Medicine and Pharmacology

Abstract: Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on pathophysiology of XLH. Particular attention was given to the interaction between systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of alteration of calcium-phosphate metabolism, systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.

Abstract: The global prevalence of type 2 diabetes continues to rise at an alarming pace, challenging existing strategies for disease prevention and management. Beyond traditional risk factors, increasing evidence indicates that glucose metabolism is temporally regulated by the body’s 24-hour biological clock and oscillates based on the time of day. Disturbances of the circadian clock function are linked to impairments in glucose homeostasis and increased risk of obesity and diabetes. This review explores the intricate relationship between the circadian system and glucose homeostatic control. We begin with an introduction to the hierarchical organization of the circadian system. Next, we examine the role of the circadian clock in regulating organs and tissues that are in-volved in glucose metabolism, i.e. the pancreas, skeletal muscles, the liver and adipose tissue. We next review evidence that supports the involvement of circadian disturbances in the pathogenesis of diabetes. Finally, we discuss chronotherapy and its potential application in clinical intervention of diabetes. As type 2 diabetes becomes increasingly common worldwide, understanding how the body’s internal clock shapes this disease may open new and powerful opportunities for its prevention and treatment.

Abstract: One of the most persistent challenges in obesity research is explaining why weight loss decelerates over time, even when dietary adherence is maintained. This phenomenon, commonly called adaptive thermogenesis, is more accurately termed metabolic adaptation, as it reflects broader reductions in energy expenditure than heat production alone. Here, I propose that this phenomenon is not a distinct biological compensation, but an inevitable physical consequence of mass loss. Building on the mass balance model (MBM), I show that the rate of mass loss follows Torricelli's Law – the same principle that describes how a water tank empties. The square-root relationship arises analytically from the body surface area–mass connection and predicts weight loss trajectories during prolonged fasting without an explicit "adaptation" term. Reframing metabolic adaptation through Torricelli's Law offers a more parsimonious, first-principles explanation for one of the most robust observations in human metabolism.

Abstract: The global obesity epidemic persists despite intensive study, partly because our conceptual framework for body weight regulation remains anchored in the energy balance model (EBM). This paradigm has struggled to reconcile the high heritability of body mass index (BMI) with the small effect sizes of common genetic variants. Here, I argue that a paradigm shift is required – one that moves from an energy-centric to a mass-centric view of metabolism. I propose that the mass balance model (MBM) provides a more precise framework for understanding the genetic architecture of obesity, focusing on the direct measurement of macronutrient fluxes. By dissecting the independent roles of fat, carbohydrate, and protein, we can reframe the function of key obesity genes. I analyze well-established genes like FTO and MC4R through the MBM lens and outline a path forward for nutrigenomics. This shift promises to resolve the "missing heritability" problem and pave the way for truly personalized metabolic health.

Abstract: Leptin is the oldest studied adipokine, and its mechanism of action in the regulation of energy metabolism remains a hot topic of current research. In this paper, we systematically review the progress of clinical and basic research on leptin and energy metabolism from 1994 to 2025. It is shown that leptin can regulate the energy metabolism homeostasis through autocrine, paracrine and neurohumoral pathways (e.g., hypothalamic-leptin-melanocortin axis). In addition, the effects of mainstream weight loss strategies such as dietary control, pharmacological interventions and exercise on leptin levels and their underlying mechanisms were investigated in this paper, with the aim of providing a theoretical basis for the clinical application of leptin in metabolic diseases (e.g., obesity, diabetes mellitus). Future studies need to further clarify the molecular mechanisms of leptin resistance and explore precise intervention strategies based on the leptin signaling pathway.

