Reproducibility of Glycemic Measures Among Dysglycemic Youth and Adults in the RISE Study.

AIMS: Previous work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs). METHODS: HbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared. RESULTS: Mean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth. CONCLUSIONS: Poor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important.

Cost-Effectiveness and Long-Term Savings of the Bright Bodies Intervention for Childhood Obesity.

OBJECTIVES: To estimate the cost and cost-effectiveness of Bright Bodies, a high-intensity, family-based intervention that has been demonstrated to improve body mass index (BMI) among children with obesity in a randomized controlled trial. METHODS: We developed a microsimulation model to project 10-year BMI trajectories of 8 to 16-year-old children with obesity, using data from the National Longitudinal Surveys and Centers for Disease Control and Prevention growth charts, and we validated the model using data from the Bright Bodies trial and a follow-up study. We used the trial data to estimate the average reduction in BMI per person-year over 10 years and the incremental costs of Bright Bodies, compared with the traditional clinical weight management (control), from a health system's perspective in 2020 US dollars. Using results from studies of Medical Expenditure Panel Survey data, we projected the long-term obesity-related medical expenditure. RESULTS: In the primary analysis, assuming depreciating effects postintervention, Bright Bodies is expected to reduce a participant's BMI by 1.67 kg/m2 (95% uncertainty interval 1.43-1.94) per year over 10 years as compared with control. The incremental intervention cost of Bright Bodies was $360 ($292-$421) per person compared with the clinical control. Nevertheless, savings in obesity-related healthcare expenditure offset these costs and the expected cost-savings of Bright Bodies is $1126 ($689-$1693) per person over 10-years. The projected time to achieve cost-savings compared with clinical control was 3.58 (2.63-5.17) years. CONCLUSIONS: Although resource-intensive, our findings suggest that Bright Bodies is cost-saving compared to the clinical control by averting future obesity-related healthcare costs among children with obesity.

Real-world effectiveness of the Bright Bodies healthy lifestyle intervention for childhood obesity.

OBJECTIVE: This study aimed to examine the extent to which Bright Bodies, a high-intensity, family-based pediatric weight management intervention, improved BMI for participants since publication of the randomized controlled trial establishing efficacy in 2007 and to describe adaptations to the program. METHODS: For participants enrolled from 2008 to 2018, linear mixed-effects models were used to estimate monthly change in BMI expressed as percentage of the 95th percentile (%BMIp95) during participants' first beginner-level program. RESULTS: The sample included 396 youth individuals (mean age: 11.7 [SD 2.8] years, 61.6% female, 37.1% non-Hispanic Black, 26.3% Hispanic or Latino, 53.8% with public insurance, 80.1% with severe obesity). Across the 11 years, participants' %BMIp95 reduced on average by 1.63% (95% CI: 1.44%-1.82%) per month during their first program (mean duration: 10 weeks) after adjusting for age, sex, season and year, starting %BMIp95, race and ethnicity, and insurance category. Greater reduction in %BMIp95 was associated with male versus female sex, spring/fall versus winter seasons, enrollment in 2008 to 2018 versus 2015 to 2018, and higher starting %BMIp95 (p value for all <0.001). Adaptations since 2007 included pragmatic changes to increase engagement and address funding shortages. CONCLUSIONS: These results suggest sustained clinical effectiveness of Bright Bodies in the context of real-world adaptations.

Reversibility of brain glucose kinetics in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA1c normalise intracerebral glucose levels. METHODS: Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m2 and HbA1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist. RESULTS: Following the intervention, mean ± SD HbA1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA1c (r = 0.71, p=0.048). CONCLUSION/INTERPRETATION: These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registration ClinicalTrials.gov NCT03469492.

A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth.

AIM: To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. MATERIALS AND METHODS: Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. RESULTS: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of ß-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and ß-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, ß-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and ß-cell function. CONCLUSIONS: We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

Changes in Weight-Related Health Behaviors and Social Determinants of Health among Youth with Overweight/Obesity during the COVID-19 Pandemic.

