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Abstract Background Interleukin-9 (IL-9) is a cytokine that has recently been proposed to be associated with type 2 diabetes mellitus (T2DM) risk, but the role it plays in the development of pre-diabetes (PD) and diabetic neuropathy (DN) is unknown. Therefore, this study analyzed serum IL-9 levels in individuals with PD (n = 89), T2DM patients without DN (n = 66), T2DM patients with DN (n = 21), and non-diabetic controls (n = 84) using an ELISA kit. Results Serum IL-9 levels (median and interquartile range) were significantly lower in the PD (18.9 [12.6–22.1] pg/mL; probability [p]

Background: Diabetes mellitus is a micro vascular disorder that is on a rapid increase in number of diagnosed and undiagnosed cases, and it is estimated that approximately 191 million people may be suffering from this disorder by year 2030. It affects major vital organ and organ systems of the body, and is frequently accompanied with neuropathy, nephropathy, cardiovascular disorders and retinopathy. The quality of life of diabetic patients is significantly impacted by diabetic neuropathy. Aims and Objectives: To investigate the difference in peripapillary retinal nerve fibre layer (RNFL) thickness between normal population and Type-II diabetic patients without diabetic retinopathy using optical coherence tomography. Materials and Methods: Between May 2021 and May 2022, this case control research was conducted at Skims MCH Bemina SRINAGAR. Out of 400 eyes, 200 eyes belonged to healthy people and 200 eyes to Type II diabetics who did not have diabetic retinopathy. Age and gender were the same for both groups. Results: Mean age of study population was 47.05±5.47 years. Mean peripapillary RNFL thickness was 126.98±10.07 μm in Group-A (normal persons), and 120.77±5.41 μm in Group-B (Type-II diabetes). Between the two groups, there was a statistically significant difference in mean RNFL thickness as well as RNFL thicknesses in each quadrant (P=0.001). Conclusion: The diagnosis of any disease based on RNFL thinning must take into consideration the fact that diabetic patients have thin RNFL in comparison to normal persons.

Background and Aims The increase in loading rate is associated with lower limb injuries such as tibial stress fracture. Quadriceps muscle activities absorb ground reaction force (GRF) shocks by eccentric activation. This study aims to evaluate the effect of aerobic training on the relationship between loading rate and quadriceps muscle activities in men with diabetic neuropathy (DN). Methods In this double-blinded, randomized, controlled clinical trial, participants were 40 men with DN who were selected by a convenience sampling method and randomly divided into two groups of training (n=20, age: 54.9±7.3, body mass index: 28.4±5.4) and control (n=20; age: 54.1±7.3, body mass index: 28.5±5.1). The GRF data was recorded using a force plate system during walking. The electrical activity of selected lower limb muscles was recorded using electromyography method. The training group performed aerobic training for 12 weeks (three sessions per week). Results The results showed an increase in the negative relationship between vertical loading rate and vastus lateralis activities after training (P=0.028). The activities of vastus medialis and rectus femoris muscles showed no significant relationship with loading rate after training (P>0.05). Conclusion Aerobic training can improve the relationship between vastus lateralis muscle activity and vertical loading rate in men with DN.

Abstract Background The prevalence of microvascular complications in type 2 diabetes mellitus (T2DM) is increasing. The effect of lipid profiles on diabetic microvascular complications remains debated. This research aimed to study the correlation between lipid profiles and microvascular complications. Methods This retrospective cross-sectional study included 1096 T2DM patients. The patients were divided into the control, diabetic retinopathy (DR), nephropathy (DKD), and peripheral neuropathy (DPN) groups based on the existence of corresponding complications. The lipid profiles were analyzed, and the effect on complications was assessed by logistic regression. Results Compared with the control group, the diabetic microvascular complications group had a higher dyslipidemia rate. The rate of high TGs increased significantly with an increasing number of complications. High TG levels contributed to the risk of DKD, DR, and DPN [odds ratios (ORs): 2.447, 2.267, 2.252; 95% confidence interval: 1.648–3.633, 1.406–3.655, 1.472–3.445]. In the age (years) > 55, T2DM duration (years) > 10, and HbA1c (%) ≥ 7 groups, the risk of high TGs was higher for DKD (ORs: 2.193, 2.419, 2.082), DR (ORs: 2.069, 2.317, 1.993), and DPN (ORs: 1.811, 1.405, 1.427). Conclusion High TG levels increase the risk of diabetic microvascular complications, and patients with older age, longer T2DM duration, and higher HbA1c levels are recommended to keep lipid levels more strictly.

Painful neuropathy is present in 13% to 35% of diabetic patients, and the reasons for the differential clinical manifestations of painful and painless diabetic neuropathy (DNP) in diabetic patients are unclear. This review focuses on the latest clinical advances. It is observed that gender, diabetes type, glycosylated hemoglobin, and blood lipid levels have certain predictive effects on painful DNP. Clinical attention should be paid to pain and paresthesia caused by small fiber neuropathy. Existing diagnostic Methods have limited differential effect, and active drug treatment is required after the diagnosis of painful DNP is confirmed. Further research on the pathogenesis of painful DNP is required in order to find new therapeutic target.

