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ABSTRACT Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30–50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches.

ABSTRACT The world is experiencing an enormous rise in the prevalence of diabetes, which is associated with massive healthcare costs that threaten to overwhelm many healthcare systems. Most of the diabetes expenditure is attributed to the management of chronic diabetes complications, including diabetic peripheral neuropathy (DPN)/diabetic foot complications, chronic kidney disease, sight‐threatening retinopathy and cardiovascular diseases. Of these complications, the most overlooked is DPN. Most consultations around the world do not even involve taking off shoes and socks to carry out a foot examination, and even when carried out, the peripheral neurological examination using the 10‐g monofilament diagnoses DPN when it is already at an advanced stage. Thus, all too often diabetes complications are diagnosed late, resulting in devastating outcomes, particularly in low‐ to middle‐income countries. There is, therefore, an urgent need to instigate new strategies to improve microvascular screening uptake using a holistic protocol for annual diabetes health checks outside the busy diabetes clinic. One such approach, the Sheffield One‐Stop Microvascular Screening Service, which involves modern point of care devices to diagnose DPN, has been shown to be feasible and effective, resulting in high uptake and early management of diabetes complications. This article outlines the advantages of this One‐Stop Microvascular Screening Service and a plan to trial an adapted version of this service to a resource‐limited country, the Philippines. If successful, this model has the potential for implementation in other countries around the world.

ABSTRACT Aims/Introduction To investigate risk factors for diabetic peripheral neuropathy (DPN) and to explore the connection between insulin‐like growth factor‐1 (IGF‐1) and DPN in individuals with type 2 diabetes. Materials and Methods A total of 790 patients with type 2 diabetes participated in a cross‐sectional study, divided into two groups: those with DPN (DPN) and those without DPN (non‐DPN). Blood samples were taken to measure IGF‐1 levels and other biochemical markers. Participants underwent nerve conduction studies and quantitative sensory testing. Results Patients with DPN exhibited significantly lower levels of IGF‐1 compared with non‐DPN patients (P 0.05), or the temperature detection threshold (P > 0.05). Multivariate regression analysis identified diabetes duration, HbA1c, and the low levels of IGF‐1 as independent risk factors (P

Abstract Aims/Introduction Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin‐1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin‐1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy. Materials and Methods A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN− n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin‐1 levels were measured by enzyme‐linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy. Results Corneal nerve fiber density, branch density, fiber length and serum netrin‐1 levels were significantly lower in the DN− and DN+ groups compared with controls (P

Abstract Background and Aims Sirtuin‐1 (SIRT1) has antidiabetic effects through the regulation of insulin secretion and modulation of inflammation. The SIRT1 rs3758391 gene polymorphism affects the level of SIRT1. The current study aimed to investigate the possible influence of SIRT1 gene variants in relation to oxidative stress parameters on the susceptibility to type 2 diabetes mellitus (T2DM) and its microvascular complications. Methods In this case‐control study 398 individuals including 300 patients with T2DM (100 T2DM without complication, 100 diabetic neuropathy patients and 100 patients with diabetic retinopathy) and 98 healthy subjects were studied for SIRT1 rs3758391 T > C variants. Also, the glutathione peroxidase (GPx) activity and the levels of glutathione (GSH), malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidative status (TOS) were determined by colorimetric methods. SIRT1 genotypes were detected using the polymerase chain reaction‐restriction fragment length polymorphism method. Results The C allele of SIRT1 reduced the risk of T2DM, diabetic neuropathy and diabetic retinopathy. Significantly lower levels of GSH, GPx, and TAC were found in diabetic patients compared to control group. However, the level of MDA was significantly higher in patients compared to healthy individuals. Considering all individuals, the GPx activity increased in the presence of the SIRT1 CC, and TC genotypes compared to the TT genotype. Among all studied individuals the activity of GPx was significantly higher in normal body mass index (BMI) subjects than overweight, and obese individuals. However, among overweight and obese diabetic, diabetic retinopathy and diabetic neuropathy patients the mean level of TOS was significantly higher compared to patients with normal BMI. Conclusions Our findings suggest a protective role for SIRT1 C allele against T2DM and diabetic neuropathy and diabetic retinopathy. We found in the presence of this allele the GPx activity increased. Also, we detected an enhanced oxidative stress level among overweight and obese patients with diabetes and its complications that could be involved in the pathogenesis of the disease.

