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Aims: Diabetic peripheral neuropathy (DPN) often coexists with sudomotor dysfunction, resulting in an increased risk of diabetic foot. This study aimed to explore an efficient method for early diagnosis of DPN by establishing a quantitative Neuropad., Methods: We recruited 518 patients with type 2 diabetes. Neuropathy Symptoms Score (NSS) combined with Neuropathy Disability Score (NDS) was used to assess distal symmetrical peripheral neuropathy (DSPN). The area under the ROC curve (AUROC), sensitivity, and specificity were used to compare the diagnostic efficacy of quantitative Neuropad (the change rate of the chromatic aberration value per minute) and two types of visual Neuropad (visual Neuropad A: whether the time to complete colour change within 10 min, visual Neuropad B: the time to complete colour change) for DPN., Results: We did not observe very good diagnostic efficacy of Neuropad (visual Neuropad A and B: 0.59 and 0.64, quantitative Neuropad AUROC: 0.62-0.64) when using standard DSPN diagnostic criteria (NDS 6-12 or NDS 3-5 combined with NSS 5-9). When DPN was assessed by NSS + NDS ≥ 4, visual Neuropad B improved the specificity (AUROC 0.72, 67.00%, specificity 71.70%) by extending the detection time compared with visual Neuropad A (AUROC 0.62, sensitivity 81.80%, specificity 41.70%). Quantitative Neuropad significantly improved the diagnostic effect (AUROC 0.81, sensitivity 80.0%, specificity 76.3%) and reduced the detection time (4 min)., Conclusions: This study provides a new quantitative Neuropad, which has great potential to be an extremely useful diagnostic tool for early screening of sudomotor dysfunction in the clinical practice., (© 2024 John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate the association of fasting C-peptide and glucagon with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2DM)., Methods: A comprehensive evaluation was conducted on 797 patients with T2DM to assess the various risk factors affecting DPN. The subjects were categorized into short duration and long duration group according to the duration of diabetes with a threshold of 10 years. Logistic regression analysis was employed to examine the association between DPN and islet function, as well as other parameters. Receiver operating characteristic curve analysis was performed to evaluate the predictive capability of glucagon., Results: The fasting C-peptide levels were significantly lower in the DPN patients with short duration of diabetes, but lost significance in the long duration group. Conversely, a decreased level of glucagon was only observed in DPN patients with long duration of diabetes. For the group with long duration of diabetes, glucagon was the sole risk factor associated with DPN. The receiver operating characteristic curve analysis revealed that glucagon in the long duration group exhibited a moderate area under the curve of 0.706., Conclusions: The serum glucagon levels in T2DM patients with DPN exhibited bidirectional changes based on the duration of diabetes. Decreased glucagon was associated with DPN in T2DM patients with long duration of diabetes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Diabetic peripheral neuropathy (DPN) occurs in >50% of diabetic patients and is a high risk-factor of balance problems and risk of falls. Impaired balance can lead to reduced function, which has a detrimental effect on patients' quality of life. Structured strength and balance training can result in sustained improvements in muscle strength, coordination, balance, functional status and quality of life., Objective: To determine the combined effects of strength and balance training versus aerobic training on balance, severity of symptoms of DPN, and quality of life in patients with DPN., Methods: This double blinded, two arm parallel design Randomized Clinical Trial. The study was conducted from March to December 2020 in the AIMS diabetic center Peshawar, Pakistan. Participants were selected through convenience sampling technique and randomly allocated into strength plus balance and aerobic training groups. Type 2 diabetic patients of both sexes, aged 40 to 80 years, with a Toronto neuropathy score ≥6 recruited, while patients with ulceration/infection of feet, medical/Surgical conditions, and non-ambulatory patients were excluded from this study. Intervention was applied 3 days a week for 8 weeks. The Toronto clinical neuropathy system was used to assess neuropathy severity, SF-36 to assess quality of life and the Berg balance scale was used for assessment of balance. Assessment was done at the baseline and after 8 weeks of intervention using SPSS. Version 22 was used for analysis., Results: The mean age of the participants was 60.80 ± 9.73. Between group analysis, which showed were statistically insignificant for neuropathy severity, balance and all domains of quality of life (p-value >0.05) except SF-36 General Health Perception Score, with Mean ± SD of 62.50 ± 7.54 in group A versus Mean ± SD of in group B 60.00 ± 15.98 (p-value = 0.05). Within group analysis showed statistically significant results for neuropathy severity, balance and all domains of quality of life (p-value<0.05)., Conclusion: This study concluded that there is a statistically significant effect of structured balance and strength training and aerobic training on severity of DPN, balance and quality of life. But there was no statistically significant difference in improvement between the two intervention groups., (© 2024 John Wiley & Sons Ltd.)

