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Aims/Introduction To assess the prevalence of diabetic polyneuropathy (DPN)‐related sensory symptoms/signs and associated factors in patients with polyneuropathy, considering non‐linear effects for numerical variables. Materials and Methods A cross‐sectional survey of patients with type 2 diabetes mellitus from 17 primary care clinics across Japan was carried out. DPN and DPN‐related sensory symptoms/signs were diagnosed according to the Diabetic Neuropathy Study Group in Japan criteria. Results Of the 9,914 patients with type 2 diabetes mellitus in this study, 2,745 had DPN and 1,689 had DPN‐related sensory symptoms/signs (61.5% of patients with DPN). There were significant correlations between DPN‐related sensory symptoms/signs and smoking status (odds ratio 2.04 for current and 1.64 for former; P < 0.001 and P = 0.002, respectively), sex (odds ratio 0.56 for male/female; P < 0.001) and alcohol consumption (odds ratio 2.02 for former/never; P = 0.004). Based on the non‐linear logistic regression model, significant correlations were observed between the presence of DPN‐related sensory symptoms/signs and higher systolic blood pressure (SBP), longer diabetes duration, and decreasing age. The logarithm of odds for SBP increased until reaching approximately 130 mmHg, then it plateaued. Conclusions Some modifiable factors assessed in the large survey database might be associated with DPN‐related sensory symptoms/signs, namely smoking, alcohol consumption and SBP. Maintaining SBP <130 mmHg was associated with lower odds of DPN‐related sensory symptoms/signs in patients with DPN. This manuscript presents the results of a cross‐sectional Japanese study that assessed the risk factors associated with diabetic peripheral neuropathy‐related symptoms among patients with type 2 diabetes and diabetic peripheral neuropathy, with consideration for non‐linear effects for numerical variables. Some of the modifiable risk factors assessed in the large survey database appeared to be associated with diabetic peripheral neuropathy‐related symptoms, namely smoking, alcohol consumption and systolic blood pressure.

This study aimed to investigate the prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes registered in the Japan Diabetes Complication and its Prevention Prospective study. In the study, 6,338 patients with diabetes who had been treated by diabetes specialists were registered in 2007–2009. Of these, patients with type 2 diabetes who could be evaluated for DSPN were analyzed using the t‐test, χ2‐test and logistic regression analyses. DSPN was diagnosed using the Simple Diagnostic Criteria for Diabetic Polyneuropathy proposed by the Diabetic Neuropathy Study Group in Japan. Of the total participants, 5,451 patients (mean age 61.4 years, duration of diabetes 10.8 years) were analyzed. Based on the criteria, 35.8% of patients were diagnosed with DSPN. The prevalence of sensory symptoms was 25.8%. The following factors increased the risk for DSPN: age (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.42–1.73), duration of diabetes (OR 1.32, 95% CI 1.21–1.43), body mass index (OR 1.19, 95% CI 1.09–1.30), systolic blood pressure (OR 1.06, 95% CI 1.01–1.10), hemoglobin A1c (OR 1.15, 95% CI 1.09–1.22), biguanides (OR 1.22, 95% CI 1.06–1.39) and insulin therapy (OR 1.59, 95% CI 1.36–1.84). The following factors decreased the risk for DSPN: total cholesterol (OR 0.98, 95% CI 0.96–1.00) and exercise therapy (OR 0.85, 95% CI 0.73–0.98). The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also showed the risk factors of DSPN. The Venn diagram illustrates the complementary relationship among the three elements of the Simple Diagnostic Criteria. The prevalence of sensory symptoms was lowest among the three items.

Aim/introduction This study aims to investigate the prevalence and characteristics of diabetic symmetric sensorimotor polyneuropathy (DSPN) in patients with type 2 diabetes registered in the Japan Diabetes Complication and its Prevention Prospective (JDCP) study. Materials and methods In the study, 6338 patients with diabetes who had been treated by diabetes specialists were registered in 2007–2009. Of these, patients with type 2 diabetes who could be evaluated for DSPN were analyzed using t test, chi-square test, and logistic regression analyses. DSPN was diagnosed using the Simple Diagnostic Criteria for Diabetic Polyneuropathy proposed by the Diabetic Neuropathy Study Group in Japan. Results Of the total participants, 5451 patients (mean age 61.4 years old and duration of diabetes 10.8 years) were analyzed. Based on the criteria, 35.8% of patients were diagnosed with DSPN. The prevalence of sensory symptoms was 25.8%. The following factors increased risk for DSPN: age [odds ratio (OR) 1.57, 95% confidence intervals (CI) 1.42–1.73], duration of diabetes (OR 1.32, 95% CI 1.21–1.43), body mass index (OR 1.19, 95% CI 1.09–1.30), systolic blood pressure (OR 1.06, 95% CI 1.01–1.10), hemoglobin A1c (OR 1.15, 95% CI 1.09–1.22), biguanides (OR 1.22, 95% CI 1.06–1.39), and insulin therapy (OR 1.59, 95% CI 1.36–1.84). The following factors decreased risk for DSPN: total cholesterol (OR 0.98, 95% CI 0.96–1.00) and exercise therapy (OR 0.85, 95% CI 0.73–0.98). Conclusions The baseline survey clarified the prevalence and characteristics of DSPN in Japanese patients with type 2 diabetes. The survey also revealed the risk factors of DSPN.