Neuropathy is a damage, disease, or dysfunction of one or more nerves especially of the peripheral nervous system. One of the most common disease causing neuropathy is diabetes mellitus. Diabetic neuropathy is a serious consequence that arises when nerve tissue is damaged by prolonged hyperglycemia. It affects a considerable portion of those who have the disease. This article covers every component of this complexed disease. We will discuss the definition, etiology, risk factors that patients can control and that are uncontrollable, and forms of neuropathies linked to diabetes such as peripheral, autonomic and focal. For more clinical approach signs and symptoms, diagnostic methods which are a mix of clinical evaluations, neurological exams, electrophysiological testing, and, in certain situations, imaging modalities and complicated nature of treating diabetic neuropathy will be explored. Moreover, challenges in treating this disease and future directions and research will be elaborated. What is more it interdisciplinary care will be explored as a key element in addressing complexed nature of diabetic neuropathy. In addition to highlighting the complexity of neuropathy in diabetes mellitus and emphasizing the vital significance of early recognition and specialized interventions for the best possible patient outcomes, the article aims to present a thorough grasp of diabetic neuropathy.

Diabetes, characterized as a well-known chronic metabolic syndrome, with its associated complications pose a substantial and escalating health and healthcare challenge on a global scale. Current strategies addressing diabetes are mainly symptomatic and there are fewer available curative pharmaceuticals for diabetic complications. Thus, there is an urgent need to identify novel pharmacological targets and agents. The impaired mitochondria have been associated with the etiology of diabetes and its complications, and the intervention of mitochondrial dysfunction represents an attractive breakthrough point for the treatments of diabetes and its complications. Natural products (NPs), with multicenter characteristics, multi-pharmacological activities and lower toxicity, have been caught attentions as the modulators of mitochondrial functions in the therapeutical filed of diabetes and its complications. This review mainly summarizes the recent progresses on the potential of 39 NPs and 2 plant-extracted mixtures to improve mitochondrial dysfunction against diabetes and its complications. It is expected that this work may be useful to accelerate the development of innovative drugs originated from NPs and improve upcoming therapeutics in diabetes and its complications.

Introduction: Diabetic neuropathy (DN) is one of the most complex and progressive disorders, characterized by symmetrical distal degeneration of peripheral nerves, resulting in features of pain and sensory loss. This study aimed to find out the effects of physiotherapy intervention on physical function, balance, and postural control of persons with DN. Materials and Methods: A computerized electronic search was performed using PEDro, Pubmed, CINAHL, and EMBASE with keywords including physiotherapy intervention, physical exercise, rehabilitation techniques, balance training, diabetic neuropathy, and diabetic peripheral neuropathy. The inclusion criteria consisted of studies that were randomized clinical trials, crossover trials, or controlled trials published in the English language from 2015 to 2021, identifying DN as the primary concern, and physiotherapy intervention as one of the treatment options. Results: The primary search of the database turned up an entire set of 58 studies, among which 11 studies were selected as potentially meeting the inclusion criteria. Ultimately, four studies were retained for the final results of the review. The evaluations provided evidence to suggest that physiotherapy has positive effects on subjects with diabetic peripheral neuropathy. Conclusion: After reviewing, it has been revealed that balance and strength training are applicable for improving balance, gait, and physical function in DN patients.

Introduction: The prevalence of fatigue in patients with diabetes mellitus (DM) can be as high as 50 %. Physical, mental, and psychosocial components of fatigue negatively impact quality of life (QOL), morbidity and mortality. Several tools have been developed to address fatigue, but none specifically for measuring fatigue in DM. The aim of this study was to assess the impact of diabetes and neuropathy on fatigue using the Norfolk QOL-Fatigue (QOL-F) survey. Methods: 605 adult participants from [Anonymous] were recruited (400 subjects with type 1 or type 2 DM and 205 subjects without diabetes (controls)). All subjects completed the Norfolk QOL-F. Demographics, weight, BMI, and duration of diabetes were obtained. The Norfolk QOL-F, a 35-item validated questionnaire, assesses five domains: subjective fatigue, physical and cognitive fatigue, reduced activities, impaired activities of daily living, and depression. Results: Subjects with DM reported significantly higher fatigue total scores (52.63vs33.89, p

