Search Results (784)

Background and Objectives: Diabetic foot gangrene remains a major cause of lower limb amputation, driven by vascular, neuropathic, and infectious mechanisms. Identifying predictors for amputation type is essential to optimizing outcomes and reducing disability. We aimed to analyze the burden of diabetic foot gangrene and the patients’ characteristics according to the type of surgery, minor or major amputations. Methods: We conducted a retrospective observational study including 295 diabetic patients who underwent surgery for foot lesions at a Romanian tertiary center (January 2023–December 2024). Patients were classified according to surgical outcome as minor (toe/foot-level) or major (below/above-knee) amputations. Clinical, demographic, and pathological variables were compared between groups. Statistical analysis was performed with IBM SPSS Statistics 20.0. Categorical variables were expressed as frequencies and percentages, and continuous variables as mean ± SD or median (min–max). Group comparisons used Student’s t-test, Mann–Whitney U, Chi-square, or Fisher’s exact test, and binary logistic regression was applied to calculate odds ratios (OR) with 95% confidence intervals (CI). Results: Among the patients included (mean age 64.8 ± 10.8 years; 69.2% male), 191 (64.7%) underwent minor amputations/debridement and 104 (35.3%) required major amputations. Patients with major amputations were older (66.8 ± 11.3 vs. 63.7 ± 10.4 years, p = 0.012) and less frequently male (56.7% vs. 75.9%, p = 0.001). Lesion extension to the foot or beyond strongly predicted major amputation (p < 0.001). Peripheral arterial disease was more prevalent in the major group (85.6% vs. 65.4%, OR = 3.13, 95% CI = 1.68–5.84), while neuropathy was associated with minor procedures (12.6% vs. 3.8%, p = 0.015). Anemia (70.2% vs. 56.5%, p = 0.021) and leukocytosis (68.3% vs. 49.2%, p = 0.002) were also independent predictors of major amputation. Conclusions: The study highlights the need for early detection, coordinated multidisciplinary care, and personalized assessment of diabetes burden and its complications to minimize the risk of major limb amputation. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as cornerstone therapies for type 2 diabetes mellitus and obesity, offering significant cardiovascular and renal protection. However, recent evidence has sparked interest and concern regarding their potential ocular effects. This review critically synthesizes current data on the impact of GLP-1RAs on diabetic retinopathy (DR), nonarteritic anterior ischemic optic neuropathy (NAION), age-related macular degeneration (AMD), and glaucoma or ocular hypertension. While preclinical studies suggest GLP-1RAs exert anti-inflammatory and neuroprotective effects in retinal tissues, clinical data remain mixed. Several large observational studies suggest a protective role against DR and glaucoma, while others raise safety concerns, particularly regarding semaglutide and NAION. Evidence on AMD is conflicting, with signals of both benefit and risk. We also discuss plausible pathophysiological mechanisms and the relevance of metabolic modulation on retinal perfusion. Overall, while GLP-1RAs hold promise for ocular protection in some contexts, vigilance is warranted, especially in patients with pre-existing eye disease. Further ophthalmology-focused prospective trials are essential to clarify long-term safety and guide clinical decision making. Full article

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, marked by Schwann cell dysfunction, demyelination, and impaired nerve regeneration. Although Schwann cells undergo phenotypic changes under hyperglycemic conditions, the underlying molecular mechanisms remain unclear. This study aimed to examine the effects of high glucose on Schwann cell phenotype and assess the involvement of the mTOR signaling pathway. Primary Schwann cells were isolated from rat sciatic nerves and cultured in media containing 5 mM (control), 25 mM, or 50 mM glucose for five days. Immunofluorescence staining and corrected total cell fluorescence (CTCF) analysis were used to evaluate expression of key markers: c-Jun, Krox-20, p75^NTR, MBP, mTOR, phosphorylated mTOR (Ser2448), and AKR1B1. Among these, significant changes were observed in MBP (p = 0.002), total mTOR (p = 0.001), and phosphorylated mTOR (Ser2448) (p = 0.0179), indicating impaired mTOR activation and loss of myelin protein expression. Non-significant changes in the other markers are discussed as preliminary observations. These findings highlight mTOR dysregulation and impaired myelin protein expression as central features of Schwann cell responses to hyperglycemia, which may contribute to the development of DPN. Full article