Diabetic peripheral neuropathy (DPN) is considered as one of the most important complications of diabetes mellitus. At present, effective treatments that might improve the damaged neurological function in DPN are sorely needed. As myricetin has been proved to possess excellent neuroprotective and antioxidant effects, it might have therapeutic potential for DPN. Therefore, the purpose of our study was to detect the potential beneficial effect of myricetin on DPN. A single dose of 50 mg/kg of streptozotocin was applied in rats for the establishment of diabetic models. Different doses of myricetin (0.5 mg/kg/day, 1.0 mg/kg/day, and 2.0 mg/kg/day) were intraperitoneally injected for 2 weeks from the 21st day after streptozotocin injection. After the final myricetin injection, behavioral, electrophysiological, biochemical, and protein analyses were performed. In the present study, myricetin significantly ameliorated diabetes-induced impairment in sensation, nerve conduction velocities, and nerve blood flow. In addition, myricetin significantly reduced the generation of advanced glycation end-products (AGEs) and reactive oxygen species (ROS), and elevated Na + , K + -ATPase activity and antioxidant activities in nerves in diabetic animals. Additional studies revealed that myricetin significantly raised the hydrogen sulfide (H 2 S) levels, and elevated the expression level of heme oxygenase-1 (HO-1) as well as nuclear factor-E2-related factor-2 (Nrf2) in diabetic rats. In addition, myricetin has the capability of decreasing plasma glucose under diabetic conditions. The findings in our present study collectively indicated that myricetin could restore the impaired motor and sensory functions under diabetic conditions. The Nrf2-dependent antioxidant action and the capability of decreasing plasma glucose might be the underlying mechanisms for the beneficial effect of myricetin on impaired neural functions. Our study showed the therapeutic potential of myricetin in the management of DPN., 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 © 2022 Ma, Liu, Chen, Yu and Xiang.)

Increasing evidence suggested that inhibiting the apoptosis of Schwann cells (SCs) and promoting nerve growth factor (NGF) expression in sciatic nerves play key roles in preventing the onset of diabetic peripheral neuropathy (DPN). Curcumin, a primary bioactive substance in turmeric with multiple characteristics, has been shown to have many therapeutic effects in a variety of diseases. However, curcumin is poorly studied in the DPN models. We aimed to explore the therapeutic benefits and underlying mechanism of curcumin in high fat/sugar diets joint streptozotocin (STZ)-induced DPN rat models. Sprague-Dawley (SD) rats were divided into five groups (6 rats per group), control group, DPN group, Curcumin groups (50, 100, and 150 mg/kg). Curcumin was administered intragastrically once per day for 4 continuous weeks. Body weight (BW) and fasting blood glucose (FBG) were monitored in all groups. The mechanical withdraw threshold (MWT) was measured. We also assessed neuropathic change by testing nerve conductance velocity (NCV) in sciatic nerves. TEM was applied to observe the sciatic nerves ultrastructure. The SCs apoptosis in sciatic nerves was stained using TUNEL kit. NGF contents in sciatic nerves and serum were detected using western blotting and ELISA analysis. The results showed curcumin had no obvious effect on the BW and FBG change. Curcumin (100 and 150 mg/kg) attenuated the MWT, NCV, and sciatic nerves ultrastructure in DPN rats. Curcumin (50, 100 and 150 mg/kg) reduced SCs apoptosis in sciatic nerves. In addition, curcumin at 150 mg/kg had the best efficacy in increasing protein expression of NGF in sciatic nerves and serum NGF level. Our work demonstrated that curcumin has neuroprotective effects for the treatment of DPN., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: To investigate the relationship between diabetic peripheral neuropathy (DPN) and gait abnormality in diabetic patients., Methods: Related research concerning the gait of diabetic patients with and without DPN was collected and analyzed by searching PubMed, Embase, and Web of Science. Statistical analysis was performed by using RevMan 5.3 software., Results: Twenty-one studies were included in this meta-analysis, consisting of 499 diabetic neuropathy patients and 467 diabetes controls without neuropathy. Meta-analysis results showed lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment in the DPN group, compared with their counterparts., Conclusion: Among diabetic patients, those complicated with DPN possess lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment., 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 © 2022 Wang, Peng, Zhang, Sun and Hu.)

