56.14 cm, 0.55 sec, 0.29 sec, 75.73 cm/sec, and 88.14 steps/min for the experimental and control group, respectively. The post-treatment overall stability index was 0.32 and 0.70 for the experimental and control group, respectively. Conclusions: Antigravity treadmill training in combination with traditional physical therapy appears to be superior to traditional physical therapy alone in terms of gait and balance training. As a result, the antigravity treadmill has been found to be an effective device for the rehabilitation of DPN patients., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Abdelaal A and El-Shamy S.)

Objective: The aim: To identify and substantiate the role of comorbidity in the clinical course and quality of life (QOL) of patients with diabetic polyneuropathy (DP)., Patients and Methods: Materials and methods: We examined 139 patients aged from 19 to 69 years with DP occured as a consequence from type I and II diabetes mellitus (DM). The examined persons were divided into two groups: DP due to type I and II DM with comorbidity (group A,n=93) and without comorbidity (group B,n=46). For the patients was done a comprehensive clinical and neurological examination, laboratory, instrumental methods of examination., Results: Results: We observe hypo- or areflexia much more in group A respect to reflexes on the upper and lower extremities than in group B, where the changes are more noticeable on the lower extremities. The level of QOL in group A is significantly lower than in group B. According to the McGill scale in group A, all indicators of pain characteristics are higher. Quite a high score in group A on the Pain Rating Index(PRI) - 32.17±1.57points. The lowest rates of the nerve conduction velocity (NCV) on the motor fibers were registered in group A, on the sensitive fibers of the upper extremities has got lower rates in groups A and B than in the control group, but in group A it is slightly higher., Conclusion: Conclusions: Clinical manifestations of DP in group A are more pronounced than in the comparison group and a wide range of comorbidity was diagnosed, including cardiovascular, which aggravates the manifestations of DP.

Background and Objecti ves : Lifestyle interventions such as exercise prescription and education may play a role in the management of peripheral neuropathy in people with diabetes. The aim of this study was to determine the effect of undertaking an exercise program in comparison with an education program on the signs and symptoms of peripheral neuropathy in people with diabetes at risk of neuropathic foot ulceration. Materials and Methods: Twenty-four adult participants with diabetes and peripheral neuropathy were enrolled in this parallel-group, assessor blinded, randomised clinical trial. Participants were randomly allocated to one of two 8-week lifestyle interventions, exercise or education. The primary outcome measures were the two-part Michigan Neuropathy Screening Instrument (MNSI) and vibratory perception threshold (VPT). Secondary outcome measures included aerobic fitness, balance and lower limb muscular endurance. Results: Participants in both lifestyle interventions significantly improved over time for MNSI clinical signs (MD: -1.04, 95% CI: -1.68 to -0.40), MNSI symptoms (MD: -1.11, 95% CI: -1.89 to -0.33) and VPT (MD: -4.22, 95% CI: -8.04 to -0.40). Although the interaction effects did not reach significance, changes in values from pre to post intervention favoured exercise in comparison to control for MNSI clinical signs (MD -0.42, 95% CI -1.72 to 0.90), MNSI clinical symptoms (MD -0.38, 95% CI -1.96 to 1.2) and VPT (MD -4.22, 95% CI -12.09 to 3.65). Conclusions: Eight weeks of exercise training or lifestyle education can improve neuropathic signs and symptoms in people with diabetes and peripheral neuropathy. These findings support a role for lifestyle interventions in the management of peripheral neuropathy.

