Search

Background Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. Objectives We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. Methods Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. Results CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. Conclusions The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

(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. 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. At initial vascular assessment, the 304 participants were a mean age of 21 years, 34% male, and had a mean diabetes duration of 8 years. In more than half the cohort pulse wave velocity, augmentation index and HRV increased over 5 years (p

Adolescents with type 1 diabetes are vulnerable to suboptimal glycemic control, generally due to insufficient self-care behaviors (1,2). Because they have some of the highest rates of mobile communication technology use (3), this modality may hold promise for providing reminders or encouragement to adolescents to engage in self-care. However, the effects of text messaging interventions on self-care and glycemic outcomes are mixed, with some reports favoring improvements in teen self-care behaviors such blood glucose monitoring frequency or medication adherence (4–7). In an alternative attempt to reach this high-risk age-group, researchers have explored the use of financial incentives to promote self-care behaviors, which yielded some glycemic benefit in the short term (8,9). However, there is limited research on the combination of a financial incentive and a mobile health intervention (10,11) and the potential benefits that could accrue from blending these approaches. Nonetheless, use of either a unimodal or a bimodal intervention requires that adolescent recipients remain engaged with the program. In this report, we describe adolescent engagement during a 6-month study of a psychoeducational text messaging intervention that incorporated financial incentives. The primary study included adolescents with type 1 diabetes in suboptimal control and showed a potential increase in self-reported self-care in those receiving the intervention as intended (10). This analysis of the primary study’s intervention group described patterns of adolescent engagement with the intervention and identified factors associated with responsiveness. We also evaluated the potential impact of engagement on glycemic outcomes and self-care. This study analyzed 6 months of data from teenagers with type 1 diabetes receiving an incentivized text messaging intervention aimed at increasing education and support for diabetes self-care. Youths were eligible for inclusion if they were 12–18 years of age, had a duration of type 1 diabetes of …

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. RESEARCH DESIGN AND METHODS We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years.Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups.A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic.The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

To understand the relationship of obesity and 27 circulating inflammatory biomarkers to the prevalence of non-proliferative diabetic retinopathy (NPDR) in youth with type 2 diabetes.Youth with type 2 diabetes who participated in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study were followed for 2-6.5 years. Digital fundus photographs were obtained in the last year of the study. Blood samples during the study were processed for inflammatory biomarkers, and these were correlated with obesity tertiles and presence of retinopathy.Higher BMI was associated with an increase in circulating levels of metabolic biomarkers including high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor 1 (PAI-1), fibrinogen, LDL-cholesterol (LDL-C) and Apolipoprotein B (ApoB), tumor necrosis factor receptors 1 and 2 (TNFR-1 and -2), interleukin 6 (IL-6), E-selectin, and homocysteine, as well as a decrease in the metabolic risk markers HDL-cholesterol (HDLC), and insulin-like growth factor binding protein 1 (IGFBP-1). Although NPDR risk decreased with increasing obesity, it was not associated with any of the measured biomarkers.Circulating levels of measured biomarkers did not elucidate the "obesity paradox" of decreased NPDR in the most obese participants in the TODAY study.clinicaltrials.govNCT00081328.

Background Non-adherence to diabetes medication leads to poor outcomes and increased healthcare costs. Multiple factors affecting adherence in adults with type 2 diabetes (T2D) have been identified, but pediatric data is sparse. We aimed to determine whether initiation of additional oral medications or insulin affects adherence to primary study medication (PSM) in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Six hundred and ninety-nine youth (aged 10–17 years) with recent-onset T2D were randomized in the TODAY study. Participants were categorized as adherent (≥80% taken by pill count) or non-adherent ( Results At 36 months, 46.3% of participants were taking additional oral medications and 31.9% were on insulin. There was no difference in study medication adherence with additional oral medications (55.1%, 67.1%, and 56.7% at month 36 in those prescribed 0, 1, or 2+ additional medications; p = 0.16). Girls on oral contraceptives (OC) had higher adherence (65.2% vs. 55.8% at month 36; p = 0.0054). Participants on insulin had lower adherence (39.7% vs. 59.3% at 36 months; p Conclusions Additional oral medications did not influence adherence to diabetes medications in TODAY. Addition of insulin led to reduced adherence. In subgroup analyses, OC use was associated with higher adherence in girls, while baseline depression was associated with lower adherence overall. Further studies examining potentially modifiable risk factors of adherence in pediatric T2D are needed.

Objectives To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. Methods Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO2; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO2; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). Results Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3–0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=−0.4, p=0.005) and SpO2 nadir (r=−0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. Conclusions Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

Context Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown. Objective This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance. Methods An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years. Results Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non–HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years. Conclusion Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity.

