Search Results (126)

Background and Objectives: This retrospective study evaluated patients with diabetes classified according to cluster-derived diabetes phenotype groups and compared their baseline metabolic characteristics, documented complication profiles, and HbA1c course during follow-up. Materials and Methods: A total of 158 patients with type 1 or type 2 diabetes followed at Zonguldak Bülent Ecevit University Endocrinology Outpatient Clinic were included. Phenotype assignment was based on baseline domains corresponding to the Ahlqvist framework: age at diagnosis, BMI category, HbA1c, beta-cell function, insulin resistance, and autoantibody status. Complications were not used for phenotype assignment. Baseline characteristics, binary complication status, exploratory phenotype-contrast logistic regression, and longitudinal HbA1c data were evaluated. Results: The groups showed significant differences in age, age at diagnosis, HbA1c, obesity status, fasting glucose, C-peptide, fasting insulin, HOMA1-%B, HDL cholesterol, ALT, and eGFR. Hepatic steatosis/suspected NAFLD, retinopathy, nephropathy, polyneuropathy, and ketosis/ketoacidosis differed among groups when complications were analyzed as ever-positive versus negative. In exploratory phenotype-contrast logistic regression, Clusters 3–4 were associated with hepatic steatosis/suspected NAFLD, Cluster 2 with retinopathy and polyneuropathy, Cluster 3 with nephropathy, and Clusters 1–2 with ketosis/ketoacidosis; the contrast for coronary artery disease did not reach statistical significance. In a linear mixed-effects model for repeated HbA1c measurements, phenotype group was associated with HbA1c levels, whereas the time effect and group-by-time interaction were not statistically significant. Conclusions: Cluster-derived diabetes phenotype groups showed distinct baseline metabolic characteristics and different documented complication profiles. These findings should be interpreted as exploratory because of the retrospective design and incomplete follow-up data. Full article

Background: Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle mass and function; however, respiratory muscle involvement has not been fully investigated, particularly in Japanese patients. This study aimed to evaluate respiratory muscle strength and identify its associated factors in Japanese patients with T2DM. Methods: This cross-sectional study included 55 patients with T2DM without respiratory disease. Maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) were measured and expressed as percentages of the predicted values (PImax %pred and PEmax %pred). Clinical variables, including age, sex, body mass index (BMI), diabetic polyneuropathy (DPN), skeletal muscle index (SMI), handgrip strength, and 6-min walk distance (6MWD), were assessed. Correlation and multiple regression analyses were performed to identify factors associated with PImax %pred. Results: PImax %pred was significantly lower than the predicted value (69.5% [95% CI: 63.1–75.9], p < 0.001), whereas PEmax %pred did not differ significantly from the predicted value (95.6% [95% CI: 86.8–104.3]). PImax %pred was significantly associated with age, BMI, SMI, handgrip strength, and 6MWD. In multiple regression analysis, age, sex, BMI, and handgrip strength were independently associated with PImax %pred, whereas DPN was not. These findings remained unchanged after adjusting for smoking habits. Conclusions: Inspiratory muscle strength was selectively reduced in Japanese patients with T2DM and was independently associated with general physical characteristics and overall muscle strength. Inspiratory muscle weakness may reflect generalized skeletal muscle dysfunction rather than solely a neuropathic impairment. This assessment of respiratory muscle strength may provide additional insights into the physical function of patients with T2DM. Full article

