Search Results (189)

Background: Diabetic neuropathy (DN) is a common complication of diabetes mellitus that remains frequently undetected by conventional diagnostic methods. Sudomotor dysfunction, reflecting small-fiber impairment, has emerged as a potential early marker. SUDOSCAN, a rapid and non-invasive device measuring electrochemical skin conductance (ESC), has been proposed as a screening tool for early DN. The objective of this study was to systematically evaluate the diagnostic performance and clinical utility of SUDOSCAN in the early detection of DN. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Studies assessing SUDOSCAN-derived ESC in adults with diabetes were included. Data on diagnostic accuracy, correlations with established neuropathy measures, and clinical applicability were extracted. Where feasible, pooled sensitivity and specificity were estimated using a random-effects model. Results: Fifteen studies (n = 7343 participants) were included in the qualitative synthesis, with five of them contributing to the quantitative analysis. Reduced ESC values were consistently associated with DN, including early and asymptomatic cases. Pooled sensitivity and specificity for detecting DN were 0.81 (95% CI 0.73–0.87) and 0.73 (95% CI 0.57–0.85), respectively. ESC values correlated with neuropathy severity scores and autonomic dysfunction measures. However, substantial heterogeneity was observed due to variability in diagnostic criteria, ESC thresholds, and study populations. Conclusions: SUDOSCAN is a feasible, rapid, and non-invasive tool for detecting DN, particularly in the early-stage or small-fiber disease. It shows promise as a screening and adjunctive diagnostic modality, especially when combined with established clinical tools. Nevertheless, the lack of standardized thresholds limits its standalone use. Full article

Background: Diabetic peripheral neuropathy (DPN) is a progressive complication of type 2 diabetes mellitus (T2DM) for which no approved disease-modifying therapy exists. Palmitoylethanolamide/Baicalin (PEA/Bai; Neuridase^®) is a nutraceutical formulation with anti-neuroinflammatory and antioxidant properties; however, real-world evidence on its associations with objective neuropathy biomarkers remains limited; nutraceutical approaches to DPN remain exploratory and adjunctive in the absence of randomised controlled trial evidence of disease modification. Methods: We conducted a single-centre, retrospective, 1:1 matched-cohort study at an Internal Medicine outpatient clinic. Forty-eight T2DM patients with clinically diagnosed DPN who received PEA/Bai supplementation (Neuridase^® group) were matched to 48 untreated controls drawn from a large institutional database, using age, sex, BMI, and diabetes duration as matching variables. Acknowledged a priori limitations include baseline imbalance in neuropathy severity (VAS and ESC) and SGLT2 inhibitor use, reflecting real-world prescribing patterns (confounding by indication) and constituting potential sources of residual confounding that preclude causal inference. The primary outcome was change in VAS neuropathic pain score from baseline (T0) to 6-month follow-up (T6). Secondary outcomes were changes in electrochemical skin conductance (ESC, µS) in hands, feet, and four-limb sum measured by Sudoscan. Results: At baseline, the Neuridase^® group exhibited significantly greater neuropathic burden: higher VAS scores (median 5.5 [IQR 3.8–7.2] vs. 2.0 [0.0–5.0]; p < 0.001) and lower ESC in both hands (53.0 vs. 72.2 µS; p < 0.001) and feet (74.5 vs. 81.0 µS; p < 0.001), reflecting real-world prescribing patterns. Over 6 months, VAS decreased significantly in the Neuridase^® group (5.5→3.0; p < 0.0001; median Δ = −2.5 points, exceeding the clinically important difference), with no change in controls (2.0→2.0; p = 0.85). Differential Sudoscan trajectories were observed: the Neuridase^® group showed significant improvement in hand ESC (53.0→60.0 µS; p = 0.035) and preservation of foot ESC (p = 0.888), while controls exhibited significant deterioration across all three sudomotor indices (hand p = 0.038; foot p = 0.008; four-limb sum p = 0.004). In a complementary categorical pain trajectory analysis, VAS worsening occurred in 31.3% of controls compared with 0% of Neuridase^®-treated patients (p = 0.00022). Among patients with pathological hand ESC at baseline (<60 µS), 27.8% of Neuridase^® patients (n = 36) transitioned to non-pathological values at T6 versus 0% of controls (n = 32; p = 0.001). Conclusions: In a real-world matched cohort, PEA/Baicalin supplementation was associated with clinically meaningful pain reduction and with differential longitudinal sudomotor trajectories compared to matched untreated controls. These exploratory, hypothesis-generating findings from a retrospective non-randomised design are consistent with possible modulatory effects of PEA/Baicalin on objective sudomotor autonomic biomarkers in DPN. Confounding by indication, baseline severity imbalance, and residual confounders including SGLT2 inhibitor use preclude causal interpretation. These observations provide a rationale for adequately powered, prospective, randomised placebo-controlled trials with extended follow-up and structural neuropathy endpoints. Full article