Diabetic foot infections (DFIs) are a significant complication in patients with diabetes, often leading to severe clinical complications including amputation and increased mortality rates. The effective management of these infections is complicated by the rise in antibiotic resistance among the microbial populations involved. In this paper, we undertake a systematic review and meta-analysis to explore the bacterial profiles, as well as their antibiotic resistance patterns in DFIs, encompassing studies published between 2014 and 2024. A total of 28 studies were selected from several databases, including PubMed, Google Scholar, EBSCOhost, and ScienceDirect, published from 2014 to 2024, specifically focusing on diabetic foot infections and antibiotic resistance. Diabetic foot infections arise from a combination of factors, including peripheral neuropathy, poor circulation, and immune system impairment, making diabetic patients prone to unnoticed injuries, impaired wound healing, and a higher risk of infections. The severity of DFIs often depends on the size and depth of the ulcers, with larger, deeper ulcers posing additional risks of infection and complications, such as osteomyelitis and sepsis. Our study synthesizes information on the total isolates of microbes, their resistance to one or more groups of antibiotics, and resistance panel results across multiple antibiotics, including amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, ciprofloxacin, and others. We meticulously catalog the resistance of key bacterial strains—Escherichia coli, Enterobacter spp., Proteus spp., Pseudomonas spp., Staphylococcus aureus, and others—highlighting patterns of resistance to single and multiple antibiotic groups. This systematic review also analyzes the correlations of various comorbidities reported by the diabetic foot infection patient populations in the included studies with multiple antibiotic resistance patterns. Subsequently, this analytical review study addresses the rising prevalence of antibiotic-resistant pathogens and underscores the need for antibiotic stewardship programs to promote judicious use of antibiotics, reduce the spread of resistant strains, and enhance therapeutic outcomes. In addition, the review discusses the implications of resistance to empirical antibiotic treatments, underscoring the necessity for tailored antibiotic therapy based on culture and sensitivity results to optimize treatment outcomes. Full article

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide exerting, among others, strong trophic and protective effects. It plays a role in several physiological functions, including glucose homeostasis. The protective effects of PACAP are mainly mediated via its specific PAC1 receptor by stimulating anti-inflammatory, anti-apoptotic and antioxidant pathways. The aim of the present review is to summarize data on the protective effects of PACAP in the three major complications of diabetes, retinopathy, nephropathy and neuropathy, as well as some other complications. In type 1 and type 2 diabetic retinopathy models and in glucose-exposed cells of the eye, PACAP counteracted the degeneration of retinal layers and inhibited apoptosis and factors leading to abnormal vessel growth. In models of nephropathy, kidney morphology was better retained after PACAP administration, with decreased apoptosis and fibrosis. In diabetic neuropathy, PACAP protected against axonal–myelin lesions and less activation in pain processing centers. This neuropeptide has several other beneficial effects in diabetes-induced complications like altered vascular response, cognitive deficits and atherosclerosis. The promising therapeutic effects of PACAP in several pathological conditions have encouraged researchers to design PACAP-related drugs and to develop ways to enhance tissue delivery. These intentions are expected to result in overcoming the hurdles preventing PACAP from being introduced into therapeutic treatments, including diabetes-related conditions. Full article