Objectives: To assess changes in weight-related health behaviors and social determinants of health (SDoH) among youth with overweight/obesity during the coronavirus disease 2019 (COVID-19) pandemic. Methods: We assessed weight-related health behaviors (physical activity, screen time, sleep, and diet) and SDoH (food insecurity, income/childcare, and caregivers' perceived stress) before vs. during the pandemic with a survey administered August-October 2020 to caregivers of 2-17-year olds and adolescents 13-17 years old with BMI ≥85th percentile seen in clinic within 6 months prepandemic. We analyzed changes in continuous variables using paired t-tests and categorical variables with McNemar's or Fisher's exact tests, and the influence of social determinants on behavior change using multivariable regression models. Results: A total of 129 caregivers and 34 adolescents completed surveys. Compared with prepandemic, caregivers reported youth decreased moderate/vigorous physical activity (-87.4 [205.7] minutes/week, p < 0.001) and increased recreational screen time (2.5 [2.1] hours/day, p < 0.001). Fewer had regular bedtimes (before: 89% and during: 44%, p < 0.001) and more ate most meals with television (before: 16% and during: 36%, p < 0.001). Food insecurity increased from 27% to 43% (p < 0.001), 45% reported reduced household income, and caregivers with moderate/high perceived stress scale scores increased from 43% to 64% (p < 0.001). Moderate/high caregiver stress and food insecurity were associated with greater magnitudes of adverse behavior change. Conclusion: Alarming changes in health behaviors among youth with overweight/obesity, particularly among those with stressed caregivers and food insecurity, may increase prevalence of obesity-related comorbidities and exacerbate health disparities. There is an urgent need to expand access to effective interventions for overweight/obesity that address psychosocial stressors.

Youth and Parent Perspectives on the Acceptability of a Group Physical Activity and Coping Intervention for Adolescents With Type 1 Diabetes.

PURPOSE: To examine youth and parent perspectives on the acceptability of Bright 1 Bodies, a group physical activity and coping intervention for adolescents with type 1 diabetes mellitus (T1DM). METHODS: Adolescents participated in 12 weekly sessions of moderate to vigorous physical activity and discussion with peers with T1DM. Adolescents completed an exit survey measuring satisfaction with the intervention on a 5-point Likert scale. Semistructured interviews were conducted with adolescents and at least one parent. Qualitative description was used to develop themes that summarize the acceptability of the intervention. RESULTS: Mean scores for survey subscales were: 4.5 (SD = 0.39) for program components and strategies, 4.4 (SD = 0.44) for comfort with the intervention, and 4.3 (SD = 0.62) for instructors. Themes included: (1) adolescents and parents valued being around others with T1DM and their families, (2) the intervention helped adolescents gain knowledge and reinforce diabetes self-management behaviors, (3) challenges included convenience and sustaining participant engagement, and (4) adolescents intended to sustain physical activity and diabetes self-management behaviors after the intervention. CONCLUSIONS: Adolescents and parents viewed the intervention as acceptable across multiple domains. Participants valued the group aspect of the intervention, and future interventions would benefit from integrating social interactions with others with T1DM.

A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.

BACKGROUND: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

Feasibility and safety of a group physical activity program for youth with type 1 diabetes.

BACKGROUND/OBJECTIVE: Many adolescents with type 1 diabetes do not achieve 60 minutes of daily moderate-to-vigorous intensity physical activity (MVPA). Recognizing the importance of peer influence during adolescence, we evaluated the feasibility and safety of a group MVPA intervention for this population. METHODS: Eighteen adolescents with type 1 diabetes (age 14.1 ± 2 .3 years, female 67%, black or Latino 67%, median body mass index 92%'ile, A1c 79.9 ± 25.1 mmol/mol, 9.5 ± 2.3%). Intervention sessions (35 minutes MVPA and 45 minutes discussion) occurred 1×/week for 12 weeks. Feasibility and safety metrics were enrollment, completion of intervention and assessments, cost, and hypoglycemia rates. Participants completed MVPA (accelerometry), and exploratory nutritional, psychosocial, clinical, and fitness variable assessments at baseline, 3 months, and 7 months. Hedges' effect sizes were calculated. RESULTS: Enrollment was 16%, and intervention completion was 56%. Assessment completion at 7 months was 67% for MVPA, nutrition, and fitness, 83% for psychosocial assessments, and 94% for clinical assessments. Cost was $1241 per completing participant. One episode of mild hypoglycemia occurred during the sessions (0.6%). Self-reported daily fruit/vegetable servings (d = -0.72) and diabetes self-management behaviors decreased over time (d = -0.40). In the 10 completers, endurance run score improved (d = 0.49) from low baseline levels, while systolic blood pressure decreased (d = -0.75) and low-density lipoprotein increased (d = 0.49) but stayed within normal ranges. CONCLUSIONS: The protocol for the group MVPA intervention was safe and had some feasibility metrics meriting further investigation. MVPA levels and glycemic control remained suboptimal, suggesting the need for more intensive interventions for this population.

