Diabetic neuropathy has typically been viewed as a peripheral nerve disorder, most commonly presenting as distal symmetrical polyneuropathy (DSPN). However, accumulating evidence suggests that diabetes affects not only peripheral somatic and autonomic fibers but also the central nervous system, indicating more widespread neurodegenerative processes.

This narrative review aims to synthesize current knowledge on how diabetes affects the nervous system across the neuroaxis, integrating peripheral, autonomic, and central mechanisms, and to provide an overview of clinical manifestations, diagnostic approaches, and management strategies.

Chronic hyperglycemia induces a range of metabolic and vascular disturbances, including oxidative stress, inflammation, and microvascular dysfunction, which contribute to peripheral nerve injury. These changes affect both small and large fibers, leading to sensory loss, neuropathic pain, and motor impairment. Autonomic involvement is common and manifests as cardiovascular, gastrointestinal, sudomotor, urogenital, and ocular dysfunction. Importantly, diabetes-related neural injury extends beyond the peripheral nervous system. Structural and functional alterations have been demonstrated in the spinal cord, brainstem and brain, including changes in white matter integrity, cortical organization, and functional connectivity. Peripheral and central mechanisms interact bidirectionally, contributing to altered sensory processing and pain modulation.

Diabetic neuropathy should be understood as a disorder of the entire neuroaxis. Integrating peripheral and central aspects is essential to gain a holistic view of diabetic neuropathy and to support the development of more targeted diagnostic and therapeutic strategies.

Background/Objectives: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, dyslipidemia, and oxidative stress, leading to severe systemic complications. Medicinal plants rich in polyphenolic compounds have gained increasing attention as complementary therapeutic agents. This study aimed to comparatively evaluate the chemical composition, as well as the antidiabetic, hypolipidemic, and antioxidant effects of Polygonum persicaria and Vaccinium myrtillus in a streptozotocin-induced diabetic model. Although Vaccinium myrtillus has been more extensively investigated for its antidiabetic potential, the pharmacological relevance of Polygonum persicaria in diabetes remains insufficiently characterized, particularly in direct comparison with a recognized phytotherapeutic comparator. Methods: Hydroalcoholic tinctures prepared from Polygonum persicaria L. herb and Vaccinium myrtillus L. leaves were subjected to phytochemical analysis using High-Performance Thin-Layer Chromatography (HPTLC) for the identification of flavonoids and phenolcarboxylic acids, alongside spectrophotometric determination of total polyphenol and flavonoid content. Experimental diabetes was induced in CD1 mice by streptozotocin administration. Animals were treated orally for 35 days, and glycemic parameters, lipid profile, body weight, food and water intake, and oxidative stress markers (MDA, SOD, TAC, and GPx) were evaluated. Results: HPTLC/CSS screening indicated the presence of rutin, chlorogenic acid, and caffeic acid in Polygonum persicaria, while Vaccinium myrtillus showed stronger densitometric signals for phenolcarboxylic acid-type compounds, particularly chlorogenic and caffeic acids. Total polyphenol and flavonoid content were also higher in Vaccinium myrtillus (433.89 ± 8.67 mg/L GAE; 154.38 ± 3.08 mg/L QE) compared to Polygonum persicaria (269.28 ± 5.25 mg/L GAE; 132.75 ± 2.65 mg/L QE). Functionally, Vaccinium myrtillus demonstrated a significant antihyperglycemic effect from day 14 (p = 0.009) and improved lipid parameters, while Polygonum persicaria showed a delayed glycemic effect, significant only at day 35 (p = 0.014), without significant hypolipidemic activity. In contrast, Polygonum persicaria exerted a marked antioxidant effect, significantly increasing GPx activity (p = 0.025) and reducing MDA levels (p = 0.053). Conclusions:Vaccinium myrtillus showed stronger antihyperglycemic and hypolipidemic effects, while Polygonum persicaria was mainly associated with antioxidant-related biochemical changes. These differences may be influenced by phytochemical composition, but they cannot be attributed solely to total polyphenol or flavonoid content.

