Search Results (1,827)

Background/Objectives: Regular physical exercise is strongly recommended for individuals with type 1 diabetes mellitus (T1DM) because of its beneficial effects on cardiovascular fitness, insulin sensitivity, metabolic control, and overall health. Nevertheless, participation in physical activity remains limited, largely due to the fear of exercise-induced hypoglycemia and glycemic instability. Glycemic responses to exercise in T1DM are influenced by the interaction between exercise modality, circulating insulin levels, nutritional status, and diabetes technologies. Continuous aerobic exercise, resistance training, high-intensity interval exercise, and mixed intermittent activities elicit distinct metabolic and hormonal responses, resulting in heterogeneous glycemic trajectories. This narrative review aimed to provide a clinically oriented synthesis of the physiological mechanisms underlying exercise-related glycemic fluctuations in T1DM and to discuss integrated insulin- and carbohydrate-based strategies to support safer participation in physical activity in the context of modern diabetes technologies. Methods: A structured narrative review was conducted using PubMed/MEDLINE, Scopus, and complementary searches in Google Scholar to identify experimental studies, observational studies, systematic reviews, consensus statements, and clinical guidelines focused on exercise-related glycemic responses in individuals with T1DM. Only articles published in English were considered. Evidence was selected and synthesized according to relevance to exercise modality, insulin therapy strategies, carbohydrate management, and diabetes technologies, including continuous glucose monitoring, continuous subcutaneous insulin infusion, and automated insulin delivery systems. The final narrative synthesis was based on 44 selected studies, reviews, consensus statements, and guidance documents considered most relevant to the objectives of this narrative review. Results: Available evidence indicates that continuous moderate-intensity aerobic exercise is most consistently associated with progressive glucose declines and increased risk of hypoglycemia, particularly when performed in the presence of elevated insulin on board. In contrast, resistance exercise and short-duration high-intensity or anaerobic exercise more frequently induce stable glycemia or transient hyperglycemia through adrenergic stimulation and increased hepatic glucose output. Mixed and intermittent exercise modalities often produce more variable responses depending on exercise sequencing, nutritional status, and insulin exposure. Across studies, integrated adjustment of basal and prandial insulin doses together with individualized carbohydrate supplementation emerged as the most effective strategy to reduce exercise-related glycemic instability. Continuous glucose monitoring and insulin pump technologies improved glucose trend awareness and management flexibility; however, physical exercise remains a challenging condition for current automated insulin delivery algorithms and still requires active user-driven decision-making. Conclusions: Exercise management in T1DM should be based on an individualized interpretation of exercise modality, glucose trends, insulin exposure, and nutritional context rather than on fixed glucose thresholds alone. Combining anticipatory insulin adjustments, tailored carbohydrate strategies, and appropriate use of diabetes technologies may substantially reduce glycemic variability and improve confidence toward physical activity participation. Structured education and individualized clinical guidance remain essential to translate physiological knowledge into effective real-world exercise management. Full article

Background: Human dental pulp stem cells (hDPSCs) are a promising source of multipotent mesenchymal stem cells (MSCs) for regenerative neurology because of their inherent neurogenic potential. However, robust and reproducible protocols for driving their terminal neuronal maturation in a fully defined, xeno-free environment are lacking. Methods: hDPSCs were isolated from a donor tooth and characterized for mesenchymal (CD105, CD90, CD73, CD13) and stemness-associated markers (SOX2, Oct3/4 and Nanog). Cells were differentiated in a novel, fully chemically defined medium 1% ITS medium (ITS: Insulin, Transferrin, Selenium) supplemented with glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF). Neuronal commitment and partial maturation were assessed via immunofluorescence, Western blot, and RT-PCR for markers such as NeuN (Neuronal nuclei) and NF-M (Neurofilament medium chain), and functionally by whole-cell patch-clamp electrophysiology. Results: Although undifferentiated hDPSCs expressed neural progenitor markers (βIII-tubulin and Nestin), only GDNF treatment in a chemically defined medium significantly upregulated mature neuronal markers (NeuN and NF-M) and downregulated mesenchymal markers. Importantly, GDNF-treated cells exhibited key functional changes, including hyperpolarized resting membrane potentials, increased membrane capacitance, and elevated input resistance, which are electrophysiological hallmarks of neural precursor or early neuronal maturation, compared to control cells cultured in medium containing fetal bovine serum (FBS). Although action potentials were not elicited, this represents a significant advancement toward achieving a functional neuronal state. Conclusion: This study demonstrates that a fully chemically defined medium enables GDNF to drive hDPSCs beyond the neural progenitor state towards a partially mature neuronal phenotype. This defined medium protocol eliminates serum variability, enhances reproducibility, and provides a critical step towards standardizing hDPSC-derived neuronal cells for disease modeling and cell-based therapy. Full article