Objective: Data related to diabetic neuropathy in youth with type 2 diabetes are limited. We examined the relationship of glycemic control, sex, race-ethnicity, BMI, and other type 2 diabetes-associated factors with the development of diabetic peripheral neuropathy (DPN) in type 2 diabetes youth enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Research Design and Methods: The Michigan Neuropathy Screening Instrument (MNSI) and a 10-gram monofilament exam were performed annually. DPN was defined as a score (>2) on the MNSI-exam or combined MNSI-exam and MNSI-survey scores (exam >2 and/or survey ≥4), or monofilament ( Results: 674 participants (35% male), with mean age 14 years and diabetes duration Conclusions: DPN was evident early in the course of youth-onset type 2 diabetes and increased over time. It was higher in males and related to glycemic control. These findings raise concern for long-term development of neuropathy-related morbidity in youth with type 2 diabetes and the need to achieve improved glycemic control.

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 7.7 ± 1.5). To reflect overall (composite) vascular stiffness, the five arterial stiffness measures were aggregated. An echocardiogram was performed in the same cohort 2 years later. Linear regression models assessed whether composite arterial stiffness was associated with left ventricular mass index, systolic and diastolic function, independent of age, sex, race-ethnicity, current cigarette smoking, and long-term exposure (time weighted mean values over 9.1 years) of hemoglobin A1c, blood pressure, and body mass index. Interactions between arterial stiffness and time weighted mean hemoglobin A1c, blood pressure, and body mass were also examined. RESULTS. After adjustment, arterial stiffness remained significantly associated with left ventricular mass index and diastolic function measured by mitral valve E/Em despite attenuation by time weighted mean body mass index. A significant interaction revealed greater adverse effect of composite arterial stiffness on mitral valve E/Em among participants with higher levels of blood pressure over time. Arterial stiffness was unrelated to left ventricular systolic function. CONCLUSIONS. The association of higher arterial stiffness with future left ventricular diastolic dysfunction suggests the path to future heart failure may begin early in life in this setting of youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328

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 multi-ethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. Research design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. Results: 93 of 3,333 participants (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs 13.6 ± 2.3 years, P=0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs 4.7 ± 3.5 ng/mL, Pvs 19.5%, P=0.007) and had higher HDL cholesterol (43.8 vs 39.7 mg/dL, P=0.006). Conclusions: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria to select individuals for genetic testing.

OBJECTIVE To determine whether prior type 2 diabetes (T2D) treatment or glycemic control over time are independently associated with heart rate variability (HRV) and whether the presence of cardiac autonomic dysfunction is associated with arterial stiffness in young adults with youth-onset T2D enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS Heartbeats over 10 min were measured to derive the normal R-Rs (NN intervals). Outcomes included the standard deviation of the NN intervals (SDNN), the root mean square differences of successive NN intervals (RMSSD), percent of NN beats that differ by more than 50 ms (PNN50), and the low-frequency (LF) power domain, high-frequency (HF) power domain, and their ratio (LF:HF). Autonomic dysfunction was defined as ≥3 of 5 abnormal HRV indices compared with obese controls from a separate study. RESULTS A total of 397 TODAY participants were evaluated 7 years after randomization. TODAY participants had reduced HRV (SDNN 58.1 ± 29.6 ms vs. controls 67.1 ± 25.4 ms; P < 0.0001) with parasympathetic loss (RMSSD 53.2 ± 36.7 ms vs. controls 67.9 ± 35.2 ms; P < 0.0001) with sympathetic overdrive (LF:HF ratio 1.4 ± 1.7 vs. controls 1.0 ± 1.1; P < 0.0001). Cardiac autonomic dysfunction was present in 8% of TODAY participants, and these participants had greater pulse wave velocity compared with those without dysfunction (P = 0.0001). HRV did not differ by randomized treatment, but higher hemoglobin A1c (HbA1c) over time was independently associated with lower SDNN and RMSSD and higher LF:HF ratio after adjustment for age, race-ethnicity, sex, and BMI. CONCLUSIONS Young adults with youth-onset T2D show evidence of cardiac autonomic dysfunction with both parasympathetic and sympathetic impairments that are associated with higher HbA1c.

OBJECTIVE: To understand the factors associated with glycemic control after starting insulin in youth with type 2 diabetes following glycemic failure (persistent HbA1c ≥8%) with metformin alone, metformin+rosiglitazone or metformin+lifestyle in the TODAY study. METHODS: Change in HbA1c after add-on insulin therapy and the factors predictive of glycemic response were evaluated. At one-year post-insulin initiation, 253 youth had a mean of 3.9±1.0 visits since the time of insulin initiation. Participants were divided into three groups according to glycemic control: consistent decrease in HbA1c by ≥0.5%, change < 0.5%, or consistent increase in HbA1c ≥0.5%, at 75% or more of the visits. RESULTS: Within one-year post-insulin initiation, 33.2% of participants had a consistent HbA1c decrease of ≥0.5%, 46.2% changed HbA1c

Purpose The purpose of this study was to determine the feasibility and functionality of MyDiaText™, a website and text messaging platform created to support behavior change in adolescents with type 1 diabetes (T1DM) and to evaluate user satisfaction of the application. Methods This study was a nonrandomized, prospective, pilot trial to test the feasibility and user interface with MyDiaText, a text message system for 10- to 17-year-old youths with newly diagnosed T1DM. Feasibility was evaluated by assessing for the user’s ability to create a profile on the website. Functionality was defined by assessing whether a subject responded to at least 2 text messages per week and by their accumulating points on the website. User satisfaction of the text messaging system was assessed using an electronic survey. The 4 phases of this study were community engagement—advisory sessions, screening and enrollment, intervention, and follow-up. Results Twenty subjects (14 male, 6 female) were enrolled. All subjects were able to create a profile, and of these, 86% responded to at least 2 text messages per week. A survey administered during follow-up showed that users enjoyed reading text messages, found them useful, and thought the frequency of messages was appropriate. Conclusion MyDiaText is a feasible, functional behavioral support tool for youth with T1DM. Users of the application reported high satisfaction with text messages and the reward system.

