Search Results (458)

Background and Objectives: Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of obesity and type 2 diabetes (T2D) affecting up to 50% of patients with long-standing disease. While chronic hyperglycemia plays a central role in its pathogenesis, intensive glycemic control provides only partial protection, suggesting the involvement of additional metabolic pathways. The primary objective of this systematic review was to evaluate the role of lipid metabolism disturbances and advanced lipidomic alterations in the development and progression of DPN in patients with obesity and T2D. Secondary objectives included identifying specific lipid species associated with DPN and exploring their potential pathophysiological and clinical implications. Methods: This systematic review included 8 studies that met the inclusion criteria and was conducted according to PRISMA guidelines and registered in PROSPERO/2026/CRD420261288920. Study quality was assessed using the Newcastle–Ottawa Scale. Results: Large population-based cohorts reported a consistent association between hypertriglyceridemia and DPN prevalence, with triglyceride levels >204 mg/dL associated with an approximately 40% increased risk. Lipidomic analysis revealed alterations in acylcarnitine, sphingolipids, and phospholipids. However, the evidence remains limited and heterogeneous, and neuropathy-specific outcomes were insufficiently evaluated in interventional studies. Conclusions: Lipid metabolism disturbances, particularly hypertriglyceridemia and specific lipidomic alterations, may contribute to DPN beyond the effects of hyperglycemia. Although not yet clinically actionable, lipidomic alterations may represent promising future biomarkers and therapeutic targets in DPN. However, the current evidence is limited by heterogeneity and predominantly observational designs. Further well-designed longitudinal and interventional studies are needed to clarify causal relationships and clinical relevance. Full article

Diabetic peripheral neuropathy is an important cause of functional disability, and current therapies have limited ability to halt its progression. Uridine, a pyrimidine nucleoside essential for the synthesis of membrane phospholipids and neuronal metabolism, appears to be a potential neuroprotective agent, but its impact on motor behavior and peripheral nerve integrity in diabetes remains insufficiently investigated. Our study investigated the effects of chronic uridine supplementation on locomotor performance, neuromuscular electrophysiological manifestations, and morphological changes in the sciatic nerve in a murine model of streptozotocin-induced diabetes. We used male C57BL/6 mice (n = 8/group) that were assigned to three groups: sham (no diabetes), diabetic (streptozotocin-induced, diabetes mellitus, DM+), and diabetic treated with uridine (DM+U). We observed that uridine did not alter the metabolic status, as the HbA1c values remained comparable between diabetic groups (9.93 ± 0.57% DM+ vs. 9.71 ± 0.55% DM+U; p = 0.72), suggesting effects independent of glycemic control. The open field test revealed that diabetic mice showed a marked reduction in spontaneous locomotion, while uridine-treated mice maintained a significantly higher level of activity (longer total distance traveled 3761.7 ± 789.1 cm vs. 2477.5 ± 1017.6 cm in DM+; p = 0.023). Electrophysiological evaluation revealed near-normal sciatic nerve function in DM+U mice, including higher compound motor action potential (CMAP) amplitudes (10.21 ± 0.64 mV vs. 5.75 ± 0.72 mV; p < 0.0001) and reduced F-wave latency (6.35 ± 0.45 ms vs. 7.29 ± 0.31 ms; p < 0.0001). Histological and immunohistochemical analyses (PGP 9.5) further confirmed reduced nerve degeneration in DM+U mice. Our data suggest that chronic uridine administration may confer both functional and structural neuroprotection in diabetic neuropathy, even in the absence of improved glycemic control. Full article

Obesity is a complex, heterogeneous, chronic, and progressive disease, which correlates with an augmented risk of developing several comorbidities, including painful conditions, such as osteoarthritis. In this review, authors present for the first time the term meta-neuroinflammation for describing how the chronic, low-grade systemic inflammation, that occurs in obesity, may trigger oxidative stress and neuroinflammatory processes. Both the peripheral and the central nervous system are involved in neuroinflammation, leading to central sensitization and pain chronification, which leads to the observed increased incidence in obese patients of chronic pain syndromes, particularly osteoarthritis, low back pain, fibromyalgia, headache, and diabetic peripheral neuropathy. Possible mechanisms by which obesity may cause meta-neuroinflammation include adiposopathy, gut microbiota dysbiosis, and compromised integrity of blood–brain barrier, which could explain obesity-related depressive and neurodegenerative disorders. Preclinical data suggest the meta-neuroinflammation as a potential target of treatment in obese patients with degenerative joint disease. Based on these observations, targeted therapeutic strategies may include systemic administration of ultramicronized palmitoylethanolamide (um-PEA), well known for its neuroprotective, anti-neuroinflammatory, and analgesic actions, and comicronized PEA–rutin and hydroxytyrosol to restore intestinal eubiosis, with beneficial effects on body weight and mental disorders. Finally, Adelmidrol, as a PEA congener, could be considered for mitigating intra-articular meta-neuroinflammation in knee osteoarthritis. Full article