Incretin receptor agonists (IRAs) such as GLP-1-based therapies improve metabolic and cognitive outcomes and enhance brain insulin signaling. One way that IRAs could have these actions is by affecting the blood–brain barrier (BBB); however, IRA-BBB interactions are poorly studied. Here, we examined the ability of insulin and IRAs to affect each other’s transport across the BBB in lean mice. We found that intracerebroventricular (ICV) administration of the insulin receptor antagonist S961 did not affect the blood-to-brain transport of the bioactive fragment of the IRA, ¹²⁵I-dulaglutide (BAF). In contrast, ¹²⁵I-dulaglutide (BAF) co-administered with intravenous (IV) insulin significantly enhanced ¹²⁵I-dulaglutide (BAF) BBB transport into whole brain, olfactory bulb, parietal cortex, and pons, demonstrating insulin-dependent modulation of IRA BBB transport. Regional transport rates for ¹²⁵I-dulaglutide (BAF) across the brain varied by ~2.5-fold, with the fastest transport into the olfactory bulb, frontal cortex, cerebellum, and pons. Co-administration of IV dulaglutide (BAF) did not alter ¹²⁵I-insulin BBB transport rates (K_i) but did reduce reversible insulin binding (V_i) at the BBB by >50%, suggesting rapid effects on BBB insulin receptors. To explore the effects of chronic IRA administration, lean mice were treated with semaglutide for two weeks. Body weight and food intake were unchanged, but female mice showed reduced fasting levels of serum insulin and GLP-1 and decreased insulin transport into whole brain, while male mice showed a reduction in insulin binding at the BBB. Chronic semaglutide also reduced ¹²⁵I-insulin BBB transport in female mice when studied with in situ perfusion, a procedure that removes the immediate influence of serum factors. Together, these findings demonstrate reciprocal and female-selective interactions between IRAs and insulin at the BBB. Acute insulin enhances the BBB transport of an IRA in female mice, whereas chronic IRA exposure selectively impairs insulin BBB transport in females, highlighting the BBB as a dynamic and hormone-sensitive interface with implications for long-term treatment in mouse models and potential for translation impact in humans. Full article

A 65-year-old man with type 2 diabetes presented with abdominal pain. Although he had no typical reflux symptoms such as heartburn or acid regurgitation, esophagogastroduodenoscopy (EGD) showed findings suggestive of reflux esophagitis, and proton pump inhibitor therapy was initiated. Two months later, he was admitted with intractable vomiting. EGD demonstrated diffuse circumferential mucosal injury without black discoloration, predominantly in the distal esophagus. These findings were interpreted as severe reflux esophagitis (Los Angeles grade D; RE-D). Symptoms improved with supportive care, glycemic control, and continued PPI therapy; follow-up EGD showed marked improvement. Six months later, he re-presented with identical symptoms and endoscopic findings. Laboratory testing confirmed diabetic ketoacidosis (DKA), with ketonuria, elevated total ketone bodies (2469 µmol/L), and high-anion gap metabolic acidosis (anion gap 17.2 mEq/L). The diagnosis was revised to DKA-associated acute esophageal mucosal lesion (AEML). He improved with fluid resuscitation and insulin therapy, and medication adherence was reinforced. Follow-up EGD showed complete healing without recurrence. AEML has been proposed as a spectrum that includes acute esophageal necrosis (AEN; “black esophagus”) and esophagitis without black-appearing mucosa. This case highlights a diagnostic pitfall in which DKA-associated AEML without black discoloration may be misattributed to severe reflux esophagitis. When the clinical presentation or endoscopic appearance is severe or atypical, clinicians should consider AEML and evaluate for underlying systemic precipitants. Full article

