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Purpose: Small fiber dysfunction is common in subjects with diabetic polyneuropathy (DPN). It is unsettled, however, whether marginal glucose intolerance is implicated in the onset and progression of small fiber dysfunction. Herein, we explored the relationship between glycated hemoglobin levels (HbA1c) and pain sensation in the Japanese population. Methods: A population-based study of 894 individuals (352 men, 542 women; average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) in the 2017 Iwaki project were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold for intraepidermal electrical stimulation (P-IES) and parameters associated with metabolic syndrome were examined. Results: P-IES was elevated with increasing of age in women but not in men. Average P-IES (mA) was increased in IFG subjects (n = 55, 0.20 ± 0.03) compared with normoglycemic/non-IFG individuals (n = 894, 0.15 ± 0.11) (p < 0.01). It was comparable between IFG and a group of normal high HbA1c (5.9–6.4%). Univariate linear regression analyses showed no influence of sex, triglyceride, or cholesterol on the value of P-IES. In contrast, there were significant correlations between P-IES and serum HbA1c level (ß = 0.120, p < 0.001) Adjustments for the multiple clinical measurements confirmed positive correlation of P-IES with HbA1c (ß = 0.077, p = 0.046). Conclusion: Individuals with normal high HbA1c exhibited an elevated P-IES in a healthy Japanese population which may be useful for the screening of subclinical DPN. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • A blood-based biomarker for DPN could support diagnosis and follow-up of DPN. • NfL levels were higher in +DPN than in -DPN individuals. • NfL's potential as a biomarker for the presence of DPN is however unlikely. • NfL was associated with worse peripheral nerve function in type 2 diabetes. • NfL's relation to nerve function indicates value of NfL in evaluation of DPN severity. To investigate the relationship between neurofilament light chain (NfL) and the presence and severity of diabetic polyneuropathy (DPN). We performed cross-sectional analysis of data from 178 participants of the ADDITION-Denmark cohort of people with screen-detected type 2 diabetes and 32 healthy controls. Biobank serum samples were analyzed for NfL using single-molecule array. DPN was defined by Toronto criteria for confirmed DPN. Original and axonal nerve conduction study (NCS) sum z-scores were used as indicators of the severity of DPN and peripheral nerve damage. 39 (21.9%) participants had DPN. Serum NfL (s-NfL) was significantly higher in participants with DPN (18.8 ng/L [IQR 14.4; 27.9]) than in participants without DPN (15.4 ng/L [IQR 11.7; 20.1]). There were no unadjusted s-NfL differences between controls (17.6 ng/L [IQR 12.7; 19.8]) and participants with or without DPN. Higher original and axonal NCS sum z-scores were associated with 10% higher s-NfL (10.2 and 12.1% [95% CI's 4.0; 16.8 and 6.6; 17.9] per 1 SD). The AUC of s-NfL for DPN was 0.63 (95% CI 0.52; 0.73). S-NfL is unlikely to be a reliable biomarker for the presence of DPN. S-NfL is however associated to the severity of the nerve damage underlying DPN. [ABSTRACT FROM AUTHOR]

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.

The article is devoted to the diabetic polyneuropathy – frequency, possibilities of diagnostics, including those with use of instrumental methods. Own data about possibilities to detect asymptomatic lesion of the peripheral nervous system in diabetes mellitus patients are provided. Effectiveness of the therapy of this state with the help of one of the drugs of the thioctic acid based drugs (Berlithione®).

Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN). Cajal bodies (CBs), unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN) proteins was reduced – a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs), also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG), and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdown in vitro enhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy.

Distal diabetic neuropathy is the leading neurological complicationof type 2 diabetes. Diabetic neuropathy is heterogeneousin its clinical entity and the pattern of peripheral neural systemdamage. In most cases the diagnosis is based on the typical neurologicalsymptoms, the results of neurological examination andneurophysiological testing, where available. Medical treatmentof pain in distal diabetic neuropathy includes symptomatic andpathogenetic medications. Effective control of diabetes is crucialfor reduction of risk of neuropathy progression and is a predictivefactor of effective symptomatic and pathogenetic treatment. Theprimary choice of medication is based on patients characteristics,diabetes control, pain severity, concomitant diseases andcommercial availability of medications.

