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OBJECTIVE The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth. RESEARCH DESIGN AND METHODS We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity. RESULTS Higher weighted GRS was associated with lower oral disposition index (β = −0.11; 95% CI −0.19, −0.02) and insulinogenic index (β = −0.08; 95% CI −0.17, −0.001), but not with fasting glucose (β = 0.01; 95% CI −0.01, 0.02), 2-h glucose (β = 0.03; 95% CI −0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI −0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels. CONCLUSIONS Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.

The limitations of self-report measures of dietary intake are well-known. Novel, technology-based measures of dietary intake may provide a more accurate, less burdensome alternative to existing tools. The first objective of this study was to compare participant burden for two technology-based measures of dietary intake among school-age children: the Automated-Self-Administered 24-hour Dietary Assessment Tool-2018 (ASA24-2018) and the Remote Food Photography Method (RFPM). The second objective was to compare reported energy intake for each method to the Estimated Energy Requirement for each child, as a benchmark for actual intake. Forty parent–child dyads participated in two, 3-d dietary assessments: a parent proxy-reported version of the ASA24 and the RFPM. A parent survey was subsequently administered to compare satisfaction, ease of use and burden with each method. A linear mixed model examined differences in total daily energy intake between assessments, and between each assessment method and the Estimated Energy Requirement (EER). Reported energy intake was 379 kcal higher with the ASA24 than the RFPM (P = 0·0002). Reported energy intake with the ASA24 was 231 kcal higher than the EER (P = 0·008). Reported energy intake with the RFPM did not differ significantly from the EER (difference in predicted means = −148 kcal, P = 0·09). Median satisfaction and ease of use scores were five out of six for both methods. A higher proportion of parents reported that the ASA24 was more time-consuming than the RFPM (74·4 % v. 25·6 %, P = 0·002). Utilisation of both methods is warranted given their high satisfaction among parents.

Objectives: Epigenetic age acceleration (EAA) occurs when DNA methylation-predicted age is older than chronological age. EAA is associated with glucose intolerance in adults. In-utero exposure to gestational diabetes (GDM) is associated with glucose intolerance in offspring. It is not known if GDM predicts EAA in offspring or if offspring EAA is associated with insulin sensitivity and secretion. Methods: We examined the association between exposure to GDM in-utero and EAA, computed at average age 10.5 years, and EAA and measures of insulin sensitivity (HOMA-2S) and secretion (HOMA-2β) at average age 10.5 and 16.7 years in 209 girls and 209 boys in the Colorado EPOCH (Exploring Perinatal Outcomes Among Children) cohort. We calculated EAA using the Horvath, Hannum, and Levine calculators. Separate general linear mixed models adjusted associations for chronologic age and sex. Results: Exposure to GDM was associated with EAA using the Hannum (beta-coefficient 1.39, p=0.009) and Levine (1.92, p=0.024) but not the Horvath calculator (-0.01, p=0.69). EAA by the Hannum calculator predicted lower insulin sensitivity and higher insulin secretion (Table). Conclusions: We conclude that GDM predicts offspring EAA, and EAA is associated with decreased insulin sensitivity and increased insulin secretion. Associations are dependent upon the EAA calculator used. Disclosure C. Kim: None. K. K. Harrall: None. D. H. Glueck: None. B. Needham: None. D. Dabelea: None. Funding National Institutes of Health (R01DK076648, R01GM121081, R01DK068001307, M01RR00069, 5UG3OD023248)

AIMS/HYPOTHESIS: We previously showed that intrauterine exposure to gestational diabetes mellitus (GDM) increases selected markers of adiposity in pre-pubertal adolescents. In the present study, we examined these associations in adolescence, and explored whether they are strengthened as the participants transition through puberty. METHODS: Data from 597 individuals (505 unexposed, 92 exposed) participating in the longitudinal Exploring Perinatal Outcomes among Children (EPOCH) study in Colorado were collected at two research visits when the participants were, on average, 10.4 and 16.7 years old. Adiposity measures included BMI, waist/height ratio, and visceral and subcutaneous adipose tissue (as determined by MRI). Separate general linear mixed models were used to assess the longitudinal relationships between exposure to maternal GDM and each adiposity outcome. We tested whether the effect changed over time by including an interaction term between exposure and age in our models, and whether the associations were explained by postnatal behaviours. RESULTS: Compared with unexposed participants, those exposed to maternal GDM had higher BMI (β = 1.28; 95% CI 0.35, 2.21; p < 0.007), waist/height ratio (β = 0.03; 95% CI 0.01, 0.04; p = 0.0004), visceral adipose tissue (β = 4.81; 95% CI 1.08, 8.54; p = 0.01) and subcutaneous adipose tissue (β = 35.15; 95% CI 12.43, 57.87; p < 0.003). The magnitude of these differences did not change over time and the associations did not appear to be explained by postnatal behaviours. CONCLUSIONS/INTERPRETATION: Our data provide further evidence that intrauterine exposure to maternal GDM is associated with increased offspring adiposity, an effect that appears early in life and tracks throughout adolescence. Efforts to prevent childhood obesity following intrauterine exposure to maternal GDM should target the prenatal or early life periods.