Aims/introduction: Carpal tunnel syndrome (CTS) and diabetic polyneuropathy (DPN) can occur together, and this concomitance is thought to be higher in diabetes patients. We aimed to examine and compare hand function in type 2 diabetes mellitus patients without CTS and DPN (CTS-DPN-), patients with CTS without DPN (CTS+DPN-), patients with DPN without CTS (CTS-DPN+), and patients with CTS and DPN (CTS+DPN+)., Materials and Methods: A total of 161 type 2 diabetes mellitus patients underwent physical examination and electrodiagnostic tests. Grip and pinch strengths, tactile sensory thresholds were measured for each participant. Purdue pegboard test was used in evaluating the hand dexterity of the participants., Results: Of the 161 type 2 diabetes mellitus participants, 36 (22.4%) had both CTS and DPN. CTS participants had lower grip (26.6 ± 10.6 vs 35.2 ± 14.3, P < 0.001) and pinch (6.3 ± 2.6 vs 7.5 ± 2.9, P = 0.026) strengths compared with non-CTS participants, whereas DPN participants had elevated tactile sensory thresholds of both the second (2.8 [2.8-3.6] vs 2.4 [2.4-2.8], P < 0.001) and the fifth (2.8 [2.8-3.6] vs 2.4 [2.4-2.8], P < 0.001) fingers compared with non-DPN participants. The CTS+DPN+ group had lower Purdue pegboard test scores than other groups. Grip (r = 0.482, 0.530, 0.467, 0.498, all P < 0.001) and pinch (r = 0.246, P = 0.003; r = 0.265, P = 0.001; r = 0.264, P = 0.001; r = 0.235, P = 0.005) strengths were positively correlated with Purdue pegboard test scores, whereas tactile sensory thresholds were negatively correlated with Purdue pegboard test scores (r = -0.447 to -0.359, all P < 0.001)., Conclusion: Type 2 diabetes mellitus patients with both DPN and CTS had lower grip and pinch strengths and decreased tactile sensation, both of which were correlated with poorer hand dexterity., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Objectives: There are controversies about the role of zinc in the development of both types 1 and 2 diabetes. The aim of this study was to assess serum zinc level in diabetic patients with and without peripheral neuropathy in comparison to healthy controls and to explore the possible relationship between serum zinc level and severity of peripheral neuropathy., Methods: This case control study was conducted on 120 subjects: 40 patients fulfilled the criteria for diagnosis of probable diabetic polyneuropathy (DPN), 40 diabetic patients without polyneuropathy (N-DPN) and 40 healthy controls. DPN patients were submitted to clinical assessment of diabetic neuropathy using neuropathy symptom and change (NSC) scale, Michigan Neuropathy Screening Instrument Physical Assessment (MNSI) scale and electrophysiological assessment using nerve conduction study. Zinc serum level was measured in all subjects included in this study using direct colorimetric test method., Results: Diabetic patients with and without neuropathy were found to have significantly lower mean values of serum zinc than healthy controls (p = .025,  .03 respectively). There is a statistically significant negative correlation between zinc serum level and hemoglobin A1C (HA1C) (p ˂ .001), NSC score (p = .001) and MNSI score (p = .003) in DPN group. There were also statistically significant correlations between zinc serum level and nerve conduction study values., Conclusion: Zinc deficiency significantly correlates with the severity of DPN and glycemic control., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Dental pulp stem cells (DPSCs) are suitable for use in regenerative medicine. Cryopreserved human DPSCs (hDPSCs) ameliorate diabetic polyneuropathy, and the effects of hDPSC transplantation are related to VEGF and NGF secretion. This study evaluated the long-term effects of a single transplantation of hDPSCs on diabetic polyneuropathy. hDPSCs were obtained from human third molars extracted for orthodontic treatment, which were then transplanted into the unilateral hindlimb skeletal muscles 8 weeks after streptozotocin injection in nude mice. The effects of hDPSC transplantation were analyzed at 16 weeks post-transplantation. DPSC transplantation significantly improved delayed nerve conduction velocity, decreased blood flow, and increased sensory perception thresholds. Furthermore, the hDPSC-conditioned medium promoted the neurite outgrowth of dorsal root ganglion neurons. In conclusion, the therapeutic effects of hDPSC transplantation with a single injection last for prolonged periods and may be beneficial in treating long-term diabetic polyneuropathy.