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. It often causes symmetrical paresthesia, loss of sensation, and hyperalgesia. Without early intervention, it might lead to diabetic foot ulceration, gangrene, and subsequent amputation in people with diabetes. DPN is an insidious disease and often underdiagnosed. This paper reviews the current national and international prevalence of DPN, screening methods for early DPN, including quantitative sensory measurement, neurological function scoring system, confocal microscopy, and high-frequency ultrasound, and summarizes the related research progress, clinical application, and development prospects of these methods in recent years., Competing Interests: The author declares 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 © 2021 Yu.)

Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes mellitus, and are major risk factors for foot ulceration, amputation and cardiovascular dysfunction. Peripheral neuropathies manifest with either painful or painless symptoms, but many patients experience both. Once diagnosed appropriately, painful diabetic neuropathy management presents a unique challenge for physicians and should be considered as a syndrome, clinically distinct from diabetic peripheral neuropathy. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue and neurodegenerative changes are precipitated by compromised nerve vascular supply. Metabolic changes include the elevated polyol pathway activity, the increased oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes. These mechanisms work in combination and interact in a mutually facilitatory fashion. This review focuses on the current therapies for the management of peripheral and cardiovascular autonomic neuropathy and of painful neuropathy as a distinct entity, based on the current knowledge of diabetic neuropathy. Moreover, the role of ACE inhibition has been explored in the treatment of Cardiovascular Autonomic Neuropathy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetic peripheral neuropathy (DPN) is a complication of diabetes connected with morbidity and mortality. DPN presents deterioration of peripheral nerves with pain, feebleness, and loss of sensation. Particular medications might display their remedial potential by controlling neuroinflammation. Palmitoylethanolamide (PEA) is an autacoid local injury antagonist distinguished for its neuroprotective, analgesic, and anti-inflammatory properties in numerous experimental models of neuroinflammation. Based on these findings, the goal of this work was to better test the neuroprotective effects of a formulation of micronized PEA (PEA-m) and the probable mechanism of action in a mouse model of DPN induced by streptozotocin (STZ) injection. Diabetic and control animals received PEA-m (10 mg/kg) by oral gavage daily starting 2 wk from STZ injection. After 16 wk, the animals were euthanized, and blood, urine, spinal cord, and sciatic nerve tissues were collected. Our results demonstrated that after diabetes induction, PEA-m was able to reduce mechanical, thermal hyperalgesia, and motor alterations as well as reduce mast cell activation and nerve growth factor expression. In addition, PEA-m decreased neural histologic damage, oxidative and nitrosative stress, cytokine release, angiogenesis, and apoptosis. Moreover, spinal microglia activation (IBA-1), phospho-P38 MAPK, and nuclear factor NF-κB inflammatory pathways were also inhibited. The protective effects of PEA-m could be correlated at least in part to peroxisome proliferator-activated receptor-α activation. In summary, we demonstrated that PEA-m represents a new therapeutic strategy for neuroinflammation pain associated with mixed neuropathies.-Impellizzeri, D., Peritore, A. F., Cordaro, M., Gugliandolo, E., Siracusa, R., Crupi, R., D'Amico, R., Fusco, R., Evangelista, M., Cuzzocrea, S., Di Paola, R. The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice.