Diabetic wounds, especially diabetic foot ulcers, pose a major global clinical challenge due to their slow healing and high infection susceptibility. Their typical pathological features include impaired angiogenesis, chronic hypoxia, persistent inflammation, oxidative stress, bacterial colonization, and neuropathy. Traditional treatment methods have limited efficacy, creating an urgent need for innovative therapeutic strategies. In recent years, biomaterials have emerged as a research focus in diabetic wound treatment, owing to their biocompatibility, versatility, and tissue regeneration potential. This article comprehensively reviews the pathological mechanisms of diabetic wounds. It also summarizes the application progress of biomaterials in diabetic wound healing. Over the past decade, researchers have explored the properties, mechanisms of action, and roles of various natural and synthetic biomaterials. These biomaterials include DNA nanomaterials, peptide hydrogels, cells, exosomes, and cytokines. These biomaterials play significant role in promoting angiogenesis, regulating inflammation, inhibiting bacteria, and enhancing cell proliferation and migration. Full article

Background/Objectives: The study aimed to pharmacologically evaluate dually acting ligands, 5-HT₇ antagonists and sodium channel inhibitors, as potential therapeutic agents for the treatment of depression, anxiety, and neuropathic pain. The designed dual ligands combined structural fragments of LP-12 (a 5-HT₇ receptor ligand) and phenytoin (a sodium channel blocker). Methods: A series of 1-(2-biphenyl)piperazine derivatives with a hydantoin core was synthesized and evaluated for 5-HT₇ receptor affinity and sodium channel inhibition. The most potent ligands were further analyzed using molecular docking, cytotoxicity assays (MTT, LDH), and in vitro metabolism studies, including microsomal stability and CYP450 inhibition. In vivo pharmacological effects were assessed in behavioral models: forced swim test, four-plate test, and a streptozotocin (STZ)-induced diabetic neuropathy model in mice. Results: Compounds 10 and 20 exhibited high 5-HT₇ receptor affinity (K_i < 10 nM) and potent sodium channel inhibition (>80% at 1 µM). Docking studies revealed binding modes consistent with established 5-HT₇ ligands. Compound 10 showed lower cytotoxicity than compound 20 in both HepG2 and SH-SY5Y cells and was therefore selected for further evaluation. Metabolic profiling indicated improved microsomal stability relative to verapamil and a low risk of CYP-mediated drug–drug interactions. In vivo, compound 10 produced significant antidepressant- and anxiolytic-like effects, though it failed to reduce neuropathic pain symptoms in the STZ-induced model. Conclusions: Compound 10 shows potential for mood disorder treatment, but further refinement may be needed to improve analgesic efficacy. Full article

Background: Diabetic eye surface disease, including dry eye syndrome, corneal neuropathy, and diabetic retinopathy, is a common complication of diabetes. Tear fluid biomarkers may aid in early diagnosis and disease monitoring. The objective of this systematic review was to identify and evaluate tear fluid biomarkers in diabetic ocular surface disease according to PRISMA guidelines. Methods: PubMed, Scopus, and Embase databases were searched through June 2025. Eligible studies included clinical and observational studies measuring proteins, lipids, cytokines, trace elements, or nucleic acids in tear fluids in patients with diabetes. Results: The search identified 198 studies, and of those, 30 studies were included, comprising 14 original investigations with 871 participants (133 with type 1 diabetes, 453 with type 2 diabetes, 16 with pre-diabetes, and 269 healthy controls). The main biomarker categories were cytokines (IL-6, IL-8, TNF-α, and MMP-9), neuropeptides (substance P, NPY), proteins (IGFBP-3, progranulin), lipids, glycans, microRNAs, circRNAs, and trace elements. Conclusions: More than a dozen biomarkers in the tear fluid have been identified that may reflect diabetes-related changes in the ocular surface. Tear fluid analysis may be a valuable tool in personalizing the diagnosis and treatment of diabetic ocular surface diseases, but further studies are needed to confirm its clinical significance. Full article