Diabetic peripheral neuropathies (DPN) are a heterogeneous group of disorders caused by neuronal dysfunction in patients with diabetes. Among all acquired polyneuropathy, diabetic polyneuropathy is the most common, and therefore the most important one. Approximately 50% of patients with diabetes develop peripheral neuropathy. Distal symmetrical polyneuropathy (DSPN) with painful diabetic neuropathy, occurring in around 20% of diabetes patients, and diabetic autonomic neuropathy (DAN) are the most common manifestations of DPN. Optimal glucose control represents the only broad- ly accepted therapeutic option though evidence. A number of symptomatic treatments are recommended in clinical guidelines for the management of painful DPN, including antidepressants, γ-aminobutyric acid analogues, opioids, and topical agents. The current treatment of DPN is largely symptomatic, the other therapy direction is focused on pathogenetic process of disease, and there is some evidence that the use of alfa-lipoic acid, aldose reductase inhibitors and fat-solubile vitamin-B may have beneficial effect in terms of development of microangiopathy in patients with diabetes.

Purpose: to estimate efficiency of pathogenetic therapy of diabetic polyneuropathy with including of benfotiaminby means of an electroneuromyography. Materials: assessment of efficiency of pathogenetic therapy of diabetic polyneuropathy with including of benfotiaminat patients with various experience of a diabetes mellitus 2 types was carried out. The research included three groups of patients with an experience of diabetes 2 type – 1-3 years (1 group), 3-7 years (the 2nd group), 7-10 years (the 3rd group). The conduction research on nerves of the lower extremities by an electroneuromyography method was the main criterion of efficiency (primary final point). Results: according to ENMG-control statistically significant improvement of conduction on peripheric nerves against the background of therapy by benfotiamin within 12 weeks was shown. More faster improvement of conduction was reached in groups with a smaller experience of a diabetes mellitus (up to 7 years) and at the patients who were earlier receiving courses of pathogenetic therapy. Conclusions: Including of benfotiamin in a complex of therapy of diabetic polyneuropathy allows to achieve reliable improvement of a condition of peripheric nerves from patients with various experience of a diabetes mellitus 2 types.

Arterial hypertension (AH) complicates the course of diabetes mellitus (DM) of both the 1st and 2nd type. In patients with diabetes type 1, the main cause of AH is diabetic nephropathy. In diabetes type 2, on the other hand, essential hypertension is diagnosed in 70-80% of cases. The choice of antihypertensive therapy in patients with diabetes is not easy; when selecting the best anti-hypertensive drug for a diabetes patient, the associated vascular complications should always be considered. Angiotensin-convertingenzyme inhibitors are the most common treatment of hypertension in diabetic patients. Damage of the nervous system - diabetic polyneuropathy (DPN) – is a key element in the clinical picture of diabetes. In the treatment of DPN, activation of neural regeneration (reinnervation) and pain management are crucial. Neurotropic B vitamins with multimodal effect play a key role in this.

α-Lipoic acid (thioctic) (ALA) is the most applicable pharmacological drug for treatment of diabetic polyneuropathy. The articles explores the results of experimental studies on α-Lipoic acid effect upon formation mechanisms of peripheral nerves affection under hyperglycemia and also the data of numerous randomized controlled trials and meta-analyses on studying ALA efficiency under symptomatic diabetic polyneuropathy. It was proved that amelioration of patients with diabetic polyneuropathy is observed both while using ALA infusions and tableted form of the drug. The authors conclude that α-lipoic acid is a drug for treatment of pathogenetic development mechanisms of diabetic polyneuropathy with the most demonstrated efficiency.

The article is an overview of the prevalence, mechanisms of development, diagnosis and treatment of diabetic neuropathy as a complication of diabetes. It also tells about the pathogenetic aspects of treatment of diabetic polyneuropathy.