Aims/introduction: To examine the performance and identify the optimal threshold of vibration perception threshold (VPT) for diagnosing diabetic polyneuropathy (DPN) in a Chinese population according to multiple definitions of DPN as gold standards., Materials and Methods: VPT was determined in 421 Chinese individuals with type 2 diabetes, who simultaneously completed a questionnaire of neuropathic symptoms, and underwent the assessment of signs of peripheral neuropathy and electromyography tests. Three definitions of DPN (i.e., clinician-diagnosed DPN, abnormal nerve conduction and confirmed DPN) were taken as reference gold standards., Results: Vibration perception threshold was a specific measure for all three groups of DPN outcomes, with the highest specificity noted for clinician-diagnosed DPN (85.1%). The specificity for abnormal nerve conduction and confirmed DPN was 77.0 and 76.6%, respectively. The sensitivity of VPT was 67.0% for clinician-diagnosed DPN, 66.5% for abnormal nerve conduction and 67.2% for confirmed DPN. The optimal cut-off threshold for abnormal nerve conduction, as well as confirmed DPN, was VPT >14.9 V. The specificity and sensitivity of VPT >14.9 V as the cut-off value for clinician-diagnosed DPN were 85.6 and 66.2%, respectively. When taking clinician-diagnosed DPN as the gold standard, the performance of VPT for diagnosing DPN was best with an area under the curve value of 0.804., Conclusions: VPT measured using the neurothesiometer had relatively high specificity and best performance for diagnosing DPN when clinician-diagnosed DPN rather than abnormal nerve conduction was taken as the gold standard in a Chinese population. A VPT value of ≥15 V might be equally applicable for diagnosing DPN in a Chinese population., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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., (© 2020 Diabetes UK.)

Objective: The aim of the present study was to gain insight into the pathophysiology of diabetic polyneuropathy (DPN) and examine the diagnostic value of sensory and motor axonal excitability testing., Methods: One hundred and eleven type 2 diabetics with and without DPN (disease duration: 6.36 ± 0.25 years) and 60 controls were included. All participants received a thorough clinical examination including Michigan Neuropathy Screening Instrument (MNSI) score, nerve conduction studies (NCS), and sensory and motor excitability tests. Patients were compared by the likelihood of neuropathy presence, ranging from no DPN (17), possible/probable DPN (46) to NCS-confirmed DPN (48)., Results: Motor excitability tests showed differences in rheobase and depolarizing threshold electrotonus measures between NCS-confirmed DPN group and controls but no changes in hyperpolarising threshold electrotonus or recovery cycle parameters. Sensory excitability showed even less changes despite pronounced sensory NCS abnormalities. There were only weak correlations between the above motor excitability parameters and clinical scores., Conclusions: Changes in excitability in the examined patient group were subtle, perhaps because of the relatively short disease duration., Significance: Less pronounced excitability changes than NCS suggest that axonal excitability testing is not of diagnostic value for early DPN and does not provide information on the mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Aims: The goal of this retrospective cohort study was to analyze the incidence of, and factors associated with the antiepileptic drug (AED) therapy in the five years following the diagnosis of diabetic polyneuropathy in patients followed in Germany., Methods: The study included patients aged 18-80 years with an initial diagnosis of diabetic polyneuropathy in 1238 general and diabetologist practices in Germany between January 2008 and December 2017 (index date). The main outcome of the study was the incidence of the AED therapy in the five years following the diagnosis of diabetic polyneuropathy. Adjusted Cox regression analyses were conducted to investigate the association between study covariates and the incidence of the AED therapy., Results: The present study included 48,324 patients (mean [standard deviation] age 65.8 [10.6] years, 55.6% male). Within five years of the diagnosis of diabetic polyneuropathy, 16.4% of patients were prescribed at least one AED. The three most frequent drugs were pregabalin, gabapentin, and carbamazepine. Female sex (HR = 1.22), private health insurance coverage (HR = 1.22), follow-up in a general practice (HR = 1.85), HbA1c ≥10% (HR = 1.36), previous referral to a neurological practice (HR = 1.47), previous hospital admission (HR = 1.51) and depression (HR = 1.15) were positively associated with the incidence of the AED therapy., Conclusions: The incidence of the AED therapy was low in patients recently diagnosed with diabetic polyneuropathy in Germany. More research is warranted to understand the infrequent use of AEDs in diabetic polyneuropathy patients from this country., (Copyright © 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