Background: Previous observational studies have indicated an association between serum uric acid (SUA) and diabetic neuropathy (DN), but confounding factors and reverse causality have left the causality of this relationship uncertain. Methods: Univariate Mendelian randomization (MR), multivariate MR and linkage disequilibrium score (LDSC) regression analysis were utilized to assess the causal link between SUA and DN. Summary-level data for SUA were drawn from the CKDGen consortium, comprising 288,648 individuals, while DN data were obtained from the FinnGen consortium, with 2,843 cases and 271,817 controls. Causal effects were estimated primarily using inverse variance weighted (IVW) analysis, supplemented by four validation methods, with additional sensitivity analyses to evaluate pleiotropy, heterogeneity, and result robustness. Results: The LDSC analysis revealed a significant genetic correlation between SUA and DN (genetic correlation = 0.293, P = 2.60 × 10-5). The primary methodology IVW indicated that each increase of 1 mg/dL in SUA would increase DN risk by 17% (OR = 1.17, 95% CI 1.02-1.34, P = 0.02), while no causal relationship was found in reverse analysis (OR = 1.00, 95% CI 0.98~1.01, P = 0.97). Multivariate MR further identified that the partial effect of SUA on DN may be mediated by physical activity, low density lipoprotein cholesterol (LDL-C), insulin resistance (IR), and alcohol use. Conclusion: The study establishes a causal link between elevated SUA levels and an increased risk of DN, with no evidence for a reverse association. This underscores the need for a comprehensive strategy in DN management, integrating urate-lowering interventions with modulations of the aforementioned mediators. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes, imposing a significant burden on individuals and healthcare systems worldwide. This study presents a comprehensive analysis of the global research landscape in DN, aiming to provide scientists, funders, and decision-makers with valuable insights into the current state of research and future directions. Methods: Through a systematic review of published articles, key trends in DN research, including epidemiology, diagnosis, treatment strategies, and gaps in knowledge, are identified and discussed. Results: The analysis reveals an increasing prevalence of DN alongside the rising incidence of diabetes, emphasizing the urgent need for effective prevention and management strategies. Furthermore, the study highlights the geographical imbalance in research activity, with a majority of studies originating from highincome countries. Discussion: This study underscores the importance of fostering international collaboration to address the global impact of DN. Key challenges and limitations in DN research are also discussed, including the need for standardized diagnostic criteria, reliable biomarkers, and innovative treatment approaches. By addressing these gaps, promoting collaboration, and increasing research funding, we can pave the way for advancements in DN research and ultimately improve the lives of individuals affected by this debilitating condition. [ABSTRACT FROM AUTHOR]

Background: Vestibular impairment is a common pathology in patients with type 2 diabetes mellitus (DM) due to ischemia of the vestibular end organs and lysis of the myelin of the vestibular nerve. We aimed to evaluate function of the vestibular end organs and vestibular nerve in patients with type 2 DM with polyneuropathy and compare results to those of the patients without polyneuropathy. Method: The participants consisted of three groups: thirty patients with type 2 diabetes mellitus without polyneuropathy (DM), thirty patients with type 2 diabetes mellitus with polyneuropathy (DPN), and thirty healthy non-diabetic individuals as the control group. Clinical examination, videonystagmography, cervical vestibular evoked myogenic potential(cVEMP), ocular vestibular evoked myogenic potential (oVEMP), Gans Sensory Organization Performance (SOP) test, and nerve conduction study were all performed on all groups. Results: P1 and N1 cVEMP latencies and n1 and p1 oVEMP latencies were statistically significantly delayed in both the DM and DPN groups than the control. Also, amplitudes of P1-N1 and n1-p1 were statistically significantly lower in the DM and DPN groups than the control group. DPN patients had longer latencies and lower amplitude of the cVEMP and oVEMP response compared to diabetes patients without neuropathy. There was a statistically significant prevalence of BPPV in the DPN group compared to the control and DM groups. DPN included the following: 4 (13.3%) had vestibular pattern, 12 had polyneuropathic pattern, and 5 (16.7%) had vestibular and polyneuropathic pattern as regards the Gans Sensory Organization Performance (SOP) test. Conclusion: VEMP is considered a promising objective tool in the assessment of the vestibular end organ disorders in patients with type 2 DM with and without polyneuropathy. Diabetics with prominent diabetic polyneuropathy showed higher vestibular impairment than diabetics without DPN, which may increase the risk of falling. [ABSTRACT FROM AUTHOR]