Objective: Detection of motor involvement in diabetic polyneuropathy (DPN) by nerve conduction studies (NCS) does not occur until there is substantial loss of motor units, because collateral reinnervation maintains compound muscle action potential (CMAP) amplitude. Motor unit number estimation (MUNE) methods may therefore be more sensitive. This study was undertaken to test whether the novel method, MScanFit MUNE (MScan) can detect motor involvement in DPN despite normal NCS., Methods: Fifty-two type-2 diabetic patients and 38 healthy controls were included. The median nerve was examined in all participants using standard NCS and a detailed CMAP scan, used for MScan. Additional lower extremity NCS in patients were used for DPN diagnosis., Results: Of 52 diabetic patients, 21 had NCS-defined DPN while lower extremity NCS were normal in 31 patients. MScan motor unit number and size showed higher sensitivity and incidence of abnormality than motor NCS parameters, and a similar sensitivity to sensory NCS., Conclusions: MScan is able to detect motor axonal damage at times when collateral reinnervation limits NCS changes., Significance: MScan is a sensitive method to detect motor involvement in DPN, which our data suggests is present as early as sensory., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The Center for Disease Control (CDC) estimates that 29 million Americans have diabetes, and 70% of diabetic patients develop diabetic peripheral neuropathy [1,2]. Up to 27% of the direct medical cost of diabetes may be attributed to DPN [3]. A 2013 article from the American Diabetes Association reported a $176 billion direct medical cost of diabetes in 2012 [4]. DPN patients often suffer from shooting and burning pain in their distal limbs and a severe loss of sensation. Diabetic foot ulcers, infections, and amputations may follow. Currently available treatments: tricyclic antidepressants, anticonvulsants such as gabapentin and pregabalin, serotonin and norepinephrine reuptake inhibitor, duloxetine, topical 5% lidocaine (applied to the most painful area) can manage painful symptoms but do not address the underlying pathologies of DPN and diabetic wound ulcers. A combination of pain-reducing medications can provide relief when individual medications fail, and opioids such as tramadol and oxycodone may be administered with these medications to reduce pain [5]. Due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. Our hypothesis is that a deficiency of nitric oxide synthase in diabetic patients leads to a lack of vascularization of the peripheral nerves, which causes DPN; and this could be treated with vasodilators such as nitric oxide. In this paper, the mechanisms of DPN are reviewed and analyzed to elucidate the potential of a transdermal nitric oxide application for the treatment of DPN and diabetic wound ulcers by increasing vasodilation., (Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux has gained attention as a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss. C57Bl6/j wild-type mice were analyzed longitudinally up to 22 weeks in the streptozotocin (STZ) model of type 1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction. Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves were only evident at 22 weeks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared with buffer-injected age-matched control mice, mice at 12 and 22 weeks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid, and malic acid were observed to be significantly reduced in sciatic nerve at 22 weeks post-STZ. In addition, we also found the increase in levels of sorbitol and L-lactate in peripheral nerve from 12 weeks post-STZ injection. Amino acid screen in serum showed that the amino acids valine (Val), isoleucine (Ile), and leucine (Leu), grouped together as BCAA, increased more than twofold from 12 weeks post-STZ. Similarly, the levels of tyrosine (Tyr), asparagine (Asn), serine (Ser), histidine (His), alanine (Ala), and proline (Pro) showed progressive increase with progression of diabetes. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fiber loss in skin and contribute to onset and progression of peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic complications. Mechanisms underlying nerve damage and sensory loss following metabolic dysfunction remain largely unclear. Recently, hyperglycemia-induced mitochondrial dysfunction and the generation of reactive oxygen species (ROS) have gained attention as possible mechanisms of organ damage in diabetes. Hypoxia-inducible factor 1 (HIF1α) is a key transcription factor activated by hypoxia, hyperglycemia, nitric oxide as well as ROS, suggesting a fundamental role in DPN susceptibility. We analyzed regulation of HIF1α in response to prolonged hyperglycemia. Genetically modified mutant mice, which conditionally lack HIF1α in peripheral sensory neurons (SNS-HIF1α -/- ), were analyzed longitudinally up to 6 months in the streptozotocin (STZ) model of type1 diabetes. Behavioral measurements of sensitivity to thermal and mechanical stimuli, quantitative morphological analyses of intraepidermal nerve fiber density, measurements of ROS, ROS-induced cyclic GMP-dependent protein kinase 1α (PKG1α), and levels of vascular endothelial growth factor (VEGF) in sensory neurons in vivo were undertaken over several months post-STZ injections to delineate the role of HIF1α in DPN. Longitudinal behavioral and morphological analyses at 5, 13, and 24 weeks post-STZ treatment revealed that SNS-HIF1α -/- developed stronger hyperglycemia-evoked losses of peripheral nociceptive sensory axons associated with stronger losses of mechano- and heat sensation with a faster onset than HIF1α fl/fl mice. Mechanistically, these histomorphologic, behavioral, and biochemical differences were associated with a significantly higher level of STZ-induced production of ROS and ROS-induced PKG1α dimerization in sensory neurons of SNS-HIF1α -/- mice as compared with HIF1α fl/fl . We found that prolonged hyperglycemia induced VEGF expression in the sciatic nerve which is impaired in SNS-HIF1α mice. Our results indicate that HIF1α is as an upstream modulator of ROS in peripheral sensory neurons and exerts a protective function in suppressing hyperglycemia-induced nerve damage by limiting ROS levels and by inducing expression of VEGF which may promote peripheral nerve survival. Our data suggested that HIF1α stabilization may be thus a new strategy target for limiting sensory loss, a debilitating late complication of diabetes. KEY MESSAGES: • Impaired hypoxia-inducible factor 1α (HIF1α) signaling leads to early onset of STZ-induced loss of sensation in mice. • STZ-induced loss of sensation in HIF1α mutant mice is associated with loss of sensory nerve fiber in skin. • Activation of HIF1α signaling in diabetic mice protects the sensory neurons by limiting ROS formation generated due to mitochondrial dysfunction and by inducing VEGF expression.

Introduction: Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes and accounts for significant morbidity by pre-disposing the foot to ulceration and lower extremity amputation. Using a large US commercial claims database, this study analyzes the drug class usage and co-morbidities associated with DPN as well as estimates the associated economic burden., Methods: Patients older than 18 and diagnosed with DPN were followed longitudinally for 2 years pre- and post-diagnosis date. Patients were analyzed for age, gender, hospital visits, ER and doctor's office visits, pharmacy claims, co-morbidities, and drug classes prescribed pre- and post-DPN diagnosis. The economic impact post-diagnosis of DPN was compared to the patients' pre-diagnosis resource use., Results: In total, 10,982 incident DPN patients were identified, with a median age of 61 years, and an equal gender distribution. Post-DPN diagnosis, there was a 20% increase in the number of patients visiting hospitals and a 46% increase in the number of visits to hospitals. Further, there was a 46% increase in the annual cost per patient associated with visits to the hospitals, emergency room (ER), doctor's office, and pharmacy claims. As per the analysis presented in this study, increase in the number of visits, cost per visit, and number of patients visiting hospitals, ER and doctor's offices added up to a 46% increase in aggregated cost associated with Medical Resource Utilization (MRU) owing to DPN, with the highest increase (60%) in costs associated with hospitalization of patients with DPN., Conclusion: This study highlights the high economic burden associated with DPN. The results indicate that resource use significantly increases post-diagnosis of DPN, which leads to an increase in costs for payers. A noticeable proportion of patients with DPN had a pain co-diagnosis signifying the need for treatments that can effectively manage painful DPN.