Background Due to high rates of comorbidities and rapid progression, youth with type 2 diabetes may benefit from early and aggressive treatment. However, until 2019, the only approved medications for this population were metformin and insulin. Objective To investigate patterns and predictors of treatment escalation within 5 years of metformin monotherapy initiation for youth with type 2 diabetes in clinical practice. Subjects Commercially-insured patients with incident youth-onset (10-18 years) type 2 diabetes initially treated with metformin only METHODS: Retrospective cohort study using a patient-level medical claims database with data from 2000 - 2020. Frequency and order of treatment escalation to insulin and non-insulin antihyperglycemics were determined and categorized by age at diagnosis. Cox proportional hazards regression was used to evaluate potential predictors of treatment escalation, including age, sex, race/ethnicity, comorbidities, complications, and metformin adherence (medication possession ratio ≥0.8). Results The cohort included 829 (66% female; median age at diagnosis 15 years; 19% Hispanic, 17% Black) patients, with median 2.9-year follow-up after metformin initiation. One-quarter underwent treatment escalation (n=207; 88 to insulin, 164 to non-insulin antihyperglycemic). Younger patients were more likely to have insulin prescribed prior to other antihyperglycemics. Age at diagnosis (HR 1.14, 95% CI 1.07-1.21), medication adherence (HR 4.10, 95% CI 2.96-5.67), Hispanic ethnicity (HR 1.83, 95% CI 1.28-2.61), and diabetes-related complications (HR 1.78, 95% CI 1.15-2.74) were positively associated with treatment escalation. Conclusions In clinical practice, treatment escalation for pediatric type 2 diabetes differs with age. Off-label use of non-insulin antihyperglycemics occurs, most commonly among older adolescents. This article is protected by copyright. All rights reserved.

Background: Onset of type 2 diabetes (T2D) in youth confers a high risk of early adverse cardiovascular outcomes. We describe the cumulative incidence of hypertension, LDL-cholesterol dyslipidemia, hypertriglyceridemia, and prevalence of smoking over time, and examine the relationships with body mass index and measures of glycemia, insulin sensitivity, and beta-cell function in an adolescent cohort with T2D enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods: Longitudinal data from the TODAY clinical trial and TODAY2 observational follow-up study were used to evaluate the relationships between hypertension, LDL-C dyslipidemia, hypertriglyceridemia, and smoking with risk factors using time-to-event models and generalized estimating equation models. Findings: Data were available on 677 participants. Mean age at baseline was 14±2 years and mean follow-up 10·2±4·5 years. The 14-year cumulative incidence of hypertension, LDL-C dyslipidemia, and hypertriglyceridemia was 59%, 33%, and 37% respectively, and the average prevalence of reported smoking was 23%. Male sex, non-Hispanic white race/ethnicity, obesity, poor glycemic control, lower insulin sensitivity, and reduced beta-cell function were significantly associated with an unfavorable cardiovascular risk profile. After an average of 10·2 years of follow-up, 54% of the cohort had ≥2 cardiovascular risk factors in addition to T2D. Interpretation: Cardiovascular risk factor incidence and prevalence was high over a decade of follow-up in young adults with youth-onset T2D. Addressing glucose control and insulin sensitivity, as well as medical management of cardiovascular risk factors will be critical in youth with T2D for prevention of cardiovascular morbidity and mortality. Trial Registration: Clinicaltrials.gov NCT00081328. Funding: United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Declaration of Interest: None of the authors reported a conflict of interest. Ethical Approval: The TODAY and TODAY2 studies were approved by institutional review boards at all 15 centers and all participants and guardians provided written informed assent and/or consent as appropriate for age.

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment compared to metformin alone or metformin plus intensive lifestyle intervention. At end of study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report post-intervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and beta-cell function outcomes. Research Design and Methods: A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA1c ≥8% over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY or a sustained HbA1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted and insulin sensitivity, insulinogenic index, and oral disposition index (oDI) were calculated. Results: During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and beta-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care, but did not differ by treatment group assignment. Conclusions: The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.

Pediatric type 2 diabetes mellitus (T2DM) is increasing in incidence, with risk factors including obesity, puberty, family history of T2DM in a first-degree or second-degree relative, history of small-for-gestational-age at birth, child of a gestational diabetes pregnancy, minority racial group, and lower socioeconomic status. The pathophysiology of T2DM consists of insulin resistance and progression to pancreatic beta-cell failure, which is more rapid in pediatric T2DM compared with adult T2DM. Treatment options are limited. Treatment failure and nonadherence rates are high in pediatric T2DM; therefore, early diagnosis and treatment and new pharmacologic options and/or effective behavioral interventions are needed. © 2020 Elsevier Inc.

