Youth-Onset Type 2 Diabetes: The Epidemiology of an Awakening Epidemic.

In this narrative review, we describe the epidemiology (prevalence, incidence, temporal trends, and projections) of type 2 diabetes among children and adolescents (<20 years), focusing on data from the U.S. and reporting global estimates where available. Secondarily, we discuss the clinical course of youth-onset type 2 diabetes, from prediabetes to complications and comorbidities, drawing comparisons with youth type 1 diabetes to highlight the aggressive course of this condition, which, only recently, has become recognized as a pediatric disease by health care providers. Finally, we end with an overview of emerging topics in type 2 diabetes research that have potential to inform strategies for effective preventive action at the community and individual levels.

Disparities in Hemoglobin A1c Testing During the Transition to Adulthood and Association With Diabetes Outcomes in Youth-Onset Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth Study.

OBJECTIVE: To identify correlates of hemoglobin A1c (HbA1c) testing frequency and associations with HbA1c levels and microvascular complications in youth-onset diabetes. RESEARCH DESIGN AND METHODS: The SEARCH for Diabetes in Youth study collected data from individuals diagnosed with diabetes before age 20 at 8 years (n=1,885 type 1, n=230 type 2) and 13 years (n=649 type 1, n = 84 type 2) diabetes duration. We identified correlates of reporting ≥3 HbA1c tests/year using logistic regression. We examined associations of HbA1c testing with HbA1c levels and microvascular complications (retinopathy, neuropathy, or nephropathy) using sequentially adjusted linear and logistic regression. RESULTS: For type 1 diabetes, odds of reporting ≥3 HbA1c tests/year at 8 and 13 years diabetes duration decreased with older age at diagnosis (odds ratio [OR] 0.91 [95% CI 0.88-0.95]), longer duration of diabetes (OR 0.90 [0.82-0.99]), not having a personal doctor (OR 0.44 [0.30-0.65]), and lapses in health insurance (OR 0.51 [0.27-0.96]). HbA1c testing ≥3 times/year over time was associated with lower HbA1c levels (OR -0.36% [-0.65 to -0.06]) and lower odds of microvascular complications (OR 0.64 [0.43-0.97]) at 13 years duration, but associations were attenuated after adjustment for HbA1c testing correlates (OR -0.17 [-0.46 to 0.13] and 0.70 [0.46-1.07], respectively). For type 2 diabetes, not seeing an endocrinologist decreased the odds of reporting ≥3 HbA1c tests/year over time (OR 0.19 [0.06-0.63]), but HbA1c testing frequency was not associated with HbA1c levels or microvascular complications. CONCLUSIONS: We observed disparities in HbA1c testing frequency predominately by health care-related factors, which were associated with diabetes outcomes in type 1 diabetes.

Genetic Risk Score for Type 2 Diabetes and Traits Related to Glucose-Insulin Homeostasis in Youth: The Exploring Perinatal Outcomes Among Children (EPOCH) Study.

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 (ß = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (ß = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (ß = 0.01; 95% CI -0.01, 0.02), 2-h glucose (ß = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (ß = 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.

Associations of Nutrient Intake Changes During Childhood with Adolescent Hepatic Fat: The Exploring Perinatal Outcomes Among CHildren Study.

OBJECTIVE: To examine associations of dietary changes from childhood to adolescence with adolescent hepatic fat and whether the PNPLA3 rs738409 risk allele, a strong genetic risk factor for hepatic fat, modifies associations. STUDY DESIGN: Data were from 358 participants in the Exploring Perinatal Outcomes among CHildren (EPOCH) study, a longitudinal cohort in Colorado. Diet was assessed by food frequency questionnaire in childhood (approximately 10 years of age) and adolescence (approximately 16 years of age) and converted to nutrient densities. Hepatic fat was assessed in adolescence by magnetic resonance imaging. Linear regression was used to test associations of dietary changes from childhood to adolescence with adolescent hepatic fat. RESULTS: Increases in fiber, vegetable protein, and polyunsaturated fat intake from childhood to adolescence were associated with lower adolescent hepatic fat, and increases in animal protein were associated with higher hepatic fat (ß per 5-unit increase on log-hepatic fat: -0.12 [95% CI, -0.21 to -0.02] for ▵fiber; -0.26 [95% CI, -0.45 to -0.07] for ▵vegetable protein; -0.18 [95% CI, -0.35 to -0.02] for ▵polyunsaturated fat; 0.13 [95% CI, 0.04-0.22] for ▵animal protein). There was evidence of effect modification by PNPLA3 variant, whereby inverse associations of ▵fiber and ▵vegetable protein and positive associations of ▵saturated fat with adolescent hepatic fat were stronger in risk allele carriers. Most conclusions were similar after adjusting for obesity in adolescence, but associations of ▵saturated fat with hepatic fat were attenuated toward the null. CONCLUSIONS: Our results suggest that nutrient intake changes between childhood and adolescence, particularly decreases in fiber and vegetable protein and increases in saturated fat intake, interact with the PNPLA3 variant to predict higher hepatic fat in adolescence, and may be targets for reducing hepatic fat in high-risk youth.