Abstract: The emergence of immune checkpoint inhibitors, targeted therapies, CAR T-cell therapy, and antibody–drug conjugates has transformed modern oncology, significantly improving survival across a wide range of malignancies. However, these advances have also introduced a growing spectrum of endocrine and metabolic complications, redefining the scope of endocrine practice. Therapy-induced endocrinopathies, including thyroid dysfunction, hypophysitis, adrenal insufficiency, diabetes, dyslipidemia, gonadal dysfunction, and metabolic syndrome, are recognized as common, clinically significant, and often long-lasting consequences of cancer treatment. Unlike classical endocrine disorders, these conditions frequently present abruptly, display atypical clinical patterns, and require complex multidisciplinary management. This review explores the evolving field of oncoendocrinology, focusing on the mechanisms, clinical manifestations, and management of endocrine toxicities associated with novel cancer therapies. We also discuss the long-term endocrine sequelae of cancer treatment and the growing need for structured survivorship care and endocrine surveillance. In addition, we discuss future directions in oncoendocrinology, including predictive biomarkers, the need for treatment standardization, integrated care models, survivorship surveillance, and precision-based approaches to endocrine care. As cancer survival continues to improve, early recognition and long-term management of endocrine complications are becoming essential to optimizing both quality of life and overall outcomes in cancer survivors.

Abstract: Type 2 diabetes mellitus (T2DM) is a highly prevalent and devastating chronic metabolic disease worldwide, with its pathogenesis centrally characterized by insulin resistance and pancreatic β-cell dysfunction. Accumulating evidence has demonstrated that glucose metabolic reprogramming represents an adaptive metabolic shift from oxidative phosphorylation to aerobic glycolysis in cells in response to a hyperglycemic microenvironment, which acts as an upstream core event driving the initiation and progression of T2DM. This review systematically elaborates the characteristics of glucose metabolic reprogramming in insulin-sensitive target organs under T2DM conditions, including the liver, skeletal muscle, adipose tissue and pancreatic β-cells, and further dissects four major downstream effector mechanisms: mitochondrial energy metabolism disturbance, augmented oxidative stress, disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) coupled with calcium homeostasis imbalance, and systemic inflammatory response. On this basis, we summarize the intervention strategies targeting the above signaling pathways, including antioxidant therapy, restoration of MAMs integrity and calcium homeostasis, systemic anti-inflammatory intervention, and multi-target regulatory effects of traditional Chinese medicine. Current studies have indicated that early intervention in downstream stress events induced by glucose metabolic reprogramming, particularly the preservation of MAMs integrity, restoration of calcium homeostasis, and inhibition of NLRP3 inflammasome activation, is expected to block or delay the progression from prediabetes to clinical T2DM. Nevertheless, substantial gaps still remain in the understanding of the dynamic regulatory mechanisms of MAMs, tissue-specific therapeutic targets, and relevant clinical translational research. Future integration of multi-omics technologies will provide novel therapeutic strategies and theoretical foundations for the early prevention and treatment of T2DM.

Abstract: Background/Objectives: There are well-established sex differences in the epidemiology of stroke, but current data does not provide a clear mechanism to explain this phenomenon. This study asked if relationships between circulating sex hormone levels and stroke incidence could explain the sex differences in stroke rates. Methods: 393,158 participants from the UK Biobank aged were followed for a mean duration of 13.2 years. The incidence of ischemic stroke (IS) and intracerebral haemorrhage (ICH) was analysed in relation to baseline and changing levels of testosterone, sex hormone binding globulin (SHBG) and oestradiol. Results: A total of 3,844 participants experienced an IS and/or ICH, with incidence higher in men than women. In both sexes, a U-shaped association between total testosterone and ICH was found, independent of common cerebrovascular disease risk factors (P=0.006). Higher SHBG levels were associated with higher risk of IS (Q4 hazard ratio=1.18; P<0.001) in both men and women, independent of common cerebrovascular risk factors. No significant associations were observed between oestradiol levels and stroke events after making demographic adjustments. Conclusions: These data highlight the nuanced roles that sex hormones play in the epidemiology of stroke between sexes. Whilst sex hormones are implicated in modulating stroke risk, this study demonstrated the complexity of this relationship.

