Real-world use of glucagon-like peptide-1 receptor agonists in youth with type 2 diabetes is associated with short-term improvements in HbA1c.

AIM: To assess the short-term, real-world use and effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) medications in the management of type 2 diabetes (T2D) in a diverse cohort of youth. METHODS: This multicentre retrospective study analysed youth prescribed a GLP-1RA for the management of T2D at two academic paediatric diabetes centres prior to June 2022. Change in HbA1c and insulin use from baseline to first (median 91 days) and second (median 190 days) follow-up were evaluated for those taking a GLP-1RA. Multivariable linear mixed effects models adjusting for baseline sex, age, race/ethnicity, insurance, insulin regimen, metformin regimen, GLP-1RA dosing frequency and the body mass index Z-score (BMI-Z) examined the change in HbA1c for participants for up to 6 months after baseline. RESULTS: A total of 136 patients with T2D (median age 16.1 [interquartile range 13.9-18.0] years, 54% female, 56% non-Hispanic Black, 24% Hispanic, 77% with public insurance) were prescribed GLP-1RAs and taking them at first or second follow-up. Median HbA1c decreased from 7.9% to 7.6% (P < .001) at a median follow-up of 91 days (n = 109) and, among those with HbA1c available at baseline and second follow-up (n = 83), from 8.4% to 7.4%. The proportion of patients prescribed insulin decreased from baseline to the first follow-up visit (basal 69% to 60% [P = .008], prandial 46% to 38% [P = .03]). In multivariable analysis, there was a mean decrease in HbA1c by 0.09 percentage points per month (P = .005, 95% confidence interval -0.15, -0.03). CONCLUSIONS: Real-world use of GLP-1RAs in youth with T2D is associated with decreased HbA1c levels, despite challenges with access and adherence. GLP-1RA treatment may reduce insulin doses for youth with T2D.

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity.

In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on ß cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in ß cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of ß cell function and weight in youths with obesity.

Comparison of Metabolic Response to Colonic Fermentation in Lean Youth vs Youth With Obesity.

Importance: Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention. Objective: To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentation of dietary fibers and its production of acetate, gut-derived hormone secretion, and adipose tissue lipolysis. Design, Setting, and Participants: Cross-sectional study of youths aged 15 to 22 years with body mass index in the 25th to 75th percentile or higher than the 85th percentile for age and sex throughout the New Haven County community in Connecticut. Recruitment, studies, and data collection occurred from June 2018 to September 2021. Youths were assigned to a lean, obese insulin sensitive (OIS), or obese insulin resistant (OIR) group. Data were analyzed from April 2022 to September 2022. Exposure: Participants consumed 20 g of lactulose during a continuous 10-hour sodium d3-acetate intravenous infusion to measure the rate of appearance of acetate in plasma. Main Outcomes and Measures: Plasma was obtained hourly to measure acetate turnover, peptide tyrosine tyrosine (PYY), ghrelin, active glucagon-like peptide 1 (GLP-1), and free fatty acids (FFA). Results: A total of 44 youths participated in the study (median [IQR] age, 17.5 [16.0-19.3] years; 25 [56.8%] were female; 23 [52.3%] were White). Consequent to lactulose ingestion, there was a reduction of plasma FFA, an improvement of adipose tissue insulin sensitivity index, an increase in colonic acetate synthesis, and an anorexigenic response characterized by an increased plasma concentration of PYY and active GLP-1 and a reduction of ghrelin in the subgroups. Compared with the lean and OIS groups, the OIR group showed a less marked median (IQR) rate of acetate appearance (OIR: 2.00 [-0.86 to 2.69] µmol × kg-1 × min-1; lean: 5.69 [3.04 to 9.77] µmol × kg-1 × min-1; lean vs OIR P = .004; OIS: 2.63 [1.22 to 4.52] µmol × kg-1 × min-1; OIS vs OIR P = .09), a blunted median (IQR) improvement of adipose insulin sensitivity index (OIR: 0.043 [ 0.006 to 0.155]; lean: 0.277 [0.220 to 0.446]; lean vs OIR P = .002; OIS: 0.340 [0.048 to 0.491]; OIS vs OIR P = .08), and a reduced median (IQR) PYY response (OIR: 25.4 [14.8 to 36.4] pg/mL; lean: 51.3 [31.6 to 83.3] pg/mL; lean vs OIR P = .002; OIS: 54.3 [39.3 to 77.2] pg/mL; OIS vs OIR P = .011). Conclusions and Relevance: In this cross-sectional study, lean, OIS, and OIR youth demonstrated different associations between colonic fermentation of indigestible dietary carbohydrates and the metabolic response, with OIR youth showing minimal metabolic modifications as compared with the other 2 groups. Trial Registration: ClinicalTrials.gov Identifier: NCT03454828.