Background: Heart failure is a prominent complication of type 2 diabetes mellitus (T2D). The goal of this study was to provide longitudinal data on cardiac structure and function (and cross-sectional comparison to normal-weight and obese controls without T2D) in individuals followed from adolescence with youth-onset T2D. Methods: In the TODAY study (Treatment Options for Type 2 Diabetes Mellitus in Adolescents and Youth), echocardiograms were performed at study years 4 to 5 and 9 to 10. Echocardiograms were also obtained at years 8 to 9 in a control population of age, race/ethnicity, and sex-matched normal-weight and obese individuals without diabetes mellitus. Study outcomes were measures of left ventricular structure and function. The cohort included 411 participants with T2D, 194 obese controls, and 51 normal-weight controls. Results: At follow-up, mean participant age was 23 years, 65% women, 20% non-Hispanic white, 35% non-Hispanic black, and 39% Hispanic. Ejection fraction was P P Conclusions: Adverse changes in cardiac structure and function changed significantly from adolescence to early adulthood in participants with youth-onset T2D. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00081328.

BACKGROUND: The Treatment Options for type 2 Diabetes in Adolescent and Youth study, a randomized clinical trial of three treatments for type 2 diabetes (T2DM) in youth, demonstrated treatment failure (defined as sustained HbA1c ≥8%, or inability to wean insulin after 3 months after acute metabolic decomposition) in over half of the participants. Given that binding of mononuclear cells to vascular endothelium, initiated by cellular adhesion molecules and chemokines, is an early step in vascular injury, we sought to evaluate (a) changes in cellular adhesion molecule levels during the trial; (b) effect of diabetes treatment; and (c) association of markers with HbA1c, hypertension, hypercholesterolemia, nephropathy, and retinopathy. METHODS: Participants (n = 515 of 699) that had baseline assessment of adhesion molecules (monocyte chemoattractant protein-1 [MCP-1], vascular cell adhesion marker [VCAM], intercellular adhesion marker [ICAM], and E-Selectin) and at least one other assessment, measured at month 12, 24, or 36, were included. RESULTS: Over 1 to 3 years, significant increases in MCP-1 and decreases in VCAM (both P < .0001) concentrations were found; however, no significant interactions were identified with treatment group for any molecule. For every 1% increase in HbA1c, ICAM increased by 1.8%, VCAM by 1.5%, and E-selectin by 6.8% (all P < .0001). E-selectin increased by 3.7% and 4.2% for every 10 mm Hg increase in systolic and diastolic blood pressure, respectively (both P < .0001). ICAM was 10.2% higher and E-selectin was 15.5% higher in participants with microalbuminuria (both P < .01). There was no significant association of adhesion molecule levels with retinopathy. CONCLUSION: Concentrations of cellular adhesion molecules rise with increasing HbA1c in youth with T2DM, and are associated with blood pressure and microalbuminuria, markers of vascular injury.

Hypocalcemia is one of the cardinal features of the chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome. Hypocalcemia and other features of 22q11.2DS including congenital heart disease (CHD) are primarily ascribed to problems with morphogenesis and function of the pharyngeal arch system derivatives including the parathyroid glands, the aortic arch, and the cardiac outflow tract. In light of the aforementioned embryology, we hypothesized that hypocalcemia would be identified more frequently in those patients with 22q11.2DS and CHD. We conducted a retrospective IRB approved chart review on 1,300 subjects with 22q11.2DS evaluated at the Children's Hospital of Philadelphia. χ2 test was used to evaluate the statistical significance of differences in hypocalcemia between the two groups. Eight hundred fifty-two patients had calcium levels available for review. Of these, 466 (54.69%) had a history of hypocalcemia and 550 (64.55%) had CHD. Of those with CHD, 343 (62.36%) had a history of hypocalcemia, and of those without CHD, only 123 (40.73%) had a history of hypocalcemia. Thus, the frequency of diagnosed hypocalcemia was greater in patients with 22q11.2DS and CHD as compared to those without CHD (p < .001). We also analyzed age of onset of hypocalcemia and found that 66.47% of CHD/hypocalcemia group had neonatal/infantile hypocalcemia versus 43.09% in the non-CHD/hypocalcemia group. In our large cohort of patients with 22q11.2DS, the prevalence of diagnosed hypocalcemia is elevated among patients with CHD, in whom it is more likely to be diagnosed during the neonatal/infancy period.