Abstract The transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2) has multifarious action with its target genes having redox‐regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy.

Abstract Aims/Introduction Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. Materials and Methods Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow‐up. Results Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P

Key Clinical Message This case highlights the biomechanical influence of toe amputation on contralateral limb force elevation, possibly through reduced ipsilateral plantar flexor torque production. These findings provide insight into toe amputation‐related compensatory gait mechanics with greater inter‐limb asymmetry, which may increase the risk of musculoskeletal comorbidities, including osteoarthritis in contralateral limb.

ABSTRACT Aims Assessment for cardiovascular autonomic neuropathy (CAN) in patients with type 1 diabetes mellitus remains time‐consuming in the clinical setting. We aimed to examine the diagnostic performance of a portable point‐of‐care diagnostic tool (POCD) for assessing sural nerve conduction during the screening of CAN. Methods Nerve amplitude (AMPPOCD) and conduction velocity (CVPOCD) were measured in a cross‐sectional study including 198 asymptomatic patients with type 1 diabetes. CAN was diagnosed by the Ewing score and power spectral heart rate [low‐frequency (LF) and high‐frequency (HF) activity]. Diagnostic accuracy was determined by ROC curves. Results CVPOCD and AMPPOCD showed positive correlations with LF and HF, and a negative correlation with age. Overall, AMPPOCD had an 81.7% accuracy in identifying CAN [AUC = 0.817 (95% CI 0.692–0.942)] with an AMPPOCD ≤6 μV showing 90% sensitivity and 73% specificity. In a stepwise binary logistic regression analysis, the model (R2: 0.297; P

Abstract Introduction To investigate whether circulating chemokines contribute to the development of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes (T1D). Methods Fifty‐two patients with childhood‐onset T1D (mean age 28 ± 4 yrs.; diabetes duration 19.5 ± 5.5 yrs.) and 19 control subjects (mean age 26.5 ± 4.5 yrs.) were included in a cross‐sectional analysis of this long‐term longitudinal cohort study. A subgroup of 24 patients was followed prospectively for a further 10 yrs. Plasma levels of Th1‐ (CXCL9, CXCL10 and CXCL11), Th2‐ (CCL17 and CCL22) and Th17‐associated (CXCL8 and CCL20) chemokines were assessed in all subjects. Additionally, the TID patients underwent clinical examination and electroneurography. Results The frequency of neuropathy was 21% (11/52). Higher levels of CXCL9 levels were found in patients with DPN compared with control subjects (p = .019); by contrast, no difference between patients without DPN and control subjects was seen after adjustment for multiple comparisons. In patients with DPN, CXCL10 correlated negatively with suralis MCV and suralis SNAP (rho −0.966, p

Peripheral neuropathy is a common cause of morbidity in diabetes. Despite recent advancements in early diagnosis methods, there is a need for practical, highly sensitive, and cost-effective screening methods in clinical practice. This study summarizes evidence from systematic reviews and meta-analyses on the diagnostic accuracy of validated screening methods for diabetic peripheral neuropathy. Two independent reviewers assessed methodological quality and bias using AMSTAR and ROBIS tools. Seven reviews with 19,531 participants were included. The monofilament test showed inconsistent sensitivity ( S : 0.53-0.93) and specificity (Sp: 0.64-1.00), along with high variability in its application. Neuropad exhibited high S (86%, 95% CI 79-91). However, variations in the interpretation of results across the included studies may have impacted its Sp (65%, 95% CI 51-76). The Ipswich touch test exhibited adequate diagnostic accuracy ( S : 0.77, Sp: 0.96, DOR: 75.24) but lacked comparison with gold standard tests. In vibration perception studies, the biothesiometer outperformed the tuning fork ( S : 0.61-0.80 vs. 0.10-0.46). In general, heterogeneity was observed due to varied reference tests, thresholds, and patient differences. The development of automated analysis methods, as well as determination of predictive value of the combination of screening tools, is needed for further studies. Based on the study results, we suggest that clinicians should select screening tools tailored to their patient population, clinical setting, and available resources, as no single test can be universally recommended for all clinical scenarios., Competing Interests: Carlos A. Calderon-Ospina has carried out consulting activities for P&G Health International., (Copyright © 2024 María Mogilevskaya et al.)