Rising NAFLD and metabolic severity during the Sars-CoV-2 pandemic among children with obesity in the United States.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), the most common liver disease among youth with obesity, precedes more severe metabolic and liver diseases. However, the impact of the Sars-CoV-2 global pandemic on the prevalence and severity of NAFLD and the associated metabolic phenotype among youth with obesity is unknown. METHODS: Participants were recruited from the Yale Pediatric Obesity Clinic during the Sars-CoV-2 global pandemic (August 2020 to May 2022) and were compared with a frequency-matched control group of youth with obesity studied before the Sars-CoV-2 global pandemic (January 2017 to November 2019). Glucose metabolism differences were assessed during an extended 180-minute oral glucose tolerance test. Magnetic resonance imaging-derived proton density fat fraction (PDFF) was used to determine intrahepatic fat content in those with NAFLD (PDFF ≥ 5.5). RESULTS: NAFLD prevalence increased in participants prior to (36.2%) versus during the Sars-CoV-2 pandemic (60.9%), with higher PDFF values observed in participants with NAFLD (PDFF ≥ 5.5%) during versus before the pandemic. An increase in visceral adipose tissue and a hyperresponsiveness in insulin secretion during the oral glucose tolerance test were also observed. CONCLUSIONS: Hepatic health differences were likely exacerbated by environmental and behavioral changes associated with the pandemic, which are critically important for clinicians to consider when engaging in patient care to help minimize the future risk for metabolic perturbations.

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.

Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach.

OBJECTIVE: In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and ß-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS: Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and ß-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and ß-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in ß-cell glucose sensitivity. CONCLUSIONS: We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by ß-cell glucose sensitivity.

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.

A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of ß-Cell Dysfunction in Obese Youth.

OBJECTIVE: The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, ß-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. RESEARCH DESIGN AND METHODS: Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT - AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. RESULTS: The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. CONCLUSIONS: A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort.

AIM: To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups. METHODS: The intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi-ethnic cohort of 632 obese youths aged 7-18 years at baseline and after a 2-year follow-up. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C-peptide data during 3-hour, 9-point oral glucose tolerance tests. RESULTS: African American youths exhibited the lowest HFF% and a prevalence of non-alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose-stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group-specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist-hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow-up was associated with decreased EIC and increased HIRI across all groups. CONCLUSIONS: Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.

How Forcefully Should Clinicians Encourage Treatment When Disagreement Persists About Obesity Risk?

Pediatric obesity is a major public health problem, and weight reduction in children and adolescents with obesity is associated with improvement in health outcomes. This case of an adolescent diagnosed with obesity whose mother disagrees with the diagnosis illustrates challenges often encountered in clinical practice, including (1) diagnosing a disease in an asymptomatic patient whose future risk for negative health outcomes is uncertain, (2) addressing ethical implications of naming a stigmatizing disease, and (3) resolving conflicting goals and opinions of a patient, caregiver, and physician. Suggestions for navigating disagreement and implementing courses of action are discussed.

Neonatal Thyrotoxicosis.

Neonatal thyrotoxicosis (hyperthyroidism) is less prevalent than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. Most cases are transient, secondary to maternal autoimmune hyperthyroidism (Graves disease [GD]). This article summarizes recommendations for screening and management of hyperthyroidism in both the fetal and neonatal periods, with a focus on neonatal thyrotoxicosis secondary to maternal GD. Early monitoring and treatment are crucial for optimizing short-term and long-term patient outcomes.

Characteristics of Follicular Variant Papillary Thyroid Carcinoma in a Pediatric Cohort.

Context: In adults, noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) is considered a low risk for metastasis and persistent/recurrent disease. Objective: The goal of this study was to assess the clinical, sonographic, and histopathologic features of FVPTC in a pediatric cohort. Design: A retrospective review of subjects <19 years of age with papillary thyroid carcinoma (PTC) who underwent thyroidectomy between January 2010 and July 2015. Setting: Multidisciplinary academic referral center. Patients: Patients with FVPTC, defined as a tumor ≥1 cm in the largest dimension with predominant follicular growth, complete lack of well-formed papillae, and nuclear features of PTC. Main Outcome Measures: Tumor size and location, presence of a tumor capsule, capsule and vascular invasion, lymph node invasion, and distant metastasis. Results: Eighteen patients with FVPTC were identified from a case cohort of 110 patients with PTC. On histopathology, 13 (72%) had unifocal nodules and 14 (78%) had completely encapsulated FVPTC. Capsule invasion was frequent (nine of 14; 64%), and vascular invasion was found in one-third of patients (six of 18; 33%). No lymph node metastases were found in the 13 patients (72%) who had a central neck lymph node dissection. One patient with vascular invasion had distant metastases. Conclusion: When strictly defined, FVPTC in pediatric patients has a low risk for bilateral disease and metastasis. Prospective studies are needed to confirm whether lobectomy with surveillance is sufficient to achieve remission in pediatric patients with low-risk FVPTC.