Background: Postural disability develops in almost all patients with diabetic polyneuropathy (DPN). While transcutaneous electrical nerve stimulation (TENS) has proven effective in regressing sensory and motor impairments, its efficacy in improving postural control remains insufficiently studied. Purpose: To evaluate and compare the efficacy of direct peroneal and tibial high-frequency low-amplitude (HFLA) TENS and low-frequency high-amplitude (LFHA) TENS in correcting DPN-related postural disability, among European female patients without a documented history of falls, motor deficits, or pronounced electromyographic impairments, using computerized static posturography and the tandem walk test. Materials and methods: In this single-center, three-arm, randomized controlled trial (registration number: ISRCTN47534508, 3 December 2024), we conducted a longitudinal prospective analysis of European women with DPN-related postural disability. All enrolled patients were non-fallers with no motor deficits and baseline compound muscle action potential (CMAP) amplitudes of the peroneal and tibial nerves of at least 1.5 mV. The intervention groups received HFLA TENS (n = 24) or LFHA TENS (n = 25), while the control group underwent sham TENS (n = 24). Primary endpoints were assessed via static posturography and the tandem walk test (TWT); secondary endpoints were evaluated using hypoesthesia and pain evaluation, the Modified Clinical Test of Sensory Interaction in Balance (mCTSIB), and electromyography. Assessments were performed before treatment, immediately post-treatment, and at the conclusion of a 2-month follow-up period. Results: Comparative analysis incorporating the Bonferroni adjustment demonstrated that LFHA TENS is significantly superior to HFLA TENS. Post-treatment, LFHA TENS induced a reduction in envelope area by 20.7% under the eyes-open (EO) condition (p < α_adj; α_adj = 0.0028) and 32.9% under the eyes-closed (EC) condition (p < α_adj; α_adj = 0.0028), alongside a 16.6% decrease in the Romberg uotient (RQ) (p < α_adj; α_adj = 0.0056). Furthermore, LFHA TENS elicited a significant 39.0% reduction in velocity of CoP sway (VCS) under the EO condition (p < α_adj; α_adj = 0.0042), and decreased total CoP sway excursion by an average of 35.8% (EO) (p < α_adj; α_adj = 0.0042) and 43.8% (EC) (p < α_adj; α_adj = 0.0042) compared to baseline. In contrast, no statistically significant changes in these parameters were observed after HFLA TENS. Ultimately, LFHA TENS outperformed HFLA TENS in improving postural stability by 7.04% under the EO condition (p < α_adj; α_adj = 0.0042) and by 25.5% under the EC condition (p < α_adj; α_adj = 0.0042) in both the tandem walk test (TWT) and the Modified Clinical Test of Sensory Interaction on Balance (mCTSIB). Notably, a statistically significant increase in the CMAP amplitude of the affected peroneal nerves by 22.2% was observed exclusively following LFHA TENS treatment (p < α_adj; α_adj = 0.0056). Conclusions: The clinical efficacy of direct peroneal and tibial TENS compared to sham stimulation in reducing postural disability during both static and dynamic conditions was established in European female patients with moderate-to-severe DPN and unremarkable EMG impairments. Comparative analysis reveals a clear therapeutic superiority of LFHA TENS over HFLA TENS, as evidenced by significantly greater improvements in both posturographic parameters (envelope area, total CoP excursion under EO and EC conditions, and VCS under the EO condition) and functional clinical tests (TWT and mCTSIB), demonstrating long-term stability for up to 2 months post-intervention. Full article

This review demonstrates that the diagnostic and prognostic significance of glial fibrillary acidic protein (GFAP) is not limited to its use as a marker of astrocytic damage but should also be considered in the context of the diversity of GFAP isoforms, their heterogeneous tissue-specific expression and their pronounced association with extracellular vesicles (EVs). The data presented in this review indicate that GFAP-positive (GFAP+) EVs possess broad clinical relevance in both acute and chronic pathologies of the nervous system, including ischemic stroke, traumatic brain injury, glioblastoma, and potentially diabetic and drug-induced polyneuropathy. Particular attention is given to the critical analysis of methodological approaches for studying GFAP+ EVs, including discussion of their proposed biogenesis, mechanisms of intravesicular incorporation of cytoskeletal fragments, and the hypothetical sorption of GFAP within the vesicular protein corona. A principal conclusion of this work is that, despite the high translational potential of GFAP+ vesicles as a novel liquid biopsy platform, further implementation of this approach in clinical practice will require standardization of EV isolation protocols, harmonization of phenotyping methodologies in accordance with MISEV 2023 recommendations, and large-scale prospective studies aimed at validating the biological nature, origin, and clinical reproducibility of identified GFAP-associated vesicular subpopulations. Full article