Abstract: Major depressive disorder (MDD) is increasingly understood as a disorder of integrated immune, endocrine, metabolic, neurovascular and synaptic regulation rather than a disease reducible to a single neurotransmitter deficit. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how a metabolic disturbance becomes a receptor-level neural signal. This review argues that the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA receptor (LPAR) axis offers a chemically and biologically coherent route for addressing that gap. LPC is not merely a readout of phospholipid remodeling; it is the direct ATX substrate from which receptor-active LPA can be generated. LPA receptors, in turn, regulate neural excitability, synaptic balance, hippocampal plasticity and stress-related behavior. Human studies report lower serum and cerebrospinal-fluid ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total-LPA findings that caution against biomarker oversimplification. Experimental studies show that ATX/LPA/LPAR perturbation alters hippocampal function, emotional behavior, stress resilience and synaptic physiology. These findings do not establish a completed depression pathway. They support a more specific hypothesis: depression-relevant ATX-LPA biology may be molecular-species resolved, compartment dependent, regionally organized and shaped by local production-inactivation balance. Reproductive endocrine transitions provide a biologically informative setting for testing this hypothesis because mood vulnerability, systemic lipid remodeling and steroid-sensitive regulation of pathway-adjacent nodes converge in the same clinical context. The decisive unresolved issue is spatial and biochemical: no depression-relevant study has yet demonstrated that defined brain-accessible LPC species, catalytically active ATX, locally generated LPA, local LPA inactivation capacity and receptor-specific circuit output coexist within a single mood-relevant CNS microenvironment. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, BBB/interface analysis, LPAR perturbation and matched circuit or behavioral readouts.

Abstract: Bioidentical hormone replacement therapy (BHRT) traditionally operates within a triad consisting of sex hormones, thyroid hormones, and adrenal glucocorticoids. Despite widespread adoption, a substantial proportion of patients experience persistent dysglycemia, adrenal instability, fluctuations in symptom control, and inconsistent responses to therapy even when laboratory values appear biochemically normalized. These clinical patterns suggest that an essential regulatory element is missing from the current BHRT conceptual model. This narrative review proposes the Insulin–Cortisol–Vitamin C (ICV) Axis as a previously unrecognized hormonal network central to metabolic and endocrine homeostasis. Insulin profoundly influences sex-hormone binding globulin (SHBG), estradiol and testosterone bioavailability, progesterone responsiveness, thyroid hormone conversion, mitochondrial ATP production, and cortisol reactivity—yet insulin is rarely evaluated in BHRT. Cortisol, in turn, directly modulates insulin sensitivity and metabolic function, while vitamin C is required for cortisol synthesis, adrenal recovery, endothelial nitric oxide signaling, mitochondrial redox regulation, and antioxidant defense. Together, disturbances in these three components can generate characteristic clinical presentations frequently encountered in BHRT practice. In parallel, emerging evidence—including metabolic insights from GLP-1 receptor agonist therapy—indicates that vitamin C status and oxidative stress modulation play broader roles in insulin sensitivity and hormonal signaling than previously recognized. Integrating these findings, the ICV Axis provides a systems-level framework capable of explaining BHRT treatment failures, variable patient responses, and persistent symptomatology despite standard hormone optimization. The purpose of this review is to synthesize biochemical, endocrine, and nutritional evidence supporting this new axis, and to outline a clinically actionable update to BHRT incorporating insulin dynamics and vitamin C sufficiency. Recognition of the ICV Axis represents a conceptual advancement that can improve therapeutic outcomes across metabolic, endocrine, and integrative medical practice.

