The C-reactive protein to albumin ratio (CAR), an integrative biomarker of inflammation and malnutrition, has shown prognostic value in various diseases, but its role in diabetic chronic kidney disease (CKD) remains inadequately defined. This study aimed to evaluate the independent association of CAR with progression of chronic kidney disease (CKD) and all-cause mortality. We retrospectively retrieved 231 CKD patients with diabetes who had not received erythropoietin stimulants or iron therapy. The primary outcomes were mortality and progression of CKD (composite), specifically, progression to end-stage renal disease (ESRD) and initiation of renal replacement therapy (RRT), or a doubling of serum creatinine (SCr) levels in patients not receiving RRT. We used Kaplan-Meier survival curves and constructed multivariate Cox proportional hazards models adjusted for potential confounding factors, to estimate the association of CAR with progression of CKD and all-cause mortality; in addition, we employed restricted cubic spline analysis to explore nonlinear relationships. We used the SHAP machine learning algorithm to evaluate the predictive performance of CAR and to analyze the predictive increment of CAR for clinical outcomes. Subgroup analyses were conducted to assess the robustness of the results across different subgroups and modeling choices. The analysis cohort included a total of 231 adults. Kaplan-Meier curves showed a progressive and significant increase in cumulative CKD progression and mortality across CAR quartiles. In the fully adjusted model of the Cox multivariate regression analysis, a 1-unit increase in CAR (log-transformed) was associated with a 59% increase in the risk of CKD progression (HR = 1.59, 95% CI 1.20-2.09; P = 0.001) and a 32% increase in the risk of mortality (HR = 1.32, 95% CI 1.03-1.68, P = 0.029); participants in the highest quartile had a significantly higher mortality risk compared to those in the lowest quartile (Q4 vs. Q1, HR = 3.8, 95% CI 1.24-11.67; P = 0.02). Restricted cubic spline analysis revealed a significant linear relationship (nonlinear P > 0.05). Subgroup analysis indicated that CAR was consistently associated with outcomes across different age, sex, and BMI groups, with no significant interactions observed, confirming the robustness of these results. In machine learning models, SHAP analysis identified CAR as a key predictor. Compared with the baseline risk model (UTP, eGFR), adding CAR improved predictive performance for CKD progression and mortality, with enhanced C-statistic, improved discriminatory index (IDI), and improved net reclassification index (NRI). The CAR serves as a robust, independent predictor of CKD progression and all-cause mortality in patients with diabetic CKD. As a readily accessible biomarker, it holds significant potential to enhance risk stratification and identify candidates warranting intensified clinical management.
Bone metabolism is typically impaired in patients with acromegaly due to increased bone turnover, increased bone resorption, and impaired bone neoformation. The pathogenetic mechanisms underlying skeletal fragility in patients with acromegaly remain not fully clarified. We aim to compare the bone proteome of patients with acromegaly to that of a control group of patients with non-secreting pituitary tumors (NSPTs). A Liquid Chromatography-Mass Spectrometry was conducted on ethmoid samples (after processing and digestion of the sample) of five patients with acromegaly and five patients with NSPTs, to identify and assay the proteome. Biological functions were investigated for proteins that were found quantitatively up- and down-regulated in the bone of acromegalic patients, with a ratio of variation based on Fold-Change (FC) >|1.50| and statistical significance (p-value < 0.05). 312 proteins belonging to each group were identified. Six proteins with positive FC (up-regulated) and 12 proteins with negative FC (down-regulated) significantly differ in patients with acromegaly than in patients with NSPTs. Among up- and down-regulated proteins, profilin-1, isoform 5 of the periostin, apolipoprotein E, and caveolin-1 were known to be involved in bone metabolism. In our cohort, a positive correlation was detected between the profilin-1, the isoform 5 of the periostin, GH, and IGF-I levels; and a negative correlation was detected between caveolin-1 and serum GH and IGF-I levels, and with apolipoprotein E and serum IGF-I levels. Our results proved that the bone of patients with acromegaly is characterized by a specific proteomic profile, which is closely correlated to GH and IGF-I hypersecretion.