Hypocalcemia has been reported in ~50% of patients 22q11.2DS and calcium regulation is known to play a role in neuronal development and synaptic plasticity. Because calcium ions play a role in neuronal function and development, we hypothesized that hypocalcemia would be associated with adverse effects on full scale IQ index (FSIQ) in patients with 22q11.2DS. A retrospective chart review cataloguing the presence or absence of hypocalcemia in 1073 subjects with a laboratory confirmed chromosome 22q11.2 deletion evaluated at the Children's Hospital of Philadelphia was conducted. 852/1073 patients had an endocrinology evaluation with laboratory confirmed calcium levels. 466/852 (54.7%) had a diagnosis of hypocalcemia. 265/1073 subjects ranging from 0 to 51 years of age had both calcium levels measured and a neuropsychological evaluation yielding a FSIQ. The mean FSIQ for 146/265 patients with hypocalcemia was 77.09 (SD = 13.56) and the mean FSIQ for 119/265 patients with normocalcemia was 77.27 (SD = 14.25). The distribution of patients with intellectual disability (ID) (FSIQ69), borderline IQ (FSIQ 70-79), and average IQ (FSIQ80) between the hypocalcemic and normocalcemic groups was not statistically significant (χ2 = 0.2676, p = 0.8748). Neonatal hypocalcemic seizures were not found to be associated with ID. We found no difference in FSIQ between the hypocalcemic and non-hypocalcemic patients with 22q11.2DS. As our findings differ from a previous report in adult subjects, we speculate that this may reflect a potential benefit from early treatment of hypocalcemia and may support early 22q11.2 deletion detection in order to offer prompt diagnosis and subsequent treatment of hypocalcemia.

Aims We aimed to determine the prevalence of arterial stiffness in young adults with youth-onset type 2 diabetes who previously participated in the TODAY clinical trial and whether arterial stiffness is influenced by their prior diabetes treatment assignment or glycemic control. Methods We measured arterial stiffness by femoral, radial, and foot pulse wave velocity (PWV), augmentation index (AIx), and brachial distensibility (BrachD) in 453 TODAY participants (age 20.8 ± 2.5 years, diabetes duration 7.6 ± 1.5 years, 36.4% male, BMI 36.7 ± 8.2 kg/m2) at a mean of 7.6 years post-randomization. Increased arterial stiffness in TODAY youth was defined compared with data from lean controls. We assessed whether glycemic control over time or diabetes treatment in TODAY was associated with arterial stiffness. Results Arterial stiffness was identified in up to 50% of TODAY participants. Prior diabetes treatment assignment was not associated with higher arterial stiffness. Glycemic control over time was associated with PWV radial and foot only. Age, race-ethnicity, sex, higher blood pressure and BMI were also associated with higher arterial stiffness. Conclusions Nearly half of TODAY youth have increased arterial stiffness. Targeting blood pressure and perhaps obesity and glycemic control may positively impact arterial health in adolescents with type 2 diabetes. Trial registration: ClinicalTrials.gov NCT00081328 .

Background Little is known about the feasibility and impact of lifestyle intervention, determined by change in diet and cardiovascular fitness (CRF), on glycemic control in youth who are overweight with type 2 diabetes. This was examined in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial cohort from across 15 US centers. Subjects TODAY enrolled 699 youth aged 10 to 17 years with type 2 diabetes

OBJECTIVE To identify factors that predict medication adherence and to examine relationships among adherence, glycemic control, and indices of insulin action in TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth). RESEARCH DESIGN AND METHODS A total of 699 youth 10–17 years old with recent-onset type 2 diabetes and ≥80% adherence to metformin therapy for ≥8 weeks during a run-in period were randomized to receive one of three treatments. Participants took two study pills twice daily. Adherence was calculated by pill count from blister packs returned at visits. High adherence was defined as taking ≥80% of medication; low adherence was defined as taking RESULTS In this low socioeconomic cohort, high and low adherence did not differ by sex, age, family income, parental education, or treatment group. Adherence declined over time (72% high adherence at 2 months, 56% adherence at 48 months, P < 0.0001). A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%, P = 0.0415). No adherence threshold predicted the loss of glycemic control. Longitudinally, participants with high adherence had significantly greater insulin sensitivity and oDI than those with low adherence. CONCLUSIONS In the cohort, the presence of baseline clinically significant depressive symptoms was associated with subsequent lower adherence. Medication adherence was positively associated with insulin sensitivity and oDI, but, because of disease progression, adherence did not predict long-term treatment success.

OBJECTIVE Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired β-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in β-cell function. RESEARCH DESIGN AND METHODS OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C30/△G30), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups. RESULTS At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity. CONCLUSIONS In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced β-cell function and foretells increased glycemic failure rates with accelerated deterioration in β-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.

OBJECTIVE To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy. RESEARCH DESIGN AND METHODS TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: 1) those who remained in glycemic control for at least 48 months of follow-up and 2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points. RESULTS In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1). CONCLUSIONS Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non–diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.

