Epidemic-specific association of maternal exposure to per- and polyfluoroalkyl substances (PFAS) and their components with maternal glucose metabolism: A cross-sectional analysis in a birth cohort from Hong Kong.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased risk of gestational diabetes mellitus (GDM) and may affect glucose metabolisms during pregnancy. We examined the associations between maternal PFAS exposure and maternal glucose metabolisms and GDM risk among 1601 mothers who joined the Hyperglycaemia-and-Adverse-Pregnancy-Outcome (HAPO) Study in Hong Kong in 2001-2006. All mothers underwent a 75 g-oral-glucose-tolerance test at 24-32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance liquid-chromatography-coupled-with-tandem-mass-spectrometry (LC-MS-MS). We fitted conventional and advanced models (quantile-g-computation [qgcomp] and Bayesian-kernel machine regression [BKMR]) to assess the associations of individual and a mixture of PFAS with glycaemic traits. Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic periods in Hong Kong between March 2003 and May 2004. PFOS and PFOA were the main components of PFAS mixture among 1601 pregnant women in the Hong Kong HAPO study, with significantly higher median PFOS concentrations (19.09 ng/mL), compared to Chinese pregnant women (9.40 ng/mL) and US women (5.27 ng/mL). Maternal exposure to PFAS mixture was associated with higher HbA1c in the qgcomp (ß = 0.04, 95 % CI: 0.01-0.06) model. We did not observe significant associations of PFAS mixture with fasting plasma glucose (PG), 1-h and 2-h PG in either model, except for 2-h PG in the qgcmop model (ß = 0.074, 95 % CI: 0.01-0.15). PFOS was the primary contributor to the overall positive effects on HbA1c. Epidemic-specific analyses showed specific associations between PFAS exposure and the odds of GDM in the pre-SARS epidemic period. The median concentration of PFOS was highest during the peri-SARS epidemic (21.2 [14.5-43.6] ng/mL) compared with the pre-SARS (12.3 [9.2-19.9] ng/mL) and post-SARS (20.3 [14.2-46.3] ng/mL) epidemic periods. Potential interactions and exposure-response relationships between PFOA and PFNA with elevated HbA1c were observed in the peri-SARS period in BKMR model. Maternal exposure to PFAS mixture was associated with altered glucose metabolism during pregnancy. SARS epidemic-specific associations call for further studies on its long-term adverse health effects, especially potential modified associations by lifestyle changes during the COVID-19 pandemic.

Use of fasting plasma glucose to determine the approach for diagnosing gestational diabetes mellitus.

AIMS: Estimate the impact of OGTTs only on women with a screening FPG of 4.5-5.0 mmol/L using data from HAPO. METHODS: HAPO participants had 75-g OGTTs (24-32 weeks' gestation). At follow-up, children had adiposity assessed (overweight/obesity, obesity) and mothers and children had OGTTs. GDM was defined retrospectively using IADPSG criteria. Odds for neonatal (birthweight, percent neonatal fat, sum of skinfolds, cord C-peptide > 90th percentiles) and follow-up outcomes were assessed in those with HAPO FPG ≤ 4.4 or > 4.4 mmol/L and GDM or no GDM focusing on women with FPG > 4.4 and no GDM (Group 3) vs women with GDM and FPG ≤ 4.4 (Group 2). RESULTS: This strategy would miss a diagnosis of GDM in 14.7%. Odds for neonatal outcomes in Groups 2 and 3 were not different (ORs: 1.14 to 1.29). Odds at follow-up for type 2 diabetes and disorders of glucose metabolism in mothers were higher in Group 2 (ORs: 3.51, 2.57). Odds for childhood impaired glucose tolerance or adiposity outcomes were not different for Groups 2 and 3. CONCLUSIONS: HAPO mothers whose GDM diagnosis would be missed were not at greater risk for adverse neonatal and childhood outcomes than mothers with FPG of 4.5-5.0 without GDM.

Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for laboratory analysis in patients with diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments in the full version of the guideline). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the patients measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring; genetic testing; and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Executive Summary: Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. An expert committee compiled evidence-based recommendations for laboratory analysis in patients with diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments in the full version of the guideline). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the patients measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring; genetic testing; and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association for Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (HbA1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of HbA1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus.