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Growing evidence indicates that metabolic syndrome components, including obesity, insulin resistance, and hyperglycemia, contribute to PCa development, and progression to more aggressive form. At the same time, standard treatments such as androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) significantly improve oncologic outcomes but are associated with adverse metabolic effects, including increased fat mass, insulin resistance, and sarcopenia, potentially worsening patients’ overall metabolic profile and quality of life. Tumor progression in PCa is strongly driven by androgen receptor (AR) signaling, which is closely linked to cellular metabolic reprogramming, highlighting metabolism as a potential therapeutic target. Aim: The aim of this study was to evaluate and synthesize current evidence on the role of the ketogenic diet (KD) in PCa, with particular emphasis on its interaction with hormonal therapies, underlying metabolic and endocrine mechanisms, and its potential application as an adjunctive strategy in integrated oncologic care. Results: The KD, characterized by high fat and very low carbohydrate intake, induces a metabolic state of ketosis that reduces circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), potentially counteracting metabolic alterations associated with PCa and its treatments. Preclinical studies consistently demonstrate that carbohydrate restriction and KD can slow tumor growth, modulate key oncogenic pathways such as PI3K/AKT/mTOR, reduce systemic insulin signaling, and enhance survival in prostate cancer models. Additionally, emerging evidence suggests possible synergistic effects when KD is combined with standard therapies, including ADT and immunotherapy. Clinical data, although limited, indicate that low-carbohydrate dietary interventions may improve metabolic parameters and could delay biochemical progression, as suggested by increased prostate-specific antigen (PSA) doubling time. However, results across studies remain heterogeneous, and robust evidence on long-term oncologic outcomes is lacking. Conclusions: Overall, the KD represents a promising but still experimental strategy in PCa management, requiring careful nutritional supervision to avoid adverse effects such as unintended weight loss or sarcopenia. Further well-designed randomized clinical trials are needed to clarify its safety, efficacy, and role in routine clinical practice. Full article

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates robust efficacy in glycemic control and weight reduction. However, substantial interindividual variability in treatment response is observed in clinical practice. In this narrative review, we summarize current evidence on clinical, genetic, and molecular predictors of tirzepatide response and discuss their implications for a precision medicine framework. Data from pivotal clinical trials, post hoc analyses, and relevant preclinical and clinical studies were evaluated to identify determinants of glycemic and weight loss responses, as well as hepatic and renal protective effects. Key clinical predictors include tirzepatide dose, duration of diabetes, β-cell function, baseline glycated hemoglobin, sex, age, race, concomitant therapies, and early treatment response. Genetic factors implicated in treatment variability include variants in GLP-1 receptor, GIP receptor, β-arrestin 1, transcription factor 7-like 2, fat mass and obesity-associated protein, and melanocortin 4 receptor, although tirzepatide-specific validation remains limited. Molecular biomarkers such as branched-chain amino acids, insulin-like growth factor–binding protein-1 and -2, the adiponectin-to-leptin ratio, high-sensitivity C-reactive protein, and interleukin-6 show potential as pharmacodynamic indicators of metabolic response. For organ-specific outcomes, procollagen type III N-terminal peptide and magnetic resonance imaging–proton density fat fraction are supported for assessing hepatoprotective effects, while cystatin C–based estimated glomerular filtration rate and urine albumin-to-creatinine ratio are validated markers of renoprotection. Additional candidates—including tumor necrosis factor receptor 1/2, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin—are promising but require prospective validation. Overall, predicting response to tirzepatide’s multifaceted therapeutic effects necessitates an integrated, multidimensional approach that incorporates clinical characteristics, genetic variation, and molecular profiling. Ongoing validation and harmonization of these predictors may help establish a precision medicine framework for optimizing tirzepatide therapy. Full article

Diabetes mellitus is a chronic and increasingly prevalent metabolic disorder characterized by persistent hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. Despite the availability of pharmacological agents that effectively manage blood glucose levels, many are associated with adverse effects, limited efficacy over time, and high costs. Consequently, there is growing interest in alternative therapies, especially those derived from traditional medicinal plants, that have long been employed in various cultures for managing diabetes. Recent advances in phytochemistry have identified bioactive plant secondary metabolites with promising antidiabetic properties. This review aims to provide a comprehensive overview of plant-derived compounds that exhibit inhibitory activity against key diabetes-related enzymes, including α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4). These enzymes play critical roles in glucose metabolism and insulin signaling pathways. The review highlights the structural diversity of these natural inhibitors, their mechanisms of action, and their effectiveness in preclinical models. Understanding the molecular interactions and pharmacological profiles of these metabolites may facilitate the development of safer and more effective antidiabetic agents. Full article

