Noel Yat Hey Ng

Background: Polyendocrine metabolic ovarian syndrome (PMOS), formerly polycystic ovary syndrome (PCOS), is associated with an increased risk of type 2 diabetes. However, dysglycaemia risk across reproductive life stages—particularly adolescence—has not been systematically quantified. We aimed to address this gap to inform evidence-based screening. Methods: We did a systematic review and meta-analysis of observational studies up to December 31,2025, of women with PMOS, diagnosed using internationally accepted criteria, reporting type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or pre‑diabetes (IGT and/or IFG and/or HbA1c 5.7–6.4%), versus controls. New studies were combined with those from our 2018 review to derive pooled effect estimates using random‑effects models, with subgroup analyses by reproductive life stage. The protocol is registered with PROSPERO (CRD420261306349). Findings: Fifty-two studies from 30 countries were included. Compared with controls, women with PMOS had increased odds of type 2 diabetes (OR 2.83; 95% CI 1.45-5.55), IGT (2.81; 1.91-4.13), IFG (1.94; 1.25-3.02) and pre-diabetes (2.37; 1.71-3.28). Type 2 diabetes odds remained elevated in BMI-matched (2.53; 1.34-4.76) and age-matched (3.32; 2.35-4.69) studies. Adolescents had higher odds of IGT (4.87; 1.69-14.06) and pre-diabetes (4.01; 1.18-13.58), but not type 2 diabetes or IFG. Premenopausal women had higher odds of type 2 diabetes (2.70; 1.22-5.95), IFG (1.97; 1.20-3.22), IGT (2.62; 1.75-3.91), and pre-diabetes (2.32, 1.60-3.37). In studies including postmenopausal women, type 2 diabetes odds were increased (3.20, 1.41-7.24), with insufficient data for other outcomes. Interpretation: PMOS is associated with two- to three-fold higher dysglycaemia odds across the reproductive lifespan, evident as early as adolescence and independent of BMI, supporting early metabolic screening regardless of body weight.

Aims/hypothesis: The study aimed to explore the association between maternal glucose levels in pregnancy and offspring’s metabolism and adiposity at approximately 18 years of age. Methods: Pregnant women from the Hong Kong Field Centre enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study underwent a 75 g OGTT at 24–32 gestational weeks. Offspring’s metabolic and adiposity traits were assessed at 18 years postpartum. Associations were evaluated using multiple linear regression and logistic regression. Results: Among the 506 mother–child pairs followed up to 18 years, maternal fasting plasma glucose (FPG) in pregnancy was positively associated with offspring’s FPG (β = 0.06 [95% CI 0.02, 0.09]), while maternal 1 h plasma glucose (PG) showed a positive association with offspring’s FPG (β = 0.05), 30 min PG (β = 0.21) and 2 h PG (β = 0.14). All maternal glycaemic levels were associated with an increased risk of offspring being overweight/obese, particularly maternal 1 h PG (OR 1.50 [95% CI 1.17, 1.93]). Offspring of mothers with gestational diabetes mellitus showed a higher prevalence of abnormal glucose tolerance (11.86% vs 7.97%), impaired fasting glucose (1.89% vs 0.49%) and impaired glucose tolerance (10.34% vs 7.13%) than offspring of mothers with normal glucose tolerance, although these associations did not reach statistical significance in fully adjusted models, underscoring the benefit of considering maternal glucose as a continuous trait. Conclusions/interpretation: Maternal glucose levels in pregnancy showed a long-term association with offspring’s metabolic health into young adulthood, with continuous associations across the full maternal glucose spectrum, suggesting a graded effect of maternal hyperglycaemia on offspring’s metabolic risk. Graphical