Background: Diabetic neuropathy is one of the most common chronic complications of diabetes mellitus and could lead to foot ulcerations, lower-limb amputations, increased mortality and reduced quality of life. This study examines the level of GPIHBP1 to assess its diagnostic and prognostic values across the metabolic continuum. Methods: This is an observational monocentric study, including 160 patients with type 2 diabetes mellitus, obesity without carbohydrate metabolism disorders and healthy controls. Clinical data and laboratory results were collected, and serum levels of GPIHBP1 were measured using an ELISA. The presence of DPN for the diabetes group was assessed using corneal confocal microscopy and NDS. The statistical analyses included t-tests, Pearson’s correlation analysis, and ROC analysis to explore associations and the predictive values of the biomarker. Results: The GPIHBP1 levels increased progressively, with the lowest levels observed in the control group, higher levels in patients with obesity, and the highest levels in those with diabetes mellitus. Higher GPIHBP1 levels were observed in patients with peripheral diabetic neuropathy compared to those without. GPIHBP1 demonstrated moderate discriminative performance for the presence of diabetes, diabetic neuropathy and nephropathy. GPIHBP1 levels were also associated with renal function parameters and markers of vascular involvement. After adjustment for confounders, including estimated glomerular filtration rate (eGFR), the association between GPIHBP1 and diabetic neuropathy remained statistically significant although attenuated. Higher levels were observed in patients with coronary artery disease, and a positive correlation was established with mean IMT and sudomotor dysfunction score. Conclusions: Circulating GPIHBP1 levels are associated with diabetes mellitus and its micro- and macrovascular complications, particularly diabetic neuropathy. Its measurement could enhance early diagnosis and personalized management of T2DM, and, while these findings support a potential role of GPIHBP1 as a biomarker of metabolic and vascular dysfunction, its clinical utility requires confirmation in longitudinal studies. Full article

Remote ischemic conditioning (RIC) is an endogenous strategy that mitigates cerebral injury in preclinical stroke models. However, its bench-to-bedside translation is frequently hindered by complex patient environments that induce RIC resistance and limit its neuroprotective efficacy. To bridge this translational gap, this review systematically examines the extrinsic pathophysiological and pharmacological barriers to RIC. We categorize RIC resistance into three mechanism-driven phenotypes. Impaired signal initiation (Type I) is often linked to diabetic sensorimotor polyneuropathy and the reactive oxygen species-scavenging effects of propofol. Signal transmission blockade (Type II) is associated with specific P2Y12 inhibitors and smoking-induced endothelial dysfunction. Furthermore, effector desensitization (Type III) involves target-organ unresponsiveness exacerbated by aging, chronic hyperglycemia, and postmenopausal estrogen depletion. To address these barriers, potential phenotype-specific optimization strategies are discussed. Ultimately, transitioning from generalized empirical protocols to mechanism-based precision strategies may help bypass RIC resistance in clinical settings and enhance stroke cerebroprotection. Full article

Small fiber neuropathy (SFN) is an early and common manifestation of diabetic polyneuropathy in type 2 diabetes mellitus (T2DM), often presenting with pain, dysesthesia, and autonomic dysfunction. Conventional diagnostic methods primarily assess large nerve fibers and may miss early small fiber damage, while skin biopsy, though considered the reference standard, is invasive. Corneal confocal microscopy (CCM) offers a rapid, noninvasive alternative for visualizing and quantifying small nerve fiber pathology in vivo. This was a monocentric observational study including 80 adults with T2DM (18–75 years), conducted at Alexandrovska Hospital, Sofia. Peripheral neuropathy was evaluated using a modified Neuropathy Disability Score and CCM-derived corneal nerve fiber density (CNFD), length (CNFL), and branching density (CNBD). Autonomic and sudomotor function were assessed by cardiovascular reflex tests and Sudoscan. Additional measures included vibration perception threshold, carotid intima–media thickness, body composition analysis, and laboratory parameters. Autonomic neuropathy was present in 66.7% and peripheral neuropathy in 57.5% of participants. Affected patients were older and had higher BMI and longer diabetes duration; peripheral neuropathy was additionally associated with higher HbA1c. Corneal nerve parameters negatively correlated with diabetes duration, HbA1c, intima–media thickness, and vibration threshold. Patients with diabetic retinopathy showed significantly reduced CNFD and CNFL. ROC analysis demonstrated significant discriminative ability of the HRV index for identifying peripheral neuropathy and of CNFD for detecting sudomotor dysfunction. These findings support CCM as a valuable, noninvasive marker of small fiber damage, closely linked to metabolic control, vascular impairment, and both sensory and autonomic dysfunction in T2DM. Full article