OBJECTIVE: It is unclear how childhood adipose tissue deposition influences sex hormone profiles in later adolescence. DESIGN: Prospective cohort study PARTICIPANTS: Children (n=418) with a mean age of 10.5 (1.5) years at visit 1 and 16.7 (1.2) at visit 2 in the Exploring Perinatal Outcomes among Children (EPOCH) Study. MEASUREMENTS: We used reverse-scale Cox proportional hazard models to assess associations between pubertal dehydroepiandrosterone (DHEA), testosterone (T), and estradiol (E2) and childhood-to-puberty rate of change in visceral (VAT) and subcutaneous adipose tissue (SAT). Models stratified by sex and adjusted for childhood adiposity, maternal factors, birthweight, and pubertal onset, and then further adjusted for insulin, luteinizing hormone (LH), leptin and hepatic fat fraction. RESULTS: Among boys, more rapid accumulation of either VAT or SAT was associated with lower testosterone at visit 2 (HR 0.86, and 0.96, respectively, both p

Objective Adiposity, particularly visceral adipose tissue (VAT), predicts adverse cardiovascular risk factor profiles in children as well as adults. Although endogenous sex steroids likely influence VAT in adults, such an association has not been established in youth. The association between childhood and adolescent sex steroids with adiposity, specifically VAT, was examined before and after adjustment for other hormone changes. Methods These analyses examined longitudinal associations between sex steroids (testosterone, estradiol, dehydroepiandrosterone [DHEA]) and magnetic resonance imaging assessments of VAT in 418 children, 49% of whom were non‐White, at approximately 10 years old at Visit 1 (V1) and 17 years old at Visit 2 (V2). Linear mixed effects models adjusted for maternal education, household income, child caloric intake, physical activity, fasting insulin and leptin, and hepatic fat fraction. Differences in associations by race and pubertal stage were also assessed. Results At V1, mean body mass index (BMI) for boys was 19.1 (4.7) kg/m2 and for girls was 18.5 (4.1) kg/m2. At V2, mean BMI for boys was 23.7 (5.5) kg/m2 and for girls was 23.6 (5.7) kg/m2. For each ng/dl (0.035 nmol/L) increase in testosterone at V1, there was a 0.25 cm2 increase in concurrent and future VAT in non‐White (p = 0.04) but not White girls (p = 0.78). Higher levels of testosterone and DHEA at V1 were associated with greater concurrent and future VAT at V2. These associations were consistent regardless of pubertal stage. In boys, higher testosterone predicted higher future VAT but lower concurrent VAT. Estradiol and DHEA did not predict future VAT in boys. In girls, DHEA predicted future subcutaneous adipose tissue (SAT), and no sex steroids predicted future SAT in boys. Conclusions Testosterone levels predict VAT in boys and girls, and DHEA predicts VAT in girls, even after adjustment for other hormone changes.

OBJECTIVES: To explore the longitudinal association of neonatal adiposity (fat mass percentage) with BMI trajectories and childhood overweight and obesity from ages 2 to 6 years. METHODS: We studied 979 children from the Healthy Start cohort. Air displacement plethysmography was used to estimate fat mass percentage. Child weight and recumbent length or standing height were abstracted from medical records. Overweight and obesity were defined as BMI levels ≥85th percentile for age and sex. Mixed-effects models were used to examine the association between neonatal fat mass percentage and BMI trajectories from age 2 to 6 years. We tested for effect modification by sex, race and/or ethnicity, and breastfeeding duration. We estimated the proportion of children classified as overweight or obese at specific levels of neonatal fat mass percentage (mean ± SD). RESULTS: The mean neonatal adiposity level was 9.1% ± 4.0%. Child BMI levels differed by neonatal adiposity. Each SD increase in neonatal adiposity resulted in a 0.12 higher overall BMI level between ages 2 to 6 years (95% confidence interval: 0.03 to 0.20; P < .01), and this association was not modified by offspring sex, race and/or ethnicity, or breastfeeding duration. Increasing neonatal adiposity was associated with an increasing proportion of childhood overweight and obesity by age 5 years (P = .02). CONCLUSIONS: We provide novel evidence that higher neonatal adiposity is significantly associated with higher overall BMI levels and an increased likelihood of overweight or obesity from ages 2 to 6 years. Because various prenatal exposures may specifically influence offspring fat accretion, neonatal adiposity may be a useful surrogate end point for prenatal interventions aimed at reducing future childhood overweight and obesity.