Early-life exposures may shape long-term effects on glucose regulation. This study aimed to stratify long-term abnormal glucose tolerance (AGT) risk from early childhood. A total of 906 children were enrolled at baseline and reevaluated in adolescence and young adulthood. By using the latent class trajectory analysis, glucose trajectories of children were measured via five–time point oral glucose tolerance tests and then grouped into three latent subclasses: mild excursion–normal reversion (MN), moderate excursion–delayed reversion (MD), and severe excursion–delayed reversion (SD). Logistic regression was performed to estimate the risk of AGT and associations between cardiometabolic factors and subclasses. In adolescence, compared with the MN subclass, the risk of AGT was 1.7-fold in the MD subclass and 5.5-fold in the SD subclass, after adjusting for age, sex, BMI, and Tanner stage. In young adulthood, the adjusted risk of AGT was 3.6-fold and 11.6-fold in the MD and SD subclasses, respectively. During the full natural history of glucose tolerance, the risk of AGT was 3.6-fold in the MD subclass and 18.1-fold in the SD subclass, after adjusting for childhood covariates. MD and SD subclass membership was strongly associated with childhood hypertension, maternal gestational diabetes, and maternal hypertension during pregnancy. Glucose trajectory subclasses in early childhood effectively stratified the long-term risk of AGT. The association between maternal cardiometabolic health and childhood subclass membership highlighted that prenatal exposures may influence metabolic outcomes in offspring. ARTICLE HIGHLIGHTS: Abnormal glucose tolerance (AGT) in youth has become an alarming global public health issue; however, approaches to identify high-risk population among young people have not been well-established. Can the long-term risk of AGT be stratified by the subclasses of glucose trajectories defined in childhood? Subclasses defined in childhood can efficiently stratify the risk of AGT in adolescence and young adulthood. The subclass membership was strongly associated with cardiometabolic disorders in childhood and maternal cardiometabolic disorders during pregnancy. This subclass method provides a potential strategy to identify those at risk of later cardiometabolic disorders from childhood for more intensive evaluation of intervention. The close relationship between maternal cardiometabolic disorders and subclass membership of children highlighted the potential influence of gestational cardiometabolic health on the development of cardiometabolic disorders in offspring.

Aims/hypothesis: We aimed to examine offspring adiposity trajectories from birth to age 9–14 years and to assess the joint associations of maternal overweight and gestational diabetes mellitus (GDM) with these trajectories. Methods: This is a prospective cohort study with 564 mother–child dyads from the Hyperglycemia and Adverse Pregnancy Outcome study Hong Kong field centre. Assessments and anthropometric measurements were taken during pregnancy, at delivery and at median ages of 7 and 10 years postpartum. Offspring adiposity was primarily assessed using sum of skinfold thickness. We used linear mixed-effect models to evaluate the independent and joint associations of maternal overweight and GDM with the offspring adiposity trajectories, and applied group-based trajectory modelling to identify distinct patterns of adiposity development based on both statistical indices and clinical interpretability. Results: Offspring skinfold thickness trajectories varied significantly based on maternal overweight and GDM (pp=0.006) of the rapidly increasing trajectory. Linear mixed-effect model analysis showed greater increases in skinfold thickness among offspring of mothers with either condition, with the highest trajectory observed in offspring of mothers with both conditions (β 1.62; 95% CI 0.69, 2.54; p=0.001). Conclusions/interpretation: Maternal overweight and GDM are independently and jointly associated with rapidly increasing adiposity trajectories from birth to early adolescence. The findings underscore the importance of considering both maternal metabolic conditions when evaluating offspring adiposity risk. Graphical

Background: Polycystic ovary syndrome (PCOS) is one of the commonest gyneco‐endocrine disorders amongst women of reproductive age. Whether PCOS and cardiometabolic traits in PCOS patients are associated with shortened telomere length (TL) or relative leukocyte telomere length (rLTL) remains unclear.Methods: 214 women with PCOS and 214 age‐matched women were recruited. rLTL was measured with an updated quantitative real‐time PCR protocol and reported as ΔΔCt between telomere and a single‐copy gene encoding β‐globin relative to a normalisation control. A two‐way Mendelian randomization analysis using the UK Biobank Resource was performed to assess the causal relationship between rLTL and PCOS.Results: Women with PCOS had significantly shortened rLTL (PCOS: 0.5 ± 0.7; control: 0.8 ± 0.6; p < 0.001). Longer rLTL was associated with a lower risk of PCOS after adjusting for age, history of smoking and other cardiometabolic traits (OR: 0.503; 95% CI: 0.342–0.730; p < 0.001). Longer rLTL was associated with reduced risk of dyslidpidemia (OR: 0.563; 95% CI: 0.450–0.968; p = 0.042) in PCOS patients. PCOS subjects with rLTL shorter than mean of the rLTL of control subjects had an elevated risk of dysglycemia (OR: 2.09; 95% CI: 1.04–4.29; p = 0.040). No causal relationships were found between rLTL and PCOS in the Mendelian randomization study.Conclusions: Women with PCOS have significantly reduced rLTL and shorter LTL may be associated with cardiometabolic risk factors in PCOS subjects. There are no causal relationship between genetically determined PCOS and TL or vice versa.