Diabetic neuropathy is a frequent and disabling complication of diabetes, encompassing distal symmetric polyneuropathy and cardiovascular autonomic neuropathy, both associated with reduced quality of life and increased cardiovascular risk. Beyond its traditional interpretation as a direct consequence of chronic hyperglycaemia, oxidative stress has emerged as a central integrative mechanism linking metabolic overload, inflammation, mitochondrial dysfunction, and microvascular injury to progressive neural damage. These processes converge within the neurovascular unit, promoting a self-perpetuating cycle of axonal degeneration, impaired nerve perfusion and altered neuronal excitability. This narrative review synthesises experimental and clinical evidence on oxidative stress-related pathways implicated in diabetic neuropathy, including hyperglycaemia-activated metabolic routes, mitochondrial dysfunction, endoplasmic reticulum stress, and chronic inflammatory signalling. Classical antioxidant and mitochondrial-supportive interventions are evaluated alongside pleiotropic glucose-lowering agents, with particular emphasis on sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, integrating mechanistic insights with biomarker and clinical outcome data. Conventional antioxidant strategies, such as α-lipoic acid, acetyl-L-carnitine, coenzyme Q10 and N-acetylcysteine, show reproducible benefits on neuropathic symptoms and oxidative stress markers, but evidence for sustained structural or disease-modifying effects remains limited. In contrast, incretin-based therapies and sodium–glucose cotransporter-2 inhibitors exert broader pleiotropic actions by attenuating oxidative and inflammatory signalling, improving mitochondrial homeostasis and endothelial function, with emerging evidence for modest but consistent neurophysiological and autonomic benefits. Overall, oxidative stress emerges as a key mechanistic hub in diabetic neuropathy. Future progress will depend on mechanism-aligned, neuropathy-specific clinical trials incorporating multidimensional endpoints and validated biomarkers. Full article

Background: Approximately half of patients with diabetes mellitus (DM) develop diabetic distal symmetric sensorimotor polyneuropathy (DM-DSPN), yet no reliable biomarkers for its early detection exist. This study assesses cystatin C (CysC), a naturally occurring protein, in diabetic persons with and without large-fiber DM-DSPN. Methods: This study involved persons with diabetes (HbA1c > 6.5%) visiting specialized diabetic clinics at King Saud University Medical City (KSUMC) in Riyadh, Saudi Arabia. Clinical features, laboratory data, nerve conduction findings, and serum CysC levels were assessed. DM-DSPN was diagnosed if signs of large nerve fiber impairment were present in the lower extremity in a symmetric and length-dependent pattern. Participants were designated as diabetic with or without large-fiber DSPN (+DM/+DSPN and +DM/−DSPN, respectively) based on validated composite scores of nerve conduction attributes. Results: A total of 52 persons with diabetes were included for analysis (24 with +DM/+DSPN and 28 with +DM/−DSPN). One participant had type 1 DM; all remaining participants had type 2 DM. In multivariate regression, serum CysC ≥ 0.88 mg/L was significantly associated with DM-DSPN. Serum CysC was significantly associated with peroneal and ulnar compound muscle action potential amplitudes (p-value = 0.003 and p-value = 0.03, respectively) and peroneal and tibial motor nerve conduction velocities (p-value = 0.009 and p-value = 0.0003, respectively). Conclusions: Serum CysC levels > 0.9 mg/L are associated with DM-DSPN (86% sensitivity and 81% specificity), independently of HbA1c or GFR. Serum CysC is also associated with peroneal and ulnar compound muscle action potential amplitudes and peroneal and tibial motor nerve conduction velocities. Larger studies are needed to determine the role of CysC as a potential biomarker of DM-DSPN. Full article