Cognitive Function in Adolescents and Young Adults With Youth-Onset Type 1 Versus Type 2 Diabetes: The SEARCH for Diabetes in Youth Study.

OBJECTIVE: Poor cognition has been observed in children and adolescents with youth-onset type 1 (T1D) and type 2 diabetes (T2D) compared with control subjects without diabetes. Differences in cognition between youth-onset T1D and T2D, however, are not known. Thus, using data from SEARCH for Diabetes in Youth, a multicenter, observational cohort study, we tested the association between diabetes type and cognitive function in adolescents and young adults with T1D (n = 1,095) or T2D (n = 285). RESEARCH DESIGN AND METHODS: Cognition was assessed via the National Institutes of Health Toolbox Cognition Battery, and age-corrected composite Fluid Cognition scores were used as the primary outcome. Confounder-adjusted linear regression models were run. Model 1 included diabetes type and clinical site. Model 2 additionally included sex, race/ethnicity, waist-to-height ratio, diabetes duration, depressive symptoms, glycemic control, any hypoglycemic episode in the past year, parental education, and household income. Model 3 additionally included the Picture Vocabulary score, a measure of receptive language and crystallized cognition. RESULTS: Having T2D was significantly associated with lower fluid cognitive scores before adjustment for confounders (model 1; P < 0.001). This association was attenuated to nonsignificance with the addition of a priori confounders (model 2; P = 0.06) and Picture Vocabulary scores (model 3; P = 0.49). Receptive language, waist-to-height ratio, and depressive symptoms remained significant in the final model (P < 0.01 for all, respectively). CONCLUSIONS: These data suggest that while youth with T2D have worse fluid cognition than youth with T1D, these differences are accounted for by differences in crystallized cognition (receptive language), central adiposity, and mental health. These potentially modifiable factors are also independently associated with fluid cognitive health, regardless of diabetes type. Future studies of cognitive health in people with youth-onset diabetes should focus on investigating these significant factors.

Pre- and Perinatal Correlates of Ideal Cardiovascular Health during Early Childhood: A Prospective Analysis in the Healthy Start Study.

OBJECTIVES: To characterize prevalence of ideal cardiovascular health (ICVH) during early childhood (4-7 years of age), and to identify pre- and perinatal biological, sociodemographic, metabolic, and behavioral correlates of ICVH. STUDY DESIGN: Among 350 mother-child pairs in the Healthy Start Study, we defined ICVH as no exposure to second hand smoke; ≥1 hour/day of moderate-to-vigorous physical activity; body mass index ≤85th percentile; systolic and diastolic blood pressure <90th percentile; cholesterol <170 mg/dL, fasting glucose <100 mg/dL; and healthy diet, per the American Heart Association. Pre- and perinatal characteristics were obtained from questionnaires, medical records, and in-person visits. Because of low prevalence of ICVH, we focused on prevalence of meeting ≥6 metrics in the analysis. We examined bivariate associations of each characteristic with % meeting ≥6 metrics and included those that were significant (P < .05) in a multivariable logistic regression model. RESULTS: ICVH prevalence at mean ± SD age 4.7±0.6 years was 6.9%; boys had twice the prevalence as girls (9% vs 4.4%). Most (>85%) children met criteria for second hand smoke, body mass index, blood pressure, cholesterol, and glucose, and only one-third met criteria for physical activity (31.4%) and diet (35.1%). In multivariable analyses, key correlates of ICVH were maternal weight status (ORoverweight/obese vs nonoverweight/obese = 0.41 [0.23, 0.73]) and offspring sex (ORmale vs female = 2.14 [1.22, 3.65]). CONCLUSIONS: At age 4-7 years, ICVH prevalence is already low, with diet and adequate physical activity being the limiting factors. Healthy maternal weight prior to pregnancy and male sex are potential determinants of childhood ICVH. Additional work is required to explore associations of early-life ICVH with future health outcomes.