Carbonyl stress, chronic inflammation, and progressive tissue injury accompany type 2 diabetes mellitus (T2DM) and obesity. Yet, the molecular systems that connect these processes with cardiac, vascular and neuronal complications are incompletely defined. This review examines the AGE–RAGE–DIAPH1 axis as a mechanistic link between metabolic dysfunction and diabetic myocardial and neuronal injury, with emphasis on vascular and myocardial remodeling and emerging implications for autonomic neuronal vulnerability. We summarize current evidence on the formation and accumulation of advanced glycation end-products and other RAGE ligands in metabolic disease, DIAPH1’s structural and signaling role as an intracellular effector of RAGE, and the cellular consequences of pathway activation in vascular, neural, and cardiac tissues. Across experimental models, this signaling axis promotes oxidative stress and inflammatory activation, leading to endothelial dysfunction and barrier failure. Subsequent fibrotic remodeling provides a biologically plausible route through which metabolic stress may be translated into persistent organ injury. In the heart, these mechanisms are linked to coronary microvascular dysfunction, altered cardiomyocyte phenotype, calcium handling abnormalities, and myocardial fibrosis. In the autonomic nervous system, limited but emerging data connect RAGE activation to oxidative injury and mitochondrial dysfunction, abnormal neuronal excitability, and structural vulnerability. Direct evidence linking DIAPH1 to autonomic neurons is lacking. We also review biomarker candidates related to this pathway, including circulating AGEs and soluble RAGE isoforms, skin AGE measurements, imaging markers of myocardial remodeling, and autonomic functional measures. Finally, we discuss pharmacological and natural compounds that target AGE formation, ligand accumulation, RAGE signaling, or intracellular protein interactions linked to this axis. Overall, the available evidence supports the AGE–RAGE–DIAPH1 axis as a credible mechanistic concept and a potentially informative translational hypothesis in T2DM. However, the AGE–RAGE component is supported more strongly than DIAPH1-specific involvement in human diabetic myocardial disorder or cardiovascular autonomic neuropathy. The value of DIAPH1 as a biomarker or therapeutic target in these neurocardiac complications remains to be established. Full article

Background and Objectives: We investigate whether a preoperative autonomic vulnerability phenotype and intraoperative regional cerebral oxygen saturation (rcSO₂) variables are associated with postoperative delirium (POD) in elderly patients undergoing non-cardiac, non-neurological surgery, and whether autonomic vulnerability modifies the association between cerebral desaturation and POD. Materials and Methods: This retrospective propensity score–matched cohort study included patients aged 65 years or older who underwent general anesthesia with intraoperative rcSO₂ monitoring. The preoperative autonomic vulnerability phenotype was defined using clinical features documented before surgery, including autonomic neuropathy, diabetic autonomic neuropathy, orthostatic hypotension, syncope or presyncope suggestive of autonomic dysfunction, and unexplained resting bradycardia or chronotropic incompetence not attributable to rate-limiting medication. The primary outcome was POD within 5 postoperative days. Patients were matched 1:1 using nearest-neighbor propensity score matching with a caliper of 0.2 standard deviations of the logit of the propensity score, and conditional logistic regression was used in the matched cohort. Results: A total of 412 patients were included; 112 had the phenotype and 300 did not. After matching, 98 pairs were analyzed. POD occurred in 27.6% of patients with the phenotype and 14.3% of patients without it. In the matched cohort, the phenotype (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.18–3.82, p = 0.012), rcSO₂ decrease ≥20% (OR 2.45, 95% CI 1.31–4.58, p = 0.005), and longer duration of rcSO₂ < 80% of baseline (OR 1.02 per min, 95% CI 1.01–1.04, p = 0.008) were independently associated with POD. The phenotype-by-desaturation interaction was exploratory (OR 2.10, p = 0.032) and was not uniformly robust across sensitivity analyses. Conclusions: A preoperative autonomic vulnerability phenotype and intraoperative cerebral desaturation were independently associated with POD. The association between rcSO₂ decrease and POD appeared stronger in patients with autonomic vulnerability, but this interaction should be interpreted as hypothesis-generating rather than confirmatory. Full article