Immunotherapy is a promising treatment option for many cancers but is associated with the development of peripheral neuropathy in some patients. This retrospective cross-sectional EMR-based prevalence study was performed at MD Anderson Cancer Center with an aim to define the prevalence and epidemiology of Programmed Cell Death Protein 1 (PD-1) inhibitor-associated polyneuropathy. A total of 12,092 patients treated with a PD-1 inhibitor between 4 March 2016 and 18 June 2023 were identified and those on immunotherapy monotherapy were isolated. A total of 817 patients had documented neuropathy-associated with PD-1 inhibitor exposure, corresponding to a prevalence of 6.76% (6.76%, 95% CI 6.31–7.22). Data was stratified to assess for association between peripheral neuropathy and agent, sex, race, ethnicity, smoking and diabetes status. Patients identifying as “Other” race had higher prevalence of neuropathy compared to White or Caucasian patients (OR 1.514, p = 0.0189) and non-Hispanic or Latino patients had higher prevalence of neuropathy compared to Hispanic or Latino patients (OR 1.502, p = 0.0078). Current-smokers had significantly lower prevalence of neuropathy compared to never-smokers (OR 0.716, p = 0.0368). These disparities underscore the importance of further investigation in genetics and mechanisms to identify therapeutic interventions for PD-1 inhibitor-associated peripheral neuropathy. Full article

Background: Diabetes Mellitus (DM) is frequently associated with diabetic peripheral neuropathy (DPN) and cardiovascular diseases (CVD). The aim of this study is to assess the relationship between DPN symptoms, vitamin B12 level, and autonomic neuropathy in DM patients with high and very high CV risk or established CVD. Material and Methods: A cross-sectional analysis of 164 patients from the Outpatient DM Department of Suceava County Hospital from September 2025 was performed. The clinical, paraclinical, and demographic data were collected, including Toronto Clinical Neuropathy Score (TCNS), Sudoscan, Orthostatic Hypotension (OH), and B12 level. Results: In total, 65.9% of patients had DPN; the mean HbA1c was 8.22% ± 1.74. No significant correlation was obtained between autonomic neuropathy (Sudoscan) and DPN severity (p = 0.163) or between vitamin B12 and DPN (p = 0.6). Vitamin B12 was associated with CV risk assessed with Sudosan (p = 0.04). OH had limited diagnostic significance for autonomic dysfunction. Conclusions: No strong link was detected between B12 levels and DPN; thus, it cannot be considered a predictive marker. Objective DPN screening remains essential. Sudoscan is practical and non-invasive in assessing autonomic neuropathy, but only when combined with TCNS may it increase the DPN screening and risk stratification in high-CV-risk populations with DM. Full article

According to the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC), type 2 diabetes mellitus (T2DM) remains a major public health issue with a considerable impact on human life, affecting over 38 million Americans of all ages, and an estimated 529 million people worldwide. It is a significant risk factor for polyneuropathy, eye problems, coronary artery disease (CAD), renal disease, heart disease, stroke, and peripheral artery disease (PAD). Nearly 9 million Americans with diabetes are unaware of their condition and, therefore, do not receive health care to prevent disease progression and complications. With T2DM being a condition that leads to increased demand for health care services due to its long-term, persistent nature and its incremental impact on the body, early diagnosis and timely initiation of effective treatments are essential. Despite the effect of metabolic memory in the development of diabetes-related complications, early intervention helps decelerate disease progression, reduce complications, and ultimately improve survival. Various blood-based biomarkers have been identified, which hold great promise to streamline the mechanisms underlying T2DM and its progression from insulin resistance and prediabetes to diabetes and end-stage diabetes. However, the greatest need is to identify and utilize reliable biomarkers that can help to assess pharmacological treatment response and guide efforts to improve insulin sensitivity, preserve pancreatic beta-cell function, and prevent or delay complications. This review explores the clinical utility of promising biomarkers and assess their potential to support more personalized pharmacological approaches tailored to the individual characteristics of T2DM patients. Full article