This study proposes OrdPrune-KD, an ordinal-consistency-driven model compression framework that integrates grade-aware structured pruning with Earth Mover's Distance (EMD)-based knowledge distillation for diabetic retinopathy (DR) grading. Unlike conventional approaches that only consider ordinal relationships at the loss level, the proposed method incorporates ordinal priors into both model compression and knowledge transfer stages. Extensive experiments on APTOS 2019, Messidor-2, and IDRiD demonstrate that the proposed framework achieves a favorable balance between model compactness and predictive performance. In particular, under a 77% parameter reduction, the student model achieves competitive performance relative to the teacher model in terms of QWK while maintaining strong high-risk sensitivity. Additional ablation studies and fairness-controlled comparisons confirm that the performance gains are primarily attributed to the proposed ordinal-aware design rather than output formulation differences. These results indicate that OrdPrune-KD provides an effective and deployable solution for lightweight DR grading systems.

A ketogenic diet (KD) is a low-carbohydrate, high-fat dietary approach. Beyond treating neurologic disorders, KDs have attracted significant media attention for their potential to improve obesity and diabetes. The diet induces a metabolic shift from glucose toward fatty acid oxidation and ketone body production. This shift leads to ketosis, which may reduce hunger, partly through the anorexigenic effects of ketone bodies, thereby contributing to weight loss and improved metabolic parameters, including glycaemic control and insulin sensitivity. In particular, the positive effects of KDs lower insulin demand and may thereby improve β-cell function. However, the long-term efficacy, safety, and sustainability of KDs, especially for diabetes, remain debated. This review offers current insights into the effects of ketogenesis and ketosis, as well as the potential mechanisms underlying them. We explore the metabolic effects of KDs in obesity and diabetes, drawing on preclinical and clinical studies, and suggest that combining KDs with antidiabetic agents may provide synergistic benefits. However, combining KDs with these pharmacotherapies, particularly SGLT-2 inhibitors, requires careful clinical supervision because of potential risks, including euglycaemic diabetic ketoacidosis. We explore how a KD alters the composition of the gut microbiota, thereby affecting host health. We conclude by highlighting challenges and future directions for optimising KD-based therapies and by outlining the limitations of the current review.

Diabetic retinal disease (DRD) has classically been defined as a microvascular complication of diabetes; however, the recent evidence highlighted the key role of neuronal degeneration during the earliest stages of its pathogenesis. Therefore, neuroprotection has emerged as a promising therapeutic strategy to prevent disease progression. Topical administration via eyedrops represents a non-invasive approach to deliver neuroprotective agents directly to the retina. This review summarizes the current advances in the field of neuroprotective therapies against early DRD with a special focus on topical delivery, including preclinical and clinical evidence, while discussing the relevance of the transscleral route of absorption in all of them. In this review, the most promising neuroprotective compounds under development will be discussed, highlighting the opportunity that they represent for treating early stages of DRD.

GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity and are increasingly relevant in periodontal and implant practice. This review covers mechanisms, preclinical and early human evidence, and practical periodontal considerations; the structured database search is conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) and the International Committee of Medical Journal Editors (ICMJE) principles. Two pathways explain GLP-1RAs' relevance: indirect effects from better glycemic control, weight loss, and reduced inflammation; and direct tissue effects involving GLP-1R signaling and the GLP-1/dipeptidyl peptidase-4 (DPP-4) axis. Preclinical studies show reduced inflammation, osteoclast activity, and alveolar bone loss, along with improved periodontal stem cell function under hyperglycemia or inflammation via Nuclear Factor-kappaB (NF-kappaB), Wingless-related integration site (Wnt)/beta-catenin, and Mitogen-Activated Protein Kinase (MAPK) pathways. Animal studies on implants and local delivery, including exendin-4 platforms, suggest osteometabolic benefits. Human data are limited and mostly observational, and confounders include metabolic status, smoking, medication, and nutrition. Oral side effects such as xerostomia and dehydration are also noted. At present, GLP-1RA therapy should be regarded as a contextual modifier of periodontal risk and healing capacity rather than as a stand-alone periodontal therapy.