Background/Objectives: Orthostatic hypotension (OH) is a clinically relevant manifestation that may reflect cardiovascular autonomic dysfunction in type 2 diabetes (T2D), yet its correlates remain incompletely characterized. This cross-sectional study evaluated clinical, neuropathic, and sudomotor factors associated with OH and explored balance-related outcomes as secondary analyses. Methods: In this cross-sectional study, 124 adults with T2D aged ≥60 years underwent standardized orthostatic blood pressure testing. Peripheral neuropathy was assessed using the Michigan Neuropathy Screening Instrument (MNSI), and sudomotor function was assessed by electrochemical skin conductance measured with Sudoscan. Balance, mobility, and fear of falling were evaluated as exploratory secondary outcomes. Active antihypertensive treatment was recorded at the time of assessment and considered a potential confounder. Multivariable logistic regression was used to identify factors associated with OH. Results: OH was associated with longer diabetes duration (OR = 1.11/year, p = 0.002), higher objective neuropathy severity (MNSI-B; OR = 1.27, p = 0.049), and increased urinary albumin-to-creatinine ratio (OR = 1.01, p = 0.035). Sudomotor parameters did not differ significantly between OH groups in univariate analyses and were not retained in the final parsimonious model. Exploratory analyses showed no significant univariate differences in balance or fear-of-falling outcomes by OH status. Model discrimination was acceptable (AUC = 0.787), whereas calibration was imperfect according to the Hosmer–Lemeshow test; therefore, model performance should be interpreted as apparent and explanatory rather than predictive. Conclusions: In older adults with T2D, OH was associated with longer disease duration, greater neuropathy burden, and microvascular involvement. Sudoscan-derived measures were not independently associated with OH in this cohort. Because of the cross-sectional design and residual medication confounding, all findings should be interpreted as associations only. These results support routine orthostatic evaluation alongside neuropathy and albuminuria assessment, while predictive modeling requires external validation in larger cohorts. Full article

Background/Objectives: Angiopoietin-like proteins 4 and 8 (ANGPTL4 and ANGPTL8) are key regulators of lipid metabolism and inflammatory processes, with a potential role in the pathogenesis of type 2 diabetes mellitus (T2DM) and its complications. This monocentric observational study evaluated serum levels of ANGPTL4 and ANGPTL8 in 160 participants (93 patients with T2DM and 67 controls without carbohydrate disturbances) and their associations with peripheral and cardiac autonomic neuropathy. Methods: This is a monocentric, cross-sectional, observational study conducted at the Endocrinology and Metabolic Disorders Clinic of Alexandrovska Hospital in Sofia, involving 160 participants and approved by the Ethics Committee of Medical University–Sofia, with all subjects providing written informed consent in accordance with the Declaration of Helsinki. The main methods included detailed clinical and anthropometric assessments, diagnosis of peripheral neuropathy via the Neuropathy Disability Score (NDS), evaluation of cardiac autonomic neuropathy using heart rate variability analysis and Ewing cardiovascular reflex tests, comprehensive laboratory investigations with fasting blood samples, measurement of serum ANGPTL4 and ANGPTL8 levels by ELISA kits, and statistical analysis performed with IBM SPSS version 25, using parametric and non-parametric tests, correlations, logistic regression, and ROC curves. Results: ANGPTL4 levels were significantly lower in patients with T2DM (12.6 ± 23.1 ng/mL vs. 21.5 ± 29.3 ng/mL; p = 0.033). In a multivariate model, higher values remained associated with lower odds of T2DM (OR per 1 SD = 0.634; p = 0.0424). ANGPTL8 demonstrated moderate discriminatory ability for cardiac autonomic neuropathy (AUC = 0.678; p = 0.007) in unadjusted analysis, but the association did not persist after covariate adjustment. ANGPTL4 showed inverse correlations with body weight, basal metabolic rate, and GGT. Conclusions: The results support the role of ANGPTL4 as a potential biomarker in metabolic disturbances and complications in T2DM, while ANGPTL8 remains mainly insignificant after correction for potential confounding factors. Full article