Among adults, higher T predicts lower VAT in men and higher VAT in women, and higher E2 predicts greater SAT in women. The degree to which the association between adiposity and sex steroids is bidirectional is controversial. Using data from a cohort of adolescents, we examined whether sex steroid levels in early puberty influenced VAT and SAT deposition in adolescents. EPOCH participants (n=418, 209 girls and 209 boys) underwent sex steroid measures at visit 1 (mean age 10 years) and magnetic resonance imaging (MRI) assessments of VAT and SAT at visit 1 and visit 2 (mean age 17 years). Using mixed models, we examined whether T and E2 at visit 1 were associated with overall VAT and SAT levels from visit 1 to visit 2. Models adjusted for maternal education and income as well as children’s race, pubertal status, caloric intake, physical activity levels, insulin, leptin, and MRI-measured hepatic fat fraction. Among girls, each unit increase in T was associated with a higher overall VAT (0.16, 95% confidence interval [CI] 0.04, 0.28) and SAT (0.33, 95% CI 0.33, 1.52) levels. Each unit increase in E2 was associated with overall higher SAT (0.56, 95% CI 0.28, 0.83) levels. Among boys, undetectable T was associated with higher VAT (5.12, 95% CI 1.90, 8.36) and lower SAT (-18.85, 95% CI -36.23, -1.46) levels. We conclude that endogenous T and E2 during the pubertal transition significantly influence adolescent adipose tissue deposition in both boys and girls. Future investigations should examine how the use of exogenous sex hormones impacts adipose tissue deposition during this critical period. Additional follow-up is needed to determine how adolescent fat deposition impacts subsequent glucose tolerance in early adulthood. Disclosure C. Kim: Research Support; Spouse/Partner; Apple. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None. Funding National Institutes of Health (R01DK068001)

Aim: We explored the feasibility of collecting and analyzing human microbiome data in a longitudinal randomized controlled trial of community gardening. Methods & materials: Participants were randomly assigned to gardening (N = 8) or control (N = 8). Participants provided stool, mouth, hand and forehead microbiome samples at six timepoints. Analyses combined mixed models with Qiita output. Results: Participant satisfaction was high, with 75% of participants completing evaluations. While no microbial effects were statistically significant due to small sample size, the analysis pipeline utility was tested. Conclusion: Longitudinal collection and analysis of microbiome data in a community gardening randomized controlled trial is feasible. The analysis pipeline will be useful in larger studies for assessment of the pathway between microbiota, gardening and health outcomes. This study was funded by the University of Colorado Boulder Population Center (CUPC, J Litt, PI), through the National Institute of Child Health & Human Development of the NIH under award number P2CHD066613-06 and the Center for Microbiome Innovation at the University of California San Diego. We also received supplemental funding through the Clinical & Translational Research Center (CTRC) to cover all laboratory costs (J Litt, PI). M Gascon received a fellowship from the Societat Econòmica Barcelonesa d'Amics del País (SEBAP) in 2018, Barcelona (Catalonia), for her research stay at the University of Colorado to conduct the statistical analysis for this work. DH Glueck was supported, in part, by R01GM121-81 and R25 GM111901

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10–20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.

Whether changes in visceral adipose tissue (VAT) in childhood predict adolescent androgens is not known. We examined the longitudinal relationship between MRI-assessed visceral adipose tissue (VAT) in childhood and future testosterone (T) among 418 EPOCH participants (209 girls and 209 boys) who were, on average 10.5 years at visit 1 and 16.7 years at visit 2. We used reverse Cox proportional hazards models in which hazard ratios less than 1 indicate greater risk for low (undetectable) sex hormones consistent with pre-puberty. Models explored the associations of baseline VAT, and change in VAT from visit 1 to visit 2, with risk of low sex hormone levels at visit 2, adjusted for covariates selected through backwards regression (race, self-reported Tanner stage, maternal income, insulin and leptin levels). All analyses were stratified by sex. In addition, due to different patterns of fat deposition in white and non-white adults, we tested for effect modification by race. In boys, the association between VAT at visit 1 and T at visit 2 differed by race; more VAT at visit 1 was associated with lower risk of low T at visit 2 among non-white boys (HR 1.02, 95% CI 1.007, 1.04) but not white boys (HR 1.00, 95% CI 0.98, 1.01). In contrast, greater fat accumulation between visits was associated with higher risk of low T at visit 2 (HR 0.90, 95% CI 0.83, 0.96), independent of race and other covariates. Among girls, neither baseline VAT levels, nor VAT accumulation between visits predicted risk of later low T concentrations. We conclude that greater VAT accumulation in childhood is associated with increased risk for low T levels, suggesting delayed puberty, in boys. These associations suggest that fat deposition may influence sex hormone profiles even in early childhood. Disclosure C. Kim: None. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None. Funding National Institutes of Health