Aims/hypothesis: Insulin requirements in the human body undergo continuous changes in response to growth and development. We assessed the life course relationships between insulin demand and insulin adequacy. Methods: Three independent Chinese cohorts (204 children, aged [mean ± SD] 7.0 ± 0.5 years; 214 adolescents, aged 15.0 ± 1.8 years; 605 adults, aged 41.5 ± 9.3 years), recruited between 1998 and 2013, underwent OGTT tests. Indices of insulin sensitivity and insulin secretion were calculated based on paired glucose/insulin values during fasting, early phase and late phase of OGTT. Insulin demand and insulin adequacy were calculated by standardised major axis (SMA) regression from the paired insulin sensitivity and secretion indices. We derived the natural logarithm of ratio between the exponential functions of insulin adequacy and insulin demand (RAD) index for further evaluating the relationship between insulin demand and adequacy. The risk of abnormal glucose tolerance (AGT) was evaluated by logistic regression analyses. Area under the receiver-operating characteristic curve (AUC-ROC) analyses, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices were used to demonstrate the discriminative value of the RAD method model. Results: Adolescents had the lowest insulin sensitivity and the highest insulin secretion in all phases (fasting, early and late phase) of the OGTT, as compared with children and adults in each phase (all pp0.05) and late phase (pp<0.001 between age groups in each of the fasting, early and late phases of the OGTT). Participants with RAD values below the 25th percentile had a higher risk of AGT compared with those above the 25th percentile (fasting-phase OR 1.86 [95% CI 1.18, 2.91]; early-phase OR 1.99 [95% CI 1.24, 3.19]; late-phase OR 2.49 [95% CI 1.57, 3.97]). The late-phase RAD index had the best performance in evaluating the risk of AGT compared with the fasting- and early-phase RAD indices (late-phase AUC-ROC = 0.635 [95% CI 0.583, 0.687]; late-phase NRI = 0.350 [95% CI 0.190, 0.510]; late-phase IDI = 0.033 [95% CI 0.015, 0.050]). Conclusions/interpretation: The relationship between insulin demand and insulin adequacy changed throughout the life course. Adolescents had an imbalanced relationship between insulin demand and insulin adequacy, while, in general, children and adults had a balanced relationship. RAD is a novel index that was used to efficiently describe this relationship and evaluate the risk of AGT. Graphical

Objectives: There is relatively scarce data regarding the association between primary hyperparathyroidism (PHPT) and incident diabetes in large population‐based longitudinal studies. We aimed to evaluate the risk of incident diabetes in individuals with and without PHPT and investigate the association between serum calcium concentrations and the risk of incident diabetes in patients with PHPT. Methods: We included 2749 PHPT patients and 13,745 age, sex and index year matched non‐PHPT individuals during 2000–2019. We used Cox regression models to compare the risk of incident diabetes in individuals with and without PHPT, and the risk of incident diabetes in PHPT patients with serum calcium concentration above and below the median value. The association between serum calcium concentrations and the risk of incident diabetes was examined by restricted cubic spline analyses in patients with PHPT. Results: During a median follow‐up time of 5.17 years (IQR 2.17, 9.58), 433 patients (15.75%) with PHPT and 2110 individuals (15.35%) without PHPT developed diabetes, respectively. Patients with PHPT had a higher incidence rate of diabetes compared to non‐PHPT individuals (27.60 [95% CI 25.00, 30.30] vs. 23.90 [95% CI 22.80, 24.90] per 1000 person‐years, log‐rank test p = .007]. Crude Cox regression model showed PHPT was associated with a 15% higher risk of incident diabetes (HR 1.15, 95%CI 1.04, 1.28). In patients with PHPT, a 44% higher risk of incident diabetes was found in patients with serum calcium concentrations above the median value (2.63 mmol/L), compared to those below the median value (HR 1.44, 95%CI 1.08, 1.90). Restricted cubic spline analyses confirmed a positive linear association between serum calcium concentrations and the risk of incident diabetes in those with PHPT ( p ‐value for nonlinear = .751) Conclusions: Patients with PHPT had a higher risk of incident diabetes compared to non‐PHPT individuals. A positive linear association was found between serum calcium concentrations and the risk of incident diabetes in patients with PHPT.

Ronald Ma and co-authors discuss Emma Norrman and colleagues’ accompanying research study on the health of children born with assisted reproductive technology.