Bone is a unique specialized connective tissue comprising inorganic and organic components which continuously undergoes remodeling through the activity of anabolic and catabolic pathways. Peptidases are enzymes cleaving peptide bonds in a broad range of substrates and hence involved in many pathophysiological mechanisms. We previously reported that lack of Dpp3 in the mouse model results in bone loss and here we aimed to establish whether it also affected bone matrix composition. We performed proteomic and lipidomics analysis of the flushed bone of 6-month-old wild type (WT) and Dpp3 knock-out (ko) male mice (4 mice/genotype); Western blot analysis of selected upregulated proteins and gene expression analysis of genes potentially involved in the identified pathways. We found that Dpp3 deficiency was associated with a proteomic signature in the bone matrix consistent with sustained oxidative stress and altered matrix turnover and pointing to a metabolic adaptation within the skeletal tissue. Accordingly, lack of Dpp3 resulted in a shift in lipid composition in the bone matrix, with enrichment of specific structural lipids and lack of others for energy production. Our work confirms the importance of DPP3 in the context of bone homeostasis and sheds some light on the matrix composition of DPP3-depleted bone. Owing to the foreseen translational implications of this evidence, further investigation is deserved to complete a comprehensive characterization.
Acquired partial lipodystrophy (APL) is characterized by loss of subcutaneous adipose tissue, primarily affecting the upper body. We aim to characterize the clinical and metabolic profiles of patients with APL and explore whether variations in clinical presentation and adipose tissue distribution are associated with the development and severity of metabolic disease. This multicenter study included 36 patients with APL (median age: 38, 24-49; 25th -75th percentiles; 12 males, 24 females). For comparison, 37 patients with familial partial lipodystrophy type 2 (FPLD2) due to typical codon 482 LMNA variants (median age: 42, 32-56, 25th -75th percentiles 10 males, 27 females) were included. The median follow-up duration was 60 months (7.5-102, 25th -75th percentiles). Low complement 3 levels were detected in 18 of 34 patients with available assessment (52.9%). Autoimmune disorders were common, affecting 14 patients (38.9%). Metabolic abnormalities were variably observed among patients with APL, with diabetes documented in 17 patients (47.2%), hypertriglyceridemia in 21 patients (58.3%), and hepatic steatosis in 22 patients (61.1%). Chronic kidney disease developed in 19 patients (52.8%), pancreatitis in 3 (8.3%), and polycystic ovaries in 8 (42.1%) of reproductive-age women. A subgroup of patients with APL (n = 11, 30.6%) had reduced gluteofemoral adipose tissue and exhibited more severe metabolic abnormalities than those with fully preserved adipose tissue in these regions. All patients in this subgroup had diabetes; 7 of 11 had triglyceride levels > 500 mg/dL, and hepatic steatosis was present in 10 of 11. Kaplan-Meier estimates indicated earlier onset of diabetes (p < 0.001) and hypertriglyceridemia (p = 0.005) in this subgroup. Patients with APL show a heterogeneous clinical profile, and our observations reveal a phenotypic overlap with more generalized adipose tissue loss in some patients diagnosed as APL under current classifications. In this subset, reduced gluteofemoral fat is linked to earlier onset and greater severity of metabolic complications, highlighting the importance of fat distribution in metabolically protective regions.
ContextDeficiency of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a rare autosomal recessive disorder of sex development affecting individuals with a 46, XY karyotype. It is caused by pathogenic variants in the HSD17B3 gene that impair the conversion of Δ4-androstenedione to testosterone.ObjectiveTo evaluate the clinical presentation and management of a female patient who exhibited masculinization during puberty and assess her long-term life satisfaction during follow-up.MethodsA female patient who exhibited masculinization during puberty underwent comprehensive endocrinological and genetic assessments. Subsequently, she underwent sex reassignment surgery and follow-up investigation.ResultsHormonal findings showed a baseline testosterone/androstenedione ratio of 1.77, which decreased to 1.32 after human chorionic gonadotropin stimulation; these findings are atypical for the diagnosis. Subsequently, compound heterozygous mutation p.I60 T(c.179T > C) and exon 1 deletion were identified. After extensive counseling, the patient's parents decided to reverse the patient's sex to male. Orchidopexy and two-stage urethroplasty were performed; histological evaluation demonstrated no malignancies of the testicular tissue. Follow-up after 1 year indicated that the patient was satisfied with their sex assignment.ConclusionsThe management of pediatric patients with rare 17β-HSD3 deficiency remains challenging. For patients diagnosed early, premature removal of the gonads is not recommended as the risk of malignancy is very low. Any decision must be carefully discussed within a multidisciplinary disorders of sex development team, together with the patient and their parents. Long-term follow-up is required to assess the impact of the chosen option on future quality of life.