Diabetic gastroparesis (DGp) is a chronic complication of diabetes characterized by delayed gastric emptying with nausea, vomiting, early satiety, bloating, and poor glycemic control. Diagnosis requires objective testing, preferably a 4-h gastric emptying scan, along with assessment of symptom severity and quality of life for affected patients. Diabetic gastroparesis is the result of complex and overlapping mechanisms: autonomic (vagal) neuropathy, loss/dysfunction of interstitial cells of Cajal (ICC), enteric neuropathy, pyloric dysfunction (increased pyloric tone), and altered gut–brain signaling. Chronic hyperglycemia precipitates and worsens gastric dysmotility. Management remains multimodal: optimize glycemic control and nutrition, use evidence-based prokinetics and antiemetics, and consider targeted procedural/device therapies (G-POEM, gastric electrical stimulation) for refractory cases. The present is characterized by renewed drug development (ghrelin agonists such as relamorelin, with promising efficacy but a not-yet-well-established commercial pathway) and growing evidence for selective prokinetics already in use for other indications (prucalopride). Neuromodulation (Enterra GES) remains an option for selected refractory patients. Recent guidelines and studies define when and how to use these options, but no randomized head-to-head comparisons of the various therapeutic options are yet available, nor are long-term, real-world safety/efficacy registries for drugs and minimally invasive surgical procedures. There is still unsatisfactory evidence on how to safely manage GLP-1 receptor agonist therapy in diabetic patients predisposed to gastroparesis (balancing cardiorenal glycemic benefits versus gastrointestinal adverse effects), considering that these drugs can worsen gastric emptying and symptoms, requiring careful clinical judgment. This review aims to analyze and update clinicians on new evidence in the diagnosis and treatment of these conditions, starting from earlier recognition to achieving more rational treatment that balances the need for good glycemic control, control of gastrointestinal symptoms related to these complications, and an acceptable quality of life for the diabetic patient. Full article

Background: Obstructive sleep apnea (OSA) is a common but underrecognized sleep-related breathing disorder characterized by intermittent hypoxemia and autonomic dysfunction. OSA prevalence and clinical relevance in Type 1 Diabetes Mellitus (T1DM), particularly in relation to diabetes-related vascular complications, remain insufficiently explored. Objective: The aim of this study was to evaluate the prevalence of high-risk OSA in adults with T1DM and controls, and to investigate the association between high-risk OSA and microvascular complications among individuals with T1DM. Methods: In this cross-sectional case–control study, 102 adults with T1DM and 126 controls were included. OSA risk was assessed using the modified Berlin Questionnaire (mBQ). Analyses of vascular complications were restricted to participants with T1DM. Multivariable logistic regression models adjusted for age and sex were used to assess associations, with additional adjustments for body mass index, hypertension, current smoking, alcohol use and glycated hemoglobin A1c. Results: High-risk OSA was identified in 18.6% of individuals with T1DM and 11.9% of controls, with no significant difference between groups. Among participants with T1DM, the prevalence of microvascular complications (retinopathy and/or neuropathy) was substantially higher in those with high-risk OSA compared with those at low risk (68.4% vs. 18.07%, p <0.001). In univariate logistic regression analysis, high-risk OSA was significantly associated with microvascular complications (odds ratio [OR] 4.85; 95% confidence interval [CI] 1.65–14.24; p = 0.004). This association remained significant in the fully adjusted model (OR 5.55; 95% CI 1.36–22.65; p = 0.017). Conclusions: High-risk OSA is not more prevalent in adults with T1DM compared with controls; however, among individuals with T1DM, high-risk OSA is strongly and independently associated with microvascular complications. Given the potential contribution of diabetic microvascular and autonomic neuropathy to upper airway dysfunction, the relationship between OSA and vascular complications in T1DM may be bidirectional, warranting further longitudinal investigation. Full article

Background: Diabetic neuropathy manifests as symmetric distal and autonomic neuropathy, including cardiovagal dysfunction. Small-fiber involvement can occur, leading to neuropathic pain and dysautonomia. The diagnostic gold standard of these two conditions comprehends skin biopsy and cardiovascular autonomic reflex tests (CARTs), respectively. Non-invasive diagnostic tools, such as laser-evoked potentials (LEPs), show promise in detecting small-fiber damage, though correlations between LEP abnormalities and cardiovascular autonomic dysfunction remain poorly investigated. Methods: We retrospectively evaluated LEPs (from hands and feet stimulation) in 33 diabetic patients, comparing them to a cohort of 33 age-matched healthy subjects, to highlight any significant abnormalities in the diabetic cohort. We further analyzed the LEP results in T2DM cohort with clinical, laboratory variables and CARTs to explore potential correlations and to assess whether any association between LEPs and CARTs could be identified. Results: N2/P2 complex amplitude was significantly reduced in diabetic patients compared to healthy subjects, with greater involvement in the lower limbs. While no association between LEP abnormalities and abnormal CARTs was observed, LEP amplitude reductions were notably associated with elevated glycated hemoglobin levels and longer disease duration, which appeared to be the strongest predictor of LEP reduction. Conclusions: Our findings corroborated literature data regarding length-dependent LEP alterations detectable even in initial diabetic stages. The lack of correlation between LEP abnormalities and autonomic dysfunction may stem from the predominant involvement of C fibers in autonomic neuropathy, which are not adequately assessed by currently used LEPs. Full article

