Sex-Specific Differences in Post-Load Insulin Dynamics Are Independent of BMI-Based Adiposity and BIA-Derived Body Composition and Pubertal Stage in Adolescents with Obesity Anelise Sonza, Aline Faquin, Graziano Grugni, Adele Bondesan, Diana Caroli, et al. Journal of Clinical Medicine, 2026 Background: Sex-related differences in insulin sensitivity during adolescence remain incompletely understood, particularly in the context of obesity. Whether these differences reflect variations in basal insulin resistance or dynamic insulin responses remains unclear. Objective: To investigate sex differences in glucose and insulin responses during the oral glucose tolerance test (OGTT) and to explore mechanisms underlying potential dissociation between glycemic and insulinemic profiles. Methods: A cross-sectional analysis of 753 adolescents with obesity who underwent a standard oral glucose tolerance test (OGTT). Plasma glucose and insulin were measured at fasting and at 30, 60, 90, and 120 min. Mixed-effects models were used to examine glucose and insulin trajectories over time, including sex-by-time interactions, and to adjust for body mass index standard deviation score (BMI_SDS), pubertal stage (Tanner), metabolic syndrome (MetS), and body composition (resistance index). Multiple linear regression models were fitted to assess associations of sex with HOMA-IR, HOMA-β, total area under the curve (AUC), and phase-specific insulin AUCs. Results: Glucose trajectories during OGTT were similar between sexes, with no significant sex or sex-by-time interaction effects after adjustment. In contrast, insulin trajectories differed significantly by sex (sex-by-time interaction β = −0.10, p < 0.001). Boys exhibited higher baseline insulin levels and greater total insulin exposure (β = −11.2, p < 0.001), independent of BMI_SDS, pubertal stage, MetS, and body composition. Sex differences were sustained across all OGTT phases. HOMA-IR did not differ by sex, whereas HOMA-β showed a sex-related difference. BMI was positively associated with both basal and dynamic insulin measures. Conclusions: In adolescents with obesity, sex differences are characterized by altered dynamic insulin responses rather than differences in glycemic control. Boys exhibit greater compensatory insulin exposure during glucose challenge, independent of BMI-based adiposity, BIA-derived body composition and pubertal development.
Quality of Life in Short Stature: Comparisons Between Normal Variants Short-Statured and Normal-Statured Children and Adolescents and Agreement with Their Parents Anna Guerrini Usubini, Nicoletta Marazzi, Laura Abbruzzese, Adele Bondesan, Graziano Grugni, et al. Healthcare Switzerland, 2025 Background/Objectives: This study aimed to evaluate quality of life in children and adolescents with normal variants of short stature compared to age- and sex-matched individuals with normal stature and to assess the agreement between children/adolescents-reported and parent-reported outcomes. Methods: A total of 65 child–parent dyads were enrolled, including 29 children and adolescents with short stature (15 males, 14 females; mean age: 11.2 + 2.0 years; mean height standard deviation score, HSDS: −2.10 + 0.57) and 36 children and adolescents with normal stature (19 males, 17 females; mean age: 11.3 + 1.93 years; mean HSDS: 0.56 + 0.78). Quality of life was assessed using the Quality of Life in Short Stature Youth (QoLISSY) questionnaire. Statistical analyses included independent samples t-tests, and effect sizes were computed using Cohen’s d. Results: Among short-statured children and adolescents, no significant correlations were found between HSDS and all domains of quality of life. Short-statured children and adolescents exhibited significantly lower QoL across all domains compared to their normal-statured peers. Coping was higher in children and adolescents with short stature compared to their peers of normal stature. Similarly, parents of short-statured children and adolescents perceived a lower QoL for their sons and daughters and reported greater concern about the future and a more perceived personal impact than parents of normal-statured children and adolescents. No statistically significant differences were found between sons/daughters and parent reports, indicating a relatively high level of agreement in quality of life (QoL) perceptions. Conclusions: These findings underscore the psychosocial impact of short stature and highlight the importance of incorporating both child and parent perspectives in the clinical assessment.