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.

Copyright of Knowledge: International Journal is the property of Institute for Knowledge Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims/Introduction: Although nerve conduction study (NCS) using a standard electromyography system (EMGS) is considered to be the gold standard in evaluating diabetic polyneuropathy, this examination requires expensive equipment and well‐trained technicians. We aimed to validate a point‐of‐care device, NC‐stat/DPNCheck™, that has been developed for widespread use of NCS in diabetic polyneuropathy. Materials and Methods: Diabetes patients underwent two kinds of NCS: DPNCheck™ and electromyography system. Inter‐/intrarater reliability of DPNCheck™ were also determined by the intraclass correlation coefficient. Results: A total of 57 patients were evaluated. The parameters of NCS between the two methods correlated well (r = 0.7734 for the sural nerve conduction velocity, r = 0.6155 for the amplitude of sural nerve action potential). The intraclass correlation coefficients were excellent (intrarater: the velocity 0.767, the amplitude 0.811; interrater: the velocity 0.974, the amplitude 0.834). Conclusions: The point‐of‐care device has excellent reproducibility and good agreement with standard electromyography system. The device might be useful to evaluate diabetic polyneuropathy. [ABSTRACT FROM AUTHOR]

Copyright of Lege Artis Medicine (LAM) is the property of LifeTime Media Kft. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Endocrinology / Mìžnarodnij Endokrinologìčnij Žurnal is the property of Zaslavsky O.Yu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Among patients with diabetic polyneuropathy, the status of folic acid, homocysteine, and nerve conduction studies (NCS) variations has been associated with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms. The objective of the present study is to assess B9 vitamin supplementation associated with MTHRF C677T polymorphism can be effective on NCS variations in patients. Materials and Methods: This study is a randomized, double blind, placebo-controlled study. Patients were randomly allocated to either intervention (1 mg of folic acid, n = 40) or placebo (n = 40) groups based on parallel group design. Blood samples were taken to determine the serum levels of folic acid and homocysteine. The NCS data were collected for the assessment of diabetic neuropathy. Genotyping was performed for C677T polymorphism of the MTHFR gene. Results: Four months after intervention, patients significantly observed change of serum folic acid and homocysteine levels based on C677T genotypes in the MTHFR gene. The amplitude of sensory peroneal nerve between intervention and placebo groups with CC genotype was significantly different (2.8 ± 1.6 vs. 1.9 ± 1.1). However, peak latency and amplitude of sensory sural nerve between CC (3.8 ± 1.8 vs. 4.0 ± 1.5 for peak latency and 3.5 ± 1.0 vs. 2.5 ± 1.0 for amplitude; and CT + TT genotypes (3.7 ± 1.7 vs. 3.9 ± 1.3 for peak latency and 3.2 ± 1.0 vs. 2.3 ± 1.1 for amplitude) were significant. Furthermore, significant difference for variables of motor tibial nerve and motor peroneal nerve amplitude was observed in different groups of MTHFR C677T genotypes (5.4 ± 2.9 vs. 4.6 ± 3.2 for onset latency of tibial nerve between CC genotype; 4.8 ± 2.8 vs. 4.6 ± 3.2 for onset-latency of tibial nerve between CT + TT genotype; 0.6 ± 0.2 vs. 0.3 ± 0.1 for amplitude of tibial nerve between CC genotype; 0.5 ± 0.3 vs. 0.3 ± 0.2 for amplitude of tibial nerve between CT + TT genotype; 26.0 ± 13.3 vs. 23.2 ± 13.4 for velocity of tibial nerve between CC genotype; 26.0 ± 13.7 vs. 23.1 ± 9.6 for velocity of tibial nerve between CT + TT genotype; 1.6 ± 1.0 vs. 0.9 ± 0.7 for amplitude of peroneal nerve between CC genotype; 1.4 ± 0.7 vs. 0.9 ± 0.5 for amplitude of peroneal nerve between CT + TT genotype). Conclusion: The study determined that MTHFR C677T polymorphism effects the efficacy of folic acid supplementation on serum folic acid, homocysteine levels and some NCS parameters in diabetic polyneuropathy patients. [ABSTRACT FROM AUTHOR]