Background/Objectives Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS’s independent contribution to macrovascular CVD risk measures in obese adolescents. Subjects/Methods This cross-sectional observational study was conducted at Children’s Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. 31 obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw, and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-à-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. Results The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. BMI associated positively with cIMTmax (r=0.52, p=0.006) and CFPWV (r=0.45, p=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=−0.63, p

Hypocalcemia is one of the cardinal features of the chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome. Hypocalcemia and other features of 22q11.2DS including congenital heart disease (CHD) are primarily ascribed to problems with morphogenesis and function of the pharyngeal arch system derivatives including the parathyroid glands, the aortic arch, and the cardiac outflow tract. In light of the aforementioned embryology, we hypothesized that hypocalcemia would be identified more frequently in those patients with 22q11.2DS and CHD. We conducted a retrospective IRB approved chart review on 1,300 subjects with 22q11.2DS evaluated at the Children’s Hospital of Philadelphia. χ(2) test was used to evaluate the statistical significance of differences in hypocalcemia between the two groups. Eight hundred fifty-two patients had calcium levels available for review. Of these, 466 (54.69%) had a history of hypocalcemia and 550 (64.55%) had CHD. Of those with CHD, 343 (62.36%) had a history of hypocalcemia, and of those without CHD, only 123 (40.73%) had a history of hypocalcemia. Thus, the frequency of diagnosed hypocalcemia was greater in patients with 22q11.2DS and CHD as compared to those without CHD (p < .001). We also analyzed age of onset of hypocalcemia and found that 66.47% of CHD/hypocalcemia group had neonatal/infantile hypocalcemia versus 43.09% in the non-CHD/hypocalcemia group. In our large cohort of patients with 22q11.2DS, the prevalence of diagnosed hypocalcemia is elevated among patients with CHD, in whom it is more likely to be diagnosed during the neonatal/infancy period.

Objectives To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function. Study design TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was a multicenter randomized trial of 3 treatments including 521 participants with type 2 diabetes, aged 10-17 years, and with 2-6 years of follow-up. Participants were 36% male, obese, and ethnically diverse. Annual serum concentrations of brain natriuretic peptide, troponin, tumor necrosis factor (TNF)-α, receptors 1 and 2 were related to blood pressure, body mass index, hemoglobin A1c, and left ventricular ejection fraction, diastolic function, relative wall thickness, and mass. Results Elevated concentrations of brain natriuretic peptide (≥100 pg/mL), TNF-α (≥5.6 pg/mL) and troponin (≥0.01 ng/mL), were present in 17.8%, 18.3%, and 34.2% of the cohort, respectively, at baseline, and in 15.4%, 17.1%, and 31.1% at the end of the study, with wide variability over time, without persistence in individuals or clear relationship to glycemia or cardiovascular structure/function. TNF receptors concentrations were increased at baseline and not significantly different from end-of-study concentrations. Adverse echocardiographic measures were more likely in the highest TNF receptor tertile (all P Conclusions Elevated serum concentrations of cardiac biomarkers were common in youth with type 2 diabetes, but their clinical significance is unclear and will require further long-term study. Trial registration ClinicalTrials.gov NCT00081328 .

Background Population-based (PB) registries of type 1 diabetes mellitus (T1DM) in children have been essential in determining the geographic, racial, and temporal patterns of the disease. There is a paucity of PB data on the prevalence of type 1 and type 2 diabetes (T2DM) in youth. Methods The prevalence of diabetes in children was determined using a PB survey of the 628 schools in Philadelphia. Data obtained included type of diabetes, date of birth, race, gender, date of diagnosis, diabetes treatment, and most recent height and weight. Results The survey was completed by nurses at 510 schools (81% of schools) representing 252,896 children (70% of children in Philadelphia). Prevalence (per 1000) was computed. The survey identified 492 cases (355 T1DM, 88 T2DM, 49 type unknown). The overall prevalence of T1DM was 1.58 (0.73 White, 0.56 African American, 0.50 Hispanic); of T2DM was 0.35 (0.03 White, 0.28 African American, 0.05 Hispanic). Mean age at diagnosis was 8.6 and 11.9 years for T1DM and T2DM, respectively. The prevalence of T1DM was higher in boys- T2DM was higher in girls. Of children with T2DM, 25% were treated with insulin. BMI was ≥95th percentile in 20% of children weighed (10% of T1DM, 57% of T2DM). Conclusions Although the Philadelphia Pediatric Diabetes Registry is the longest ongoing US registry of its kind, these are the first PB diabetes prevalence data of children in Philadelphia. PB studies in schools are able to capture children with diabetes who are diagnosed and treated in a variety of settings. 摘要 背景 基于人口的1型糖尿病儿童登记表对于确定疾病的地理、种族以及时间规律来说很有必要。目前还缺乏有关青年人中1型与2型糖尿病患病率的基于人口的数据。 方法 在费城628所学校里采用基于人口的调查获取儿童中的糖尿病患病率。获取的数据包括糖尿病类型、出生日期、种族、性别、诊断日期、糖尿病治疗方案以及最近的身高与体重。 结果 由护士在510所学校（81%的学校）中对252896名儿童（70%的费城儿童）进行了调查。计算出（每1000名）患病率。这个调查鉴定出了492名病例（355名1型糖尿病，88名2型糖尿病，49名类型不明确）。1型糖尿病的总患病率为1.58（白人为0.73，非裔美国人为0.56，西班牙人裔为0.50）；2型糖尿病为0.35（白人为0.03，非裔美国人为0.28，西班牙人裔为0.05）。诊断1型糖尿病与2型糖尿病时的平均年龄分别为8.6岁与11.9岁。男孩中的1型糖尿病患病率更高，而女孩中的2型糖尿病患病率更高。在2型糖尿病儿童中，有25%的人使用胰岛素治疗。有20%的儿童BMI超过了第95百分位（1型糖尿病有10%，2型糖尿病有57%）。 结论 虽然费城儿科糖尿病登记表在美国同类登记表中持续时间最长，但这些是费城儿童第一份基于人口的糖尿病患病率的数据。在学校中进行的基于人口的研究能够获得在不同的机构进行诊断与治疗的儿童糖尿病数据。