Pharmacotherapy of neuropathic pain (NP) remains challenging due to its heterogeneous etiology, lack of objective diagnostic tools, and the limited efficacy of currently available treatments, including antidepressants, anticonvulsants, and local anesthetics. Therefore, the search for novel therapies with improved analgesic efficacy and reduced adverse effects is of growing importance. In this context, natural alkaloids have emerged as promising candidates, demonstrating analgesic potential in both diabetes-induced neuropathy and various experimental models of NP. This review outlines NP pathophysiology, emphasizing maladaptive changes within the somatosensory nervous system, including peripheral and central sensitization, as well as glial cell activation. Furthermore, it discusses the mechanisms through which alkaloids may modulate NP-related pathways, with particular focus on their interactions with ion channels, signaling pathways, inflammatory responses, and oxidative stress. A literature search was conducted using the Scopus, Google Scholar and PubMed databases for papers published between 2015 and 2026, using the keywords “alkaloids” and “neuropathic pain”, and focused on recent findings regarding the antinociceptive effects of berbamine, tetrandrine, fangchinoline, and sinomenine, and their derivatives. The analysis indicates that, despite promising preclinical evidence, further rigorous preclinical and clinical studies are necessary to fully assess their therapeutic potential in the treatment of NP. Full article

Background: Diabetic peripheral neuropathy (DPN) affects up to 50% of diabetes patients and is driven by hyperglycemia-induced oxidative stress, mitochondrial dysfunction, polyol pathway activation, advanced glycation end-product formation, and inflammation. Current management is largely symptomatic, prompting interest in metabolic/nutritional therapies. This review critically evaluates the mechanistic rationale and clinical evidence for alpha-lipoic acid (ALA) and benfotiamine as adjunctive treatments for DPN. Methods: A structured narrative review of PubMed/MEDLINE was conducted using predefined keywords for DPN, oxidative stress, metabolic therapy, and thiamine derivatives. Randomized controlled trials, clinical studies, systematic reviews, and relevant experimental studies were included. Evidence was synthesized qualitatively with emphasis on mechanistic plausibility, clinical efficacy, intervention duration, and methodological rigor. Results: ALA consistently improves short-term symptoms across multiple randomized trials. The long-term NATHAN 1 trial reported a marginal, borderline significant effect on the primary composite endpoint (NIS-LL, p = 0.05) without significant improvements in nerve conduction studies; therefore, evidence for functional stabilization is very limited and inconclusive. ALA’s effects are attributed to antioxidant activity, mitochondrial protection, and improved microvascular function. Benfotiamine has a strong biochemical rationale (transketolase activation, diversion of glycolytic intermediates from damaging pathways), but clinical evidence remains limited to short-duration, symptom-based studies, with no large-scale, long-term trials published. Conclusions: Both agents target key pathways in DPN pathogenesis. ALA is the most established adjunctive metabolic therapy for symptomatic DPN, although no study has demonstrated structural nerve regeneration or a definitive disease-modifying effect. Benfotiamine is biologically plausible but requires further validation in long-term randomized trials with structural and biomarker-based endpoints. Outside of documented thiamine deficiency, its routine use cannot be recommended based on current evidence. 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

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. 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

Introduction: Diabetes mellitus (DM) is associated with multiple systemic complications, yet its effects on respiratory muscle structure remain insufficiently characterized. This study aimed to evaluate diaphragmatic morphology in patients with type 2 DM and to determine whether glycemic control is associated with diaphragmatic thickness. Methods: A total of 120 participants were enrolled, including 60 patients with type 2 DM and 60 healthy controls. Demographic, biochemical, and diaphragmatic ultrasound parameters were assessed, including right and left diaphragm thickness (DT) during inspiration and expiration, diaphragmatic excursion (DE), and costophrenic angle (CPA). All patients with DM underwent electromyography for evaluation of peripheral neuropathy. Diabetic participants were further stratified according to glycemic control using an HbA1c threshold of 7%. Correlation analyses and multivariable linear regression models adjusted for age and body mass index (BMI) were performed to examine the association between HbA1c and diaphragmatic parameters. Results: Compared with controls, patients with DM were older and had higher fasting glucose levels but lower total cholesterol, whereas BMI and other biochemical parameters were comparable. Peripheral neuropathy was identified in 28.3% of patients with DM, but was not associated with significant differences in DT, DE, or CPA. In the three-group analysis, right and left DT measured during both inspiration and expiration differed significantly among well-controlled DM, poorly controlled DM, and control groups, whereas DE and CPA remained similar. Within the DM cohort, higher HbA1c levels were significantly associated with lower right and left DT values. These inverse associations remained independent after adjustment for age and BMI, while no independent associations were observed between HbA1c and either DE or CPA. Conclusions: Poorer glycemic control was associated with reduced diaphragmatic thickness in patients with T2DM. Ultrasonographic assessment may offer a non-invasive approach for detecting early respiratory muscle involvement, although its clinical and functional relevance should be validated in future prospective studies. Full article