Abstract: Background and Objectives: GLP-1 receptor agonists (GLP-1 RAs) are effective weight-loss therapies, but data on body composition changes in pediatric obesity remain scarce. The primary objective was to evaluate the effects of GLP-1 RAs on body composition in children with obesity. Materials and Methods: We conducted a retrospective study of children with obesity evaluated at the National Institute for Mother and Child Health “Alessandrescu-Rusescu”, Bucharest, Romania, who initiated weekly injectable GLP-1 RA therapy (semaglutide) between January and December 2025. Patients were assessed at baseline and after a median follow-up of 5 months. Eight of ten participants with complete paired data were included in the final analysis; two were excluded because one was non-responder with weight gain and suspected non-compliance, while one responder could not maintain the standing position for bioimpedance measurement. Bioimpedance analysis and anthropometry were performed at both visits. Paired data were analyzed using Wilcoxon signed-rank tests. Results: Eight children (4 boys, 4 girls; mean age 14.9±1.8 years) completed the study. Significant Body Mass Index (BMI) Z-score improvements were observed (CDC: -0.14, p=0.012; WHO: -0.37, p=0.012), with median weight reduction of 4.75 kg (p=0.036). While absolute muscle mass showed non-significant change (-1.3 kg, p=0.362), predicted muscle mass percentage increased significantly (+1.9%, p=0.012), suggesting selective fat loss. Fat-free mass percentage increased (+2.0%, p=0.012) with reciprocal fat mass reduction (absolute: -3.85 kg, p=0.017; percentage: -2.0%, p=0.012). Fat-free mass index remained stable (-0.67 kg/m², p=0.161). No serious adverse events occurred. Sensitivity analysis (n=10) confirmed the robustness of the results, with BMI Z-score improvements remaining significant. Conclusions: GLP-1 RA therapy in children with obesity leads to notable improvements in BMI Z-scores and beneficial body composition changes, suggesting muscle mass preservation along with weight loss, even at submaximal doses. These findings support conducting a larger prospective study with body composition as the primary endpoint.

Abstract: Background and Objectives: Emerging clinical data indicate that glucose levels in women with type 1 diabetes (T1D) fluctuate throughout the menstrual cycle. However, data concerning the adolescent population remain sparse. This study aimed to compare continuous glucose monitoring (CGM)-derived glycemic metrics between the early follicular and late luteal phases in adolescent girls with T1D in order to establish a clinical basis for phase-specific treatment adjustments. Materials and Methods: Ninety-nine menstrual cycles from 34 female adolescents with T1D were retrospectively analyzed. Time in range (TIR), time above range (TAR), time below range (TBR), mean glucose, and glucose variability were compared between the early follicular and late luteal phases. Additional analyses were performed to evaluate the impact of different insulin delivery methods and to assess glycemic metrics across subgroups by glycemic control. Results: During the late luteal phase, TIR was significantly lower, while TAR and mean glucose were significantly higher compared to the early follicular phase (p < 0.05). Although the continuous subcutaneous insulin infusion (CSII) group achieved better overall glycemic metrics then the multiple daily injections (MDI) group, phase-related fluctuations in TIR and TAR reached significance precisely within the CSII group. Furthermore, glycemic shifts in TAR, TBR and mean glucose were especially pronounced in adolescents with tight glycemic control (HbA1c < 7.0%). Conclusions: The late luteal phase is associated with significant glycemic deterioration in adolescent girls with T1D, particularly in those with optimal glycemic control. These findings underscore the need for targeted education and menstrual-cycle-tailored insulin dose adjustments.