OBJECTIVE The purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000–2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS Diabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period. RESULTS The overall age-adjusted incidence rate in 2000–2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0–4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children. CONCLUSIONS The incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985–1989 cohort. The most marked increases were among white children ages 10–14 years and black children ages 0–4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.

OBJECTIVE Type 2 diabetes increases cardiovascular risk. We examined lipid profiles and inflammatory markers in 699 youth with recent-onset type 2 diabetes in the TODAY clinical trial and compared changes across treatment groups: metformin alone (M), metformin plus rosiglitazone (M+R), and metformin plus intensive lifestyle program (M+L). RESEARCH DESIGN AND METHODS Multiethnic youth with type 2 diabetes received M, M+R, or M+L. Statin drugs were begun for LDL cholesterol (LDL) ≥130 mg/dL or triglycerides ≥300 mg/dL. Lipids, apolipoprotein B (apoB), LDL particle size, high-sensitivity c-reactive protein (hsCRP), homocysteine, plasminogen activator inhibitor-1 (PAI-1), and HbA1c were measured over 36 months or until loss of glycemic control. RESULTS LDL, apoB, triglycerides, and non-HDL cholesterol (HDL) rose over 12 months and then stabilized over the next 24 months. Participants with LDL ≥130 mg/dL or using LDL-lowering therapy increased from 4.5 to 10.7% over 36 months, while 55.9% remained at LDL goal ( CONCLUSIONS Dyslipidemia and chronic inflammation were common in youth with type 2 diabetes and worsened over time. Diabetes treatment, despite some treatment group differences in lipid and inflammatory marker change over time, is generally inadequate to control this worsening risk.

Background. Insulin resistance increases type 2 diabetes risk in obese adolescents. Thus, quantitative tools measuring insulin sensitivity and secretion are important for risk assessment. Methods. Forty-four obese pubertal adolescents underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). We correlated OGTT-derived whole body sensitivity index (WBISI) with FSIGT-derived insulin sensitivity index (Si). Insulinogenic index (IGI) from OGTT was compared with acute insulin response to glucose (AIRg) from FSIGT. Results. Fasting insulin ( r = −.64, P < .0005) and glucose ( r = −.39 P ≤ .0005) predicted Si. The OGTT-derived index WBISI correlated with the FSIGT-derived Si ( r = .608, P < .0005). IGI correlated with AIRg from FSIGT ( r = .704, P < .0005). Conclusions. OGTT-based measures correlated with FSIGT-derived measures of insulin sensitivity and secretion. In particular, we demonstrated that WBISI can be a reliable alternative to FSIGT-derived Si in clinical settings where OGTT is a more feasible option.

To investigate the relationships of cardiac structure and function with body composition and cardiorespiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study.Cross-sectional evaluation of 233 participants (median age 18.3 [min-max 12.4-24.2] years, 63% females, median hemoglobin A1c 6.8%) who had echocardiography measurements of left ventricular (LV) mass, ejection fraction, left atrial dimensions, LV diastolic function (early transmitral flow velocity to early mitral annular velocity ratio from tissue Doppler imaging), and right ventricular function (tricuspid annular plane systolic excursion [TAPSE]) and body composition (dual-energy x-ray absorptiometry) and CRF (cycle ergometry determination of physical work capacity at heart rate of 170 beats per minute).LV mass correlated positively with CRF (r = 0.5, P .0001), lean body mass (LBM) (r = 0.7, P .0001), and fat mass (FM) (r = 0.2, P = .00047); LV ejection fraction did not. Early transmitral flow velocity to early mitral annular velocity was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007), and left atrial internal diameter correlated with FM (r = 0.4, P .0001), LBM (r = 0.3, P .001), and CRF (r = 0.2, P = .0033). TAPSE weakly correlated with CRF (r = 0.2, P = .0014) and LBM (r = 0.13, P .05) but not with FM. In multivariable regression analyses, LBM (β = 2.13, P .0001) and CRF (β = 0.023, P = .008) were related to LV mass independent of race, sex, age, hemoglobin A1c, hypertension, smoking, and diabetes medications. CRF (β = 0.0002, P = .0187) and hemoglobin A1c (β = -0.022, P = .0142) were associated with TAPSE.In youth with type 2 diabetes, LV size is related to physical fitness. LV ejection fraction is within normal limits. LV diastolic function is inversely related to FM. Greater fitness may counteract adverse effects of poor glycemic control on right ventricular function.ClinicalTrials.gov:NCT00081328.