Background/Objectives: Diabetic neuropathy (DN) is a prevalent complication of diabetes mellitus, affecting up to 50% of long-term patients and causing significant pain, reduced quality of life, and healthcare burden. Conventional treatments, including anticonvulsants, antidepressants, and opioids, offer limited efficacy and are associated with adverse effects. Emerging evidence suggests that cannabis, acting via the endocannabinoid system, may provide analgesic and neuroprotective benefits. This study evaluates the long-term effects of inhaled cannabis as adjunctive therapy for refractory painful DN. Inhaled cannabis exhibits rapid onset pharmacokinetics (within minutes, lasting 2–4 h) due to pulmonary absorption, targeting CB1 and CB2 receptors to modulate pain and inflammation. Methods: In this prospective, observational study, 52 patients with confirmed painful DN, unresponsive to at least three prior analgesics plus non-pharmacological interventions, were recruited from a single clinic. Following a 1-month washout, patients initiated inhaled medical-grade cannabis (20% THC, <1% CBD), titrated individually. Assessments occurred at baseline and annually for 5 years, including the Brief Pain Inventory (BPI) for pain severity and interference; the degree of pain relief; Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) score; HbA1c; and medication usage. Statistical analyses used repeated-measures ANOVA, Kruskal–Wallis tests, Welch’s t-tests, and Pearson’s correlations via Analyze-it for Excel. Results: Of 52 patients (mean age 45.3 ± 17.8 years; 71.2% male; diabetes duration 23.3 ± 17.8 years), 50 completed follow-up visits. Significant reductions occurred in BPI pain severity (9.0 ± 0.8 to 2.0 ± 0.7, p < 0.001), interference (7.5 ± 1.7 to 2.2 ± 0.9, p < 0.001), LANSS score (19.4 ± 3.8 to 10.2 ± 6.4, p < 0.001), and HbA1c (9.77% ± 1.50 to 7.79% ± 1.51, p < 0.001). Analgesic use decreased markedly (e.g., morphine equivalents: 66.8 ± 49.2 mg to 4.5 ± 9.6 mg). Cannabis dose correlated positively with pain relief (r = 0.74, p < 0.001) and negatively with narcotic use (r = −0.43, p < 0.001) and pain interference (r = −0.43, p < 0.001). No serious adverse events were reported; mild side effects (e.g., dry mouth or euphoria) occurred in 15.4% of patients. Conclusions: Inhaled cannabis showed sustained pain relief, improved glycemic control, and opioid-sparing effects in refractory DN over 5 years, with a favorable safety profile. These findings are associative due to the observational design, and randomized controlled trials (RCTs) are needed to confirm efficacy and determine optimal usage, addressing limitations such as single-center bias and small sample size (n = 52). Future studies incorporating biomarker analysis (e.g., endocannabinoid levels) could elucidate mechanisms and enhance precision in cannabis therapy. Full article

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes that impairs gait and balance, increasing fall risk. This study investigated gait characteristics and postural control in individuals with DPN, compared to age- and gender-matched healthy controls. Fifteen DPN patients and fifteen controls underwent assessments of gait, static balance, and mobility. Gait parameters were measured during overground walking using motion capture and force platforms. Static balance was evaluated via tandem stance tests (eyes open/closed), while mobility was assessed with the Timed-Up-and-Go (TUG) test. Dynamic stability was assessed by computing the center-of-pressure Time-to-Contact (TTC) with the mediolateral (ML) stability boundary. We hypothesized that patients with DPN would exhibit an altered gait and reduced ML postural stability during walking. The study results show no significant differences in ML center-of-pressure (COP) excursion or its velocity during walking between groups. Patients with DPN walked relatively slowly, with shorter steps, and showed markedly poorer static balance (earlier failure during tandem stance test), as well as slower TUG performance. Clinically, these findings support routine fall risk screening in DPN using both static balance tests (e.g., tandem stance) and mobility measures (e.g., TUG or gait speed). These findings further suggest that while dynamic postural control during walking may be preserved, DPN patients exhibit gait adaptations and significant static balance deficits, highlighting the need for comprehensive balance assessment in this population. Full article