Background/Objectives: Vitamin B12 deficiency is a common but often underdiagnosed complication in patients with type 2 diabetes (T2D) undergoing long-term metformin therapy. Accurate early prediction could enable targeted screening and timely intervention. This study aimed to develop and interpret a machine learning model for predicting vitamin B12 deficiency in metformin-treated patients with T2D, using eXtreme Gradient Boosting (XGBoost). Methods: A retrospective cross-sectional study was conducted at a single endocrinology centre (La Rabta University Hospital, Tunis, Tunisia). Patients with T2D treated with metformin for at least three years were included (n = 257); those with conditions independently affecting vitamin B12 metabolism were excluded. Vitamin B12 deficiency was defined as a serum B12 level below 150 pmol/L or a borderline level (150–221 pmol/L) with concurrent hyperhomocysteinemia (>15 μmol/L). XGBoost was selected after comparison with Logistic Regression (L2), Random Forest, and Support Vector Machine on the same 5-fold stratified cross-validated pipeline. Hyperparameters were optimized via Bayesian search (100 iterations × 5-fold stratified cross-validation), with the Matthews correlation coefficient (MCC) as the primary optimization metric to account for class imbalance. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Discrimination and calibration were assessed on an independent test set using bootstrap 95% confidence intervals (2000 resamples). Results: Of 257 patients, 95 (37.0%) presented with vitamin B12 deficiency. On the independent test set (n = 52), the optimized XGBoost model achieved an ROC-AUC of 0.671 [95% CI: 0.514–0.818], sensitivity of 0.737 [95% CI: 0.533–0.938], specificity of 0.545 [95% CI: 0.375–0.710], MCC of 0.273 [95% CI: 0.018–0.517], and a Brier Score of 0.259. SHAP analysis identified HbA1c, microalbuminuria, autonomic neuropathy, BMI, DN4 score, and fasting glucose as the most influential predictors. Nonlinear SHAP interaction plots revealed an increased predicted risk in patients with low HbA1c combined with a high cumulative metformin dose. Conclusions: The XGBoost–SHAP framework provided interpretable predictions of vitamin B12 deficiency in patients with T2D on metformin, identifying key clinical profiles for targeted screening. External multi-centre validation is required before clinical deployment. Full article

Background: Diabetic retinopathy (DR) remains one of the most frequent and severe complications in patients with type 2 diabetes (T2DM), with significant implications for vision and quality of life. While classical screening methods are effective, they are not always accessible or systematically used. Sudoscan, a device that evaluates sweat gland function by measuring electrochemical skin conductance (ESC)—an indicator of chloride ion flow through sweat glands and a marker of peripheral autonomic nerve function—has recently attracted attention as a potential adjunct tool for risk assessment of microvascular complications. Objectives: In this cross-sectional study, we investigated its utility in identifying DR among 271 adults with T2DM. DR was diagnosed in 35.8% of patients, and those affected showed lower Sudoscan scores in the lower limbs and higher scores indicating cardiovascular autonomic neuropathy. Methods: Statistical analyses, including ROC curve evaluation and multiple linear regression, revealed moderate diagnostic accuracy and significant correlations between Sudoscan parameters and DR severity. Results: Our results suggest that Sudoscan could serve as a fast, painless, and informative screening tool, particularly valuable in settings with limited access to ophthalmologic services. Conclusions: Although it does not replace fundus examination, it may offer complementary insights and help stratify patients by risk level, guiding more targeted monitoring and intervention strategies. Full article