Children and adolescents frequently experience fractures related to accidental injuries; however, fractures may also result from non-accidental trauma in abused children or from underlying bone fragility due to primary or secondary osteoporosis. In pediatric patients with fragility fractures diagnosis and treatment may be delayed. This document aims to provide clinicians with a practical approach to the diagnosis and management of fragility fractures in children and adolescents. Between November 2024 and June 2025, a group of Italian pediatric endocrinologists with expertise in bone and mineral metabolism held regular online meetings to discuss key issues related to the diagnosis and management of pediatric bone fragility and developed experts opinion statements based on clinical experience and a review of the relevant literature. The expert panel formulated consensus statements on the clinical management of children and adolescents with fragility fractures. Seven main areas were addressed: 1) definition of fragility fractures and pediatric osteoporosis; 2) diagnostic approach; 3) main causes of primary and secondary osteoporosis; 4) assessment of the potential for spontaneous recovery from bone fragility; 5) management of bisphosphonate therapy; 6) other therapeutic options; 7) conservative measures. The diagnosis of osteoporosis in pediatric patients should follow a clinically oriented approach. Genetic testing plays a crucial role in identifying primary forms of osteoporosis. Vertebral reshaping may occur in some patients with secondary osteoporosis. Bisphosphonates represent the mainstay of treatment in children and adolescents with bone fragility. Conservative measures aimed at optimizing bone strength may be beneficial in selected cases.
Primary osteoporosis (OP) has traditionally been viewed as a skeletal disorder; however, its complex interactions with muscle and adipose tissue are increasingly recognized. Nevertheless, the specific characteristics of body composition alterations in OP, particularly regional distribution and qualitative changes, and their independent roles remain poorly defined. This study aimed to systematically investigate the characteristics of whole-body and regional body composition changes in patients with primary osteoporosis, and to specifically assess the independent associations of paravertebral muscle fat infiltration and trunk-to-appendicular fat distribution with osteoporosis risk. Based on diagnostic criteria, participants were categorized into an OP group and a non-OP group. Dual-energy X-ray absorptiometry (DXA) was used to assess bone mineral density (BMD), muscle mass, and fat mass across the whole body and specific regions (trunk, limbs, upper limbs, lower limbs). Computed tomography (CT) was employed to quantitatively evaluate fat infiltration (represented by muscle density) in the psoas major, erector spinae, and multifidus muscles. Spearman correlation analysis was used to assess associations between body composition indicators. Multivariable logistic regression models and restricted cubic spline (RCS) analyses were applied to examine the independent associations of fat infiltration and distribution with OP. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminative ability of the identified adipose measures, with area under the curve (AUC) calculated before and after adjustment for confounders.dipose measures, with area under the curve (AUC) calculated before and after adjustment for confounders. Compared to the non-OP group, OP patients exhibited significant systemic alterations, including concurrent reductions in whole-body skeletal muscle mass, fat mass, and bone mineral content (all P < 0.01). Regional analysis revealed that bone and fat loss were more pronounced in the trunk than in the limbs (both P < 0.05). CT analysis revealed significantly lower muscle density in the paravertebral muscles of OP patients (all P < 0.05). After adjusting for sex, age, height, weight, total muscle mass, smoking, and alcohol consumption, multivariable logistic regression identified both decreased multifidus muscle density (OR: 0.98 per HU, 95% CI: 0.96-1.00; P = 0.023) and an increased limbs-to-trunk fat ratio (OR: 14.35, 95% CI: 2.90-76.35; P = 0.001) as factors independently associated with OP. Further analysis revealed distinct risk patterns: the limbs-to-trunk fat ratio demonstrated a significant linear dose-response relationship (P for overall association from RCS = 0.015). For multifidus muscle density, while a significant association was observed in the linear model, the more flexible RCS model did not confirm a significant overall association (P for overall = 0.065). ROC analysis showed that after adjustment, the limbs-to-trunk fat ratio had an AUC of 0.777, with a cut-off of 0.785 yielding 51.1% sensitivity and 80.0% specificity; multifidus muscle density had an adjusted AUC of 0.774, with a cut-off of 24.75 HU yielding 80.9% sensitivity and 46.8% specificity. This study characterizes the body composition profile of primary osteoporosis as a composite of changes, including proportional whole-body reduction of muscle and fat, preferential loss of trunk tissues, and significant fat infiltration in paravertebral muscles. Decreased multifidus muscle density and an increased limbs-to-trunk fat ratio are independently associated with OP, showing different association patterns. Both measures demonstrated moderate discriminative ability for osteoporosis after adjustment for confounders, with the limbs-to-trunk fat ratio showing higher specificity and multifidus muscle density showing higher sensitivity. These findings support the concept that OP is a systemic disorder involving bone, muscle, and adipose tissue, providing new perspectives for future risk assessment and intervention strategies.