Hyperglycemia, which arises in type 1 or 2 diabetes, leads to different complications, such as macrovascular disease, nephropathy, retinopathy, and neuropathy. In addition, different cognitive variations are associated with type 1 diabetes. Long-term changes in glucose metabolism might induce effects on the central nervous system (CNS) such as reduced mental performance and loss of consciousness, which could be implicated in neurotoxicity. The direct impact of hyperglycemia and elevated glucose concentrations on neuronal cells remains to be fully elucidated, primarily due to the multifaceted mechanisms underlying glucose neurotoxicity, including apoptosis, oxidative stress, and alterations in signaling cascades. The multifaceted mechanisms further complicate the study of the relationship between diabetes and neurodegeneration. Research in this field is continually advancing, with the aim of investigating these eventual connections and developing more effective preventive and therapeutic strategies. The present study aims to assess the damage induced by different glucose concentrations (from 25 to 150 mM) in a neuronal model, such as PC12 cells, rat pheochromocytoma cells. In glucose-exposed PC12 cells, we have tested oxidative stress, apoptosis, and cell migration by (a) viability screening, (b) intracellular levels of anion superoxide (O₂⁻), (c) extracellular levels of MDA and nitrites, (d) apoptosis, and (e) the wound healing assay. By the cell viability assay, it has emerged that glucose (25–150 mM) showed a stronger effect at the highest concentrations (100 and 150 mM). The increase in MDA and O₂⁻ levels was determined in PC12 cells treated with high glucose concentrations (6.5–8.8 fold for MDA). High concentrations (100 and 150 mM) significantly reduced the expression of full-length caspase-3 (2.8-fold and 4.2-fold decrease at 24 and 72 h) and caspase-9 (3.4-fold and 2.8-fold decrease at 24 h and 5-fold decrease at 72 h) compared with control conditions. Finally, the wound healing assay showed different scenarios during the several time points. Indeed, the wound closure rate was reduced in a dose-dependent manner (24 h: control 18%, G 50 mM 9%, 100 and 150 mM 8%; 48 h: control 26%, G 50 mM 20%, G 100 mM 13%, 150 mM 11%), following the treatment with three concentrations considered (50, 100, 150 mM). The results obtained in these experimental conditions highlight that glucose, at high concentrations, induced cell damage and corroborate the hypothesis that it could be involved in neurodegenerative diseases. Full article

While capsaicin topical formulations are established treatments, conventional creams using this substance have limited application due to handling-related adverse events. This study aimed to demonstrate that the efficacy of a novel 0.75 mg/g capsaicin roll-on solution is non-inferior to the approved 0.75 mg/g cream in patients with painful diabetic neuropathy (PDN). In total, 160 patients were randomized to receive either the roll-on or the cream, applied four times daily for 8 weeks, followed by a 4-week washout period and crossover to the alternate treatment. The primary endpoint was pain intensity (numerical rating scale), with secondary endpoints including quality of life (EQ-5D) and safety. Both groups showed significant reductions in pain, with no statistically significant differences in absolute (p = 0.115) or relative (p = 0.157) pain reduction. Non-inferiority was confirmed with a 95% CI for the difference in mean pain reduction [−0.86–0.07], remaining within the pre-specified margin (1.0 unit). Quality of life improved in both groups, with no significant differences (p = 0.266). The incidence of adverse events was low and predominantly mild, with no significant differences between groups (p = 0.424) and a favorable trend for the roll-on formulation. The roll-on capsaicin formulation demonstrated non-inferiority in efficacy and safety compared with the conventional cream formulation. Full article