BACKGROUND: Numerous laboratory tests are used in the diagnosis and management of diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. APPROACH: An expert committee compiled evidence-based recommendations for laboratory analysis in screening, diagnosis, or monitoring of diabetes. The overall quality of the evidence and the strength of the recommendations were evaluated. The draft consensus recommendations were evaluated by invited reviewers and presented for public comment. Suggestions were incorporated as deemed appropriate by the authors (see Acknowledgments). The guidelines were reviewed by the Evidence Based Laboratory Medicine Committee and the Board of Directors of the American Association of Clinical Chemistry and by the Professional Practice Committee of the American Diabetes Association. CONTENT: Diabetes can be diagnosed by demonstrating increased concentrations of glucose in venous plasma or increased hemoglobin A1c (Hb A1c) in the blood. Glycemic control is monitored by the people with diabetes measuring their own blood glucose with meters and/or with continuous interstitial glucose monitoring (CGM) devices and also by laboratory analysis of Hb A1c. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of ketones, autoantibodies, urine albumin, insulin, proinsulin, and C-peptide are addressed. SUMMARY: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are found to have minimal clinical value at the present time, and measurement of them is not recommended.

Urinary metal profiles in mother-offspring pairs and their association with early dysglycemia in the International Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study (HAPO-FUS).

BACKGROUND: Variations in dietary intake and environmental exposure patterns of essential and non-essential trace metals influence many aspects of human health throughout the life span. OBJECTIVE: To examine the relationship between urine profiles of essential and non-essential metals in mother-offspring pairs and their association with early dysglycemia. METHODS: Herein, we report findings from an ancillary study to the international Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study (HAPO-FUS) that examined urinary essential and non-essential metal profiles from mothers and offspring ages 10-14 years (1012 mothers, 1013 offspring, 968 matched pairs) from 10 international sites. RESULTS: Our analysis demonstrated a diverse exposure pattern across participating sites. In multiple regression modelling, a positive association between markers of early dysglycemia and urinary zinc was found in both mothers and offspring after adjustment for common risk factors for diabetes. The analysis showed weaker, positive, and negative associations of the 2-h glucose value with urinary selenium and arsenic respectively. A positive association between 2-h glucose values and cadmium was found only in mothers in the fully adjusted model when participants with established diabetes were excluded. There was a high degree of concordance between mother and offspring urinary metal profiles. Mother-to-offspring urinary metal ratios were unique for each metal, providing insights into changes in their homeostasis across the lifespan. SIGNIFICANCE: Urinary levels of essential and non-essential metals are closely correlated between mothers and their offspring in an international cohort. Urinary levels of zinc, selenium, arsenic, and cadmium showed varying degrees of association with early dysglycemia in a comparatively healthy cohort with a low rate of preexisting diabetes. IMPACT STATEMENT: Our data provides novel evidence for a strong correlation between mother and offspring urinary metal patterns with a unique mother-to-offspring ratio for each metal. The study also provides new evidence for a strong positive association between early dysglycemia and urinary zinc, both in mothers and offspring. Weaker positive associations with urinary selenium and cadmium and negative associations with arsenic were also found. The low rate of preexisting diabetes in this population provides the unique advantage of minimizing the confounding effect of preexisting, diabetes related renal changes that would alter the relationship between dysglycemia and renal metal excretion.

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.

BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life. METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction. RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (ß=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels. CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

Vitamin D Levels During Pregnancy Are Associated With Offspring Telomere Length: A Longitudinal Mother-Child Study.

CONTEXT: Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes. OBJECTIVE: This study investigates the relationship between vitamin D levels and offspring LTL at early life. METHODS: This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ±â€…0.44 (mean ±â€…SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry. RESULTS: LTL at follow-up was significantly shorter in boys compared with girls (P < 0.001) at age 7. Childhood LTL was negatively associated with childhood BMI (ß ±â€…SE = -0.016 ±â€…0.007)(P = 0.02) and HOMA-IR (ß ±â€…SE = -0.065 ±â€…0.021)(P = 0.002). Multiple linear regression was used to evaluate the relationship between 25(OH)D and LTL, with covariate adjustments. Childhood LTL was positively correlated with total maternal 25(OH)D (0.048 ±â€…0.017) (P = 0.004) and maternal 3-epi-25(OH)D3 (0.05 ±â€…0.017) (P = 0.003), even after adjustment for covariates. A similar association was also noted for cord 3-epi-25(OH)D3 (0.037 ±â€…0.018) (P = 0.035) after adjustment for offspring sex and age. CONCLUSION: Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.

Associations of glycemia and lipid levels in pregnancy with dyslipidemia 10-14 years later: The HAPO follow-up study.