Background: Diabetic neuropathy is a debilitating manifestation of long-term diabetes mellitus. The present study explored the effects of the roots of Rubia cordifolia L. (R. cordifolia L.) in the Wistar rat model for diabetic neuropathy and possible neuroprotective, antidiabetic, and analgesic mechanisms underlying this effect. Materials and Methods: Rats were divided into five experimental groups. An amount of 0.25% carboxy methyl cellulose (CMC) in saline and streptozotocin (STZ) (60 mg/kg) was given to group 1 and group 2, respectively. Group 3 was treated with STZ and glibenclamide simultaneously while groups 4 and 5 were simultaneously treated with STZ and hydroalcoholic extract of the root of R. cordifolia, respectively. Hot plate and cold allodynias were used to evaluate the pain threshold. The antioxidant effects of R. cordifolia were assessed by measuring Thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). At the end of the study, sciatic nerve and brain tissues were collected for histopathological study. Bcl-2 proteins, cleaved caspase-3, and Bax were assessed through the Western blot method. Results: R. cordifolia significantly attenuated paw withdrawal and tail flick latency in diabetic neuropathic rats. R. cordifolia significantly (p < 0.01) improved the levels of oxidative stress. It was found to decrease blood glucose levels and to increase animal weight in R. cordifolia-treated groups. Treatment with R. cordifolia suppressed the cleaved caspase-3 and reduced the Bax:Bcl2 ratio in sciatic nerve and brain tissue compared to the diabetic group. Histopathological analysis also revealed a marked improvement in architecture and loss of axons in brain and sciatic nerve tissues at a higher dose of R. cordifolia (400 mg/kg). Conclusion: R. cordifolia attenuated diabetic neuropathy through its antidiabetic and analgesic properties by ameliorating apoptosis and oxidative stress. [ABSTRACT FROM AUTHOR]

Background At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. Methods A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. Results Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep. Variability in dosing paradigms and the time to patient response was present in the reviewed studies. Conclusions Evidence synthesized for this scoping review supports the ongoing use of LDN for the treatment of refractory pain in various centralized chronic pain conditions. Upon review of the currently available published studies, it is apparent that further high-quality, well-powered randomized control trials need to be conducted to establish efficacy, standardization for dosing, and response times. In summary, LDN continues to offer promising results in the management of pain and other distressing symptoms in patients with chronic centralized pain conditions. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic neuropathy is a well-known complication of diabetes. Recently, hyperglycemia-induced toxicity has been confirmed to participates in multiple cellular pathways typical for neural deterioration. Nicotinamide phosphoribosyltransferase/pre-b cell colony-enhancing factor (Nampt/PBEF)/visfatin is a novel endogenous ligand that some studies have shown its neuroprotective effects on neurodegenerative disease. Therefore, we hypothesized that visfatin may prevent high glucose (HG)-induced neurotoxicity by inhibiting apoptosis, autophagy, and reactive oxygen species (ROS) responses properly. Methods: In this study, pheochromocytoma cell line 12 (PC12) cells were exposed to both HG concentrations (50, 75, 100, 125, 150 mM) and visfatin (50, 100, 150 ng/mL) at different time -points to determine the optimum time and dose of glucose and visfatin. To investigate the effects of visfatin on HG-induced damage in the PC12 diabetic neuropathy model, we examined ROS response, apoptosis, and autophagy using ROS detection kit, flow cytometry, and real-time PCR/Western blot, respectively. Results: We determined that HG concentration significantly increased the ROS level and apoptosis of diabetic PC12 cells. However, visfatin treatment significantly decreased the ROS production (P<0.05) and apoptosis of diabetic PC12 cells (P<0.0001). Beclin-1 messenger ribonucleic acid (mRNA) level (P<0.05) and light chain 3 (Lc3)-II protein level (P<0.05) showed that the autophagy pathway is impaired by HG concentrations. Conclusion: We concluded that visfatin can sufficiently decrease neural damage caused by ROS production and apoptosis under HG-induced toxicity. [ABSTRACT FROM AUTHOR]

Objective: To determine the neuroprotective effects of apigenin against streptozotocin (STZ)-induced diabetic neuropathy (DN). Methods: To induce DN, Wistar rats (150-200 g) were administered with STZ (55 mg/kg, i.p.). Then they were randomly assigned to various groups, viz., normal, diabetic control, insulin (10 IU/kg, s.c.), apigenin (5, 10, and 20 mg/kg, p.o.), and insulin (10 IU/kg) plus apigenin (20 mg/kg, p.o.). Various behavioral, biochemical, and molecular markers [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor erythroid 2-related factor 2 (Nrf2)] were assessed. Results: Apigenin (10 and 20 mg/kg, p.o.) substantially reduced plasma glucose levels, lipid profile, aspartate transaminase, alanine transaminase, glycated hemoglobin, and neural advanced glycation end products in STZ-induced DN rats (P<0.05). After apigenin intervention, STZ-induced changes in food and water intake, body weight, urine output, allodynia, hyperalgesia, and insulin levels were markedly improved (P<0.05). Neural antioxidant enzymes (superoxide dismutase and glutathione) and Na+ K+ ATPase activity were also considerably elevated (P<0.05) while the level of lipid peroxidation was diminished following apigenin therapy (P<0.05). Furthermore, apigenin markedly upregulated the Nrf2 mRNA level while downregulating the mRNA expressions of TNF-α and ILs and the protein expressions of TLR4 and MyD88 (P<0.05). STZ-induced histological abnormalities in the sciatic nerve were also improved by apigenin treatment. Conclusions: Apigenin exerts its neuroprotective effect by modulating the inflammatory and oxidative stress pathways via regulating the TLR4-MyD88 signaling pathway. [ABSTRACT FROM AUTHOR]