Background: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron–sulfur clusters are essential cofactors for numerous iron–sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. Methods: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. Results: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. Conclusions: Iron–sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) is a prominent complication in persons with type 2 diabetes mellitus (T2DM) and has a major influence on morbidity. Emerging evidence suggests that elevated plasma fibrinogen (FIB) levels, which are indicative of inflammation and coagulation, may be linked to various diabetic complications. Nevertheless, there hasn't been much research done on the connection between PN and plasma fibrinogen levels in T2DM. Objective: This study aimed to investigate the correlation between plasma fibrinogen levels and the presence of PN in patients with T2DM. Patients and methods: A cross-sectional study that included 120 patients diagnosed with T2DM. They were divided into 2 equal groups: Group I contained 60 patients with diabetic peripheral neuropathy (DPN) and group II that involved 60 patients without DPN. Results: The study revealed a significant increase in serum fibrinogen levels in patients with diabetic neuropathy. Those with diabetic neuropathy had a mean fibrinogen level of 11.585 ± 4.256, compared to 1.798 ± 0.566 in patients without neuropathy (p-value < 0.001). Furthermore, the study indicated that plasma fibrinogen levels were significantly higher in patients with severe diabetic neuropathy, with a mean of 14.813 ± 3.713, followed by those with moderate neuropathy (mean 10.315 ± 2.562), and the lowest levels were observed in patients with mild neuropathy (mean 8.331 ± 3.558), with a p-value of 0.001. Conclusion: Increased plasma fibrinogen levels are substantially related with DPN in patients with T2DM. These results indicate that plasma fibrinogen could potentially act as a biomarker for identifying T2DM patients who are at increased risk of developing PN. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is the most frequent kind of neuropathy globally. DPN is one of the most prevalent and serious microvascular consequences of diabetes. Objective: To assess prevalence of DPN, its pattern, severity and associated risk factors in Benha City, Egypt. Patients and methods: This cross-sectional observational study was conducted on 500 diabetic patients (type 1 and type 2). All patients were subjected to complications of diabetes especially microvascular and macrovascular complications, diabetic foot and history of previous operations, physical examinations (general, neurological, sensory examination and Toronto clinical scoring system (TCSS)) and laboratory investigations (CBC, hemoglobin A1c (HbA1c), kidney function tests, liver function tests, serum thyroid-stimulating hormone and lipogram). Results: Body mass index (BMI), height, duration of diabetes, HbA1c, and thyroid-stimulating hormone (TSH) had a strong positive significant correlation with TCSS score (r=0.338, P< 0.001; r=0.335, P< 0.001; r=0.630, P< 0.001; r=0.806, P< 0.001; r=0.332, P< 0.001 respectively). Low-density lipoprotein-cholesterol (LDL-C) level and triglycerides level had no significant correlation with TCSS score (r= 0.015, P= 0.743; r= 0.074, P= 0.097 respectively). Conclusions: The primary risk factors include higher BMI, height, hard working, smoking, poor glycemic management, extended diabetes mellitus (DM), metformin use, chronic kidney disease (CKD), and an abnormal thyroid profile. After documenting these findings, a greater effort should be made to lower the frequency and severity of PDN in diabetic patients by education emphasising regular foot care, strict glucose control, and lifestyle adjustment. [ABSTRACT FROM AUTHOR]

Diabetic Peripheral Neuropathy (DPN) poses an escalating threat to public health, profoundly impacting well-being and quality of life. Despite its rising prevalence, the pathogenesis of DPN remains enigmatic, and existing clinical interventions fall short of achieving meaningful reversals of the condition. Notably, neurostimulation techniques have shown promising efficacy in alleviating DPN symptoms, underscoring the imperative to elucidate the neurobiochemical mechanisms underlying DPN. This study employs an integrated multi-omics approach to explore DPN and its response to neurostimulation therapy. Our investigation unveiled a distinctive pattern of vesicular glutamate transporter 2 (VGLUT2) expression in DPN, rigorously confirmed through qPCR and Western blot analyses in DPN C57 mouse model induced by intraperitoneal Streptozotocin (STZ) injection. Additionally, combining microarray and qPCR methodologies, we revealed and substantiated variations in the expression of the Amyloid Precursor