Premature pubarche (PP), defined as the early onset of pubic hair and often associated with mild androgen excess, is a common reason for referral to a pediatric endocrinologist. A small proportion of cases may progress to central precocious puberty (CPP). Data on the factors determining pubertal tempo and associated growth outcomes in these individuals are limited. To identify predictors of pubertal progression and final height (FH) in girls with PP and to evaluate growth outcomes in those progressing to CPP. We retrospectively analyzed 88 girls with PP who attained FH; 13 progressed to CPP (PP-to-CPP). Auxological data, bone age (BA), pubertal development, and plasma androgen profiles were evaluated. At presentation, corrected height SDS (CH-SDS) in girls with PP correlated with BA-SDS and BA/chronological age (BA/CA) ratio (p=0.03 and p=0.007). Corrected FH-SDS was positively associated with baseline CH-SDS in both PP and PP-to-CPP groups (p<0.001 and p=0.0002). Compared with PP, the PP-to-CPP group had higher baseline CH-SDS, BA-SDS and BA/CA ratio (all p=0.02). Baseline CH-SDS was the strongest independent predictor of corrected FH-SDS (p<0.001), while BMI-SDS showed a negative association (p=0.003). Baseline dehydroepiandrosterone-sulfate (DHEA-S) was not associated with CH-SDS, BA advancement, progression to CPP, or corrected FH-SDS in either group. Receiver operating characteristic (ROC) analyses for progression to CPP identified a BA/CA cutoff of 1.2; and a CH-SDS cutoff of 1.8 (p=0.01). Growth relative to genetic potential and skeletal maturation at presentation were the strongest predictors of progression to CPP and FH outcomes in girls with PP. Although DHEA-S reflects adrenal maturation and early androgen exposure, baseline DHEA-S concentrations were not associated with progression to CPP or long-term growth outcomes in our cohort.
This study aimed to investigate the relationship between serum metabolomic profiles and continuous glucose monitoring (CGM) metrics in adults with type 1 diabetes (T1D), given that glycaemic control differences influence distinct metabolic pathways. In this cross-sectional study, 325 adults with T1D were evaluated. CGM metrics were derived from 14-day recordings. Participants were stratified by achievement of clinical glycaemic targets [time in range (TIR70-180) > 70%, coefficient of variation (CV) < 36%, and time below range (TBR < 70) < 5%] into "on-target" and "off-target" groups. Serum metabolomic profiles were quantified using proton nuclear magnetic resonance spectroscopy (1 H-NMR). Among the 325 participants (46% female; mean age 41 ± 14 years; diabetes duration 20 ± 12 years), 57 (18%) achieved all clinical glycaemic targets. These patients had higher concentrations of glutamine, valine, and isoleucine, and lower lactate levels. TIR70-180 correlated negatively with lactate, Glyc B, and Glyc B H/W. Mean glucose was positively associated with IDL-C, IDL-TG, LDL-P, small LDL-P, Glyc A H/W, and lactate, and negatively with glutamine and acetone. Hypoglycaemia metrics were associated with small LDL-P, while glucose variability correlated with alanine [β: - 0.026 (95% CI: - 0.057 to - 0.008); P = 0.013]. In logistic regression analyses adjusted for duration of T1D, glutamine [Exp(B) = 0.993 (95% CI: 0.987-0.999), P = 0.022] and lactate [Exp(B) = 1.004 (95% CI: 1.001-1.007, P = 0.003] were significantly associated with glycaemic control. Serum metabolomic profiles reflect CGM-derived glycaemic metrics in T1D, highlighting their potential role as biomarkers for a refined assessment of metabolic control.