Aims: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population. Methods: This cross‐sectional study enroled patients with T2DM between July and December 2017 from 24 provinces in China. Diabetic peripheral neuropathy and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score (NSS) and neuropathy disability score. The prevalence of DPN and its risk factors were analysed. Results: A total of 14,908 patients with T2DM were enroled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN in females was higher than in males (69.0% vs. 66.6%, P = 0.002). The prevalence of DPN increased with age and course of diabetes and decreased with body mass index (BMI) and education level (all P for trend <0.05). The comorbidities and complications in patients with DPN were higher than in those without DPN, including hypertension, myocardial infarction, diabetic retinopathy, and diabetic nephropathy (all P < 0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated haemoglobin, high‐density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C‐peptide, and uric acid were negatively associated with DPN. Conclusions: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low‐income, and undereducated patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims Diabetes is a set of complex disorders in the metabolism of proteins, fats, and carbohydrates, which cause physiological and biochemical changes in nerve cells, causing chronic psychomotor and musculoskeletal disorders such as muscle strength and balance disorders. This study aimed to compare the dynamic balance and muscle strength of the lower limbs in type 2 diabetic patients with healthy individuals. Instruments & Methods In this cross-sectional descriptive study, 70 patients with type 2 diabetes and 70 healthy people aged 40 to 70 years without skeletal-muscular and cognitive problems were selected by a multistage sampling (convenience, random block) method. In each group, the demographic questionnaire, Berg Balance Scale, and muscle strength were measured with a manual dynamometer. Chi-square, Fisher's exact test, and independent t-test were used to analyze the data. Findings The mean score of the Berg Balance Scale was higher in the control group than in the type 2 diabetes patients (p<0.05). Also, the strength of the selected muscles of the lower limbs, except the plantar flexor, was higher in the control group than in the diabetic patients (p<0.05). Conclusion Dynamic balance and walking independence are more in healthy people than in diabetic patients. [ABSTRACT FROM AUTHOR]

2 Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Effects of baricitinib, empagliflozin, linagliptin and telmisartan on cardiovascular autonomic neuropathy in type 1 diabetes: An exploratory, randomized, open-label, crossover trial The primary aim was to determine the individual albuminuria-lowering response of four albuminuria-lowering drug classes in persons with type 1 diabetes. Keywords: clinical trial; diabetes complications; diabetic neuropathy; empagliflozin; linagliptin; SGLT2 inhibitor EN clinical trial diabetes complications diabetic neuropathy empagliflozin linagliptin SGLT2 inhibitor 3064 3067 4 09/06/23 20231001 NES 231001 INTRODUCTION Cardiovascular autonomic neuropathy (CAN) is a prevalent complication in type 1 diabetes and a risk factor for cardiovascular mortality.[1] CAN is preventable to some extent: Intensive glucose control demonstrated a 45% risk reduction of CAN in persons with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC).[2] To our knowledge, however, no treatment is available when CAN is incident. [Extracted from the article]

This retrospective cohort study describes the utilization of opioids and gabapentin among patients with diabetic neuropathy who were gabapentin and opioid naïve, and assesses predictors of concomitant use of opioids and gabapentin. Using Medicare claims data (2012–2016), 22 037 patients were identified, of whom 23.42% (N = 5161) initiated opioids without concomitant gabapentin, 4.56% (N = 1004) initiated gabapentin without concomitant opioids, and 3.87% (N = 852) had concomitant use of gabapentin and opioids 12 months following their index date (date of earliest diagnosis). Concomitant gabapentin and opioid use were more common for lower doses of both drugs and for 15 days or more cumulatively. Compared to individuals aged 65–74, those aged 75–84 (OR:.759; 95% CI: 0.653–.882) or ≥ 85 years (OR:.586, 95% CI: 0.462–.743) had lower odds of concomitant use. People residing in the Northeast had lower odds of concomitant use, compared to those residing in the South (OR:.646 95% CI: 0.535–.779). Females compared to males (OR: 1.185, 95% CI: 1.027–1.367), people with higher Charlson's Comorbidity Index (CCI) scores (OR: 1.085, 95% CI: 1.037–1.135) or those having anxiety (OR: 1.462, 95% CI: 1.131–1.889) had higher odds of concomitant use. Concomitant prescriptions of opioids and gabapentin were more common for longer durations, indicating the need for interventions aimed at minimizing this prescribing practice. [ABSTRACT FROM AUTHOR]