BACKGROUND: Intrauterine exposure to gestational diabetes (GDM) is associated with increased adiposity; however, not all offspring exposed to GDM exhibit excess adiposity. OBJECTIVES: Examine whether optimal diet and activity behaviors in infancy, childhood, and adolescence modify the association between GDM exposure and adiposity. METHODS: In 564 offspring (84 exposed to GDM), we assessed breastfeeding (maternal recall), dietary intake (food frequency questionnaire), physical activity (3-day recall) and adiposity (BMI, waist-to-height ratio, visceral and subcutaneous adipose tissue, subscapular-to-triceps skinfold ratio) at 10.4 (SD 1.5) and 16.7 (SD 1.2) years. Optimal behaviors were defined as ≥6 breastmilk months, Healthy Eating Index score ≥60, and daily vigorous activity >1 hour. Linear mixed models assessed the association between GDM exposure and adiposity among those with optimal versus suboptimal health behaviors, adjusting for sex, race/ethnicity, age, and pubertal status. RESULTS: GDM exposure was associated with increased skinfold ratio, visceral and subcutaneous adipose tissue among those with 0.10). GDM exposure was associated with increased BMI and subcutaneous adipose tissue among those with >1 hour vigorous activity (p0.30). CONCLUSIONS: The association of GDM exposure with excess adiposity is attenuated in offspring with more optimal diet and activity behaviors in infancy, childhood, and adolescence.

Background People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. Methods Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m2) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m2) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. Results Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E’ (P P = 0.92), or VO2peak (P = 0.33) in any participants. Conclusion Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets. Trial registration NCT00786019. Prospectively registered May 2008

Objectives: Studies suggest that rheumatoid arthritis (RA)-related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at-risk for future RA. Therefore, we tested anti-cyclic citrullinated peptide (anti-CCP) antibodies in the sputum of RA-free first-degree relatives (FDRs) of RA patients and patients with classifiable RA. Methods: We evaluated induced sputum and serum from 67 FDRs and 20 RA subjects for anti-CCP-IgA and anti-CCP-IgG, with cut-off levels for positivity determined in a control population. Sputum was also evaluated for cell counts, neutrophil extracellular traps (NETs) using sandwich ELISAs for protein/nucleic acid complexes, and total citrulline. Results: Sputum anti-CCP-IgA and/or anti-CCP-IgG was positive in 17/67 (25%) FDRs and 14/20 (70%) RA subjects, including a portion of FDRs who were serum anti-CCP negative. In FDRs, elevations of sputum anti-CCP-IgA and anti-CCP-IgG were associated with elevated sputum cell counts and levels of NET complexes. Anti-CCP-IgA was associated with ever-smoking and elevated sputum citrulline levels. Conclusions: Anti-CCP is elevated in the sputum of FDRs, including seronegative FDRs, suggesting the lung may be one site of anti-CCP generation in this population. The association of anti-CCP with elevated cell counts and NET levels in FDRs supports a hypothesis that local airway inflammation and NET formation may drive anti-CCP production in the lung and may promote the early stages of RA development. Longitudinal studies are needed to follow the evolution of these processes relative to the development of systemic autoimmunity and articular RA. This article is protected by copyright. All rights reserved.

Background: Hispanic women have lower breast cancer incidence rates than non-Hispanic white (NHW) women. To what extent genetic versus nongenetic factors account for this difference is unknown. Methods: Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2,326 Hispanic and 1,854 NHW postmenopausal women from the United States and Mexico in the Breast Cancer Health Disparities Study. Results: The inverse association between the percentage of Native American (NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio (OR) =1.39, 95% confidence interval (CI) = 1.00–1.92 among U.S. Hispanics; OR = 1.92 (95% CI, 1.29–2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher body mass index (BMI) was associated with reduced risk among women with lower NA ancestry only [BMI 30: OR = 0.65 (95% CI, 0.44–0.98) among U.S. Hispanics; OR = 0.53 (95% CI, 0.29–0.97) among Mexicans]. The average number of risk factors among cases was inversely related to the percentage of NA ancestry. Conclusions: The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. Although the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry. Impact: These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry. Cancer Epidemiol Biomarkers Prev; 26(5); 692–701. ©2016 AACR.