Protein (APP) family in STZ-induced DPN mice. Analyzing the transcriptomic dataset generated from neurostimulation therapy for DPN, we intricately explored the differential expression patterns of VGLUT2 and APPs. Through correlation analysis, protein-protein interaction predictions, and functional enrichment analyses, we predicted the key biological processes involving VGLUT2 and the APP family in the pathogenesis of DPN and during neurostimulation therapy. This comprehensive study not only advances our understanding of the pathogenesis of DPN but also provides a theoretical foundation for innovative strategies in neurostimulation therapy for DPN. The integration of multi-omics data facilitates a holistic view of the molecular intricacies of DPN, paving the way for more targeted and effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic distal symmetric polyneuropathy (DDSP) is the most prevalent form of diabetic peripheral neuropathy, and 25% of patients develop pain in their toes. DDSP is associated with increased cutaneous microvessel density (MVD), reduced skin blood flow, endothelial dysfunction, and impaired fluid filtration with vasodilation. The Piezo family of mechanosensitive channels is known to be involved in the control of vascular caliber by converting mechanical force into intracellular signals. Furthermore, Piezo2 is particularly involved in peripheral pain mechanisms of DDSP patients. To date, very little is known about the number, structure, and PIEZO expression in cutaneous blood vessels (BVs) of individuals with DDSP and their relation with pain and time span of diabetes. Methods and results: We studied microvessels using endothelial markers (CD34 and CD31) and smooth cell marker (a-SMA) by indirect immunohistochemical assay in sections of the glabrous skin of the toes from patients and controls. MVD was assessed through CD34 and CD31 immunoreaction. MVD determined by CD34 is higher in short-term DDSP patients (less than 15 years of evolution), regardless of pain. However, long-term DDSP patients only had increased BV density in the painful group for CD31. BVs of patients with DDSP showed structural disorganization and loss of shape. The BVs affected by painful DDSP underwent the most dramatic structural changes, showing rupture, leakage, and abundance of material that occluded the BV lumen. Moreover, BVs of DDSP patients displayed a Piezo1 slight immunoreaction, whereas painful DDSP patients showed an increase in Piezo2 immunoreaction. Discussion: These results suggest that alterations in the number, structure, and immunohistochemical profile of specific BVs can explain the vascular impairment associated with painful DDSP, as well as the temporal span of diabetes. Finally, this study points out a possible correlation between increased vascular Piezo2 immunostaining and pain and decreased vascular Piezo1 immunostaining and the development of vasodilation deficiency. [ABSTRACT FROM AUTHOR]

Background: Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods: All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate composite Z scores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN. Results: We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the composite Z score for latency (β = 0.132, t = 2.330, p = 0.021), amplitude (β = − 0.164, t = − 2.838, p = 0.005) and NCV (β = − 0.210, t = − 3.662, p < 0.001). Moreover, the prevalence of DPN in the first, second, third and fourth quartiles of CEA level was 12.9%, 19.0%, 29.4% and 40.4%, respectively (p for trend < 0.001); the corresponding adjusted odds ratios and 95% CIs for DPN in CEA quartiles were 1, 1.47 (0.45–4.82), 1.72 (0.54–5.53) and 4.58 (1.39–15.06), respectively. Furthermore, the optimal cut-off value of high-normal serum CEA to discriminate DPN was ≥ 2.66 ng/mL, with a Youden index of 0.28, sensitivity of 66.67% and specificity of 61.00%. Conclusions: Increased serum CEA levels within the normal range are closely linked to dysfunction of peripheral nerve conduction and the risk of DPN, and high-normal serum CEA levels are a potential risk factor for DPN in T2D. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is considered as one of the most important complications of diabetes mellitus. At present, effective treatments that might improve the damaged neurological function in DPN are sorely needed. As myricetin has been proved to possess excellent neuroprotective and antioxidant effects, it might have therapeutic potential for DPN. Therefore, the purpose of our study was to detect the potential beneficial effect of myricetin on DPN. A single dose of 50 mg/kg of streptozotocin was applied in rats for the establishment of diabeticmodels. Different doses of myricetin (0.5mg/kg/day, 1.0mg/kg/day, and 2.0 mg/kg/day) were intraperitoneally injected for 2 weeks from the 21st day after