Background. Diabetic neuropathy mostly causes physical disabilities that will reduce social participation, medical/psychological rehabilitation, and enjoyable activities. These factors in turn create a cycle of depression, anxiety, and sleep disorders. Variables related to pain perception play an important role, pain catastrophizing will increase anxiety so that sufferers feel they have a disability that is worse than reality. In the end, patients will give up and reduce their self-efficacy. Results. Data from 68 subjects was collected and analyzed. After eight weeks of treatment, the experimental group showed a more significant mood improvement (88.2% vs. 70.6%, p=0.031). There were no adverse events recorded in this study. Conclusions. Vitamin D addition along with standard treatment significantly improve mood more effectively than standard treatment alone in diabetic neuropathy patients. [ABSTRACT FROM AUTHOR]

Objective Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. Design Prospective cohort study in an outpatient clinical practice at a tertiary care center. Methods Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. Results Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. Conclusions The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. Trial registration ClinicalTrials.gov ID NCT03769675. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress mediates the pathophysiology of diabetic neuropathy (DN) with activation of apoptotic pathway and reduction of autophagy. Arctigenin (ARC) is a natural lignan isolated from some plants of the Asteraceae family that shows antioxidant property. The present study aimed to explore the mechanistic neuroprotective effect of ARC on animal model for DN. Methods: DN was induced using streptozotocin (STZ) at a dose of 45 mg/kg, i.p, for five consecutive days and ARC was administered orally (25 or 50 mg) for 3 weeks. The mechanical sensitivity and thermal latency were determined using von Frey and hotplate, respectively. Beclin, p62, and LC3 were detected as markers for autophagy by western blot. Levels of reduced glutathione, lipid peroxides, and activities of catalase and superoxide dismutase were detected as readout for oxidative stress. Apoptotic parameters and histopathological changes were revealed in all experimental groups. Results: The present study showed deterioration of the function and structure of neurons as a result of hyperglycemia. Oxidative stress and impaired autophagy were observed in diabetic neurons as well as the activation of apoptotic pathway. ARC improved the behavioral and histopathological changes of diabetic mice. ARC combated oxidative stress through diminishing lipid peroxidation and improving the activity of antioxidant enzymes. This was concomitant by reducing the biomarkers of apoptosis. ARC augmented the expression of Beclin and LC3 while it lessened the expression of p62 indicating the activation of autophagy. These findings suggest that ARC can ameliorate DN by combating apoptosis and oxidative stress and improving autophagy. [ABSTRACT FROM AUTHOR]

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Background: Diabetic neuropathy, including autonomic neuropathy, is a severe complication in patients with poorly controlled diabetes. Specifically, cardiovascular autonomic neuropathy (CAN) plays a significant prognostic role in cardiovascular morbidity and mortality. Exercise, an essential component of diabetes treatment, may have a therapeutic effect on patients with diabetes complicated by CAN. However, it remains unclear whether exercise has a therapeutic or protective effect in diabetes patients with CAN. Methods: The author conducted a systematic search of PubMed/MEDLINE, Embase, and The Cochrane Library, resulting in the identification of eight eligible randomized controlled trials for this review. Results: Exercise, including aerobic exercise combined with resistance training (RT), high-intensity interval training, and progressive RT, has shown a beneficial effect on cardiac autonomic function (CAF) in patients with type 2 diabetes, as measured by heart rate variability, heart rate recovery, and baroreflex sensitivity. However, most studies had low quality. Moreover, there were no relevant studies examining the effect of exercise on CAF in older patients, patients with poorly controlled diabetes, and patients with type 1 diabetes. Conclusions: Exercise has the potential to manage patients with CAN by balancing sympathetic and parasympathetic nervous system functions; however, further studies are warranted in the future. [ABSTRACT FROM AUTHOR]

Aims: This study analyzed the gait patterns of diabetic peripheral neuropathy (DPN) patients and changes in the center of mass sway to prevent the formation and recurrence of foot ulcers. Methods: Forty-two subjects were divided into the diabetes mellitus (DM), DPN, and diabetic foot ulcer (DFU) groups. We measured the range of motion (ROM) of the lower limb joints in the resting position and the center of mass sway in the standing position. Joint angles, ROM during walking, and distance factors were evaluated. Results: In the DFU group, ROM limitation during walking was detected at the knee joint, and functional and ROM limitations were found at the ankle joint. The step length ratio and step width in the DFU group were significantly lower and higher than those in the DM group, respectively. The sway distances in the DFU group were greater than those in the DM and DPN groups. Conclusions: Functional joint limitations and gait changes due to the decreased ability to maintain the center of gravity were observed in the DFU group. As DPN progressed, the patients' gait became small, wide, and shuffled. Thus, supporting joint movement during walking may help reduce the incidence and recurrence of foot ulcers. [ABSTRACT FROM AUTHOR]

This document provides an overview of the current understanding and management of diabetic neuropathy, a common complication of diabetes that affects the peripheral nervous system. The authors discuss various treatment options, including low-level laser therapy, transcutaneous electrical nerve stimulation, certain medications, and stem cell therapy. They also explore emerging therapies such as virtual reality, gene editing, nanotherapy, monoclonal antibody therapy, brain stimulation technologies, light therapy, artificial intelligence, and telehealth. The document emphasizes the need for further research to establish the safety and effectiveness of these treatments. [Extracted from the article]