The cornea's intense innervation is responsible for corneal trophism and ocular surface hemostasis maintenance. Corneal diabetic neuropathy affects subbasal nerve plexus, with progressive alteration of nerves' morphology and density. The quantitative analysis of nerve fibers can be performed with in vivo corneal confocal microscopy considering the main parameters such as corneal nerve fibers length, corneal nerve fibers density, corneal nerve branching density, tortuosity coefficient, and beadings frequency. As the nerve examination permits the detection of early changes occurring in diabetes, the invivo corneal confocal microscopy becomes, over time, an important tool for diabetic polyneuropathy assessment and follow-up. In this review, we summarize the actual evidence about corneal nerve changes in diabetes and the relationship between the grade of alterations and the duration and severity of the disease. We aim at understanding how diabetes impacts corneal nerves and how it correlates with sensorimotor peripheral polyneuropathy and retinal complications. We also attempt to analyze the safety of the most common surgical procedures such as cataract and refractive surgery in diabetic patients and to highlight the specific risk factors. We believe that information about the corneal nerve fibers' condition obtained from the in vivo subbasal nerve plexus investigation may be crucial in monitoring peripheral small fiber polyneuropathy and that it will help with decision-making in ophthalmic surgery in diabetic patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diabetic sensorimotor polyneuropathy (DSPN) is encountered in approximately one-third of people with diabetes. This, in turn, might markedly impoverish their quality of life, mainly owing to neuropathic pain and foot ulcerations. Painful DSPN might be as frequent as 25% in diabetes patients. Symptoms as a result of DSPN typically comprise pain, paresthesia and numbness in the distal lower limbs. Asymptomatic DSPN might reach 50% among patients with this condition. Unfortunately, DSPN is still not adequately diagnosed and treated. Its management has three priorities: (i) lifestyle improvement, near-normoglycemia and multifactorial cardiovascular risk intervention; (ii) pathogenesis-oriented pharmacotherapy; and (iii) symptomatic alleviation of pain. Intensive diabetes therapy showed evidence for favorable effects on the incidence and deterioration of DSPN in type 1 diabetes, but not type 2 diabetes. Among pathogenesis-oriented treatments, α-lipoic acid, actovegin, benfotiamine and epalrestat are currently authorized to treat DSPN in several countries. Symptomatic therapy uses analgesics, notably antidepressants, opioids and anticonvulsants, reducing pain by ≥50% in approximately 50% of individuals, but might be limited, particularly by central nervous system-related adverse events. Local treatment with the capsaicin 8% patch might offer an alternative. In addition to pain relief, therapy should improve sleep, mobility and quality of life. In conclusion, multimodal treatment of DSPN should consider the individual risk profile, pathogenetic treatment and pain management using pharmacotherapy (combinations, if required), as well as non-pharmacological options., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Although gait disturbances are relatively common symptoms in diabetic polyneuropathy (DPN), few studies have quantitatively analyzed gait and posture in DPN patients. This study aimed to analyze gait and posture quantitatively in DPN patients and to determine the association between clinical and electrophysiological parameters and gait and posture parameters., Methods: Sixty-four DPN patients were enrolled in this study. DPN was clinically assessed using the Toronto clinical neuropathy score (TCNS). All participants underwent nerve conduction study (NCS), three-dimensional motion analysis, and static posturography. We evaluate the correlation of gait and posture parameters with electrophysiological and clinical parameters., Results: Foot height, step length, and stride length among gait parameters were inversely correlated with the TCNS. Anteroposterior range during eyes-closed and mediolateral distance and range during eyes-open and eyes-closed were inversely correlated with the sensory nerve action potential amplitude in the sural nerve. Mediolateral distance during eyes-open and eyes-closed was correlated with the compound muscle action potential amplitude in the peroneal nerve., Conclusions: Gait parameters are associated with clinical parameters, and postural parameters are associated with electrophysiological parameters, particularly sensory NCS. Gait and postural analysis can be a useful tool for assessing the neurological status in DPN patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Összefoglaló. Bevezetés: Az idegrendszeri károsodás az egyik leggyakrabban kialakuló komplikáció a cukorbetegek körében, mely az egyénnek és a finanszírozónak is jelentős terhet jelent. Célkitűzés: Elemzésünk célja volt a diabeteses polyneuropathia okozta epidemiológiai és egészségbiztosítási betegségteher elemzése. Adatok és módszerek: Az adatok a Nemzeti Egészségbiztosítási Alapkezelő (NEAK) finanszírozási adatbázisából származnak, és a 2018. évet fedik le. Meghatároztuk az éves betegszámokat és a 100 000 lakosra jutó igénybevételi prevalenciát, továbbá az éves egészségbiztosítási kiadásokat korcsoportos és nemenkénti bontásban és ellátási típusonként. A vizsgált kórképet a Betegségek Nemzetközi Osztályozása (10. revízió) szerinti G6320-as kóddal azonosítottuk. Eredmények: A diabeteses polyneuropathia kezelésére a NEAK 6,63 milliárd Ft (24,52 millió USD; 20,78 millió EUR) egészségbiztosítási kiadást fordított 2018-ban. E költségek legnagyobb hányadát a gyógyszerek ártámogatása adta (78,29%). A teljes népességre számolt, 100 000 főre vetített prevalencia 862/100 000 fő volt a férfiak, 981/100 000 fő a nők esetében, együtt 924/100 000 fő a járóbeteg-szakellátásban. A 65-74 évesek jelentek meg a legnagyobb számban az egyes ellátási szinteken. A nemek eloszlása között a legtöbb vizsgált korcsoport tekintetében számottevő különbség nem tapasztalható, 65 év felett azonban már jóval magasabb a nők aránya. Következtetés: A betegség előfordulási gyakorisága a nők esetében 15,6%-kal magasabb. Idősebb korban jelentősen magasabb betegszámot figyeltünk meg. A neuropathiás szövődmények elkerülése érdekében a terápiás kezelésen túl a megelőzésre is sokkal nagyobb figyelmet javasolunk fordítani. Orv Hetil. 2021; 162(Suppl 1): 38-45., Introduction: Neurological complications are the most common type of complications among type 2 diabetes mellitus patients, which put a heavy burden on both individuals and health insurance organizations., Objective: The aim of our study was to determine the epidemiological and health insurance disease burden of non-insulin-dependent diabetes with neurological complications., Data and Methods: Data were derived from the financial database of the National Health Insurance Fund Administration (NHIFA) of Hungary for the year 2018. Data analysed included annual patient numbers and prevalence of care utilisation per 100 000 population according to age groups and sex. Patients were identified with the following code of the International Classification of Diseases, 10th revision: G6320., Results: In 2018, NHIFA spent 6.63 billion HUF (24.52 million USD; 20.78 million EUR) on treating diabetic polyneuropathy. Reimbursement of pharmaceuticals was the main cost driver (78.29% of total expenditure). Based on patient numbers in outpatient care, prevalence in 100 000 population was 862 men, 981 women, together 924 people based on outpatient-care utilization. Most patients were aged between 65-74 years in all forms of care. Regarding sex, no significant differences were found among most age groups, however, the ratio of women tends to be higher above 65 years of age., Conclusion: Prevalence was found to be by 15.6% higher among women. Significantly higher patient numbers were found in old age. Besides therapeutic interventions, prevention should gain considerably more attention to avoid polyneuropathic complications. Orv Hetil. 2021; 162(Suppl 1): 38-45.

Diabetic polyneuropathy (DPN) can be classified based on fiber diameter into three subtypes: small fiber neuropathy (SFN), large fiber neuropathy (LFN), and mixed fiber neuropathy (MFN). We examined the effect of different diagnostic models on the frequency of polyneuropathy subtypes in type 2 diabetes patients with DPN. This study was based on patients from the Danish Center for Strategic Research in Type 2 Diabetes cohort. We defined DPN as probable or definite DPN according to the Toronto Consensus Criteria. DPN was then subtyped according to four distinct diagnostic models. A total of 277 diabetes patients (214 with DPN and 63 with no DPN) were included in the study. We found a considerable variation in polyneuropathy subtypes by applying different diagnostic models independent of the degree of certainty of DPN diagnosis. For probable and definite DPN, the frequency of subtypes across diagnostic models varied from: 1.4% to 13.1% for SFN, 9.3% to 21.5% for LFN, 51.4% to 83.2% for MFN, and 0.5% to 14.5% for non-classifiable neuropathy (NCN). For the definite DPN group, the frequency of subtypes varied from: 1.6% to 13.5% for SFN, 5.6% to 20.6% for LFN, 61.9% to 89.7% for MFN, and 0.0% to 6.3% for NCN. The frequency of polyneuropathy subtypes depends on the type and number of criteria applied in a diagnostic model. Future consensus criteria should clearly define sensory functions to be tested, methods of testing, and how findings should be interpreted for both clinical practice and research purpose., (© 2020 Peripheral Nerve Society.)