AIMS: To examine associations of pregnancy glycemia with future dyslipidemia. METHODS: We analyzed data from Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study participants. We examined associations of gestational diabetes (GDM), sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24-32 weeks' gestation with dyslipidemia 10-14 years postpartum. RESULTS: Among 4,693 women, 14.3% had GDM. At follow-up, mean (SD) age was 41.7 (5.7) years, 32.3% had total cholesterol (TC) ≥ 5.17, 27.2% had HDL cholesterol < 1.29, 22.4% had LDL cholesterol (LDL-C) ≥ 3.36, 10.9% had triglycerides ≥ 1.69 mmol/L, and 2.9% had type 2 diabetes. After covariate adjustment, pregnancy glycemic measures were associated with all follow-up dyslipidemias. After additional adjustment for pregnancy lipids, GDM remained associated with TC ≥ 5.17 mmol/L (odds ratio [95% CI], 1.63 [1.22-2.18]) and LDL-C ≥ 3.36 mmol/L (1.63 [1.20-2.22]), even in the absence of type 2 diabetes development (1.55 [1.15-2.10] and 1.56 [1.13-2.16], respectively). Continuous glycemic measures in pregnancy were significantly associated with all follow-up dyslipidemias, independent of pregnancy lipids and type 2 diabetes. CONCLUSIONS: Pregnancy glycemia was associated with dyslipidemia 10-14 years later, independent of pregnancy lipid levels and in the absence of type 2 diabetes development. Lipid screening after GDM deserves special consideration.

Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.

CONTEXT: Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic changes during pregnancy, beyond glucose levels, to identify women at high risk for progression to a disorder of glucose metabolism has been examined. OBJECTIVE: This work aims to identify circulating metabolites present at approximately 28 weeks' gestation associated with gestational diabetes mellitus (GDM) and development of a disorder of glucose metabolism 10 to 14 years later. METHODS: Conventional clinical and targeted metabolomics analyses were performed on fasting and 1-hour serum samples following a 75-g glucose load at approximately 28 weeks' gestation from 2290 women who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Postpartum metabolic traits included fasting and 2-hour plasma glucose following a 75-g glucose load, insulin resistance estimated by the homeostasis model assessment of insulin resistance, and disorders of glucose metabolism (prediabetes and type 2 diabetes) during the HAPO Follow-Up Study. RESULTS: Per-metabolite analyses identified numerous metabolites, ranging from amino acids and carbohydrates to fatty acids and lipids, before and 1-hour after a glucose load that were associated with GDM as well as development of a disorder of glucose metabolism and metabolic traits 10 to 14 years post partum. A core group of fasting and 1-hour metabolites mediated, in part, the relationship between GDM and postpartum disorders of glucose metabolism, with the fasting and 1-hour metabolites accounting for 15.7% (7.1%-30.8%) and 35.4% (14.3%-101.0%) of the total effect size, respectively. For prediction of a postpartum disorder of glucose metabolism, the addition of circulating fasting or 1-hour metabolites at approximately 28 weeks' gestation showed little improvement in prediction performance compared to clinical factors alone. CONCLUSION: The results demonstrate an association of multiple metabolites with GDM and postpartum metabolic traits and begin to define the underlying pathophysiology of the transition from GDM to a postpartum disorder of glucose metabolism.

One-step or 2-step testing for gestational diabetes: which is better?

In the United States, the common approach to detecting gestational diabetes mellitus is the 2-step protocol recommended by the American College of Obstetricians and Gynecologists. A 50 g, 1-hour glucose challenge at 24 to 28 weeks' gestation is followed by a 100 g, 3-hour oral glucose tolerance test when a screening test threshold is exceeded. Notably, 2 or more elevated values diagnose gestational diabetes mellitus. The 2-step screening test is administered without regard to the time of the last meal, providing convenience by eliminating the requirement for fasting. However, depending upon the cutoff used and population risk factors, approximately 15% to 20% of screened women require the 100 g, 3-hour oral glucose tolerance test. The International Association of Diabetes and Pregnancy Study Groups recommends a protocol of no screening test but rather a diagnostic 75 g, 2-hour oral glucose tolerance test. One or more values above threshold diagnose gestational diabetes mellitus. The 1-step approach requires that women be fasting for the test but does not require a second visit and lasts 2 hours rather than 3. Primarily because of needing only a single elevated value, the 1-step approach identifies 18% to 20% of pregnant women as having gestational diabetes mellitus, 2 to 3 times the rate with the 2-step procedure, but lower than the current United States prediabetes rate of 24% in reproductive aged women. The resources needed for the increase in gestational diabetes mellitus are parallel to the resources needed for the increased prediabetes and diabetes in the nonpregnant population. A recent randomized controlled trial sought to assess the relative population benefits of the above 2 approaches to gestational diabetes mellitus screening and diagnosis. The investigators concluded that there was no significant difference between the 2-step screening protocol and 1-step diagnostic testing protocol in their impact on population adverse short-term pregnancy outcomes. An accompanying editorial concluded that perinatal benefits of the 1-step approach to diagnosing gestational diabetes mellitus "appear to be insufficient to justify the associated patient and healthcare costs of broadening the diagnosis." We raise several concerns about this conclusion. The investigators posited that a 20% improvement in adverse outcomes among the entire pregnancy cohort would be necessary to demonstrate an advantage to the 1-step approach and estimated the sample size based on that presumption, which we believe to be unlikely given the number of cases that would be identified. In addition, 27% of the women randomized to the 1-step protocol underwent 2-step testing; 6% of the study cohort had no testing at all. A subset of women assigned to 2-step testing did not meet the criteria for gestational diabetes mellitus but were treated as such because of elevated fasting plasma glucose levels, presumably contributing to the reduction in adverse outcomes but not to the number of gestational diabetes mellitus identified, increasing the apparent efficacy of the 2-step approach. No consideration was given to long-term benefits for mothers and offspring. All these factors may have contributed to obscuring the benefits of 1-step testing; most importantly, the study was not powered to identify what we understand to be the likely impact of 1-step testing on population health.

Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity.

OBJECTIVE: Excessive childhood adiposity is a risk factor for adverse metabolic health. The objective was to investigate associations of newborn body composition and cord C-peptide with childhood anthropometrics and explore whether these newborn measures mediate associations of maternal midpregnancy glucose and BMI with childhood adiposity. RESEARCH DESIGN AND METHODS: Data on mother/offspring pairs (N = 4,832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow-up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. RESULTS: In models including maternal glucose and BMI adjustments, newborn adiposity as measured by the sum of skinfolds was associated with child outcomes (adjusted mean difference, 95% CI, P value) BMI (0.26, 0.12-0.39, <0.001), BMI z-score (0.072, 0.033-0.11, <0.001), fat mass (kg) (0.51, 0.26-0.76, <0.001), percentage of body fat (0.61, 0.27-0.95, <0.001), and sum of skinfolds (mm) (1.14, 0.43-1.86, 0.0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2.5% and 1%, respectively), fat mass (3.1%, 1.2%), percentage of body fat (3.6%, 1.8%), and sum of skinfolds (2.9%, 1.8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22.0% and 21.0%, respectively), percentage of body fat (15.0%, 18.0%), and sum of skinfolds (15.0%, 20.0%). CONCLUSIONS: Newborn adiposity is independently associated with childhood adiposity and, along with fetal hyperinsulinemia, mediates, in part, associations of maternal glucose and BMI with childhood adiposity.

Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

AIMS/HYPOTHESIS: We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity. METHODS: Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study. RESULTS: In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30 min and 1 h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30 min, 1 h and 2 h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (ß = 1.388; 95% CI 0.870, 1.906; p < 0.001; ß = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (ß = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (ß = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. CONCLUSIONS/INTERPRETATION: This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.

Metabolomic and genetic associations with insulin resistance in pregnancy.

AIMS/HYPOTHESIS: Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS: Fasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at ∼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load. RESULTS: Per-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (ß = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect. CONCLUSIONS/INTERPRETATION: The present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.

The Joint Associations of Maternal BMI and Glycemia with Childhood Adiposity.

CONTEXT: An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to account for potential confounders. OBJECTIVE: Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring. DESIGN AND SETTING: International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively. PARTICIPANTS AND MAIN OUTCOME MEASURES: In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years. RESULTS: Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR [95% confidence interval; CI], GDM OR [95% CI]; combined OR [95% CI]) of childhood overweight/obese BMI (3.00 [2.42-3.74], 1.39 [1.14-1.71], 3.55 [2.49-5.05]), obese BMI (3.54 [2.70-4.64], 1.73 [1.29-2.30], 6.10 [4.14-8.99]), percent body fat >85th percentile (2.15 [1.68-2.75], 1.33 [1.03-1.72], 3.88 [2.72-5.55]), sum of skinfolds >85th percentile (2.35 [1.83-3.00], 1.75 [1.37-2.24], 3.66 [2.55-5.27]), and waist circumference >85th percentile (2.52 [1.99-3.21], 1.39 [1.07-1.80], 4.18 [2.93-5.96]). CONCLUSIONS: Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity.

Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.

CONTEXT: Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE: To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns. DESIGN: Cross-sectional, observational study. SETTING: Hyperglycemia and Adverse Pregnancy Outcome study. PARTICIPANTS: One thousand six hundred multiethnic mother-newborn pairs. MAIN OUTCOME MEASURE: Cord blood C-peptide, birthweight, and newborn sum of skinfolds. RESULTS: Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes. CONCLUSIONS: Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.