Abstract To study whether diabetes mellitus (DM) would cause electrophysiological alterations in nodose ganglion (NG) neurons, we used patch clamp and intracellular recording for voltage and current clamp configuration, respectively, on cell bodies of NG from rats with DM. Intracellular microelectrodes recording, according to the waveform of the first derivative of the action potential, revealed three neuronal groups (A0, Ainf, and Cinf), which were differently affected. Diabetes only depolarized the resting potential of A0 (from −55 to −44 mV) and Cinf (from −49 to −45 mV) somas. In Ainf neurons, diabetes increased action potential and the after‐hyperpolarization durations (from 1.9 and 18 to 2.3 and 32 ms, respectively) and reduced dV/dtdesc (from −63 to ‐52 V s−1). Diabetes reduced the action potential amplitude while increasing the after‐hyperpolarization amplitude of Cinf neurons (from 83 and −14 mV to 75 and −16 mV, respectively). Using whole cell patch clamp recording, we observed that diabetes produced an increase in peak amplitude of sodium current density (from −68 to −176 pA pF−1) and displacement of steady‐state inactivation to more negative values of transmembrane potential only in a group of neurons from diabetic animals (DB2). In the other group (DB1), diabetes did not change this parameter (−58 pA pF−1). This change in sodium current did not cause an increase in membrane excitability, probably explainable by the alterations in sodium current kinetics, which are also induced by diabetes. Our data demonstrate that diabetes differently affects membrane properties of different nodose neuron subpopulations, which likely have pathophysiological implications for diabetes mellitus.

Abstract Diabetic neuropathy is a disorder that affects various regions of the nervous system and there is no specific treatment available for it. This study evaluated the protective effect of molsidomine in diabetic neuropathy in rats. Diabetes was induced in male Wistar rats by administrating streptozotocin (52 mg/kg ip). Diabetic rats were treated with molsidomine 5 mg/kg po and 10 mg/kg po. After 8 weeks of treatment, motor coordination, mechanical allodynia, mechanical hyperalgesia, nerve conduction velocity, and glycosylated hemoglobin were assessed. Thereafter, animals were killed and the sciatic nerve was isolated for measurement of reduced glutathione and lipid peroxidation, and histopathological analysis. Treatment with molsidomine significantly improved motor coordination, paw withdrawal threshold, mechanical threshold, and nerve conduction velocity. Furthermore, molsidomine treatment also reduced malondialdehyde levels and prevented depletion of reduced glutathione in the sciatic nerve homogenate. Histopathology revealed that molsidomine treatment maintained normal architecture of the sciatic nerve. The results of our study strengthen the alternative use of molsidomine in diabetic neuropathy.

Abstract Aims/Introduction Diabetic polyneuropathy (DPN) is a factor that reduces lower extremity muscle strength (LEMS) in older type 2 diabetes patients. This relationship remains unclear in longitudinal studies. Therefore, we longitudinally investigated the apparent effects of DPN on changes in LEMS. Furthermore, we cross‐sectionally examined relationships among DPN, LEMS, mobility and health‐related quality of life. Materials and Methods Bodyweight‐normalized (relative) knee extension force (KEF) was examined in 51 DPN and 54 non‐DPN patients (68.9 ± 5.6 and 70.2 ± 5.9 years, respectively) at baseline and follow up at 3.6 ± 0.6 years. At follow up, mobility was measured using a 25‐question geriatric locomotive function scale. Health‐related quality of life was assessed using the five‐dimensions of EuroQol for quality‐adjusted life years calculation. Results Relative KEF in the DPN group was significantly lower at follow up (1.22 ± 0.47 Nm/kg) than at baseline (1.31 ± 0.47 Nm/kg; P