Preventing Childhood Obesity Through a Mindfulness-Based Parent Stress Intervention: A Randomized Pilot Study.

OBJECTIVE: To assess the feasibility of engaging stressed, low-income parents with obesity in a novel mindfulness-based parent stress intervention aimed at decreasing the risk of early childhood obesity. STUDY DESIGN: An 8-week mindfulness-based parent stress group intervention (parenting mindfully for health) plus nutrition and physical activity counseling (PMH+N) was developed for parents with obesity aimed at preventing obesity in their at-risk 2- to 5-year-old children. PMH+N was compared with a control group intervention (C+N), and improvement in parenting was assessed before and after the intervention using the laboratory-based toy wait task (TWT). In addition, nutrition, physical activity, and stress were assessed using a multimethod approach. RESULTS: After establishing feasibility in 20 parent-child dyads (phase 1), 42 dyads were randomized to PMH+N vs C+N (phase 2). Compared with the C+N group, the PMH+N group demonstrated significantly better group attendance (P < .015), greater improvement in parental involvement (P < .05), and decreased parental emotional eating rating (P < .011). Furthermore, C+N, but not PMH+N, was associated with significant increases in child body mass index percentile during treatment (P < .03) when accounting for the TWT before and after changes in parenting scores. CONCLUSIONS: These findings suggest that a mindfulness-based parent stress intervention to decrease childhood obesity risk is feasible, requires further testing of therapeutic mechanisms in larger samples, and may be a potential way to attenuate the risk of childhood obesity. TRIAL REGISTRATION: ClinicalTrials.govNCT01974102.

Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis.

BACKGROUND: Type 2 diabetes is preceded by a prediabetic stage of impaired glucose tolerance that affects 10-23% of youth and is expected to double over the next decade. The natural history of impaired glucose tolerance and the determinants of ß-cell dynamic response have never been investigated longitudinally in young people. We aimed to investigate the clinical and metabolic determinants of longitudinal glucose tolerance changes and ß-cell function in a multiethnic cohort of obese youth. METHODS: We followed up prospectively a multiethnic cohort of overweight and obese (body-mass index >85th percentile) adolescents with baseline normal glucose tolerance (plasma glucose <140 mg/dL) or impaired glucose tolerance (plasma glucose 140-199 mg/dL) at the Yale Pediatric Obesity Clinic (CT, USA). All participants underwent a 3-h oral glucose tolerance test at baseline and after 2 years to estimate insulin secretion (oral disposition index) in the context of body insulin sensitivity. As part of standard care at the clinic, all participants received dietary advice and underwent dietary assessment every 5-6 months. No structured lifestyle or pharmacological intervention was administered. FINDINGS: Between January, 2010, and December, 2016, 526 adolescents (mean age 12·7 years, range 10·6-14·2) were enrolled to our study. At baseline, 364 had normal and 162 had impaired glucose tolerance. Median follow-up was 2·9 years (IQR 2·7-3·1). 105 (65%) of 162 with impaired glucose tolerance at baseline reverted to normal glucose tolerance at follow-up, 44 (27%) had persistent impaired glucose tolerance, and 13 (8%) progressed to type 2 diabetes. A feature of reversion to normal glucose tolerance was a roughly four-fold increase in the oral disposition index (from median 0·94 [IQR 0·68-1·35] at baseline to 3·90 [2·58-6·08] at follow-up; p<0·0001) and a significantly higher oral disposition index at follow-up compared with participants who maintained normal glucose tolerance across the study period (median 3·90 [IQR 2·58-6·08] vs 1·59 [1·12-2·23]; p<0·0001). By contrast, a decrease in insulin secretion was seen in participants who had persistent impaired glucose tolerance (median 1·31 [IQR 1·01-1·85]; p<0·0001) or who progressed to type 2 diabetes (0·20 [0·12-0·58]; p<0·0001), compared with participants who maintained normal glucose tolerance across the study period. Non-Hispanic white ethnic origin conferred five times the odds of reversion to normal glucose tolerance compared with non-Hispanic black ethnic origin (OR 5·06, 95% CI 1·86-13·76; p=0·001), with a two times greater annual increase in the oral disposition index (ß 2·32, 95% CI 0·05-4·60; p=0·045). INTERPRETATION: Impaired glucose tolerance is highly reversible in obese adolescents. Ethnic origin is the main clinical modifier of the dynamic ß-cell response to prediabetic hyperglycaemia and, thus, determines the reversibility of impaired glucose tolerance, or its persistence. Therapeutic interventions for impaired glucose tolerance should target the specific mechanisms underpinning glucose tolerance changes in high-risk ethnic groups. FUNDING: National Institutes of Health (National Institute of Child Health and Human Development, National Center for Research Resources, and National Institute of Diabetes and Digestive and Kidney Diseases), American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, Robert Leet Patterson and Clara Guthrie Patterson Trust, European Society for Pediatric Endocrinology, American Heart Association, and the Allen Foundation.