Background/Objectives: Peripheral neuropathy (PN) is a common complication of diabetes mellitus (DM) with prevalence estimates showing considerable variation across studies. This study aimed to assess the prevalence and risk factors of PN in adult Greek subjects with type 2 diabetes mellitus (T2DM). Methods: Τhe PRENEDIG (PREvalence of peripheral NEuropathy in type 2 DIabetes in Greece) study was a nationwide, cross-sectional multicenter study based on data collected from hospital-based diabetes clinics and primary care practices from January 2024 to June 2024 in Greece. Diabetic peripheral neuropathy (DPN) prevalence and severity were evaluated using the Neuropathy Symptom Score (NSS) and the Neuropathy Disability Score (NDS). Additional sensory assessment tools were considered to support clinical evaluation. Multivariate regression analysis examined the association between DPN and potential risk factors. Results: Among the study population (n = 1807), the overall DPN prevalence was 18.87% and increased with longer diabetes duration. DPN prevalence among participants with over 10 years of T2DM reached 26.49%. Logistic regression analysis identified several independent predictors of DPN including diabetes duration > 10 years (p < 0.001), arterial hypertension in participants with diabetes duration < 10 years (OR = 2.69, CI: 1.68–4.30, p < 0.001), HbA1c levels (OR = 1.20, CI: 1.10–1.31, p < 0.001), and age (OR = 1.02, CI: 1.00–1.03, p = 0.024). An interaction-related association was observed, with arterial hypertension not increasing the risk of DPN any further in participants with disease duration > 10 years (OR: 3.73 vs. 3.80 with or without arterial hypertension, respectively). Sensory assessment tools further validated DPN diagnosis. Conclusions: In Greece, DPN is a common complication, affecting nearly one in five T2DM patients. The results of the study reinforce the importance of routine screening, particularly among older patients and those with longer diabetes duration to facilitate early detection and timely management of DPN and its associated complications. Full article

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia and associated complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy, and chronic non-healing wounds. Current antidiabetic therapies offer only partial glycemic control and are limited by poor bioavailability, adverse effects, and an inability to prevent disease progression. Plant-derived exosome-like nanoparticles (PENPs) have emerged as a promising class of natural nanocarriers with excellent biocompatibility, low immunogenicity, and intrinsic multi-component bioactivity. However, few reviews have addressed recent progress in PENPs for DM therapy. To capture the recent developments in this area, this review provides a systematic synthesis of recent advances in PENPs for DM therapy, covering plant sources, extraction and purification methods, molecular compositions, and therapeutic mechanisms. Preclinical studies have demonstrated that PENPs can improve hyperglycemia, enhance insulin sensitivity, regulate hepatic lipid metabolism, and promote wound healing by modulating oxidative stress, inflammation, gut microbiota, glucose metabolism, and insulin signaling. Additionally, PENPs have been shown to promote angiogenesis via glycolytic reprogramming. Despite these promising findings, challenges including scalable isolation, standardized physicochemical characterization, and clinical translation remain. Future directions include engineering multifunctional PENPs, establishing Good Manufacturing Practice (GMP)-compliant production, and conducting clinical trials to facilitate their integration into precision therapeutics for diabetes management. Full article

Podocyte injury is a central event in the pathogenesis of diabetic nephropathy (DN). We conducted a systematic review across four major databases, identifying 7769 records and including 130 studies that met predefined eligibility criteria. Methodological quality was assessed with Joanna Briggs Institute tools, yielding a mean score of 81.3%, indicating overall moderate-to-high rigor despite design-contingent limitations. Publication activity was sparse until 2018 but increased markedly thereafter, with more than 80% of studies published between 2019 and 2025. Temporal analyses confirmed a strong positive trend (p = 0.86, p < 0.0001), reflecting the rapid expansion of this field. Study designs evolved from early human-only descriptions to integrated multi-model approaches combining human tissue, animal experiments, and in vitro systems, thus balancing clinical relevance with mechanistic exploration. Geographically, Asia emerged as the leading contributor, complemented by increasing multinational collaborations. Mechanistic synthesis highlighted five reproducible pillars of podocyte injury: slit-diaphragm and adhesion failure, mTOR–autophagy–ER stress disequilibrium, mitochondrial and lipid-driven oxidative injury, immune, complement, and inflammasome activation, and epigenetic and transcriptomic reprogramming. Collectively, these findings underscore a convergent mechanistic cascade driving podocyte dysfunction, while also providing a framework for therapeutic interventions aimed at restoring barrier integrity, metabolic balance, and immune regulation in DN. Full article