Aims/introduction: As the extensor digitorum brevis muscle is a small muscle in the most distal part of the legs, its atrophy (EDBA) might reflect symmetric polyneuropathy (SPN). We aimed to clarify the EDBA-related factors and the usefulness of bilateral EDBA detection for diagnosing SPN, especially diabetic SPN (DSPN)., Materials and Methods: In 1,893 participants from the Japanese general population (investigation I) and 133 established diabetes patients (investigation II), relationships between EDBA and various factors including the traditional sitting style called "seiza'" (kneeling and sitting on one's heels) were investigated. Analyses were carried out by univariate and multivariate analysis, and SPN or DSPN was diagnosed by the criteria of "Probable DSPN" of the Toronto Consensus. The validity of EDBA detection for diagnosing SPN/DSPN was also evaluated., Results: Investigation I: EDBA was more prevalent in women than men (44% vs 20%). Significant EDBA-related factors were aging and seiza habit regardless of sex. Male-specific EDBA-related factors were SPN and known diabetes. In men without seiza habit, EDBA was significantly associated with SPN regardless of diabetes, so EDBA seemed to be a useful sign for diagnosing SPN/DSPN. Investigation II: In men, DSPN was more prevalent in the EDBA group than the non-EDBA group (71% vs 33%). Sensitivity, specificity, positive predictive value and kappa coefficient of EDBA detection for diagnosing DSPN were 44, 87, 67% and 0.323, showing fair agreement., Conclusions: EDBA detection might be a useful method to screen for distal symmetric polyneuropathy, such as DSPN in men, although the exclusion of individuals with seiza habit is necessary to improve accuracy., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Although diabetic polyneuropathy (DPN) is a frequent diabetic complication, no effective therapeutic approach has been established. Glucagon is a crucial hormone for glucose homeostasis but has pleiotropic effects, including neuroprotective effects in the central nervous system. However, the importance of glucagon in the peripheral nervous system (PNS) has not been clarified. Here, we hypothesized that glucagon might have a neuroprotective function in the PNS. The immortalized rat dorsal root ganglion (DRG) neuronal cell line 50B11 was treated with methylglyoxal (MG) to mimic an in vitro DPN model. The cells were cultured with or without glucagon or MG. Neurotoxicity, survival, apoptosis, neurite projection, cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA) were examined. Glucagon had no cytotoxicity and rescued the cells from neurotoxicity. Cell survival was increased by glucagon. The ratio of apoptotic cells, which was increased by MG, was reduced by glucagon. Neurite outgrowth was accelerated in glucagon-treated cells. Cyclic AMP and PKA accumulated in the cells after glucagon stimulation. In conclusion, glucagon protected the DRG neuronal cells from MG-induced cellular stress. The cAMP/PKA pathway may have significant roles in those protective effects of glucagon. Glucagon may be a potential target for the treatment of DPN.

Objective: The aim: Is to investigate the impact of comprehensive treatment on diabetic polyneuropathy (DPN) patients' quality of life by including rehabilitation approaches with increased physical activity in standard drug treatment regimens., Patients and Methods: Materials and methods: 117 patients with type 2 diabetes and DPN were examined. The patients under examination were divided into 4 groups: the control group (group I) included 32 patients who received medicinal (drug) treatment. 12 supplementary daily treatment procedures with polarized light were additionally prescribed to 32 patients of the second experimental group. In addition to drug treatment and polarizing light procedures, 31 patients of group III and 22 patients of group IV were prescribed dosed therapeutic walking 3 times a week №12 (group III) or Nordic walking 3 times a week №12 (group IV)., Results: Results: The supplemental use of dosed therapeutic walking and Nordic walking in addition to the protocol treatment regimens contributes to the positive dynamics of quality of life of patients with DPN-complicated type 2 diabetes mellitus, which is confirmed by significant positive dynamics reflected in the following sections of the EQ-5D-3L questionnaire, such as motor (2.3 times, p<0.05), self-care (1.4 times, p<0.05), resumption of normal daily activities (2.9 times p<0.05) reduction of the frequency of discomfort (4.2 times, p<0.05) and anxiety-depressive states (2.7 times, p<0.05)., Conclusion: Conclusions: Increased physical activity of patients with DPN significantly affects their life quality and proves to be a clinically effective approach to such patients.