Thyroid cancer is the most common malignancy of the endocrine system, with a rising global incidence. Radioactive iodine (RAI) therapy with 131I is used post-surgery to ablate residual thyroid tissue and cancer cells in differentiated thyroid cancer. However, in radioiodine-refractory cases, tumor cells often undergo dedifferentiation and develop RAI resistance, severely limiting therapeutic efficacy. Therefore, elucidating the mechanisms underlying dedifferentiation and developing strategies to restore differentiation have become a hot topic in thyroid cancer research. In this study, a three-dimensional (3D) culture model of TPC-1 thyroid cancer cells was developed using hanging drop and low-adhesion methods to mimic the dedifferentiation process in vitro. Cells cultured under 3D conditions exhibited typical dedifferentiated features, including upregulation of cancer stem cell markers, downregulation of thyroid functional proteins, and impaired radioiodine uptake. Through integrated bioinformatic analysis and immunohistochemical staining of in-house papillary thyroid carcinoma (PTC) samples, we identified transforming growth factor beta 1 (TGF-β1) as a potent inducer of thyroid cancer dedifferentiation. The TGF-β1/Smad signaling pathway was activated in PTC tissues, where it played a critical role in regulating tumor stemness and the expression of iodine-metabolizing proteins. Galunisertib, a TGF-β type I receptor kinase inhibitor, effectively blocked TGF-β1 signaling in spheroids, suppressed cancer stem cell marker expression, and enhanced radioiodine uptake through upregulation of thyroid functional proteins, establishing TGF-β1 as a therapeutic target in thyroid cancer. Collectively, the established 3D culture model serves as a robust platform for investigating dedifferentiation in thyroid cancer and provides a basis for developing novel therapies against radioiodine resistance.Plain Language.
To investigate the prevalence, classification, and clinical impact of genetic variants in leptin-melanocortin (MC4R) pathway- and ciliopathy related genes, and in some key neurodevelopmental and pleiotropic genes whose dysfunction may cause hyperphagia in a sample of youths with severe obesity regardless of age of obesity onset and presence of hyperphagia. Cross-sectional evaluation of patients consecutively referred for severe obesity having had prior next-generation sequencing targeting genes of interest as for the Rare Obesity Advanced Diagnosis (ROAD) program gene panel. Variants were classified according to guidelines as likely benign (LB), pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VOUS). Clinical and metabolic features were compared across groups of controls (mutant negative and LB carriers), VOUS, and LP/P carriers. A total of 164 patients were included: 91 patients (54.5%) carried at least one variant. Most variants were heterozygous and classified as VOUS (n = 82, 89%); 10 patients (11%) had LP/P variants. Genes most frequently associated with LP/P findings included MC4R (n = 2), ALMS1 (n = 3), and CEP290 (n = 2). No significant differences were found across groups in obesity degree, lipid profile, glucose metabolism, or behavioural symptoms. A non-significant trend toward earlier onset of obesity was observed in the LP/P group. Children with severe obesity often carry gene variants in the leptin-MC4R pathway or associated to ciliopathies, which appear even in cohorts unselected for early onset or hyperphagia. Their clinical significance remains uncertain. Although genetic testing may inform clinical stratification and personalised treatment, its integration into the diagnostic workup of severe obesity should currently be restricted to specialised obesity clinics and research contexts. Findings highlight the need for improved interpretation of LP and VOUS through functional studies and long-term phenotyping.
To evaluate the short- and mid-term volume reduction rate(VRR) after percutaneous ethanol injection(PEI), at 1,3 and 6 months, in patients with cystic or predominantly cystic thyroid nodules(CNs/pCNs, respectively), conducting a systematic review and meta-analysis of published data on VRR outcomes across these intervals. A systematic search of articles published up to October 30,2025 identified studies reporting PEI treatment for CNs/pCNs.Characteristics of the study design, CNs/pCNs cohorts, and outcomes of interest(VRR at 1,3 and 6 months of follow up)were extracted.Statistical analysis included a random-effects meta-analysis, assessment of heterogeneity with use of the I2 statistic, and meta-regression and subgroup analyses to explore potential sources of heterogeneity. Six studies comprising 431 CNs/pCNs were included.The pooled VRRs at 1,3 and 6 months post-PEI were 85.18%(95% CI: 80.72-89.64),91.50%(95% CI: 88.88-94.12) and 93.11%(95% CI: 90.91-95.31),respectively. Stratifying by nodule cystic composition, the VRR at consecutive follow-up time points was significantly different between the 1- and 3-month intervals in both subgroups [CN: VRRs at 1, 3 and 6 months were 91.16% (88.38-93.93), 95.69% (94.16-97.22) and 96.02% (94.16-97.87), respectively; pCN: VRRs at 1,3 and 6 months were respectively 80.19% (77.04-83.33), 87.08% (84.95-89.2) and 90.01%(88.83-91.19)].A secondary meta-regression analysis with baseline mean volume as covariate demonstrated a significant inverse association with VRR at 1 and 3 months in pCN(p = 0.02). By providing pooled VRRs for the short- and mid-term follow-up, this meta-analysis should be regarded as an initial step, paving the way for larger, high-quality studies aimed at standardizing the PEI procedure and supporting its incorporation into future dedicated guidelines.