Abstract Background Charcot’s Neuroarthropathy (Charcot foot) is a debilitating and destructive disorder resulting from neurological changes in the foot. Whilst the majority of cases are painless, as a result of disruption to sensory function, a common outcome is severe deformity that impacts considerably on foot function. The purpose of this study was to develop and validate a radiological severity scale to quantify resultant damage from acute mid foot Charcot’s. This in turn can be used to evaluate clinical outcomes related to different degrees of offloading. Methods A four round Delphi process was used to develop five tool items. Level of consensus and agreement was set at 80%. Inter-rater and intra-rater reliability was evaluated using 3 raters and 24 plain x-rays of chronic mid-foot Charcot’s. Strength of agreement of individual items and overall scores was calculated using weighted Kappa coefficients (S.E). Cronbach’s α was used to determine internal consistency. Floor (> 15% score 0) and ceiling (> 15% score 11) effects were examined at each time point. Spearman’s correlation coefficient was used to assess construct validity using Mobility and Usual Activity scores taken from the EQ-5D-5 L. Results Twenty two patients participated. The five item severity scale demonstrated a Cronbach’s α of 0.91. Intra-rater Kappa coefficients (SE) for total scores ranged from 0.84 (0.20) to 0.86 (0.20). Inter rater coefficients (SE) ranged from 0.72 (0.14) to 0.83 (0.14). Distribution was normal and no floor or ceiling effects were identified. Conclusion/interpretation This study suggests it may be possible to quantify resultant damage from mid foot Charcot’s. Given the physical and emotional impacts from long periods of complete immobilisation defining a minimum standard would be an important development in the management of Charcot foot.

Abstract Diabetic neuropathy (DN) is a common complication of diabetes and can be either painful or non‐painful. It is challenging to diagnose this complication, as no biomarker or clear consensus on the clinical definition of either painful or non‐painful DN exists. Hence, a hierarchical classification has been developed categorizing the probability of the diagnosis into: possible, probable or definite, based on the clinical presentation of symptoms and signs. Pain is a warning signal of tissue damage, and non‐painful DN therefore represents a clinical and diagnostic challenge because it often goes unnoticed until irreversible nerve damage has occurred. Simple clinical tests seem to be the best for evaluation of DN in the general care for diabetes. Screening programs at regular intervals might be the most optimal strategy for early detection and interventions to possibly prevent further neuronal damage and to lower the economic burden of this complication.

Abstract Aims/Introduction Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated. Results The administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells. Conclusions We showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy.

Abstract Aims/Introduction Recent studies advocate that omega‐3 polyunsaturated fatty acids (ω‐3 PUFAs) have direct anti‐oxidative and anti‐inflammatory effects in the vasculature; however, the role of ω‐3 PUFAs in Schwann cells remains undetermined. Materials and methods Immortalized mouse Schwann (IMS32) cells were incubated with the ω‐3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). The messenger ribonucleic acid levels of several anti‐oxidant enzymes (heme oxygenase‐1 [Ho‐1], nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1, catalase, superoxide dismutase and glutathione peroxidase) were identified using real‐time reverse transcription polymerase chain reaction. Ho‐1 and nicotinamide adenine dinucleotide [phosphate] H quinone oxidoreductase 1 protein levels were evaluated using Western blotting. Nuclear factor (erythroid‐derived 2)‐related factor 2 (Nrf2) of the nuclear fraction was also quantified using western blotting. Catalase activity and glutathione content were determined by colorimetric assay kits. Nrf2 promoter‐luciferase activity was evaluated by a dual luciferase assay system. Results Treatment with tert‐butyl hydroperoxide decreased cell viability dose‐dependently. DHA or EPA pretreatment significantly alleviated tert‐butyl hydroperoxide‐induced cytotoxicity. DHA or EPA increased the messenger ribonucleic acid levels of Ho‐1, nicotinamide adenine dinucleotide (phosphate) H quinone oxidoreductase 1 and catalase dose‐dependently. Ho‐1 protein level, catalase activity, Nrf2 promoter‐luciferase activity and intracellular glutathione content were significantly increased by DHA and EPA. Conclusions These findings show that DHA and EPA can induce Ho‐1 and catalase through Nrf2, thus protecting Schwann cells against oxidative stress. ω‐3 PUFAs appear to exert their neuroprotective effect by increasing defense mechanisms against oxidative stress in diabetic neuropathies.