Background/Objectives: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition often managed exclusively with insulin. However, the search for adjuvant therapies has gained attention, including dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), despite limited evidence in pediatric populations. To evaluate the impact of DPP4i, alone or combined with SGLT2i, on glycemic control (HbA1c), lipid profile (ApoB and ApoA-I), and renal function (eGFR and albuminuria) in children, adolescents, and young adults with T1DM, this study was conducted. Methods: This cohort study analyzed data from 76 patients with T1DM aged under 25, followed for 4 to 20 months. Patients were grouped based on exposure to DPP4i alone, DPP4i + SGLT2i, or no additional therapy. Glycemic, lipid, and renal parameters were assessed at baseline and follow-up. Results: A significant reduction in HbA1c was observed in the overall sample (p < 0.001), regardless of treatment group, suggesting a positive effect of interdisciplinary care. There were no statistically significant differences in HbA1c variation among the groups. ApoB decreased significantly over time (p < 0.001), and ApoA-I levels were initially higher in the DPP4i + SGLT2i group. A significant reduction in albuminuria was identified in the DPP4i-only group compared to controls (p = 0.029), indicating a potential renoprotective effect. No significant changes in eGFR were observed. The use of DPP4i, with or without SGLT2i, was not associated with significant improvements in glycemic or lipid outcomes compared to standard therapy. However, DPP4i monotherapy was associated with a reduction in albuminuria, suggesting a possible benefit for renal protection. Conclusions: These findings highlight the need for larger, randomized studies to confirm the therapeutic role of these agents in young individuals with T1DM. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited. Full article

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer’s disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: “GH and dementia,” “GH and Alzheimer’s disease,” “GH and TBI,” and “GH and stroke.” Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer’s disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results. Full article

Background and Aims: Automated insulin delivery (AID) systems are standard of care for type 1 diabetes mellitus (T1DM). Tubeless AID systems may improve treatment acceptance, but real-world European data in patients transitioning from multiple daily injections (MDI) or open-loop patch pump therapy are limited. This study evaluated real-world glycemic, safety, and quality-of-life (QoL) outcomes after transition to a tubeless automated closed-loop system (Omnipod 5^®, OP5^®). Research Design and Methods: In this prospective, multicenter observational study, adults with T1DM transitioned from MDI or open-loop continuous subcutaneous insulin infusion to OP5^® and were followed for 180 days. Continuous glucose monitoring-derived metrics and validated patient-reported outcome measures were assessed. Subgroup analyses were performed by prior therapy. Results: Of the 94 enrolled participants, 88 completed the study. At 180 days, HbA1c decreased from 7.5% to 7.1% (p < 0.001), and time in range increased from 59.0% to 68.0% (p < 0.001) without increased hypoglycemia. The proportion achieving TIR_70–180 ≥ 70% rose from 12.5% to 43.2%. Improvements were greater among prior MDI users. Treatment satisfaction and diabetes-related QoL improved significantly. The mean time in automated mode was 90.9%. Conclusions. Transition to tubeless AID significantly improved glycemic and psychosocial outcomes, supporting its effectiveness in routine clinical practice. Full article

Objective: To investigate whether gestational diabetes mellitus (GDM), including insulin-treated GDM, affects cerebroplacental ratio (CPR) values in monochorionic diamniotic (MCDA) twin pregnancies. Methods: This retrospective single-center cohort study included a total of 262 MCDA twin pregnancies managed at a tertiary referral center, comprising pregnancies without GDM (n = 120), with diet-controlled GDM (n = 80), and with insulin-treated GDM (n = 62). Doppler ultrasound examinations were performed at three gestational time points between 24 and 36 weeks of gestation. CPR, umbilical artery pulsatility index (UA-PI), and middle cerebral artery pulsatility index (MCA-PI) were compared longitudinally between groups. Doppler indices were compared between groups without adjustment for baseline differences such as BMI and parity Results: Maternal body mass index was significantly higher in pregnancies complicated by GDM, particularly in those requiring insulin therapy (p < 0.001). Estimated fetal weight was higher in the insulin-treated GDM group at mid-gestation (28–32 weeks; p = 0.01). However, CPR values remained within normal ranges throughout all screening points across all three groups. No relevant differences in UA-PI, MCA-PI, gestational age at delivery, Apgar scores, or umbilical cord pH were observed between groups. Conclusions: In MCDA twin pregnancies, gestational diabetes—regardless of insulin treatment—does not appear to significantly influence cerebroplacental ratio values throughout gestation. No statistically significant differences in CPR values were observed between groups. No statistically significant differences in CPR values were detected between groups. However, given the exploratory design and lack of adjustment for confounders, subtle effects cannot be excluded. The clinical utility of CPR in this population requires further investigation. Full article