Abstract: The rs1544410 (BsmI) polymorphism of the vitamin D receptor (VDR) gene has been implicated in metabolic regulation, although its role in metabolic syndrome (MetS) and related phenotypes remains unclear. This study aimed to evaluate associations between rs1544410, MetS status, and anthropometric and biochemical parameters in institutionalized older adults. A total of 95 participants were included, of whom 40% met the criteria for MetS. Anthropometric and biochemical profiles were assessed, and rs1544410 genotyping was performed. Differences between MetS and non-MetS groups were analyzed, and two-way ANOVA was used to evaluate genotype, MetS status, and their interaction effects. Participants with MetS showed an adverse cardiometabolic profile, characterized by higher triglycerides (TG), waist-to-hip ratio (WHR), and atherogenic index of plasma (AIP), as well as lower HDL-C levels compared with non-MetS individuals. No differences were observed for total cholesterol (TC), LDL-C, or non-esterified fatty acids (NEFA) between groups. Genotype distributions did not differ between MetS and non-MetS participants. However, significant genotype × MetS interactions were observed for TG and NEFA, with a borderline interaction for WHR that was not confirmed in post hoc analyses. Carriers of the rs1544410 AA genotype within the MetS group exhibited higher TG and NEFA levels compared with other genotypes, whereas no genotype-dependent differences were observed in the non-MetS group. Importantly, AIP was higher in participants with MetS, with the highest values observed in AA genotype carriers. In conclusion, the rs1544410 polymorphism was not associated with MetS status but was linked to MetS-related differences in TG, NEFA, and AIP, suggesting selective effects on lipid metabolism.

Abstract: The energy balance model (EBM) and its operational form, calories-in-calories-out (CICO), have dominated obesity research for nearly a century. While these frameworks have delivered valuable public-health insights, they rest on indirect mass-to-energy conversions and persistent misconceptions about thermodynamic principles. Here I demonstrate that a first-principles mass balance model (MBM) provides a conceptually simpler, mathematically consistent, and mechanistically superior alternative. By tracking macronutrient mass directly in grams – without intermediate energy conversions – the MBM aligns analysis with physiological reality and delivers 40–65% lower propagated uncertainty than conventional energy-balance approaches. I clarify that calories cannot be eaten or oxidized, that E = mc² is irrelevant to human metabolism, and that the First Law of Thermodynamics concerns only energy, not mass. I further show that both the carbohydrate-insulin model and the recently proposed protein partitioning model remain anchored in the same energy-accounting framework the MBM transcends. Extending the analysis to practical domains, I demonstrate why the body senses mass restriction, not calorie restriction; why exercise induces weight loss only when it produces a net negative mass balance; how the MBM explains adaptive thermogenesis as an emergent property of mass-clearance down-regulation rather than an unexplained residual; and what mass-balance principles demand of pharmacotherapy and supplementation. Together, these arguments establish the MBM as a more parsimonious, mechanistically faithful, and clinically actionable paradigm for human body weight regulation.

Abstract: Hyperprolactinemia, defined as persistently elevated serum prolactin levels, is a common endocrine disorder with systemic metabolic consequences that extend beyond its classical roles in lactation and reproductive function. This review summarizes current evidence regarding the interplay between prolactin excess and metabolic regulation. Chronic hyperprolactinemia is associated with increased appetite, weight gain, and elevated BMI, likely mediated through altered dopaminergic tone, leptin resistance, and direct effects on adipose tissue. Dyslipidemia is frequently observed, characterized by elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, alongside reduced high-density lipoprotein cholesterol (HDL-C). Additionally, prolactin excess contributes to impaired glucose homeostasis, manifesting as increased fasting glucose levels, elevated HbA1c, and insulin resistance. Emerging data also suggest associations with endothelial dysfunction, cardiovascular risk, neuropsychiatric disturbances, and reduced bone mineral density. These findings support the conceptualization of hyperprolactinemia as a multisystem disorder requiring comprehensive clinical evaluation and management. Further studies are needed to elucidate the underlying mechanisms and optimize therapeutic strategies.

Abstract:

Overweight has become a global health problem, reaching 1 billion cases in 2022. In Indonesia, its prevalence increased from 8.8% in 2013 to 21.8% in 2018, contributing to cardiovascular risk through elevated plasma and renal endothelin-1 (ET-1) levels. This study aimed to evaluate the effect of alternate-day fasting (ADF) on plasma and renal ET-1 levels in male Wistar rats induced by a high-calorie diet, and to assess the anti-endothelin effect of bosentan (125 mg). A post-test-only control group experimental design was used with 18 rats divided into three groups: healthy control, ADF, and anti-endothelin. Obesity was induced for 9 weeks using a high-fat diet, followed by a 4-week intervention. ET-1 levels were measured using ELISA and analyzed using SPSS. The results showed significant weight loss in the ADF group (p = 0.001), but no significant difference in plasma ET-1 levels (p = 0.566). Renal ET-1 levels remained higher compared to the control group (p = 0.001). The anti-endothelin group showed no significant changes in body weight or plasma ET-1, while renal ET-1 levels also remained elevated. In conclusion, ADF reduces body weight but does not normalize renal ET-1 levels. Longer interventions and combined approaches are recommended.