Abstract Diabetic neuropathy (DN) is one of the major complications of diabetes. However, there are few approved effective therapies for painful or insensate DN. Recent studies have implicated oxidative stress and inflammation in the pathogenesis of DN, and suppressing these could be an important therapeutic strategy. We previously reported that Stachybotrys microspora triprenyl phenol‐44D (SMTP‐44D) exhibits both antioxidant and anti‐inflammatory activities. The aim of this study was to evaluate the effects of SMTP‐44D in a mouse model of streptozotocin‐induced DN. SMTP‐44D was administered for 3 weeks after the disease induction, and its effects were evaluated on the basis of mechanical and thermal thresholds, blood flow in the bilateral hind paw, and blood flow and conduction velocity in the sciatic nerve. Furthermore, the levels of inflammatory factors, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6 and malondialdehyde (MDA), in the sciatic nerve were assessed. Neurological degeneration was assessed by measuring myelin thickness and g‐ratio in the sciatic nerve. SMTP‐44D treatment significantly improved allodynia, hyperalgesia, blood flow, and conduction velocity in DN model mice in a dose‐dependent manner. Neurological degeneration was also significantly improved, accompanied by decreased levels of inflammatory factors (TNF‐α, 57.8%; IL‐1β, 51.4%; IL‐6, 62.8%; and MDA, 40.7% reduction rate against the diabetes mellitus + normal saline group). Thus, SMTP‐44D can improve allodynia and hyperalgesia in DN without affecting the body weight and blood glucose levels, which may be due to its antioxidant and anti‐inflammatory properties. In conclusion, SMTP‐44D could be a potential therapeutic agent for the treatment of DN.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia due to insulin deficiency and/or resistance. Vitamin K (VK) is a group of fat-soluble molecules, including naturally occurring vitamin K1 (phylloquinone). vitamin K2 (menaquinone), and synthetic vitamin K3 (menadione). Beyond coagulation, the health benefits of VK have been described to play different roles in both physiological and pathological processes such as inflammation, energy metabolism, neuroprotection, cellular growth, and survival. It was aimed to observe the antioxidant and/or neuroprotective activity of vitamin K1 in our model of chick embryo diabetic neuropathy (DN) induced by streptozotocin (STZ). Ninety White Leghorn, fertile and 0-day-old SPF (specific pathogen-free) eggs (57 ± 4 gr) were used in the study. Chick embryo blood brain tissues were taken for biochemical evaluation. Plasma insulin and glucose levels were measured. In addition, brain tissue total antioxidant level (TAS), total oxidant level (TOS), malondialdehyde (MDA), and vascular endothelial growth factor (VEGF) levels were measured. Plasma glucose levels were higher in the STZ-treated groups and lower in the treatment groups. Plasma insulin levels were observed to be higher in STZ groups in groups treated with high VK. Low TAS, high MDA, TOS, and VEGF levels were recorded in brain tissue STZ groups. Low VEGF, TOS, and MDA levels were recorded in the group treated with the highest VK, while high TAS levels were observed. In our STZ-induced chick embryo diabetic neuropathy model, we observed that VK1 reduced oxidant damage by showing antioxidant properties or by modulating antioxidant enzymes., (© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Diabetic neuropathy (DN) is the most prevalent complication of diabetes. Pharmacological treatments for DN are often limited in efficacy, so the development of new agents to alleviate DN is essential. The aim of this study was to evaluate the effects of rolipram, a selective phosphodiesterase-4 inhibitor (PDE-4I), and pentoxifylline, a general PDE inhibitor, using a rat model of DN. In this study, a diabetic rat model was established by i.p. injection of STZ (55 mg/kg). Rats were treated with rolipram (1 mg/kg), pentoxifylline (100 mg/kg), and combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for 5 weeks. After treatments, sensory function was assessed by hot plate test. Then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP, adenosine diphosphate and mitochondrial membrane potential (MMP) levels, Cytochrome c release, Bax, Bcl-2, caspase-3 proteins expression in DRG neurons were assessed by biochemical and ELISA methods, and western blot analysis. DRG neurons were histologically examined using hematoxylin and eosin (H&E) staining method. Rolipram and/or pentoxifylline significantly attenuated sensory dysfunction by modulating nociceptive threshold. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, prevented mitochondrial dysfunction, apoptosis and degeneration of DRG neurons, which appears to be mediated by inducing ATP and MMP, improving cytochrome c release, as well as regulating the expression of Bax, Bcl-2, and caspase-3 proteins, and improving morphological abnormalities of DRG neurons. We found maximum effectiveness with rolipram and pentoxifylline combination on mentioned factors. These findings encourage the use of rolipram and pentoxifylline combination as a novel experimental evidence for further clinical investigations in the treatment of DN., (© 2023 Wiley Periodicals LLC.)

