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.

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.

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.

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.

Low-calorie diet-induced weight loss is associated with altered brain connectivity and food desire in obesity.

OBJECTIVE: The main objective of this study is to better understand the effects of diet-induced weight loss on brain connectivity in response to changes in glucose levels in individuals with obesity. METHODS: A total of 25 individuals with obesity, among whom 9 had a diagnosis of type 2 diabetes, underwent functional magnetic resonance imaging (fMRI) scans before and after an 8-week low-calorie diet. We used a two-step hypereuglycemia clamp approach to mimic the changes in glucose levels observed in the postprandial period in combination with task-mediated fMRI intrinsic connectivity distribution (ICD) analysis. RESULTS: After the diet, participants lost an average of 3.3% body weight. Diet-induced weight loss led to a decrease in leptin levels, an increase in hunger and food intake, and greater brain connectivity in the parahippocampus, right hippocampus, and temporal cortex (limbic-temporal network). Group differences (with vs. without type 2 diabetes) were noted in several brain networks. Connectivity in the limbic-temporal and frontal-parietal brain clusters inversely correlated with hunger. CONCLUSIONS: A short-term low-calorie diet led to a multifaceted body response in patients with obesity, with an increase in connectivity in the limbic-temporal network (emotion and memory) and hormone and eating behavior changes that may be important for recovering the weight lost.

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.

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.

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.

A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents.

UNLABELLED: The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). CONCLUSION: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.

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.

Glucose dysregulation and hepatic steatosis in obese adolescents: is there a link?

UNLABELLED: Fatty liver is increasingly common in obese adolescents. We determined its association with glucose dysregulation in 118 (37M/81F) obese adolescents of similar age and percent total fat. Fast-magnetic resonance imaging (MRI) and simple MRI were used to quantify hepatic fat content and abdominal fat distribution. All subjects had a standard oral glucose tolerance test. Insulin sensitivity was estimated by the Matsuda Index and homeostasis model assessment of insulin resistance. Baseline total and high molecular weight (HMW)-adiponectin and interleukin (IL)-6 levels were measured. The cohort was stratified according to tertiles of hepatic fat content. Whereas age and %fat were comparable across tertiles, ethnicity differed in that fewer Blacks and more Whites and Hispanics were in the moderate and high category of hepatic fat fraction (HFF). Visceral and the visceral-to-subcutaneous fat ratio increased and insulin sensitivity decreased across tertiles. Two-hour plasma glucose rose with increasing hepatic steatosis (P < 0.008). 73.7% of the subjects in the high HFF had the metabolic syndrome compared to 19.5% and 30.6%, respectively, in the low and moderate categories. Both total and HMW-adiponectin decreased, and IL-6 increased with increasing hepatic steatosis. CONCLUSION: In obese adolescents, independent of total fat, increasing severity of fatty liver is associated with glucose dysregulation, metabolic syndrome, and with a proinflammatory milieu.

Obesity dynamics and cardiovascular risk factor stability in obese adolescents.

AIM: Cross-sectional studies showed worsening of cardiovascular risk factors with increasing severity of childhood obesity. The aim of this study was to investigate the impact of obesity dynamics on cardiovascular risk factors and on the stability of the diagnosis of metabolic syndrome (MS) in obese youth. METHODS AND RESULTS: A longitudinal assessment of components of the MS using two definitions was performed in 186 obese adolescents (106 females/80 males, age 13.1 +/- 2.5 yr). Components of the MS were assessed at baseline and after 19 +/- 7 months. We stratified the cohort into three categories based on the 25th and 75th percentile of body mass index (BMI) z-score change: category 1 reduced BMI z-score by 0.09 or more, category 2 had a BMI z-score change of between -0.09 and 0.12, and category 3 increased BMI z-score by >0.12. Subjects who reduced their BMI z-score significantly decreased their fasting and 2-h glucose levels and triglyceride levels and increased their high density lipoprotein cholesterol in comparison to subjects who increased their BMI z-score. BMI z-score changes negatively correlated with changes in insulin sensitivity (r = -0.36, p < 0.001). Among those with no MS at baseline (n = 119), 10 (8%), most of whom significantly increased their BMI z-score, developed MS. Of 67 who had MS at baseline, 33 (50%), most of whom decreased their BMI z-score, lost the diagnosis. CONCLUSIONS: Obesity dynamics, tightly linked to changes in insulin sensitivity, have an impact on each individual component of the MS and on the stability of the diagnosis of MS in obese youth.

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.

Obesity and the metabolic syndrome in children and adolescents.

BACKGROUND: The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents. METHODS: We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score. RESULTS: The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the body-mass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity. CONCLUSIONS: The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.

Prevalence of impaired glucose tolerance among children and adolescents with marked obesity.

BACKGROUND: Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents. METHODS: All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. RESULTS: Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance. CONCLUSIONS: Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.

Effects of a weight management program on body composition and metabolic parameters in overweight children: a randomized controlled trial.

CONTEXT: Pediatric obesity has escalated to epidemic proportions, leading to an array of comorbidities, including type 2 diabetes in youth. Since most overweight children become overweight adults, this chronic condition results in serious metabolic complications by early adulthood. To curtail this major health issue, effective pediatric interventions are essential. OBJECTIVE: To compare effects of a weight management program, Bright Bodies, on adiposity and metabolic complications of overweight children with a control group. DESIGN: One-year randomized controlled trial conducted May 2002-September 2005. SETTING: Recruitment and follow-up conducted at Yale Pediatric Obesity Clinic in New Haven, Conn, and intervention at nearby school. PARTICIPANTS: Random sample of 209 overweight children (body mass index [BMI] >95th percentile for age and sex), ages 8 to 16 years of mixed ethnic groups were recruited. A total of 135 participants (60%) completed 6 months of study, 119 (53%) completed 12 months. INTERVENTION: Participants were randomly assigned to either a control or weight management group. The control group (n = 69) received traditional clinical weight management counseling every 6 months, and the weight management group (n = 105) received an intensive family-based program including exercise, nutrition, and behavior modification. Intervention occurred biweekly the first 6 months, bimonthly thereafter. The second randomization within the weight management group assigned participants (n = 35) to a structured meal plan approach (dieting), but this arm of the study was discontinued while enrollment was ongoing due to a high dropout rate. MAIN OUTCOME MEASURES: Change in weight, BMI, body fat, and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 and 12 months. RESULTS: Six-month improvements were sustained at 12 months in weight management vs control, including changes in the following (mean [95% confidence interval]): weight (+0.3 kg [-1.4 to 2.0] vs +7.7 kg [5.3 to 10.0]); BMI (-1.7 [-2.3 to -1.1] vs +1.6 [0.8 to 2.3]); body fat (-3.7 kg [-5.4 to -2.1] vs +5.5 kg [3.2 to 7.8]); and HOMA-IR (-1.52 [-1.93 to -1.01] vs +0.90 [-0.07 to 2.05]). CONCLUSION: The Bright Bodies weight management program had beneficial effects on body composition and insulin resistance in overweight children that were sustained up to 12 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00409422.

Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat.

BACKGROUND: Concurrent with the rise in obesity, nonalcoholic fatty liver disease is recognized as the leading cause of serum aminotransferase elevations in obese youth. Nevertheless, the complete metabolic phenotype associated with abnormalities in biomarkers of liver injury and intrahepatic fat accumulation remains to be established. METHODS: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging. FINDINGS: Elevated ALT (> 35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18-35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver. INTERPRETATION: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.