Abstract: Background: Patients with type 2 diabetes (T2D) frequently exhibit impaired erythrocyte deformability, which contributes to microvascular dysfunction. We previously reported that imeglimin, a mitochondrial-targeted antidiabetic agent, prolongs erythrocyte lifespan. This study investigated the effects of imeglimin on erythrocyte deformability and its clinical implications in patients with T2D. Methods: This post hoc analysis of the INFINITY study included 25 patients with T2D who completed 6 months of imeglimin treatment (2000 mg/day) followed by a 3-month follow-up. Erythrocyte deformability was evaluated using a microchannel array flow analyzer. Hematological parameters, glycemic markers, and vascular indices, including brachial-ankle pulse wave velocity (baPWV) and toe-brachial index (TBI), were also assessed. Results: Erythrocyte deformability, assessed by 3-month averages, showed an improvement trend at 1–3 months (P = 0.058) and a significant improvement at 4–6 months (P = 0.016) compared with baseline; this effect was reversed after discontinuation. Erythrocyte lifespan significantly increased by 10%–20% during treatment and persisted after discontinuation. Conversely, red blood cell count, hemoglobin, and hematocrit decreased during treatment and recovered post-discontinuation. At 6 months, baPWV increased and TBI decreased, both showing reversibility after treatment cessation. Conclusion: Imeglimin treatment significantly improved erythrocyte deformability in patients with T2D. Although this study did not definitively prove the direct clinical benefits of improved deformability on overall hemorheology or microvascular outcomes, these findings suggest that imeglimin exerts potential pleiotropic effects on circulatory function beyond glycemic control.

Abstract: Lipedema is a chronic, progressive adipose tissue disorder predominantly affecting women and has been widely proposed as an estrogen-dependent condition despite the lack of objective causal evidence. In contrast, increasing data implicate genetic heterogeneity, endothelial dysfunction, and altered vascular permeability as central features of the disease. This review critically reassesses the estrogen-dependence hypothesis in light of emerging genetic and vascular evidence. These findings highlight molecular pathways linking endothelial dysfunction and adipose tissue dysregulation as central features of the disease. Methods: A narrative literature review was conducted using PubMed, Cochrane Library, and Google Scholar databases. Searches combined the terms “lipedema,” “lipoedema,” “estrogen,” “hormonal dependence,” “genetic polymorphism,” “endothelial dysfunction,” “vascular permeability,” “microangiopathy,” and “adipose tissue,”. Original research articles, reviews, consensus statements, and experimental studies were included. Given the narrative design, no formal inclusion criteria, quality assessment, or meta-analytic procedures were applied. Results: Across multiple cohorts, no studies demonstrated that estrogen levels, estrogen receptor expression, aromatase activity, or estrogen-related signaling pathways act as primary causal triggers of lipedema. Conversely, consistent genetic, transcriptomic, and histopathological findings reveal marked genetic heterogeneity, dysregulated adipose tissue proliferation, extracellular matrix remodeling, microangiopathy, and increased endothelial permeability. Variants affecting adipogenesis, connective tissue integrity, vascular function, and lymphatic regulation have been repeatedly identified, alongside early endothelial structural and functional abnormalities. Conclusion: Current evidence does not consistently support classifying lipedema as an estrogen-dependent disease. While estrogen may modulate inflammatory and metabolic processes relevant to disease expression, its role appears secondary rather than causative. Genetic predisposition and vascular dysfunction emerge as more consistent contributors to lipedema pathophysiology, supporting integrative, mechanism-based models to guide future research and clinical approaches.