Data about clinical implications of subclinical hypothyroidism (SH) in children are scanty, and the management of this condition is still challenging particularly for mild forms (TSH levels ranging between 4.5 and 10 mU/L). Aim of this study is to compare left ventricular (LV) geometry and function in SH children and matched euthyroid controls, and to evaluate the cardiac effects of L-thyroxine (L-T4) therapy. Thirty-six children (19 females), aged 8.3 ± 0.7 years, with persistent and idiopathic SH were enrolled in the study. Thirty-six euthyroid children comparable for sex, age and body mass index were enrolled as controls. Baseline echocardiography and biochemical assessment was performed in all subjects. Thereafter, SH children started L-T4 therapy. Both assessments were repeated after 2 years of therapy in patients and 2 year -follow-up in controls. The LV cavity size was comparable between SH and controls, at baseline, and increased similarly over time. LV systolic function was normal at baseline in both groups and remained comparable at end-study. With regard to diastolic function, SH children showed a significant prolongation of isovolumic relaxation time (IVRT) compared with controls (92.95 ± 3.74 vs 76.13 ± 2.75 msec, p = 0.0006), with normal E/A and E/E' ratios in both populations, consistent with subclinical, mild diastolic dysfunction. After L-T4 therapy, IVRT significantly decreased (81.43 ± 4.28 msec p < 0.05) becoming similar to controls (82.20 ± 2.14 msec). Long-lasting mild SH in children is associated with subtle abnormality of LV relaxation which improves with L-T4 therapy. Whether these subtle alterations may lead to significant clinical consequences require further investigation.
Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexists with type 2 diabetes mellitus (T2DM), complicating its management. In this population, we aimed to compare the effectiveness of subcutaneous GLP-1 receptor agonists (scGLP-1RA) to SGLT2 inhibitors (SGLT2i) on metabolic and hepatic parameters, while investigating the influence of GLP1R and PNPLA3 genetic variants on treatment response. This retrospective study included patients with T2DM starting scGLP-1RA or SGLT2i, balanced through Propensity Score Matching (PSM) to account for baseline clinical differences. Clinical and biochemical data were compared at baseline and after one year of treatment. Genotyping was performed for PNPLA3 (rs738409) and GLP1R (rs761387, rs6923761) polymorphisms. Multivariable linear regression was used to identify independent predictors of HbA1c, BMI, and transaminase reduction. Both drug classes significantly improved glycemic control and BMI. However, scGLP-1RA demonstrated superior efficacy in HbA1c and BMI reduction compared to SGLT2i (β = -0.349, p = 0.001; β = -0.711, p = 0.045). In MASLD subgroups (baseline ALT > 35 U/L or hepatic steatosis), only scGLP-1RA led to a significant reduction in ALT levels (p = 0.02). Multivariable analysis identified the GLP1R rs761387 G allele as an independent predictor of a blunted glycemic response (β = -0.277, p = 0.018). In a real-world setting, scGLP-1RA showed higher potency than SGLT2i on metabolic and hepatic parameters. These findings support the preferential use of scGLP-1RA in patients with T2DM and MASLD and are consistent with current international recommendations. The association between GLP1R rs761387 variant and HbA1c reduction sheds light on the impact of this variant on treatment response. Further studies are needed to validate this genetic predictor in broader populations.
Complete androgen insensitivity syndrome (CAIS) is a rare condition affecting sex development. Due to limited literature, especially for providing care in adulthood, clinical management remains challenging, and several issues remain inadequately addressed. We conducted an international survey to examine current clinical practices in the management of CAIS across the Referral Centres (RC) of Main Thematic Group 7 (MTG7) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), with the aim of identifying needs for standardization and potential gaps in care. We collected responses from 24 RC in 11 countries for a total of 256 individuals with CAIS. The majority of respondents were paediatric centres (62.5%), highlighting the challenges in obtaining comprehensive data on adults with CAIS. The survey addressed various aspects of care, including diagnosis, genetic testing, gonadectomy, hormone replacement therapy (HRT), bone health, management of vaginal hypoplasia, and sexual outcomes. Key findings highlight significant variability in HRT protocols across centres, especially in adulthood, and reveal a lack of standardization in assessing potential long-term outcomes such as bone and sexual health. Given the complexity and rarity of CAIS, a centralized approach referring patients to centres with expertise in the management of the condition and the development of a clinical practice expert opinion for the management of CAIS beyond the paediatric age could help address current gaps, particularly in the transition from paediatric to adult care. All participating experts emphasized the need to develop such document to optimize CAIS care.