Placenta-derived extracellular vesicles (EVs), particularly exosomes, serve as key mediators that influence metabolic programming in offspring under adverse early nutritional conditions, such as maternal obesity or gestational diabetes. They respond to maternal nutritional disturbances-such as obesity or gestational diabetes-by altering the composition of the miRNAs and proteins they carry. Evidence from in vivo and in vitro studies suggests that these modified EVs influence offspring metabolic programming through multiple putative pathways: regulating fetal pancreatic β-cell development and function, modulating lipogenesis via PPARγ signaling, affecting placental angiogenesis, and promoting inflammation and epigenetic alterations. By transmitting maternal environmental signals to the fetus, placental EVs are hypothesized to contribute to long-term metabolic phenotypes and disease susceptibility. This review critically examines the current evidence positioning placental EVs as key messengers in maternal-fetal communication, evaluates the strength of evidence supporting their role in shaping offspring metabolic health, identifies major knowledge gaps (e.g., limited direct evidence in human offspring, lack of standardized isolation methods), and suggests their potential as early intervention biomarkers or therapeutic targets for preventing metabolic disorders in offspring. We also highlight the need for prospective cohort studies and mechanistic validation in appropriate animal models to establish causality.

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia-reperfusion (RIR) injury, and Alzheimer's disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood-retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β-driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders.

Diabetic nephropathy (DN) is characterized by a decline in renal function resulting from hyperglycaemia and is often requiring dialysis or renal transplantation. Yet, the signalling events causing DN and the effective treatment options are poorly understood. Changes in the signalling of cyclic nucleotides and their regulated kinases are hypothesized to be involved in its development. Protein kinase A (PKA) signalling pathways are known to modulate extracellular matrix metabolism and exert antifibrotic effects. Multiple isoforms of PKA regulatory and catalytic subunits exist, leading to functional specificities of the kinase arising from different combinations of these isoforms. However, localization of the specific PKA subunits, as well as other signalling proteins involved in this pathway, still need to be explored comprehensively. To gain an overview about PKA distribution, kidneys were analysed by immunohistochemistry and stained for different PKA subunits. Type 1 diabetes was induced by streptozotocin in wildtype (WT) and endothelial NOS knockout (eNOS-KO) mice. The catalytic subunit expression was quantified and compared between healthy and diabetic kidneys. Analysis of expression patterns of the PKA catalytic subunits Cα and Cβ reveal differences across segments of the kidney and in intracellular localization. Cα exhibited ubiquitous expression in all renal cell types. In contrast, Cβ only shows a high expression in proximal tubules, while its expression in other segments is comparatively weak. No significant changes in Cα or Cβ expression are detectable in diabetic mice or eNOS-KO mice compared to WT mice.

Heavy metals and trace elements can act as endocrine-disrupting chemicals and have been linked to thyroid, glucose, lipid, and hepatic abnormalities. We aimed to explore associations between routinely measured metal concentrations and biochemical/endocrinological parameters in a large occupational screening dataset from Türkiye.

Records from 37,763 individuals evaluated at a national occupational and environmental diseases hospital between November 2021 and October 2023 were retrospectively reviewed; after prespecified exclusions, 34,595 unique participants were included. Metal measurements were performed in whole blood, serum, and urine samples as requested in routine surveillance; for each analyte, results were categorized as within or above the interpretive limit by the laboratory information system. Primary comparisons focused on arsenic, cadmium, lead, manganese, and zinc because of occupational relevance and sample size. Routine biochemistry, lipid profile, and thyroid function tests were extracted when available, and estimated glomerular filtration rate (eGFR, CKD‑EPI) was calculated.

Among participants with available thyroid function tests (n = 9,956), thyroid dysfunction was observed in 14.3% (subclinical hypothyroidism 11.9%). Among participants with available fasting glucose and/or HbA1c data (n = 20,738), diabetes mellitus and prediabetes criteria were met in 12.8% and 10.0%, respectively. In univariable comparisons, several metals above the interpretive limit were associated with differences in metabolic biomarkers, including lower HDL with elevated cadmium, lower HDL/LDL with elevated manganese, and higher ALT/AST and triglycerides with elevated zinc. Elevated metal strata differed in age and sex distribution. After within-metal false discovery rate correction, only a limited subset of biomarker differences remained significant.

Among tested participants, thyroid dysfunction and dysglycemia were observed, and selected metal measurements above interpretive limits were associated with lipid and liver enzyme patterns. Given the clinically driven testing and limited covariate data, these findings should be interpreted as exploratory surveillance signals rather than workforce-level prevalence estimates. Heavy metal exposure may exert endocrine-disrupting effects on workers in relevant industries, particularly on thyroid function and glycemic regulation, suggesting that periodic surveillance of these parameters is warranted in exposure-prone workforces.