Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial.

Aims/hypothesis: Insulin resistance and compensatory hyperinsulinaemia are core features leading to beta cell failure in youth-onset type 2 diabetes. Insulin clearance (IC) is also a key regulator of insulin concentrations, but few data exist on IC in youth-onset type 2 diabetes. In a secondary analysis of our Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomised clinical trial, we investigated potential sex-, race-, ethnicity- and treatment-related differences in IC in youth-onset type 2 diabetes and aimed to identify metabolic phenotypes associated with IC at baseline and in response to metformin, metformin plus a lifestyle intervention, and metformin plus rosiglitazone.

Prediction models of basal energy expenditure in children and adolescents across the BMI spectrum based on room calorimetry: a cross-sectional cohort study.

Background: Existing equations for prediction of basal energy expenditure (BEE) may not be accurate in children with overweight or obesity (OW/OB).

Objectives: We aimed to develop BEE prediction equations applicable to children and adolescents across a wide BMI spectrum using gold standard room calorimetry.

Methods: We measured weight, height, waist and hip circumferences, body composition (DXA), and BEE (whole room calorimetry) in a cross-sectional cohort of 1155 healthy children, 5-19 years of age.

Proteomic Analysis Uncovers Multiprotein Signatures Associated with Early Diabetic Kidney Disease in Youth with Type 2 Diabetes Mellitus.

Key Points: Proteomics analyses identified seven proteins predictive of time to development of albuminuria among youth with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth cohort, 118 proteins predictive of time to development of hyperfiltration, and three proteins predictive of time to rapid eGFR decline. Seven proteins were predictive of all three outcomes (SEM4A, PSB3, dihydroxyphenylalanine decarboxylase, C1RL1, T132A, pyruvate carboxylase, and C1-esterase inhibitor) and have been implicated in immune regulatory mechanisms, metabolic dysregulation, proteostasis, and cellular signaling pathways. Elastic net Cox proportional hazards model identified distinct multiprotein signatures (38–68 proteins) of time to albuminuria, hyperfiltration, and rapid eGFR decline with concordance for models with clinical covariates and selected proteins between 0.

Fluoxetine and Sertraline Inhibit Height Growth and Growth Hormone Signaling During Puberty.

Purpose: The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty.

Methods: In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion.

Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth.

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications.

The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy.

Distinct Amino Acid Profile Characterizes Youth With or at Risk for Type 2 Diabetes.

Branched-chain amino acids (BCAAs) and aromatic AAs (AAAs) are associated with increased risk for type 2 diabetes in adults. Studies in youth show conflicting results. We hypothesized that an AA metabolomic signature can be defined to identify youth at risk for β-cell failure and the development of type 2 diabetes.

Prognostic factors in resolution of nonalcoholic fatty liver disease post bariatric surgery in adolescents.

Background: The long-term effect of bariatric surgery on adolescent non-alcoholic fatty liver disease is not clear.

Objectives: To evaluate longitudinal change in serum alanine aminotransferase (ALT) levels and to determine the factors independently associated with this change over 2 years after bariatric surgery in adolescents with severe obesity.

Setting: An observational prospective cohort from the Teen-LABS Consortium.

Re-analysis and meta-analysis of summary statistics from gene-environment interaction studies.

Motivation: statistics from genome-wide association studies enable many valuable downstream analyses that are more efficient than individual-level data analysis while also reducing privacy concerns. As growing sample sizes enable better-powered analysis of gene-environment interactions, there is a need for gene-environment interaction-specific methods that manipulate and use summary statistics.

Results: We introduce two tools to facilitate such analysis, with a focus on statistical models containing multiple gene-exposure and/or gene-covariate interaction terms.

Hyperglycemia: A determinant of cardiac autonomic dysfunction in youth with obesity across the spectrum of glycemic regulation.

Objectives: To characterize the determinants of heart rate variability (HRV) in youth with obesity across the glycemia spectrum.

Methods: A total of 94 adolescents, 15 ± 2.1 years (21 with normal weight, 23 with overweight-normal glucose tolerance, 26 with prediabetes and 24 with type 2 diabetes [T2D]) underwent an assessment of body composition (dual-energy x-ray absorptiometry), 2-h oral glucose tolerance test with the calculation of indices of glycemia and insulin sensitivity (IS), inflammatory markers (high-sensitivity C-reactive protein [hs-CRP] and tumour necrosis factor-α [TNF-α]), and HRV by peripheral arterial tonometry.

Characteristics of Type 2 Diabetes in Female and Male Youth.