Introduction: Type 2 diabetes mellitus predisposes patients to neuropathy, peripheral arterial disease, and diabetic foot ulcers, which may become infected and progress to osteomyelitis, increasing the risk of amputation. The growing prevalence of multidrug-resistant organisms complicates management. Photodynamic therapy (PDT), which combines a photosensitizer with light-emitting diode irradiation to generate reactive oxygen species, has emerged as a potential adjunctive antimicrobial strategy without inducing resistance. Objective: To describe clinical outcomes observed in patients with diabetic foot osteomyelitis treated with adjunctive photodynamic therapy (PDT), with emphasis on wound evolution, limb preservation, and healing time. Methods: This prospective case series included patients with osteomyelitis secondary to infected diabetic foot ulcers treated at a university hospital. Demographic and clinical data were collected from medical records. Serial photographic documentation was used to monitor wound progression and tissue response during therapy. Results: Sixteen patients with diabetic foot osteomyelitis were included. Complete healing was achieved in 13 patients (81.25%), while 2 patients (12.5%) remained under treatment with partial healing and 1 (6.25%) underwent major amputation. Among healed patients, healing time ranged from 19 to 546 days, with a median of 118 days. The number of photodynamic therapy sessions ranged from 2 to 12, depending on the clinical course of each case. Healing time varied among patients, and the hallux was the most frequent site of osteomyelitis. During follow-up, only one patient underwent major amputation, whereas the remaining patients either achieved complete healing or were still under treatment at the time of analysis. Healing time was comparable between insulin-dependent and non-insulin-dependent diabetes, although numerically shorter in the latter. Longer healing periods were associated with more treatment sessions. Conclusions: In this prospective uncontrolled case series, adjunctive PDT was associated with favorable clinical evolution in a subset of patients with diabetic foot osteomyelitis. However, because of the small sample size and the absence of a control group, these findings should be considered preliminary and hypothesis-generating. Full article

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article

Background/Objectives: The co-occurrence of diabetic peripheral neuropathy and depression increases the symptom burden and risk of long-term complications. Methods: This cross-sectional study enrolled 131 patients with type 1 (age: 58.47 years; duration of diabetes: 35.61 years) and type 2 diabetes (age: 63.60 years; duration of diabetes: 11.49 years). All patients underwent assessment of socioeconomic status and evaluation using the Hospital Anxiety and Depression Scale, the Mental Component Score of the Short Form Healthy Survey Questionnaire, neuropathy disability score, nerve conduction studies, corneal confocal microscopy and intraepidermal nerve fibre density (IENFD) assessment. Results: The prevalence of foot pain (45% vs. 23.9%, p = 0.019), tingling (56.7% vs. 32.9%, p = 0.013), weakness (35% vs. 9.9%, p < 0.001), ataxia (40% vs. 16.9%, p = 0.001), and upper limb symptoms (45% vs. 19.7%, p = 0.001) were statistically significantly higher, while cold perception threshold (22.50 ± 8.47 vs. 26.34 ± 3.08, p = 0.007), corneal nerve fibre density (20.49 ± 7.55 vs. 24.16 ± 5.68, p = 0.002) and length (20.06 ± 6.98 vs. 22.95 ± 6.22, p = 0.014) were statistically significantly lower, but no differences in nerve conduction studies or IENFD were observed in patients with depression compared to patients without depression. Furthermore, patients with depression were from a lower socioeconomic class (51.7% vs. 21.1%, p < 0.001), had lower educational attainment (37.9% vs. 12.9%, p < 0.001), had lower income < £37,000 (29.3% vs. 11.4%, p = 0.010) and lived in areas of high deprivation (62.1% vs. 31.4%, p < 0.001). Conclusions: Comorbid depression in people with diabetes was linked to increased socioeconomic deprivation and a greater prevalence of neuropathic symptoms and small fibre pathology. Full article