Role of Gut Microbiota and Short Chain Fatty Acids in Modulating Energy Harvest and Fat Partitioning in Youth.

OBJECTIVE: We aimed at determining the relationship of the gut microbiota and short chain fatty acids with obesity and fat partitioning and at testing potential differences in the ability of gut microbiota to ferment equal amounts of carbohydrates (CHO) between lean and obese youth. RESEARCH DESIGN AND METHODS: We analyzed the gut microbiota of 84 youth in whom body fat distribution was measured by fast-magnetic resonance imaging, de novo lipogenesis (DNL) quantitated using deuterated water, and the capability of gut flora to ferment CHO was assessed by 13C-fructose treatment in vitro. RESULTS: A significant association was found between the Firmicutes to Bacteroidetes ratio, and the abundance of Bacteroidetes and Actinobacteria with body mass index, visceral and SC fat (all P < .05). Plasma acetate, propionate, and butyrate were associated with body mass index and visceral and SC fat (all P < .05) and with hepatic DNL (P = .01, P = .09, P = .04, respectively). Moreover, the rate of CHO fermentation from the gut flora was higher in obese than in lean subjects (P = .018). CONCLUSIONS: These data demonstrate that obese youth show a different gut flora composition than lean and that short chain fatty acids are associated with body fat partitioning and DNL. Also, the gut microbiota of obese youth have a higher capability than the gut flora of lean to oxidize CHO.

Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain.

Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study.

UNLABELLED: We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P < 0.05), with high alanine aminotransferase levels in Hispanics (P < 0.05) and a more favorable lipoprotein profile (lower low-density lipoprotein, small dense low-density lipoprotein, and very small low-density lipoprotein) in Caucasians and Hispanics (all P < 0.05). The liver biopsy showed a higher prevalence of fibrosis (P = 0.04) and a higher nonalcoholic fatty liver disease activity score (P = 0.05) in subjects carrying the minor allele than in those homozygous for the common allele. Moreover, we observed a joint effect among the TM6SF2 rs58542926, the PNPLA3 rs738409, and the GCKR rs1260326 SNPs in determining intrahepatic fat accumulation (P < 0.05). CONCLUSION: The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk.

Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene.

OBJECTIVE: This study's aim was to evaluate whether the GCKR rs1260326 variant increases hepatic de novo lipogenesis (DNL). SETTING AND DESIGN: To test this hypothesis, 14 adolescents, seven homozygous for the common allele (CC) and seven homozygous for the risk allele (TT), underwent measurement of hepatic DNL during the fasting state and after consumption of a carbohydrate (CHO) drink (75 g glucose and 25 g fructose). DNL was assessed through incorporation of deuterium in the palmitate contained in the very low-density lipoprotein. RESULTS: Subjects with TT demonstrated higher fasting fractional DNL (P = .036) and a lower increase in fractional DNL after the CHO challenge (P = .016). With regard to absolute lipogenesis, TT subjects had both higher fasting rates (P = .015) and 44% greater area under the curve of absolute lipogenesis during the study (P = .016), compared to CC subjects. Furthermore, subjects carrying the TT genotype showed higher basal rates of glucose oxidation (P = .0028) and a lower ability than CC subjects to increase the rates of glucose oxidation after the CHO load (P = .054). CONCLUSIONS: This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters.