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Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate newtherapeutic targets aswell asmethodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications. [ABSTRACT FROM AUTHOR]

The prognostic nutritional index (PNI) is associated with inflammatory conditions. Since type 2 diabetes mellitus (T2DM) and its microvascular complications produce a significant inflammatory burden, we aimed to compare the PNI levels of the subjects with T2DM to those of healthy individuals. Furthermore, we aimed to compare the PNI levels of the diabetic subjects, with and without microvascular complications. The study cohort consisted of T2DM patients and healthy volunteers. The general characteristics, laboratory data, and PNI of the T2DM and control groups were compared. We further compared the PNI levels of the diabetic patients, with and without diabetic microvascular complications. The PNI levels of the T2DM patients and the control group were 51.6 (30.1–73.8)% and 64.8 (49.4–76)%, respectively (p < 0.001). Subgroup analyses revealed that the PNI was lower in the diabetic subjects with diabetic microvascular complications than in the diabetic patients without microvascular complications (p < 0.001), in patients with diabetic nephropathy compared to those without nephropathy (p < 0.001), in patients with diabetic retinopathy compared to those without retinopathy (p < 0.001), and in patients with diabetic neuropathy compared to those without neuropathy (p < 0.001). In conclusion, we assert that assessing the PNI may yield additional diagnostic value in regards to the timely determination of diabetic microvascular complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aging is an inevitable process that impacts the peripheral and central nervous systems and is considered one of the strongest risk factors for neurodegenerative diseases. In addition, when it also presents with diabetes mellitus, the risk of neurological damage may be further increased. This current study aimed to explore the relationships between peripheral sensory system decline and cognitive functions, the symptoms of depression, and quality of life (QoL) as metrics of central nervous system impairment in institutionalized older adults. A total of 95 individuals participated in this case-control study, which included diabetics and non-diabetics. The superficial sensory pathway was assessed in terms of thermal sensation, nociception, and non-discriminative touch, and the deep sensory pathway was evaluated by assessing vibration and light touch-pressure sensations. To assess function at the intellectual level, the Mini-Mental State Examination (MMSE) and Trail Making Test (TMT) cognitive functional tests were used, while the symptoms of depression and QoL were explored by employing the Yesavage Geriatric Depression Scale and EuroQol 5D questionnaire (EQ-5D), respectively. In the overall population analyses, altered thermal sensation was significantly associated with cognitive impairment (CI; p < 0.05). In turn, bivariate analyses and a binary logistic regression showed that the symptoms of depression and QoL were significantly related to altered vibratory sensation when assessed using a medical tuning fork (p < 0.05). In the group of diabetic patients, those with CI also had significantly lower thermal sensation (p < 0.05) and non-discriminative touch sensation, although this was only a trend (p = 0.055). Diabetics with depression had a significantly worse non-discriminative touch (p < 0.05) and vibratory sensation when tested with a tuning fork (p < 0.05). In addition, poorer QoL was associated with reduced sensitivity to heat (p < 0.05), light touch pressure (p < 0.05), and vibrations when assessed either with a tuning fork (p < 0.05) or a biothesiometer (p < 0.05). In contrast, no relationships were found between sensory functions and cognitive assessments in non-diabetic patients. These findings indicate that superficial sensitivity damage was related to CI, while deep sensation alterations were related to depression and poor QoL, with diabetes apparently further strengthening these relationships. [ABSTRACT FROM AUTHOR]

Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy. Inducers of ER stress also give rise to peripheral neuropathy. ER stress leads to the formation of autophagosome but as their degradation is also stalled during ER stress accumulation of autophagosomes is seen. Accumulation of autophagosomes has deleterious effects on cells. In the present study, we show that treatment with tunicamycin (TM) (ER stress inducer) in mice leads to peripheral neuropathy as assessed by Von Frey and Hot plate method. Administration of a promoter of autophagy viz. 6‐bromoindirubin‐3′‐oxime (6‐BIO) subsequent to ER stress induced by TM exhibits a decrease in peripheral neuropathy. 6‐BIO was also effective in reducing diabetic peripheral neuropathy. To understand the type of autophagy activated, SH‐SY5Y cells were treated with 6‐BIO after TM treatment. Levels of cathepsin D (CTSD), a marker for degradative autophagy was higher in cells treated with 6‐BIO after TM treatment compared to only TM‐treated SH‐SY5Y cells while levels of Rab8A,—a marker for secretory autophagy was reduced. Furthermore, in parallel during ER stress secretory, we noted increased levels of lysozyme in autophagosomes destined for secretion. Cells treated with 6‐BIO showed reduction of lysozyme in secretory autophagosomes. This shows that 6‐BIO increased degradative autophagy and reduced the secretory autophagy. 6‐BIO also reduced the caspase‐3 activity in 6‐BIO‐treated cells. Thus, 6‐BIO reduced neuropathy in animals by activating degradative autophagy and reducing the secretory autophagy. [ABSTRACT FROM AUTHOR]