Placental Insulin/IGF-1 Signaling, PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4-6 Years of Age: The ECHO Healthy Start Cohort.

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4-6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3ß phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator-activated receptor γ coactivator (PGC)-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

Genetic Risk for Hepatic Fat among an Ethnically Diverse Cohort of Youth: The Exploring Perinatal Outcomes among Children Study.

OBJECTIVE: To assess the importance of genetic and nongenetic risk factors contributing to hepatic fat accumulation in a multiethnic population of youth. STUDY DESIGN: We investigated the relationship between genetic factors and hepatic fat fraction (HFF) in 347 children aged 12.5-19.5 years. We examined 5 single nucleotide polymorphisms previously associated with HFF and a weighted genetic risk score (GRS) and examined how these associations varied with ethnicity (Hispanic vs non-Hispanic white) and body mass index (BMI) category. We also compared how much variation in HFF was explained by genetic factors vs cardiometabolic factors (BMI z-score and the Homeostasis Model of Insulin Resistance) or diet. RESULTS: PNPLA3 rs738409 and the GRS were each associated with HFF among Hispanic (ß = 0.39; 95% CI, 0.16-0.62; P = .001; and ß = 0.20; 95% CI, 0.05-0.34; P = .007, respectively) but not non-Hispanic white (ß = 0.04; 95% CI, -0.18 to 0.26; P = .696; and ß = 0.03; 95% CI, -0.09 to 0.14; P = .651, respectively) youth. Cardiometabolic risk factors explained more of the variation in HFF than genetic risk factors among non-lean Hispanic individuals (27.2% for cardiometabolic markers vs 6.4% for rs738409 and 4.3% for the GRS), and genetic risk factors were more important among lean individuals (2.7% for cardiometabolic markers vs 12.6% for rs738409 and 4.4% for the GRS). CONCLUSIONS: Poor cardiometabolic health may be more important than genetic factors when predicting HFF in overweight and obese young populations. Genetic risk is an important contributor to pediatric HFF among lean Hispanics, but further studies are necessary to elucidate the strength of the association between genetic risk and HFF in non-Hispanic white youth.

Prenatal Exposure to Tobacco and Offspring Neurocognitive Development in the Healthy Start Study.

OBJECTIVE: To explore the associations between prenatal exposure to tobacco and neurocognitive development, in the absence of prematurity or low birth weight. STUDY DESIGN: We followed mother-child pairs within Healthy Start through 6 years of age. Children were born at ≥37 weeks of gestation with a birth weight of ≥2500 g. Parents completed the Third Edition Ages and Stages Questionnaire (n = 246) and children completed a subset of the National Institutes of Health Toolbox Cognition Battery (n = 200). The Ages and Stages Questionnaire domains were dichotomized as fail/monitor and pass. Maternal urinary cotinine was measured at approximately 27 weeks of gestation. Separate logistic regression models estimated associations between prenatal exposure to tobacco (cotinine below vs above the limit of detection) and the Ages and Stages Questionnaire domains. Separate linear regression models estimated associations between prenatal exposure to tobacco and fully corrected T-scores for inhibitory control, cognitive flexibility, and receptive language, as assessed by the National Institutes of Health Toolbox. A priori covariates included sex, maternal age, maternal education, daily caloric intake during pregnancy, race/ethnicity, household income, maternal psychiatric disorders, and, in secondary models, postnatal exposure to tobacco. RESULTS: Compared with unexposed offspring, exposed offspring were more likely to receive a fail/monitor score for fine motor skills (OR, 3.9; 95% CI, 1.5-10.3) and decreased inhibitory control (B: -3.0; 95% CI, -6.1 to -0.7). After adjusting for postnatal exposure, only the association with fine motor skills persisted. CONCLUSIONS: Prenatal and postnatal exposures to tobacco may influence neurocognitive development, in the absence of preterm delivery or low birth weight. Increased developmental screening may be warranted for exposed children.

Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS).

OBJECTIVE: Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD). RESEARCH DESIGN AND METHODS: Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up. RESULTS: Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65-0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78-1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75-1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. CONCLUSIONS: Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range.

Childhood Metabolic Biomarkers Are Associated with Performance on Cognitive Tasks in Young Children.

OBJECTIVE: To evaluate the hypothesis that metabolic measures (fasting glucose, insulin, and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks using data from young (4- to 6-year-old), typically developing, healthy children. STUDY DESIGN: Data were obtained from children participating in the Healthy Start study, a pre-birth cohort in Colorado. HOMA-IR, glucose, and insulin values were centered and scaled using the study sample means and SD. Thus, they are reported in number of SD units from the mean. Fully corrected T scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and receptive language (Picture Vocabulary test) were obtained via the National Institutes of Health Toolbox cognition battery. RESULTS: Children included in this analysis (n = 137) were 4.6 years old, on average. Per 1-SD unit, fasting glucose (B = -2.0, 95% CI -3.5, -0.5), insulin (B = -1.7, 95% CI -3.0, -0.4), and HOMA-IR values (B = -1.8, 95% CI -3.1, -0.5) were each significantly and inversely associated with inhibitory control (P < .05 for all, respectively). Fasting glucose levels were also inversely associated with cognitive flexibility (B = -2.0, 95% CI -3.7, -0.2, P = .03). CONCLUSIONS: Our data suggest that metabolic health may impact fluid cognitive function in healthy, young children.

Exposure to Diabetes in Utero Is Associated with Earlier Pubertal Timing and Faster Pubertal Growth in the Offspring: The EPOCH Study.

OBJECTIVE: To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed of pubertal growth (peak height velocity [PHV]). STUDY DESIGN: Data from 77 exposed and 340 unexposed youth followed from age 2 to 19 years (51% non-Hispanic white, 50% female) were analyzed using the Exploring Perinatal Outcomes among Children study, a historical prospective cohort. Maternal diabetes status was collected from obstetric records, and child heights from 2 years to current age from pediatric records. Other covariates were collected during research visits. The superimposition by translation and rotation method, using height measurements (4-52 per participant), modeled APHV and PHV. Accelerated failure time analyses were used to test whether exposure to maternal diabetes was associated with younger APHV and faster PHV. RESULTS: Adjusting for child's sex, race/ethnicity, and socioeconomic status, median APHV was reached ~3 months earlier in youth exposed to maternal diabetes compared with unexposed youth (P < .03). Youth exposed to maternal diabetes had a faster PHV than unexposed youth: exposed girls had 10.5% greater median PHV compared with unexposed girls and exposed boys had a 4.0% greater median PHV compared with unexposed boys (P < .001 for exposure by sex interaction). CONCLUSIONS: Our findings provide evidence that exposure to maternal diabetes in utero is associated with earlier pubertal timing and faster pubertal growth. Whether earlier puberty or faster speed of pubertal growth mediates the association between maternal diabetes exposure and later chronic disease risk remains to be studied.

Dietary Patterns Over Time and Microalbuminuria in Youth and Young Adults With Type 1 Diabetes: The SEARCH Nutrition Ancillary Study.

OBJECTIVE: We assessed the association between diet quality and microalbuminuria in youth-onset type 1 diabetes using three indices: a modified Mediterranean diet score for children and adolescents (mKIDMED), the Dietary Approaches to Stop Hypertension (DASH), and the Healthy Eating Index-2010 (HEI). RESEARCH DESIGN AND METHODS: Youth and young adults from the SEARCH (SEARCH for Diabetes in Youth) Nutrition Ancillary Study (SNAS) diagnosed with type 1 diabetes in 2002-2008, who had repeated dietary assessments at baseline and follow-up visits and urine albumin-to-creatinine ratio (UACR) measured at the outcome visit (2012-2015) (n = 461), were selected for study. Regression models estimated the association between each longitudinally assessed diet score and UACR and microalbuminuria (UACR ≥30 µg/mg). RESULTS: The cohort was 43% female, and at follow-up, mean age was 20 years, disease duration was 108 months, and 7% had microalbuminuria. Adherence to a higher-quality diet was low for the mKIDMED (mean 3.7 of a possible range of -3 to 12) and the DASH (mean 42 of 80) and better, for the HEI (mean 56.3 of 100). A borderline inverse association was observed between the HEI score and microalbuminuria after adjustment for caloric and protein intake and demographic and disease factors (odds ratio [OR]HEI 0.83, P = 0.07), which lost significance with further adjustment for HbA1c and systolic blood pressure (ORHEI 0.86, P = 0.19). Results were similar for continuous UACR. No significant associations were observed for diet quality characterized by the mKIDMED or DASH indices. CONCLUSIONS: Greater adherence to the HEI may be beneficial for kidney health in youth and young adults with type 1 diabetes. Low adherence to the mKIDMED and DASH diets may explain the lack of association with microalbuminuria.