Obesity contributes to an increase in the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and is diagnosed when hepatic steatosis is accompanied by at least one of the following factors: obesity or overweight, diabetes mellitus, or signs of metabolic abnormalities. MAFLD is a term that encompasses a wide range of liver disorders, ranging from simple steatosis to metabolic steatohepatitis, which can progress to cirrhosis and eventually, hepatocellular carcinoma (HCC). Lipotoxicity generated by a high-fat diet causes liver inflammation, therefore, blocking inflammatory pathways is considered a promising strategy to prevent MAFLD progression. Inflammatory responses and oxidative stress are linked to endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR) pathway. Although drugs such as resmetirom and semaglutide have recently been approved for the treatment of MAFLD, there is still a need to identify complementary therapies with different mechanisms of action. In this context, the present study evaluated the hepatoprotective effect of ellagic acid through the modulation of mRNAs of proteins in the UPR-Perk pathway in a murine model fed a high-calorie diet. This study revealed that the high-calorie diet activated the UPR pathway in response to stress, increasing the expression of the Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 genes in the liver and epididymal adipose tissue. Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin, and could therefore be considered a hepatoprotective agent. Full article

Background: Algorithm-based insulin dosing systems are increasingly used in hospitals and have shown the potential to efficiently and safely enable glycemic control. The goal of this study was to evaluate glycemic control using the ultralong-acting basal insulin degludec (IDeg) in combination with insulin aspart (IAsp) within an algorithm-driven electronic clinical decision support system (cDSS) in inpatients with type 2 diabetes (T2D). Methods: In this non-controlled single-arm pilot study, an electronic, algorithm-based cDSS was applied for the management of insulin treatment in an internal general ward. Thirty hospitalized patients with T2D (18 female, age 74.1 ± 10.9 years, HbA1c 72.4 ± 22.3 mmol/mol, BMI 28.6 ± 5.6 kg/m², diabetes duration 13.2 ± 11.6 years, creatinine 1.5 ± 1.2 mg/dL, length of hospital stay 9.1 ± 4.0 days) were included in the study. Capillary blood glucose (BG) was evaluated four times daily using a point-of-care device integrated into the hospital information system. In addition, all participants received a blinded continuous glucose monitoring (CGM; Abbott Freestyle Libre Pro) system. The primary endpoint was defined as the percentage of BG measurements within the target range of 3.9–7.8 mmol/L. Results: Overall, 722 BG values and 17,242 CGM data points were available. Of those, 52.2% and 55.0% were in the specified target area (3.9–7.8 mmol/L), respectively. Mean BG prior to study start was 11.9 ± 4.4 mmol/L and improved to 7.5 ± 1.9 mmol/L and 7.4 ± 1.4 mmol/L after 6 and 10 days of treatment. BG < 3.9, <3.0 and <2.2 mmol/L was 1.25%, 0.28% and 0%, respectively. Adherence to the total daily insulin dose suggested by the cDSS was 94.2%, and 99.5% of all basal and 85.3% of all bolus insulin suggestions were accepted by the nurses in charge. Basal-bolus therapy using the cDSS covered 85% of the participants’ total hospital stay. Conclusions: Glycemic control using IDeg within an algorithm-driven cDSS could effectively and safely be achieved in the hospital and was highly accepted. Full article

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease traditionally viewed through a purely dermatologic lens. However, this perspective fails to explain stress-induced flares, menstrual cycle-linked exacerbations, and severe pain and itch disproportionate to visible cutaneous inflammation. This narrative review synthesizes evidence supporting a neuroendocrine–immune model of HS pathogenesis, with emphasis on mechanisms underlying pain and itch. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases (January 1990–September 2025) with terms including hidradenitis suppurativa, neuroendocrine mechanisms, HPA axis, sex hormones, neuropeptides, pain (including nociceptive and neuropathic pain, burning, and dysesthesia), and pruritus (itch). Eligible studies included peer-reviewed research examining hormonal, stress-related, or neuropeptide mechanisms in HS. Data were synthesized into thematic categories: endocrine influences, HPA axis function, neuropeptide signaling, immune crosstalk, and clinical implications. Results: Sex hormones promote follicular occlusion and modulate immune responses, explaining perimenstrual flares. Prolactin amplifies inflammation during stress through immune cell activation. Insulin resistance and adipokine imbalance create pro-inflammatory conditions. Chronic stress induces HPA axis dysfunction with cortisol resistance, exacerbating inflammation. Neuropeptides released from cutaneous nerves amplify immune activation and directly mediate pain and itch. These pathways establish self-perpetuating feedback loops wherein inflammation drives stress, and neuroendocrine dysfunction amplifies immune responses. Conclusions: HS represents a systemic disorder with a strong neuroendocrine–immune component, rather than a purely dermatologic condition. This framework supports multidisciplinary management integrating hormonal therapies, targeted immunomodulation, and stress reduction. Future research should characterize neuroendocrine biomarkers and test combination therapies targeting multiple system nodes. Full article