Assessing Metabolic Syndrome Risk in Children and Adolescents with Prader–Willi Syndrome: A Comparison of Index Performance Graziano Grugni, Fiorenzo Lupi, Mirko Bonetti, Sarah Bocchini, Carmen Bucolo, et al. Journal of Clinical Medicine, 2025 Background: Currently, there is a lack of data regarding the reliability of different anthropometric, instrumental, and biochemical indexes in detecting metabolic syndrome (MetS) in pediatric patients with Prader–Willi syndrome (PWS). Therefore, this study aimed to compare the accuracy of different indices to identify the simplest and most accurate predictor of MetS in this at-risk population. Methods: We conducted a multicenter study involving 124 children and adolescents with PWS (61 males and 63 females), aged 13.6 ± 3.7 years. For each participant, we assessed all components of MetS, defined according to either the Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study or the International Diabetes Federation (IDF) criteria, based on age. The following indexes were calculated: Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), tri-ponderal mass index, body mass fat index, fat mass index, fat-free mass index, body shape index, visceral adiposity index, waist-to-height ratio, cardiometabolic index, total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, and triglycerides/HDL-C (TG/HDL-C) ratio. Results: MetS was identified in 24 subjects (9 females and 15 males), representing 19.4% of the sample. When comparing the receiver operating characteristic (ROC) curves, the TG/HDL-C ratio and cardiometabolic index demonstrated significantly better performance than the other indices in detecting MetS, with no difference between the two. As a result, we focused on the TG/HDL-C ratio since it is the simplest measure, requiring no additional anthropometric data compared to the cardiometabolic index. Additionally, applying age- and gender-specific thresholds can further improve its accuracy. Conclusions: The TG/HDL-C ratio, which requires only two standard biochemical markers, provides the same accuracy as more complex indexes in detecting MetS in children and adolescents with PWS, making it the optimal predictor for MetS in this population.
Comparison of Body Composition, Basal Metabolic Rate and Metabolic Outcomes of Adults with Prader-Willi Syndrome and Age- and BMI-Matched Patients with Essential Obesity Stefano Lazzer, Alessandro Gatti, Mattia D’Alleva, Lara Mari, Simone Zaccaron, et al. Journal of Clinical Medicine, 2025 Background/Objectives: This study compared metabolic syndrome (MetS) features in patients with Prader-Willi syndrome (PWS) to those in age-, BMI-, and gender-matched subjects with essential obesity (EOB). Methods: Thirty-two PWS patients (23 females, 9 males; median age 31.6 years; BMI 42.0 kg/m2) underwent several assessments, including anthropometric measurements, body composition via bio-impedance analysis, basal metabolic rate (BMR) using indirect calorimetry, and blood sampling. Results: Their data were compared to a matched EOB group (23 females, 9 males; median age 31.4 years; BMI 43.5 kg/m2). The study groups (PWS and EOB) were subsequently divided into two subgroups based on the International Diabetes Federation criteria for the definition of MetS. Results showed that individuals with PWS had significantly lower (p < 0.001) body weight (BW, −20.9%), height (−8.9%), fat-free mass (FFM, −23.5%), and fat mass (FM, −19.2%) in absolute terms compared to EOB subjects. However, the relative percentages of FFM and FM were similar. Absolute BMR was 25.5% (p < 0.001) lower in the PWS group; however, this difference disappeared when adjusted for FFM or body weight (BW). Metabolic outcomes were broadly similar between the groups, except for higher fasting glucose (+7.3%) and HbA1c levels (+7.9%), and lower fasting insulin (−29.0%) in PWS patients. Conclusions: Moreover, PWS subjects exhibited higher total cholesterol (+9.6%) and HDL-cholesterol (+19.8%), suggesting a more favourable lipid profile and no extra risk beyond severe obesity.
Epigenetic Age in Prader–Willi Syndrome and Essential Obesity: A Comparison with Chronological and Vascular Ages Antonello E. Rigamonti, Valentina Bollati, Benedetta Albetti, Diana Caroli, Adele Bondesan, et al. Journal of Clinical Medicine, 2025 Background: Prader–Willi syndrome (PWS) is a rare genetic disorder mapping to the imprinted 15q11-13 locus, specifically at the paternally expressed snord116 region, which has been implicated in controlling epigenetic mechanisms. Some aspects of the PWS-related clinical phenotype, such as the high mortality rate in adulthood, might be attributed to accelerated epigenetic ageing. Objectives: The aim of the present case–control study was to evaluate epigenetic age, age acceleration, vascular age (VA), and vascular ageing in adults with PWS (n = 24; F/M = 11/13; age = 36.8 [26.6; 45.3] years; body mass index, BMI = 36.8 [33.9; 44.8] kg/m2), compared with a sex- and age-matched group of subjects with essential obesity (EOB) (n = 36; F/M = 19/17; age = 43.4 [30.6; 49.5] years; BMI = 44.8 [41.2; 51.7] kg/m2). Results: In subjects with PWS, there was a younger epigenetic age and a lower age acceleration than in subjects with EOB. No differences were found between VA and vascular ageing in the two groups. Epigenetic age was associated with chronological age and VA within each group. For each group, no relevant associations of epigenetic age or age acceleration with demographic, biochemical, and clinical parameters were found. When considering individuals with PWS, there were no associations of epigenetic age with growth hormone (GH) deficiency, duration of hormone replacement therapy, and plasma levels of insulin-like growth factor 1 (IGF-1). Conclusions: The hypothesis of accelerated epigenetic ageing in PWS should be rejected. Additionally, considering the existence of a SNORD116-dependent epigenetic dysregulation in PWS, the results of the present study might be misleading, since an epigenetics-based approach was used to measure ageing.