The incidence of type 2 diabetes in children is rising and carries a worse prognosis than in adults. The influence of sex on pediatric type 2 diabetes outcomes has not been well investigated. We studied 715 youth with type 2 diabetes diagnosed at a median age of 13.

Candidate biomarkers as predictors of future kidney disease and cardiovascular dysfunction in adolescents with type 2 diabetes.

Aims: Evaluate changes in circulating biomarkers as predictors of kidney disease, and cardiac/vascular dysfunction in participants from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

Methods: Candidate biomarkers were assessed annually in 507 participants over a mean follow-up of 6.9 ± 2.

The roles of sleep and eating patterns in adiposity gain among preschool-aged children.

Background: Short sleep durations are related to risks for obesity in preschool children. However, the underlying mechanism or mechanisms are not clear.

Objectives: We evaluated the relationships between sleep characteristics and body composition, energetics, and weight-regulating behaviors in preschool-aged children, as well as the longitudinal associations between children's sleep and eating patterns and body composition at a 1-year follow-up.

Adiposity, Insulin Resistance, Cardiorespiratory Fitness, and Bone Health in Hispanic Children.

Context: Childhood obesity disproportionately affects Hispanic youth. The skeletal system appears to be a target organ of the adverse effects of obesity. Yet, the relationship between adiposity and bone health in youth and the modulating factors are not well understood.

Estimating circadian phase in elementary school children: leveraging advances in physiologically informed models of circadian entrainment and wearable devices.

Study Objectives: Examine the ability of a physiologically based mathematical model of human circadian rhythms to predict circadian phase, as measured by salivary dim light melatonin onset (DLMO), in children compared to other proxy measurements of circadian phase (bedtime, sleep midpoint, and wake time).

Methods: As part of an ongoing clinical trial, a sample of 29 elementary school children (mean age: 7.4 ± .

Relationship between Arterial Stiffness and Subsequent Cardiac Structure and Function in Young Adults with Youth-Onset Type 2 Diabetes: Results from the TODAY Study.

Background: Higher arterial stiffness may contribute to future alterations in left ventricular systolic and diastolic function. We tested this hypothesis in individuals with youth-onset type 2 diabetes from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

Methods: Arterial stiffness (pulse wave velocity [carotid-femoral, femoral-foot, and carotid-radial], augmentation index, brachial distensibility) was measured in 388 participants with type 2 diabetes (mean age, 21 years; diabetes duration, 7.

Longitudinal changes in vascular stiffness and heart rate variability among young adults with youth-onset type 2 diabetes: results from the follow-up observational treatment options for type 2 diabetes in adolescents and youth (TODAY) study.

Aims: (1) To describe changes in arterial stiffness and heart rate variability (HRV) over a 5-year interval, (2) examine changes by sex and race-ethnicity, and (3) evaluate the risk factors associated with the longitudinal changes in arterial stiffness and HRV.

Methods: Participants with youth-onset type 2 diabetes enrolled in the observational follow-up phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial had arterial stiffness [(pulse wave velocity, augmentation index, brachial distensibility] and six indices of HRV measured 5 years apart. Multivariable linear regression models assessed risk factors associated with changes in the outcomes over time.

Racial and Ethnic Disparities in Comorbidities in Youth With Type 2 Diabetes in the Pediatric Diabetes Consortium (PDC).

Background: Type 2 diabetes in the U.S. is more prevalent in youth of minority racial-ethnic background, but disparities in health outcomes have not been examined in this population.

Type 2 diabetes in prepubertal children.

Objective: Puberty-induced insulin resistance is considered critical in the pathogenesis of type 2 diabetes (T2D) in youth. The development of T2D before puberty suggests distinct risk factors and pathophysiology but, because of its rarity, this has not been well studied. We aimed to describe the clinical characteristics of children with T2D diagnosed before the onset of puberty.

Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration.

Objective: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.

Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

Objective: We aimed to test whether type 2 diabetes (T2D)-associated genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).

Research Design And Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants ( = 1,061) (mean age 16.3 years) with single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion.

The Shape of the Oral Glucose Tolerance Test-Glucose Response Curve in Islet Cell Antibody-Positive vs. -Negative Obese Youth Clinically Diagnosed with Type 2 Diabetes.

Background: The oral glucose tolerance test (OGTT)-glucose response curves (GRCs; incessant increase, monophasic, and biphasic) reflect insulin sensitivity and β-cell function, being worse in the former and superior in the latter. Here, we examined if the OGTT-GRC pattern is worse in obese antibody (glutamic acid decarboxylase 65-kDa [GAD65] and insulinoma-associated protein-2 [IA-2])-positive (Ab) vs. -negative (Ab) youth clinically diagnosed with type 2 diabetes (CDX-T2D).