Background: Diabetic foot ulcers (DFUs) and lower extremity amputations are major contributors to morbidity and mortality in individuals with diabetes. Among patients undergoing active cancer treatment, the risks are compounded by immunosuppression, peripheral neuropathy, and vascular complications. Even minor foot infections or wounds in these patients can necessitate the suspension of cancer therapy, with potentially lifethreatening consequences. This study evaluated the impaqt of integrating symptom-focused patient education with coordinated podiatric care to reduce DFUs and amputations in this highrisk population with concurrent cancer and diabetes. Methods: A five-year retrospective review was conducted at a National Cancer Institute (NCl)designated comprehensive cancer center as part of the Novel Limb Preservation Initiative. The cohort included patients with Type II diabetes undergoing treatment for prostate, breast, colorectal, lymphoma, leukemia, thyroid, or lung cancers. Patients were assigned targeted educational modules based on self-reported diabetic foot symptoms. Podiatric care was individualized according to each patient's signs and symptoms, including routine diabetic foot examinations and close, timely monitoring when indicated. Results: The intervention yielded a DFU incidence of 2. 8% and an amputation rate of 0. 43%, both lower than national benchmarks. Enhanced patient engagement through diabetic foot symptom-focused education and earlier detection of foot complications-including diabetic foot ssues that may appear minor to laypersons-contributed to these improved outcomes. Conclusion: Integrating diabetic foot symptom-focused education with proactive podiatric monitoring significantly reduced DFUs and amputations in this high-risk population. This model, developed under the Novel Limb Preservation Initiative, offers a scalable strategy for broader implementation, particularly in high-risk communities, including Hispanic, African American, low socioeconomic, and rural populations across the United States. Full article

Background: Corneal sensitivity is a key indicator of ocular surface health. This prospective, cross-sectional study evaluated agreement between corneal sensitivity thresholds obtained from equivalent stimulus settings on a contemporary, enhanced dual-temperature non-contact corneal aesthesiometer (NCCA) and a previously validated (standard) device. Methods: Central corneal sensitivity thresholds were measured in the right eyes of healthy participants using both devices. Participants with previous ocular surgery, laser treatment, trauma, contact lens wear, diabetes, or peripheral neuropathy were excluded. Sensitivity thresholds were determined using a forced-response, double-staircase protocol. Inter-device agreement was assessed using Bland–Altman analysis, and consistency was assessed using intraclass correlation coefficients. Results: Median corneal sensitivity thresholds in 51 healthy participants (32 female, 19 male; mean age: 33 ± 14 years) did not differ between enhanced (0.23 [0.18 to 0.38]) and standard (0.25 [0.15 to 0.35]) NCCA instruments (p = 0.73). Bland–Altman analysis demonstrated moderate inter-device agreement, with a mean difference of −0.01 mbar (95% limits of agreement: −0.41 to 0.39 mbar). Linear regression analysis identified greater measurement discrepancies at higher thresholds (p < 0.05), indicating greater variability in individuals with reduced corneal sensitivity. Conclusions: The enhanced NCCA yields reliable corneal sensitivity measures for a room-temperature stimulus and acceptable agreement with the existing (standard) model. Full article

Background: Diabetic foot ulcer (DFU) is a major complication of type 2 diabetes (T2D), frequently resulting in disability, lower-limb amputation, and substantial healthcare burden. Early identification of patients at high risk of progressing to severe DFU is essential for timely intervention, yet evidence on associated risk factors remains limited in Bangladesh. This study aims to identify demographic, clinical, and behavioral predictors of severe DFU to support early management strategies. Methods: A cross-sectional study was conducted among 159 DFU patients attending the Rajshahi Diabetic Association General Hospital, Bangladesh. Data on demographic characteristics, clinical variables, and behavioral factors were obtained through structured questionnaires and standardized examinations. Severe DFU was defined as Wagner grades 3–5, while grades 0–2 were considered non-severe. Firth’s penalized logistic regression was used to identify determinants of severe DFU. Model performance was assessed using ROC analysis, calibration belt analysis, and decision curve analysis (DCA). Results: Among the 159 participants, 101 (63.5%) presented with severe DFU. Patients with severe DFU had significantly higher BMI (26.1 vs. 23.7 kg/m²), treatment costs (50,000 vs. 20,000 BDT), and were older (57 vs. 54 years). Severe DFU was also associated with higher prevalence of peripheral arterial disease (PAD) (29.7% vs. 3.4%), prior amputation (31.7% vs. 3.4%), peripheral neuropathy (PN) (86.1% vs. 58.6%), and poor glycemic control (71.3% vs. 30.7%) (all p < 0.05). Firth’s regression identified older age (aOR 1.08), poor glycemic control (aOR 3.90), PN (aOR 3.41), PAD (aOR 7.54), and previous amputation (aOR 13.67) as independent predictors of severe DFU. Conclusions: Older age, uncontrolled glycemia, PN, PAD, and prior amputation were significantly associated with severe stages of DFU. Early detection and targeted management of these factors are critical to reducing complications and lowering the healthcare burden. Full article