Background: Chronic low-grade inflammation plays a central role in the pathogenesis of type 2 diabetes (T2DM) and its complications. Neopterin, a marker of macrophage activation and Th1-mediated immune response, has been associated with cardiovascular disease and metabolic disorders. However, its relationship with diabetic autonomic neuropathy remains insufficiently investigated. Methods: We conducted a cross-sectional study including 129 participants (93 with T2DM and 36 with obesity without carbohydrate disturbances). Clinical, anthropometric, and biochemical assessments were performed. Cardiovascular autonomic neuropathy was evaluated using Ewing cardiovascular reflex tests and sudomotor dysfunction scoring. Neopterin concentrations were measured in serum. Correlation, ROC, and logistic regression analyses were performed. Results: Neopterin levels were not significantly different between T2DM and obesity groups. No differences were observed in patients with versus without peripheral neuropathy, nephropathy, or retinopathy. However, neopterin levels were significantly higher in individuals with cardiovascular autonomic neuropathy (p = 0.013). Neopterin correlated with cardiovascular autonomic neuropathy score, sudomotor dysfunction, fasting glucose, fasting insulin, and HOMA-IR. It showed a moderate negative monotonic correlation with eGFR (Spearman’s rho = −0.41, p< 0.001). In multivariable logistic regression adjusted for age, HbA1c, BMI, eGFR, and diabetes duration, each 1-SD increase in neopterin was associated with 2.67-fold higher odds of cardiovascular autonomic neuropathy (95% CI 1.21–5.89; p = 0.015). Conclusions: Circulating neopterin is independently associated with cardiovascular autonomic neuropathy in T2DM but not with classical microvascular complications. These findings suggest a potential role of immune-mediated mechanisms in the pathogenesis of diabetic cardiovascular autonomic neuropathy. 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

Type 2 diabetes mellitus is associated with major cardiovascular complications, including cardiac autonomic neuropathy, which contributes to sympathetic–parasympathetic imbalance and increases susceptibility to arrhythmias and sudden cardiac death. Heart rate variability, assessed through R–R intervals on electrocardiography and 24 h Holter monitoring, represents a sensitive, non-invasive marker of autonomic dysfunction and arrhythmogenic risk. In patients with type 2 diabetes mellitus, chronic hyperglycaemia, oxidative stress, and metabolic inflammation lead to early impairment of the autonomic nervous system, manifested by consistent reductions in SDNN, RMSSD, pNN50, total power, and the high-frequency component, indicating diminished parasympathetic tone and sympathetic predominance. Nonlinear HRV indices demonstrate a loss of complexity and fractal organisation, providing additional prognostic value beyond conventional time- and frequency-domain analyses. Reduced HRV correlates with the severity of cardiac autonomic neuropathy, duration of diabetes, and poor glycaemic control, identifying patients with increased arrhythmogenic vulnerability. HRV analysis enables prediction of arrhythmic risk, facilitating the identification of high-risk individuals and guiding personalised interventions. The integration of HRV assessment into routine clinical practice may improve the early detection of subclinical autonomic neuropathy and optimise cardiovascular risk stratification and management in patients with type 2 diabetes mellitus. Full article

Background and Objectives: Peripheral neuropathy (PNP) is a frequent and debilitating complication among patients with diabetes mellitus (DM) and other metabolic conditions, substantially affecting morbidity, functional status, and quality of life. Identifying predictors of PNP is essential for optimizing early diagnostic strategies and improving long-term management outcomes. The aim of this study was to determine the predictive factors of PNP in a cohort of patients with DM. Materials and Methods: A cross-sectional study including 117 patients diagnosed with DM assessed for PNP was conducted. All patients were evaluated clinically and biologically. PNP was clinically assessed using the Toronto Clinical Scoring System (TCSS) score and sudomotor function by Sudoscan. Results: The patients included were mostly males with type 2 DM and metabolic syndrome phenotypes. Moreover, the patients with PNP were much older than those without PNP (65 [57–69] vs. 59.50 [46–68] years, p = 0.008), with a longer duration of DM (10 [6–15.50] vs. 5.5 (2–14] years, p = 0.019), and associated autonomic diabetic neuropathy (χ² = 24.382, p < 0.001). Furthermore, TCSS and Sudoscan were correlated with a history of PNP, especially Sudoscan, which showed a very good discriminative ability for diabetic neuropathy diagnosis (AUC = 0.816). In a multivariable logistic regression including age, DM duration, and HbA1c, age was independently associated with PNP, with each additional year increasing the odds of neuropathy by approximately 6% (OR = 1.06, 95% CI 0.02–1.09, p = 0.002). When age was excluded, DM duration showed a borderline association with PNP (OR = 1.055, CI95% 0.997–1.117), suggesting potential overlap between these variables. Adding sudomotor assessment to the initial model improved the model performance (AUC 0.70–0.72). Conclusions: Age emerged as the main independent predictor of diabetic neuropathy, highlighting the role of cumulative metabolic exposure in the development of neural damage. Moreover, sudomotor assessment may have a complementary role in PNP assessment. Full article