Exogenous Cushing's syndrome (CS) is most commonly caused by therapeutic glucocorticoids (GC), but rare and atypical sources can mimic endogenous GC. This narrative review provides a concise overview of these uncommon causes and their diagnostic implications. A PubMed search was performed using the keywords "Cushing syndrome," "factitious Cushing syndrome," "herbal medicine", "supplements" and "endocrine disruption" on March 9th, 2026. Additional articles were identified through manual screening of reference lists. No restrictions were applied regarding language or study design, and the most relevant publications were selected. Three main categories of rare exogenous CS were identified. First, herbal or traditional remedies adulterated with undeclared GC. Second, compounds with GC-like activity, which activate the glucocorticoid receptor and suppress the hypothalamic-pituitary-adrenal axis. Third, factitious CS due to covert GC self-administration, often associated with psychiatric or caregiver-fabricated conditions. Diagnosis can be challenging; advanced analytical methods, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS), are essential to detect synthetic or undeclared GC and differentiate these cases from endogenous hypercortisolism. Rare exogenous causes of CS represent important diagnostic challenges. Careful evaluation of patient history, combined with the use of LC-MS/MS or LC-HRMS, is crucial to identify these conditions, prevent misdiagnosis, and avoid unnecessary diagnostic or surgical interventions.
This study aimed to determine serum levels of aquaporin-7 (AQP7), adiponectin (ADPN), and tumor necrosis factor-alpha (TNF-α) and to investigate their associations with metabolic parameters in children with obesity. This study included 60 healthy control children (Group 1), 39 overweight/obese (Group 2), and 60 morbidly obese (Group 3) children aged 5-18 years. Serum AQP7, ADPN, and TNF-α levels were measured using enzyme-linked immunosorbent assay (ELISA). Insulin resistance (IR) was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). ADPN and AQP7 levels were significantly lower in Group 2 compared with Group 1, however a partial increase was observed in Group 3 (p < 0.001). TNF-α levels did not differ significantly among the groups (p = 0.532). Metabolic parameters including body mass index (BMI), HOMA-IR, homeostasis model assessment of beta-cell function (HOMA-β), glycated hemoglobin (HbA1c), and lipid profile progressively deteriorated with increasing obesity severity (p < 0.05 to p < 0.0001). Cardiovascular risk indices were significantly higher in Group 2 and Group 3 (p < 0.001). Childhood obesity is associated with significant alterations in AQP7 and ADPN levels, which vary according to obesity severity. Compensatory mechanisms might emerge in morbid obesity, consistent with the partial increase in these biomarkers. The progressive worsening of metabolic parameters and cardiovascular risk indices with increasing BMI highlights the importance of early intervention. AQP7 and ADPN, alongside conventional metabolic markers, may serve as useful indicators of obesity-related metabolic dysfunction in children.