Diabetes in Youth-Looking Backwards to Inform the Future: Kelly West Award Lecture 2017.

The Kelly West Award for Outstanding Achievement in Epidemiology is presented in honor of the memory of Kelly M. West, widely regarded as the "father of diabetes epidemiology." Harry Keen described West as characterized by "generosity of spirit, deeply human and humorous, deliberate of address, modest, conciliatory and untiringly persevering. Few people have done so much to change the landscape of diabetes" (1). The award and lecture recognize a leading epidemiologist in the field of diabetes. Dana Dabelea, MD, PhD, received this award at the American Diabetes Association's 77th Scientific Sessions, 9-13 June 2017, in San Diego, CA. She presented the Kelly West Award Lecture, "Diabetes in Youth-Looking Backwards to Inform the Future," on Sunday, 11 June 2017.

Proinflammatory Diets during Pregnancy and Neonatal Adiposity in the Healthy Start Study.

OBJECTIVE: To evaluate the association between dietary inflammatory index (DII) scores during pregnancy and neonatal adiposity. STUDY DESIGN: The analysis included 1078 mother-neonate pairs in Healthy Start, a prospective prebirth cohort. Diet was assessed using repeated 24-hour dietary recalls. DII scores were obtained by summing nutrient intakes, which were standardized to global means and multiplied by inflammatory effect scores. Air displacement plethysmography measured fat mass and fat-free mass within 72 hours of birth. Linear and logistic models evaluated the associations of DII scores with birth weight, fat mass, fat-free mass, and percent fat mass, and with categorical outcomes of small- and large-for-gestational age. We tested for interactions with prepregnancy BMI and gestational weight gain. RESULTS: The interaction between prepregnancy BMI and DII was statistically significant for birth weight, neonatal fat mass, and neonatal percent fat mass. Among neonates born to obese women, each 1-unit increase in DII was associated with increased birth weight (53 g; 95% CI, 20, 87), fat mass (20 g; 95% CI, 7-33), and percent fat mass (0.5%; 95% CI, 0.2-0.8). No interaction was detected for small- and large-for-gestational age. Each 1-unit increase in DII score was associated a 40% increase in odds of a large-for-gestational age neonate (1.4; 95% CI, 1.0-2.0; P = .04), but not a small-for-gestational age neonate (1.0; 95% CI, 0.8-1.2; P = .80). There was no evidence of an interaction with gestational weight gain. CONCLUSIONS: Our findings support the hypothesis that an increased inflammatory milieu during pregnancy may be a risk factor for neonatal adiposity. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02273297.

Fetal Overnutrition and Adolescent Hepatic Fat Fraction: the Exploring Perinatal Outcomes in Children Study.

OBJECTIVE: To determine if fetal overnutrition resulting from maternal obesity or gestational diabetes mellitus (GDM) is associated with increased liver fat during adolescence, adjusting for past and current metabolic risk factors. STUDY DESIGN: Data come from a historical prospective cohort study (Exploring Perinatal Outcomes in Children) of 254 mother-child pairs in Colorado who participated in 2 research visits at T1 (mean age 10.4, SD = 1.5 years) and at T2 (mean age 16.4, SD = 1.5 years), and had complete exposure and outcome data. Multiple linear regression was used to evaluate the effects of pre-pregnancy body mass index (BMI) and GDM on hepatic fat fraction (HFF) by magnetic resonance imaging at T2. RESULTS: Maternal pre-pregnancy obesity (BMI 30+) was significantly associated (ß = 1.59, CI = 0.66, 2.52) with increased HFF relative to mothers with normal pre-pregnancy weight (BMI <25) independent of maternal GDM and sociodemographic factors. Moreover, this association was independent of T2 and T1 metabolic risk factors (acanthosis nigricans, BMI, fasting glucose) (ß = 1.03, CI = 0.10, 1.97). Prenatal GDM exposure was not associated with HFF in either unadjusted or adjusted models. CONCLUSIONS: Maternal pre-pregnancy obesity was associated with increased HFF in offspring independent of childhood and adolescent adiposity. Intervention studies are needed to test the hypothesis that maternal obesity is a modifiable risk factor for childhood fatty liver disease.

Predictors of Infant Body Composition at 5 Months of Age: The Healthy Start Study.

OBJECTIVE: To examine associations of demographic, perinatal, and infant feeding characteristics with offspring body composition at approximately 5 months of age. STUDY DESIGN: We collected data on 640 mother/offspring pairs from early pregnancy through approximately 5 months of age. We assessed offspring body composition with air displacement plethysmography at birth and approximately 5 months of age. Linear regression analyses examined associations between predictors and fat-free mass, fat mass, and percent fat mass (adiposity) at approximately 5 months. Secondary models further adjusted for body composition at birth and rapid infant growth. RESULTS: Greater prepregnant body mass index and gestational weight gain were associated with greater fat-free mass at approximately 5 months of age, but not after adjustment for fat-free mass at birth. Greater gestational weight gain was also associated with greater fat mass at approximately 5 months of age, independent of fat mass at birth and rapid infant growth, although this did not translate into increased adiposity. Greater percent time of exclusive breastfeeding was associated with lower fat-free mass (-311 g; P < .001), greater fat mass (+224 g; P < .001), and greater adiposity (+3.51%; P < .001). Compared with offspring of non-Hispanic white mothers, offspring of Hispanic mothers had greater adiposity (+2.72%; P < .001) and offspring of non-Hispanic black mothers had lower adiposity (-1.93%; P < .001). Greater adiposity at birth predicted greater adiposity at approximately 5 months of age, independent of infant feeding and rapid infant growth. CONCLUSIONS: There are clear differences in infant body composition by demographic, perinatal, and infant feeding characteristics, although our data also show that increased adiposity at birth persists through approximately 5 months of age. Our findings warrant further research into implications of differences in infant body composition.

Mesenchymal Stem Cells From Infants Born to Obese Mothers Exhibit Greater Potential for Adipogenesis: The Healthy Start BabyBUMP Project.

Maternal obesity increases the risk for pediatric obesity; however, the molecular mechanisms in human infants remain poorly understood. We hypothesized that mesenchymal stem cells (MSCs) from infants born to obese mothers would demonstrate greater potential for adipogenesis and less potential for myogenesis, driven by differences in ß-catenin, a regulator of MSC commitment. MSCs were cultured from the umbilical cords of infants born to normal-weight (prepregnancy [pp] BMI 21.1 ± 0.3 kg/m(2); n = 15; NW-MSCs) and obese mothers (ppBMI 34.6 ± 1.0 kg/m(2); n = 14; Ob-MSCs). Upon differentiation, Ob-MSCs exhibit evidence of greater adipogenesis (+30% Oil Red O stain [ORO], +50% peroxisome proliferator-activated receptor (PPAR)-γ protein; P < 0.05) compared with NW-MSCs. In undifferentiated cells, total ß-catenin protein content was 10% lower and phosphorylated Thr41Ser45/total ß-catenin was 25% higher (P < 0.05) in Ob-MSCs versus NW-MSCs (P < 0.05). Coupled with 25% lower inhibitory phosphorylation of GSK-3ß in Ob-MSCs (P < 0.05), these data suggest greater ß-catenin degradation in Ob-MSCs. Lithium chloride inhibition of GSK-3ß increased nuclear ß-catenin content and normalized nuclear PPAR-γ in Ob-MSCs. Last, ORO in adipogenic differentiating cells was positively correlated with the percent fat mass in infants (r = 0.475; P < 0.05). These results suggest that altered GSK-3ß/ß-catenin signaling in MSCs of infants exposed to maternal obesity may have important consequences for MSC lineage commitment, fetal fat accrual, and offspring obesity risk.

The SEARCH for Diabetes in Youth study: rationale, findings, and future directions.

The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.