Blunted suppression of acyl-ghrelin in response to fructose ingestion in obese adolescents: the role of insulin resistance.

OBJECTIVE: Fructose consumption has risen alongside obesity and diabetes. Gut hormones involved in hunger and satiety (ghrelin and PYY) may respond differently to fructose compared with glucose ingestion. This study evaluated the effects of glucose and fructose ingestion on ghrelin and PYY in lean and obese adolescents with differing insulin sensitivity. METHODS: Adolescents were divided into lean (n = 14), obese insulin sensitive (n = 12) (OIS), and obese insulin resistant (n = 15) (OIR). In a double-blind, cross-over design, subjects drank 75 g of glucose or fructose in random order, serum was obtained every 10 minutes for 60 minutes. RESULTS: Baseline acyl-ghrelin was highest in lean and lowest in OIR (P = 0.02). After glucose ingestion, acyl-ghrelin decreased similarly in lean and OIS but was lower in OIR (vs. lean, P = 0.03). Suppression differences were more pronounced after fructose (lean vs. OIS, P = 0.008, lean vs. OIR, P < 0.001). OIS became significantly hungrier after fructose (P = 0.015). PYY was not significantly different at baseline, varied minimally after glucose, and rose after fructose. CONCLUSIONS: Compared with lean, OIS adolescents have impaired acyl-ghrelin responses to fructose but not glucose, whereas OIR adolescents have blunted responses to both. Diminished suppression of acyl-ghrelin in childhood obesity, particularly if accompanied by insulin resistance, may promote hunger and overeating.

Leptin is associated with exaggerated brain reward and emotion responses to food images in adolescent obesity.

OBJECTIVE: In the U.S., an astonishing 12.5 million children and adolescents are now obese, predisposing 17% of our nation's youth to metabolic complications of obesity, such as type 2 diabetes (T2D). Adolescent obesity has tripled over the last three decades in the setting of food advertising directed at children. Obese adults exhibit increased brain responses to food images in motivation-reward pathways. These neural alterations may be attributed to obesity-related metabolic changes, which promote food craving and high-calorie food (HCF) consumption. It is not known whether these metabolic changes affect neural responses in the adolescent brain during a crucial period for establishing healthy eating behaviors. RESEARCH DESIGN AND METHODS: Twenty-five obese (BMI 34.4 kg/m2, age 15.7 years) and fifteen lean (BMI 20.96 kg/m2, age 15.5 years) adolescents underwent functional MRI during exposure to HCF, low-calorie food (LCF), and nonfood (NF) visual stimuli 2 h after isocaloric meal consumption. RESULTS: Brain responses to HCF relative to NF cues increased in obese versus lean adolescents in striatal-limbic regions (i.e., putamen/caudate, insula, amygdala) (P < 0.05, family-wise error [FWE]), involved in motivation-reward and emotion processing. Higher endogenous leptin levels correlated with increased neural activation to HCF images in all subjects (P < 0.05, FWE). CONCLUSIONS: This significant association between higher circulating leptin and hyperresponsiveness of brain motivation-reward regions to HCF images suggests that dysfunctional leptin signaling may contribute to the risk of overconsumption of these foods, thus further predisposing adolescents to the development of obesity and T2D.

Reversal of early abnormalities in glucose metabolism in obese youth: results of an intensive lifestyle randomized controlled trial.

OBJECTIVE: The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have "prediabetes," a precursor to diabetes marked by insulin resistance, ß-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Program demonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care. RESEARCH DESIGN AND METHODS: A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10-16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130-199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (<130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data. RESULTS: Reductions in 2-h glucose were more favorable in BB compared with CC (-27.2 vs. -10.1 mg/dL; difference = -17.1, 95% CI; P = 0.005). Moreover, greater conversion to <130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved. CONCLUSIONS: Compared with standard of care, the Yale BB Program is a more effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels.

Preventing diabetes among Fair Haven families: a community-based approach to quality improvement.

In this paper, we describe our efforts to integrate the Diabetes Prevention Program and the Bright Bodies program into a coordinated intensive lifestyle intervention program for families living in Fair Haven, an underserved Hispanic neighborhood in New Haven, Connecticut with high rates of obesity and prediabetes in adults and children.

Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake.

BACKGROUND: A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake. MATERIALS AND METHODS: We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing. RESULTS: As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively). CONCLUSIONS: These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype.