(Abstracted from Lancet 2024;404:175–192) The International Association of Diabetes and Pregnancy Study Groups (IADPSG) estimates the prevalence of gestational diabetes mellitus (GDM) to be 14% worldwide. Of those with GDM, 30% to 70% have early GDM, which is diagnosed before 20 weeks of gestation.
OBJECTIVE Subtypes of gestational diabetes mellitus (GDM) based on insulin sensitivity and secretion have been described. We addressed the hypothesis that GDM subtypes are differentially associated with newborn and child anthropometric and glycemic outcomes. RESEARCH DESIGN AND METHODS Newborn and child (age 11–14 years) outcomes were examined in 7,970 and 4,160 mother-offspring dyads, respectively, who participated in the Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) and Follow-Up Study. GDM was classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity), insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion), or mixed-defect GDM (both <25th percentile). Regression models for newborn and child outcomes included adjustment for field center, maternal BMI, and other pregnancy covariates. Child models also included adjustment for child age, sex, and family history of diabetes. RESULTS Compared with mothers with normal glucose tolerance, all three GDM subtypes were associated with birth weight and sum of skinfolds >90th percentile. Insulin-resistant and mixed-defect GDM were associated with higher risk of cord C-peptide levels >90th percentile. Insulin-resistant GDM was associated with higher risk of neonatal hypoglycemia. Insulin-resistant GDM was associated with higher risk of neonatal hypoglycemia and childhood obesity (odds ratio [OR] 1.53, 95% CI 1.127–2.08). The risk of child-impaired glucose tolerance was higher with insulin-resistant (OR 2.21, 95% CI 1.50–3.25) and mixed-defect GDM (OR 3.01, 95% CI 1.47–6.19). CONCLUSIONS GDM subtypes are differentially associated with newborn and childhood outcomes. Better characterizing individuals with GDM could help identify at-risk offspring to offer targeted, preventative interventions early in life.
Aims Our objective is to identify first-trimester plasmatic miRNAs associated with and predictive of GDM. Methods We quantified miRNA using next-generation sequencing in discovery (Gen3G: n = 443/GDM = 56) and replication (3D: n = 139/GDM = 76) cohorts. We have diagnosed GDM using a 75-g oral glucose tolerance test and the IADPSG criteria. We applied stepwise logistic regression analysis among replicated miRNAs to build prediction models. Results We identified 17 miRNAs associated with GDM development in both cohorts. The prediction performance of hsa-miR-517a-3p|hsa-miR-517b-3p, hsa-miR-218-5p, and hsa-let7a-3p was slightly better than GDM classic risk factors (age, BMI, familial history of type 2 diabetes, history of GDM or macrosomia, and HbA1c) (AUC 0.78 vs. 0.75). MiRNAs and GDM classic risk factors together further improved the prediction values [AUC 0.84 (95% CI 0.73–0.94)]. These results were replicated in 3D, although weaker predictive values were obtained. We suggest very low and higher risk GDM thresholds, which could be used to identify women who could do without a diagnostic test for GDM and women most likely to benefit from an early GDM prevention program. Conclusions In summary, three miRNAs combined with classic GDM risk factors provide excellent prediction values, potentially strong enough to improve early detection and prevention of GDM.
Additional file 1. Table S1: “Summary of the studies in the meta-analysis for the association between Season of Birth and DNA methylation at birth and in children (age: 1 to 11 years)”. Baseline summary of participants from each of the individual cohorts.
Background: Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity. Methods: We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715–859), waist circumference (cm) (N = 717–882), and body mass index (BMI) (z-score) (N = 716–875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511–599). We estimated associations using adjusted quantile g-computation and linear regression. Results: The nonessential metal mixture was associated with higher total (β = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (β = 0.12, CI = 0.02, 0.22), waist circumference (β = 0.01, CI = 0.00, 0.01), and BMI (β = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (β = 0.07, CI = 0.01, 0.14), and BMI (β = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(β = –0.11, CI = –0.17, –0.04) and trunk- fat mass index (β = –0.13, CI = –0.21, –0.05), subscapular+tricep skinfold thickness (β = –0.02, CI = –0.03, –0.00), waist circumference (β = –0.003, CI = –0.01, –0.00), and BMI (β = –0.16, CI = –0.28, –0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints. Conclusions: Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence.
The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child’s sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quantified placental mRNA levels for annotated gene using qRT-PCR and tested for correlation with DNAm. Lower DNAm at cg22593959 and cg22436429 was associated with higher adiposity (β = −1.18, q = 0.002 and β = −0.82, q = 0.04). The cg22593959 is located in an intergenic region (chr7q31.3), whereas cg22436429 is within the TFAP2E gene (1p34.3). DNAm at cg22593959 and cg22436429 was correlated with mRNA levels at FAM3C (rs = −0.279, p = 0.005) and TFAP2E (rs = 0.216, p = 0.03). In an independent cohort, the association between placental DNAm at cg22593959 and childhood adiposity was of similar strength and direction (β = −3.8 ± 4.1, p = 0.36), yet non-significant. Four genomic regions were also associated with skinfold thickness within FMN1, MAGI2, SKAP2 and BMPR1B genes. We identified placental epigenetic variations associated with adiposity at 3 years of age suggesting that childhood fat accretion patterns might be established during fetal life.
<p dir="ltr">Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, <i>P</i>=9.6 x 10<sup>-7</sup>; -8.45 uU/mg, <i>P</i>=5.6 x 10<sup>-6</sup>, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, <i>P</i>=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, <i>P</i>=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.</p>