Background and Aims: Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes. The Toronto Clinical Neuropathy Score (TCNS) is a useful tool for detecting DSP. However, it is not available in Spanish. The study aimed to translate and culturally adapt the TCNS and modified (mTCNS) scales into Spanish and evaluate their measurement properties., Methods: A multistep forward-backward method was used for translation and cultural adaptation. A panel of physicians subjected the final Spanish versions of TCNS and mTCNS (TCÑS, mTCÑS) to cognitive debriefing. Consecutive patients with diabetes mellitus and DSP were recruited from an outpatient clinic, and the TCÑS and mTCÑS were tested for construct validity, along with other measures., Results: The internal consistency of both TCÑS and mTCÑS was excellent, as evidenced by Cronbach's Alpha coefficients of 0.83 and 0.85, respectively. Furthermore, there was a robust positive correlation between TCÑS and mTCÑS. In addition, TCÑS was found to exhibit a strong negative correlation with sural sensory nerve action potential amplitude (r = -0.9206) and peroneal compound motor action potential amplitude (r = -0.729), while demonstrating a positive and strong correlation with the Michigan Neuropathy Screening Instrument (r = 0.713)., Interpretation: The TCÑS and mTCÑS are reliable and valid translations of the original TCNS. The TCÑS and mTCÑS can be used to diagnose and measure the severity of neuropathy in Spanish-speaking patients with diabetes., (© 2023 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background and Aims: The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed., Methods: A nested case-control study was performed on participants with youth-onset type 2 diabetes enrolled in the prospective Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Plasma NFL concentrations were measured at 4-year intervals from 2008 to 2020 in 50 participants who developed DN and 50 participants with type 2 diabetes who did not develop DN., Results: NFL concentrations were similar in the DN and no DN groups at the first assessment. Concentrations were higher in DN participants at all subsequent assessment periods (all p < .01). NFL concentrations increased over time in both groups, with higher degrees of change in DN participants (interaction p = .045). A doubling of the NFL value at Assessment 2 in those without DN increased the odds of ultimate DN outcome by an estimated ratio of 2.86 (95% CI: [1.30, 6.33], p = .0046). At the final study visit, positive Spearman correlations (controlled for age, sex, diabetes duration, and BMI) were observed between NFL and HbA1c (0.48, p < .0001), total cholesterol (0.25, p = .018), and low-density lipoprotein (LDL (0.30, p = .0037)). Negative correlations were observed with measures of heart rate variability (-0.42 to -0.46, p = <.0001)., Interpretation: The findings that NFL concentrations are elevated in individuals with youth-onset type 2 diabetes, and increase more rapidly in those who develop DN, suggest that NFL could be a valuable biomarker for DN., (© 2023 Peripheral Nerve Society.)

Diabetic neuropathy is a common complication of diabetes mellitus. Effective blood glucose control retards changes in nerve conduction velocity in type 1 diabetes. This study examined the relationship between glycemic control and electrophysiologic changes in diabetic neuropathy in 57 type 2 diabetic patients. Nerve conduction in the peroneal motor nerve, tibial motor nerve, and sural nerve were measured at study entry and at follow-up 24 ± 3.12 months later. Changes in individual nerves are expressed as a percentage change (PC) and overall electrophysiologic changes are expressed as the sum of individual PCs. The PCs for peroneal motor nerve velocity, tibial motor nerve velocity, and sural nerve velocity were all lower in patients with a mean HbA1c of 8.5% or less compared with those in patients with a mean HbA1c of more than 8.5%, and SPCV (sum of PC in velocity) was significantly inversely correlated with mean HbA1c. However, there was no significant difference in SPCV in subjects with or without hypertension, hypertriglyceridemia, or low high-density lipoprotein cholesterol concentration. In conclusion, hyperglycemia is the most important etiology for electrophysiologic progression in type 2 diabetic patients. Furthermore, a mean HbA1c of more than 8.5% will result in significant deterioration in electrophysiology.