Serum uric acid to creatinine ratio (SUA/sCr) has emerged as potential biomarker for non-albuminuric diabetic kidney disease (NA-DKD), a recently recognized high-prevalence DKD phenotype. However, the relationship between SUA/sCr and cardiovascular and renal injury profile in this population is not well established. This study aimed to evaluate SUA/sCr across the spectrum of DKD, particularly focusing on NA-DKD, and to test its association with subclinical vascular damage, urinary biomarkers and ultrasound features of kidney damage. Presence of carotid plaques, pulse wave velocity (PWV), renal resistive index (RRI), and urinary biomarkers of tubular injury were assessed in 207 individuals with type 2 diabetes. Participants were split based on estimated-glomerular-filtration-rate (eGFR) and urinary-albumin-to-creatinine-ratio (UACR) into four groups: controls (UACR < 30 mg/g, eGFR ≥ 60 ml/min/1.73m2), A-DKD (Albuminuric-DKD; UACR ≥ 30 mg/g, eGFR ≥ 60 ml/min/1.73m2), NA-DKD (Non-albuminuric-DKD; UACR < 30 mg/g, eGFR < 60 ml/min/1.73m2), A&L-DKD (Albuminuric-and-Low-eGFR-DKD; UACR ≥ 30 mg/g, eGFR < 60 ml/min/1.73m2). Participants with NA-DKD showed a lower SUA/sCr than those with A-DKD and controls (4.71 ± 1.52 vs 6.06 ± 1.70 vs 6.67 ± 1.87, both P < 0.0001). A lower SUA/sCr was independently correlated with NA-DKD (β = -1.63, P < 0.0001) and A&L-DKD (β = -2.01, P < 0.0001). SUA/sCr was inversely and independently associated with urinary β2-microglobulin (β = -0.21, P = 0.0082). Moreover, lower SUA/sCr was associated with PWV > 10 m/s (OR 0.77, 95%CI 0.63-0.95, P = 0.014), the presence of carotid plaques (OR 0.78, 95%CI 0.63-0.96, P = 0.020), and higher RRI (β = -0.18, P = 0.0082). In T2D, lower SUA/sCr correlated with NA-DKD, but not with A-DKD. Lower SUA/sCr was associated with subclinical vascular and tubular damage. Future studies are needed to test SUA/sCr as candidate biomarker to improve DKD risk stratification.
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance, dyslipidemia and inflammation. Although probiotics have shown potential in improving glycemic control in T2DM, the systemic mechanisms underlying their therapeutic effects remain largely unclear. A high glucose-induced insulin-resistant zebrafish model was established to explore the interventional effects of Lactobacillus gasseri GDMCC AM63 (L. gasseri). Biochemical assays combined with untargeted metabolomics were used to comprehensively evaluate the efficacy of L. gasseri intervention. L. gasseri intervention significantly reduced fasting blood glucose levels, inhibited the expression of pro-inflammatory cytokines (tnfα and il-6), and upregulated the anti-inflammatory cytokine il-10. Metabolomic profiling identified 210 shared annotated DAMs in pairwise comparisons (T2DM_vs_control (Ctrl) group, and L. gasseri intervention (LG)_vs_T2DM group), which were mainly involved in lipid, amino acid, and carbohydrate metabolism. Pathway enrichment analysis showed significant enrichment of glycerophospholipid, fructose-mannose, pentose phosphate, riboflavin, and linoleic acid metabolic pathways. After FDR correction, 27 shared annotated significant DAMs (SDAMs) were identified. Integrated metabolomics and network pharmacology analysis suggested that L. gasseri may exert a therapeutic effect on T2DM by indirectly regulating signaling pathways such as PI3K/Akt and JAK/STAT. Randomforest analysis highlighted 18R-Hepe and Azii as potential metabolic biomarkers with predictive value. This study systematically investigated the metabolic regulatory mechanisms by which L. gasseri ameliorates T2DM, providing experimental evidence to support its potential as an effective interventional strategy for improving insulin resistance and related metabolic dysfunctions.
Traditional markers such as HbA1c and BMI are commonly used to assess metabolic risk in adolescents with type 1 diabetes mellitus (T1DM), but novel biomarkers like the triglyceride-glucose (TyG) index and phase angle (PA) may provide a more comprehensive evaluation of metabolic risk. However, their potential role in this population remains unclear. We aimed (1) to evaluate the association of the TyG index and PA with glycemic control, cardiovascular risk and body composition in adolescents with T1DM, and (2) to determine optimal cut-off points for these biomarkers to predict metabolic risk. Seventy-three adolescents (46.6% female, 10-19 years) with T1DM from two hospitals were included in this cross-sectional study. Sociodemographic, bioelectrical impedance (BIA) and clinical data were collected during routine visits. The TyG index was calculated from fasting triglyceride and glucose levels, and PA was measured via BIA. Correlations were analyzed using Pearson or Spearman coefficients, and ROC curve analyses were used to determine optimal cut-off points. PA correlated positively with skeletal muscle and fat-free mass and inversely with cardiovascular risk indicators. TyG was strongly associated with adiposity, glycemic variability and cardiovascular risk markers. A preliminary TyG threshold of 8.09 was identified, while no PA cut-off could be established. PA and the TyG index are promising, non-invasive biomarkers that complement traditional measures in assessing metabolic risk in adolescents with T1DM. Integrating these biomarkers into routine evaluation may enhance early risk detection and support holistic management in this population. NCT07021326.