Objectives: In diabetic polyneuropathy (DPN) patients, the effect of folic acid and homocysteine has been related to components of nerve conduction velocity (NCV). The objective of this study was to determine the effect of folic acid supplementation on NCV in DPN patients. Methods: Patients were randomized to receive either 1 mg of folic acid (n = 40) or placebo (n = 40) for 16 weeks. Blood samples were collected to assess serum folic acid and homocysteine concentrations, and NCV was performed for assessment of diabetic neuropathy. Results: At 16 weeks, in the supplemented group, serum levels of folic acid (p < 0.001) increased, homocysteine concentrations decreased (p < 0.001), with no change in serum vitamin B12 levels. There was a significant increase in sensory sural amplitude (p < 0.001), and components of motor nerves, including amplitude (p = 0.001) and velocity (p < 0.001), but decreased onset latency of peroneal (p = 0.019) and tibial (p = 0.011) motor nerves. Conclusion: Our data suggest that supplementation with 1 mg of folic acid for 16 weeks may be useful for enhancing NCV in DPN patients. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Physical Medicine & Rehabilitation Sciences is the property of Turkiye Klinikleri and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims/Introduction: Diabetic polyneuropathy is one of the most frequent diabetic complications, and impairs patients' quality of life. We evaluated the efficacy and safety of ranirestat (40 mg/day) in patients with diabetic polyneuropathy. Materials and Methods: This was a multicenter, placebo‐controlled, randomized double‐blind, parallel‐group, phase III study in which 557 patients were randomly assigned to either the ranirestat or placebo group and assessed for 52 weeks. The co‐primary end‐points were the changes in tibial motor nerve conduction velocity and total modified Toronto Clinical Neuropathy Score as a measure of clinical symptoms. Results: There was a significant increase in tibial motor nerve conduction velocity in the ranirestat group compared with the placebo group. The difference between groups in the change at last observation was 0.52 m/s (P = 0.021). Increases in nerve conduction velocity in the ranirestat group were found not only in the tibial motor nerves, but also in the median motor nerves, proximal median sensory nerves and distal median sensory nerves. No significant differences in modified Toronto Clinical Neuropathy Score or safety parameters were found between the two groups. Conclusions: Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment. This study shows that ranirestat, aldose reductase inhibitor, significantly improves nerve conduction velocity in patients with diabetic polyneuropathy. [ABSTRACT FROM AUTHOR]