streptozotocin injection. After the final myricetin injection, behavioral, electrophysiological, biochemical, and protein analyses were performed. In the present study, myricetin significantly ameliorated diabetes-induced impairment in sensation, nerve conduction velocities, and nerve blood flow. In addition, myricetin significantly reduced the generation of advanced glycation end-products (AGEs) and reactive oxygen species (ROS), and elevated Na+, K+-ATPase activity and antioxidant activities in nerves in diabetic animals. Additional studies revealed that myricetin significantly raised the hydrogen sulfide (H2S) levels, and elevated the expression level of heme oxygenase-1 (HO-1) as well as nuclear factor-E2-related factor-2 (Nrf2) in diabetic rats. In addition, myricetin has the capability of decreasing plasma glucose under diabetic conditions. The findings in our present study collectively indicated that myricetin could restore the impaired motor and sensory functions under diabetic conditions. The Nrf2-dependent antioxidant action and the capability of decreasing plasma glucose might be the underlying mechanisms for the beneficial effect of myricetin on impaired neural functions. Our study showed the therapeutic potential of myricetin in the management of DPN. [ABSTRACT FROM AUTHOR]

Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the in vitro growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a metabolic disease which is complicated by occurrence of diabetic peripheral neuropathy (DPN). Vitamin D deficiency contributes to the etiology and progression of type 2 DM and development of micro-vascular complications so in this study we assessed vitamin D level in diabetic patients to evaluate the association between vitamin D level and occurrence of diabetic neuropathy and to assess if there is relationship with certain subtypes of diabetic neuropathy. This case–control study was conducted on 80 type 2 diabetic patients divided into four groups equally. (A): Diabetic patients with painful diabetic neuropathy. (B): Diabetic patients with painless diabetic neuropathy. (C): Diabetic patients with painless neuropathy, but have neuropathic ulcer. (D): Diabetic patients without neuropathy. All patients underwent clinical, neurological examination and nerve conduction study. Then CBC and vitamin D were estimated in the studied groups. Results: Vitamin D level among the studied painful diabetic neuropathy group (A) ranged from 5.3 to 40.5 ng/dl with mean 17.4 ± 10.9. 70% of them had deficient vitamin D level. In the painless diabetic neuropathy group (B), vitamin D level ranged from 6.5 to 35.5 ng/dl with mean 18.9 ± 8.49. 60% of them had deficient vitamin D level, while only 5% of the diabetic patients without neuropathy had deficient vitamin D level. There is significant negative correlation between vitamin D level and score of neuropathy where the lower vitamin D level the higher neuropathy score. Conclusion: Lower vitamin D levels were found in diabetic patients with neuropathy especially those with painful neuropathy. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is one of the most common and complex chronic complications of diabetes, but it is clinically lacking effective means for early diagnosis and early treatment. MicroRNA, in the occurrence and development of the disease, has an important regulatory role. Its role in diabetes has been reported more. However, specific research on microRNA in DPN is rare. Methods: Based on the results of bioinformatics screening, miR-377 and miR-216a, their respective target molecules growth association protein 43 (GAP-43) and angiopoietin-like 4 protein (ANGPTL4), and related pathways peroxisome proliferator activated receptor gamma (PPARG) and chemerin were tested by RT-qPCR and ELISA in blood samples of DPN to analyze the correlation between these differentially expressed molecules and clinico-pathological factors of DPN. Results: In this study, we found that miR-377, miR-216a, GAP-43, ANGPTL4, and PPARG were significantly differentially expressed genes for DPN. The correlation analysis showed that they were closely related to the clinical indicators of DPN suggesting that they may be involved in the development of DPN. In addition, receiver operating characteristic (ROC) curves generated for miR216a, miR377, ANGPTL4, GAP43, PPARG revealed that they can be used as new molecular diagnostic markers of DPN. Conclusions: miR-216a, miR-377, ANGPTL4, GAP-43, and PPARG could potentially be biomarkers of DPN. [ABSTRACT FROM AUTHOR]

Patients with diabetes mellitus may experience painful and nonpainful diabetic peripheral neuropathy (DPN). This article offers an overview of DPN and the clinical assessment and management of patients with DPN, as well as the nurse's role in supporting these patients. [ABSTRACT FROM AUTHOR]