Abstract: Background: Individuals with long-standing type 1 diabetes (T1D) remain at elevated cardiovascular risk (CVR). Adiponectin (ADNC) and leptin (LEP) are adipokines involved in metabolic and vascular homeostasis, yet their relevance for CVR stratification in T1D is unclear. This study examined the associations of ADNC and LEP with CVR categories derived from the Steno Type 1 Risk Engine (ST1RE) and the 2019 ESC Guidelines on Diabetes, Pre-diabetes and Cardiovascular Diseases (ESC 2019), with particular attention to potential sex-related differences. Methods: A cross-sectional study included 124 adults with long-standing T1D and 59 age- and sex-matched non-diabetic participants. Serum ADNC and LEP concentrations were measured using standardized immunoassays. CVR was assessed using ST1RE and ESC 2019 algorithms. Multivariable models adjusted for age and body mass index (BMI) were used to examine determinants of adipokine concentrations and their associations with CVR categories. Results: Participants with T1D exhibited higher circulating ADNC concentrations than non-diabetic individuals (p < 0.001). LEP levels were significantly associated with sex (p < 0.001). In adjusted analyses, sex and BMI remained significantly associated with adipokine concentrations. Higher LEP levels showed a significant positive association with higher ESC 2019 CVR category (OR 1.84; 95% CI 1.19–2.84; p = 0.006), whereas ADNC and the LEP×sex interaction showed no significant association. Neither adipokine was significantly associated with ST1RE-derived risk categories. Conclusion: In adults with long-standing T1D, LEP showed an association with ESC 2019-based CVR stratification, whereas neither LEP nor ADNC was associated with ST1RE-derived risk categories.

Abstract: Background/Objectives: The prevalence of gestational diabetes mellitus (GDM) has in-creased worldwide over recent years. This rise has been attributed to changes in diagnostic criteria and to evolving demographic and metabolic risk profiles. The present study aimed to evaluate temporal trends in GDM prevalence in Tuscany, Italy, from 2010 to 2021, and to assess whether these trends were associated with changes in major risk factors and GDM-associated maternal–neonatal outcomes. Methods: This population-based retrospective study included all singleton pregnancies recorded in regional Delivery Assistance Certificates (CeDAP) registry between 2010 and 2021 filled by midwives at almost every delivery in Tuscany. GDM was identified using vali-dated clinical algorithms, in accordance with IADPSG criteria implemented from 2013. Temporal trends in GDM prevalence, major risk factors (pregestational obesity, maternal age, origin from High Pressure Migration Countries—HPMC, and adverse maternal and neonatal outcomes were analyzed. Multivariate log linear Poisson regression models were used to assess independent asso-ciations and yearly trends after adjustment for confounders. Results: Among 266,394 pregnancies, mean GDM prevalence was 11.37% and increased progressively over time, despite a concomitant decline in birth rates. Parallel increases were observed in pregestational obesity and in pregnancies among women from HPMC. Multivariate analysis found pregestational obesity, older maternal age, and HPMC ethnicity as the main factors driving the rise in GDM prevalence over time. Ce-sarean deliveries and fetal macrosomia decreased over time, whereas preterm birth increased among GDM pregnancies. Adverse maternal and neonatal outcomes were more strongly associat-ed with pregestational obesity and maternal age than with GDM itself. Conclusions: A true in-crease in GDM prevalence occurred in Tuscany between 2010 and 2021, primarily driven by rising pregestational obesity, advanced maternal age, and HPMC migration. Fetal macrosomia, cesarean delivery, and neonatal distress, were primarily associated with pregestational obesity and mater-nal age, rather than GDM itself. These findings highlight the importance of preventive strategies targeting metabolic health before pregnancy and support the effectiveness of organized GDM screening and management in reducing adverse outcomes.