Current evidence supports the association of metabolic syndrome (MetS) with neuropathy. Limited data are available on proper strategies to control metabolic disorders and neuropathy among patients with type2 diabetes mellitus (T2DM). We aimed to determine hesperidin and diosmin efficacy individually and in combination among T2DM patients with neuropathy and meet MetS criteria. In this parallel-group designed trial, 129 T2DM patients with MetS and neuropathy were recruited and randomized to receive their oral hypoglycemics with either hesperidin (1g/day), or diosmin (1g/day), or combination of both or oral hypoglycemics without intervention for 12 weeks. Diabetic neuropathy was evaluated using Michigan Neuropathy Screening Instrument (MNSI) at baseline and after trial. Anthropometric parameters, blood glucose and lipid profile were also assessed before and after the intervention using paired student t-test within groups. The trial is registered at clinicaltrials.gov as NCT05243238. By completion of the trial duration, both hesperidin and diosmin groups showed significant reduction in blood glucose, triglycerides (TGs) and low density lipoprotein (LDL) from baseline (p<0.05). However, the magnitude of improvement in metabolic components significantly increased with hesperidin and diosmin combination. Although MNSI scores improved significantly in both groups, the reduction was more significant with the combination of hesperidin and diosmin. Moreover, the change in MNSI score was significantly correlated with the improvement in metabolic profile components including LDL, TGs and fasting blood glucose. Oral supplementation of hesperidin and diosmin was associated with improvement in metabolic syndrome and diabetic neuropathy and the combination of both was superior in efficacy. [ABSTRACT FROM AUTHOR]

Having lived through a pandemic and witnessed how regulatory approval processes can evolve rapidly; it is lamentable how we continue to rely on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. Small (Aδ and C) fibers are key to the genesis of pain, regulate skin blood flow, and play an integral role in the development of diabetic foot ulceration but continue to be ignored. This article challenges the rationale for the FDA insisting on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. Quantitative sensory testing, intraepidermal nerve fiber density, and especially corneal confocal microscopy remain an after-thought, demoted at best to exploratory secondary endpoints in clinical trials of diabetic neuropathy. If pharma are to be given a fighting chance to secure approval for a new therapy for diabetic neuropathy, the FDA needs to reassess the evidence rather than rely on 'opinion' for the most suitable endpoint(s) in clinical trials of diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Purpose: The study aimed to ascertain the potential effects of chronic kidney disease (CKD) on substance P concentration in the tear film of people with type 2 diabetes. Methods: Participants were classified into two groups: type 2 diabetes with concurrent chronic kidney disease (T2DM–CKD (n = 25)) and type 2 diabetes without chronic kidney disease (T2DM–no CKD (n = 25)). Ocular surface discomfort assessment, flush tear collection, in-vivo corneal confocal microscopy, and peripheral neuropathy assessment were conducted. Enzyme-linked immunosorbent assays were utilized to ascertain the levels of tear film substance P in collected flush tears. Correlation analysis, hierarchical multiple linear regression analysis, and t-tests or Mann–Whitney U tests were used in the analysis of data for two-group comparisons. Results: There was no substantial difference between the T2DM–CKD and T2DM–no CKD groups for tear film substance P concentration (4.4 (0.2–50.4) and 5.9 (0.2–47.2) ng/mL, respectively; p = 0.54). No difference was observed in tear film substance P concentration between the low-severity peripheral neuropathy and high-severity peripheral neuropathy groups (4.4 (0.2–50.4) and 3.3 (0.3–40.7) ng/mL, respectively; p = 0.80). Corneal nerve fiber length (9.8 ± 4.6 and 12.4 ± 3.8 mm/mm2, respectively; p = 0.04) and corneal nerve fiber density (14.7 ± 8.5 and 21.1 ± 7.0 no/mm2, respectively; p < 0.01) were reduced significantly in the T2DM–CKD group compared to the T2DM–no CKD group. There were significant differences in corneal nerve fiber density (21.0 ± 8.1 and 15.8 ± 7.7 no/mm2, respectively; p = 0.04) and corneal nerve fiber length (12.9 ± 4.2 and 9.7 ± 3.8 mm/mm2, respectively; p = 0.03) between the low- and high-severity peripheral neuropathy groups. Conclusion: In conclusion, no significant difference in tear film substance P concentration was observed between type 2 diabetes with and without CKD. Corneal nerve loss, however, was more significant in type 2 diabetes with chronic kidney disease compared to type 2 diabetes alone, indicating that corneal nerve morphological measures could serve greater utility as a tool to detect neuropathy and nephropathy-related corneal nerve changes. [ABSTRACT FROM AUTHOR]