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. Approximately one of three people with diabetes is affected by diabetic sensorimotor polyneuropathy, which is associated with marked impairment in quality of life primarily as a result of neuropathic pain and foot ulcers, but still remains underdiagnosed and undertreated. The management of diabetic sensorimotor polyneuropathy includes three cornerstones: (i) lifestyle modification, causal treatment aimed at near‐normoglycemia and multifactorial cardiovascular risk intervention; (ii) pathogenesis‐derived pharmacotherapy; and (iii) symptomatic treatment of neuropathic pain using analgesic compounds (combinations, if required) and non‐pharmacological options.

Diabetic neuropathies (DNs) differ in clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical type being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement. The pathogenesis of diabetic DSP is multifactorial, including increased mitochondrial production of free radicals due to hyperglycemia-induced oxidative stress. Mechanisms that impact neuronal activity, mitochondrial function, membrane permeability, and endothelial function include formation of advanced glycosylation end products, activation of polyol aldose reductase signaling, activation of poly(ADP ribose) polymerase, and altered function of the Na + /K + -ATPase pump. Hyperglycemia-induced endoplasmic reticulum stress triggers several neuronal apoptotic processes. Additional mechanisms include impaired nerve perfusion, dyslipidemia, altered redox status, low-grade inflammation, and perturbation of calcium balance. Successful therapies require an integrated approach targeting these mechanisms. Intensive glycemic control is essential but is insufficient to prevent onset or progression of DSP, and disease-modifying treatments for DSP have been disappointing. Atypical forms of DN include subacute-onset sensory (symmetric) or motor (asymmetric) predominant conditions that are frequently painful but generally self-limited. DNs are a major cause of disability, associated with reduced quality of life and increased mortality.

Background Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available. Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus. Methods Diabetic BKS db/db mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated. Results Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS db/db mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer. Conclusions Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.

Abstract Context Due to the heterogenous clinical symptoms and deficits, the diagnosis of diabetic polyneuropathy (DPN) is still difficult in clinical routines, leading to increased morbidity and mortality. Objective We studied the correlation of phase angle (PhA) of bioelectrical impedance analysis (BIA) with clinical, laboratory, and physical markers of DPN to evaluate PhA as a possible diagnostic method for DPN. Materials and methods In this cross-sectional observational study as part of the Heidelberg Study on Diabetes and Complications, we examined 104 healthy individuals and 205 patients with type 2 diabetes mellitus (T2D), among which 63 had DPN. The PhA was calculated from multifrequency BIA. Nerve conduction studies, quantitative sensory testing (QST) and diffusion-weighted magnetic resonance neurography to determine fractional anisotropy (FA) reflecting peripheral nerve integrity were performed. Results T2D patients with DPN had lower PhA values (5.71 ± 0.10) compared to T2D patients without DPN (6.07 ± 0.08, P = .007, + 6.1%) and healthy controls (6.18 ± 0.08, P < .001, + 7.9%). Confounder-adjusted analyses showed correlations of the PhA with conduction velocities and amplitudes of the peroneal (β=.28; β=.31, P < .001) and tibial nerves (β=.28; β=.32, P < .001), Z-scores of QST (thermal detection β=.30, P < .05) and the FA (β=.60, P < .001). Receiver-operating characteristic analysis showed similar performance of PhA in comparison to the mentioned diagnostic methods. Conclusion The study shows that PhA is, in comparison to other test systems used, at least an equally good and much easier to handle investigator-independent marker for detection of DPN.

Distal diabetic sensorimotor polyneuropathy (DDSP) is the most prevalent form of diabetic neuropathy, and some of the patients develop gradual pain. Specialized sensory structures present in the skin encode different modalities of somatosensitivity such as temperature, touch, and pain. The cutaneous sensory structures responsible for the qualities of mechanosensitivity (fine touch, vibration) are collectively known as cutaneous mechanoreceptors (Meissner corpuscles, Pacinian corpuscles, and Merkel cell–axonal complexes), which results are altered during diabetes. Here, we used immunohistochemistry to analyze the density, localization within the dermis, arrangement of corpuscular components (axons and Schwann-like cells), and expression of putative mechanoproteins (PIEZO2, ASIC2, and TRPV4) in cutaneous mechanoreceptors of subjects suffering clinically diagnosed non-painful and painful distal diabetic sensorimotor polyneuropathy. The number of Meissner corpuscles, Pacinian corpuscles, and Merkel cells was found to be severely decreased in the non-painful presentation of the disease, and almost disappeared in the painful presentation. Furthermore, there was a marked reduction in the expression of axonal and Schwann-like cell markers (with are characteristics of corpuscular denervation) as well as of all investigated mechanoproteins in the non-painful distal diabetic sensorimotor polyneuropathy, and these were absent in the painful form. Taken together, these alterations might explain, at least partly, the impairment of mechanosensitivity system associated with distal diabetic sensorimotor polyneuropathy. Furthermore, our results support that an increasing severity of DDSP may increase the risk of developing painful neuropathic symptoms. However, why the absence of cutaneous mechanoreceptors is associated with pain remains to be elucidated.

Diabetic polyneuropathy (DPN) continues to be generally considered as a “microvascular” complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron‐specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end‐products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3‐kinase–protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon‐like peptide‐1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let‐7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre‐messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration. Diabetic sensory neurodegeneration is a potential mechanism for the selectivity of sensory neurons in diabetic neuropathy. The pathogenesis is linked to dysregulated mRNA processing including miRNAs and RNA splicing. Understanding of aberrant RNA processing in diabetic neuropathy may give rise to new therapeutic targets.

Aims/hypothesisThe 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.MethodsThis 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.ResultsA 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/interpretationPRT 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 registrationClinicalTrials.gov NCT03252132FundingResearch 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