Clinicians caring for feet may be hearing stories of canines masticating the foot/digits on unsuspecting persons with diabetes and neuropathy. For the most part, these reports are anecdotal. Actual publications on this topic are scarce. The following discussion and case reports depict a typical presentation with a sleeping person with diabetic polyneuropathy and infection, which attracts the canine and results in tissue mastication. The workup and care for such clinical presentations appear straightforward and effective; however, the authors highly recommend that providers that care for persons with diabetes who own pets take precautions, especially during sleep. Full article

Background/Objectives: Diabetic sensorimotor polyneuropathy (DSPN) is a frequent microvascular complication of diabetes mellitus, associated with increased morbidity and reduced quality of life. The existing literature offers a limited understanding of sex-specific cardiovascular risk profiles and their association with DSPN, particularly within Central and Eastern European populations. Methods: A retrospective analysis was conducted using data from 621 individuals with type 1 or type 2 diabetes mellitus who underwent comprehensive neuropathy screening at the University of Debrecen between 2017 and 2021. The diagnosis of DSPN was made in accordance with international criteria, incorporating symptom scores, and electrophysiological measurements. Multivariate logistic regression was applied in order to identify independent predictors. Results: The diagnosis of DSPN was made in 444 individuals (71.5%), of whom 58.2% were female. Despite similar glycemic control (HbA1c: 7.81% in men vs. 7.65% in women, p = 0.297), men had significantly more frequent occurrences of previous myocardial infarction (11.8% vs. 5.0%, p = 0.008), peripheral vascular disease (19.9% vs. 12.7%, p = 0.041) and atherosclerosis (31.7% vs. 22.0%, p = 0.021). Multivariate analysis showed that female gender was independently associated with a lower incidence of DSPN (odds ratio [OR] = 0.592, 95% confidence interval [CI]: 0.369–0.950, p = 0.030), while diabetic retinopathy was a significant predictor (OR = 2.728, 95% CI: 1.300–5.725, p = 0.008). Electrophysiological testing revealed lower nerve conduction amplitudes in females for selected nerves. Conclusions: Our findings highlight sex-specific differences in neuropathy risk and support the implementation of individualized screening strategies in diabetic populations with region-specific risk factors. Full article

Aim: To compare diabetic polyneuropathy (DPN) and cardiac autonomic neuropathy (CAN) between T1DM and T2DM patients. Methods: This study enrolled 66 T1DM and 79 T2DM patients. DPN was evaluated using three different methods: clinical examination, using neuropathy symptom score (NSS) and neuropathy disability score (NDS), current perception threshold (CPT) using Neurometer, and nerve conduction studies (NCSs). CAN was assessed by cardiovascular autonomic reflex tests (CARTs). Results: The prevalence of DPN did not differ between T1DM and T2DM (p > 0.05 for all), however, the proportion of DPN depended on the method used and was highest with CPT (53.0% vs. 46.8%), followed by NCSs (44.1% vs. 41.2%) and clinical examination (25.8% vs. 31.6%). T2DM vs. T1DM patients were more often diagnosed with painful DPN (51.9% vs. 27.3%, p = 0.004), reduced perception of vibration (72.2% vs. 48.5%, p = 0.006), and autonomic neuropathy (59.5% vs. 32.3%, p = 0.001), while NCSs revealed more prevalent motor nerve dysfunction in T1DM compared to T2DM (41.2% vs. 19.6%). Multivariate regression analysis showed increased DPN risk with age and CAN risk with worsening of eGFR in T1DM. No significant associations remained after multivariate adjustment for T2DM. Conclusions: The prevalence of DPN is highly varied and depends on the diagnostic method used. T2DM patients more often had symptoms and signs of diabetic neuropathy. However, stronger associations with risk factors were observed in T1DM. Full article