Introduction: Rapid and accessible methods for diagnosing diabetic polyneuropathy (DPN) have been developed, but not validated, in large cohorts of people with diabetes.Methods: The performance of a point-of-care device (POCD) was studied in 168 patients with type 2 diabetes, estimating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) compared with conventional sural nerve conduction studies (NCS).Results: A POCD amplitude limit of 6 µV increased the sensitivity (96%) and NPV (98%), but decreased the specificity (71%) and PPV (54%) compared with the 4-µV limit, which had values of 78%, 92%, 89%, and 71%, respectively. POCD on both legs showed better performance than on 1 leg. POCD amplitudes and conduction velocities correlated significantly with conventional sural NCS, but POCD values were underestimated compared with NCS.Discussion: The POCD may be used as a suitable screening tool for detection of DPN. Patients with abnormal and borderline results should undergo conventional NCS. Muscle Nerve 59:187-193, 2019. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of left ventricular (LV) dysfunction in diabetes has been attracting attention. It has been reported that LV longitudinal systolic myocardial function determined by speckle tracking echocardiography (STE) is associated with diabetic polyneuropathy (DPN). However, the relationship between the severity of peripheral neuropathy and LV myocardial dysfunction is unknown. This study examined the relationship between the severity of DPN and echocardiographic parameters as well as clinical features.Methods: The subjects were 166 patients (57 ± 14 years old) with diabetes who had a normal LV ejection fraction (≥ 55%). To assess LV longitudinal systolic function, global longitudinal strain (GLS) was calculated by two-dimensional STE as the average peak strain of 18 LV segments in three standard apical views. A nerve conduction study (NCS) was performed in each subject to assess the severity of neuropathy based on the NCS Baba Classification (Grade 0: no apparent abnormalities-Grade IV: abolition). Three nerves in the lower extremity were examined: tibial nerve (F-wave latency, motor nerve conduction velocity, and amplitude), sural nerve (sensory conduction velocity and amplitude), and peroneal nerve (motor nerve conduction velocity and amplitude).Results: Of the 166 subjects, 112 subjects (67.5%) were confirmed to have DPN, and all the subjects were divided into two groups according to the presence/absence of DPN. When multivariate analysis was performed using significant factors from univariate logistic regression analysis as explanatory variables, GLS was found to be an independent determinant of DPN (odds ratio: 0.55, p < 0.001). In multivariate analysis of NCS data, F-wave latency was the most important determinant of DPN (odds ratio: 1.43, p < 0.001). There was a significant negative correlation between F-wave latency and GLS (r = − 0.43, p < 0.001). Regarding the relation between GLS and the severity of DPN, GLS was significantly lower in patients with Grade I or higher DPN than in patients without DPN, but showed no significant difference between the grades of neuropathy. In addition, GLS was significantly lower when 2-3 lower extremity nerves were affected by DPN than in patients without DPN.Conclusion: Patients with diabetes may already have subclinical LV myocardial dysfunction when DPN is Grade I. Assessment of LV longitudinal systolic function by GLS may be important in diabetic patients with DPN. [ABSTRACT FROM AUTHOR]

Abstract Aims In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes. Methods CCM, nerve conduction studies, and assessment of symptoms and clinical deficits of DPN were undertaken in 144 participants with type 2 diabetes and 25 controls. DPN was defined according to the Toronto criteria for confirmed DPN. Results Corneal nerve fiber density (CNFD) was lower both in participants with confirmed DPN (n = 27) and in participants without confirmed DPN (n = 117) compared with controls (P = 0.04 and P = 0.01, respectively). No differences were observed for CNFD (P = 0.98) between participants with and without DPN. There were no differences in CNFL and CNBD between groups (P = 0.06 and P = 0.29, respectively). CNFD was associated with age, height, total- and LDL cholesterol. Conclusions CCM could not distinguish patients with and without neuropathy, but CNFD was lower in patients with type 2 diabetes compared to controls. Age may influence the level of CCM measures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Microangiopathy is a major cause in diabetic polyneuropathy (DPN). This review examines evidence from both human and animal studies to elucidate the important microvascular factors in DPN. MATERIALS AND METHODS: This is a literature review of articles published on PubMed in English. RESULTS: There is an abundance of evidence linking endoneurial microvascular abnormalities to peripheral nerve dysfunction and pathology in patients with diabetes. These structural changes result in an abnormal diffusion barrier leading to endoneurial hypoxia. Furthermore, the functional changes of endoneurial microvessels characterized by reduced vasodilation and potentiated vasoconstriction also exacerbate the endoneurial hypoxia. Although reduced endoneurial blood flow has also been widely reported in established DPN, there is some evidence that blood flow may be elevated early in the course of the disease. Capillary dysfunction in DPN, which reduces the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow, may explain that the tissue may be hypoxic even in the context of normal or elevated nerve blood flow. The pathogenesis of painful DPN also remains unclear although neural hemodynamic changes have been demonstrated both in the peripheral and central nervous system, offering potential new insights for the treatments of this distressing condition. CONCLUSIONS: Compelling experimental and human work has highlighted the close association connection between endoneurial microangiopathy and diabetic polyneuropathy. Future investigations will need to investigate the role of microvascular factors both in the periphery and the central nervous system in the pathogenesis of painful DPN. [ABSTRACT FROM AUTHOR]

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.

Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2′-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.