Objective To compare lipoprotein profiles of prediabetic to normoglycemic obese adolescents. Study design Cross-sectional study of 95 obese, pubertal adolescents (12-17 years), who underwent oral glucose tolerance test, lipid panel, and lipoprotein subclass particle analysis (nuclear magnetic resonance spectroscopy). Univariate and linear regression analyses compared prediabetic and normoglycemic groups. Results Of 95 obese adolescents enrolled in the study, 22.1% (n = 21) had prediabetes. They were similar to normoglycemic adolescents (n = 74) in age, race, body mass index, standard lipids, total low-density lipoprotein particles (LDL-P), and total high-density lipoprotein particles (HDL-P). However, prediabetics had higher concentrations of small LDL-P (714.0 ± 288.0 vs 537.7 ± 266.5 nmol/L, P = .01) and smaller LDL-P size (20.73 ± 0.41 vs 21.18 ± 0.65 nm, P = .003), than normoglycemic youth. Prediabetics had higher small HDL-P (18.5 ± 3.8 vs 16.6 ± 3.9 umol/L, P = .046), lower large HDL-P (4.49 ± 2.0 vs 6.32 ± 2.6 umol/L, P = .004), and smaller HDL-P size (8.73 ± 0.31 vs 9.01 ± 0.39 nm, P = .003). After adjusting for demographics, Tanner stage, and body mass index using multiple linear regression, all differences remained significant except for small HDL-P. After additional adjustment for Homeostasis Model Assessment–Insulin Resistance Index, only LDL-P size difference remained significant. Conclusion Obese prediabetic adolescents have a significantly more atherogenic lipoprotein profile compared with obese normoglycemic peers. Prediabetic adolescents may benefit from more aggressive interventions to decrease future cardiovascular risk.

Use of meal replacements (MRs) in lifestyle modification programs (LMPs) for obese adults significantly increases weight loss, compared with prescription of an isocaloric conventional diet (CD). This 12-month randomized trial examined 113 obese adolescents (mean ± s.d. age of 15.0 ± 1.3 years and BMI of 37.1 ± 5.1 kg/m2) who were assigned to a LMP, combined with meal plans of 1,300–1,500 kcal/day of CD (self-selected foods) or MR (three SlimFast shakes, one prepackaged meal, five vegetable/fruit servings). After month 4 (phase 1), participants originally treated with MR were unmasked to their phase 2 (months 5–12) random assignment: continued use of MR (i.e., MR+MR) or transitioned to CD (i.e., MR+CD). Participants initially treated with CD in phase 1, continued with CD (i.e., CD). All three groups were treated for an additional 8 months (phase 2). Regression models were used to evaluate percentage change in BMI from baseline to month 4 (phase 1), months 5–12 (phase 2), and baseline to month 12. At month 4, participants assigned to MR (N = 65) achieved a mean (±s.e.) 6.3 ± 0.6% reduction in BMI, compared to a significantly (P = 0.01) smaller 3.8 ± 0.8% for CD participants (N = 37). In phase 2, BMI increased significantly (P < 0.001) in all three conditions, resulting in no significant (P = 0.39) differences between groups in percentage change in BMI at month 12. Across groups, mean reduction in BMI from baseline to month 12 was 3.4 ± 0.7% (P < 0.01). Use of MR significantly improved short-term weight loss, compared with CD, but its continued use did not improve maintenance of lost weight.

PURPOSE OF REVIEW Childhood obesity is rising to epidemic proportions throughout the world, and much emphasis has been placed on the long-term consequences that can result later, in adulthood. This article reviews the metabolic consequences of obesity that can manifest as disease during the childhood years. RECENT FINDINGS Obese children suffer from many disease processes once thought to affect only adults. They can have type 2 diabetes mellitus, and potentially early β cell failure with rapid progression to an insulin requirement. There is a high prevalence of fatty liver disease in obese children, and complications such as steatohepatitis and even cirrhosis can develop during childhood. Visceral fat has been shown to have many different properties than subcutaneous fat, and children with central adiposity can develop the metabolic syndrome with insulin resistance, hypertension, and dyslipidemia. Hyperandrogenism, sleep disturbances, and many types of orthopedic complications can also develop in young children. SUMMARY Physicians should not only warn obese children and their families about the long-term consequences of obesity for which they are at risk in adulthood, they should also screen for the many diseases that may already be present.

Objectives Data regarding atherogenic dyslipidemia and the inflammation profile in youth with type 2 diabetes is limited and the effect of insulin therapy on these variables has not previously been studied in youth. We determined the impact of insulin therapy on lipid and inflammatory markers in youth with poorly controlled type 2 diabetes. Study design In the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) multicenter trial, 285 participants failed to sustain glycemic control on randomized treatment (primary outcome, glycated hemoglobin A1c [HbA1c] at ≥8% for 6 months); 363 maintained glycemic control (never reached primary outcome). Statins were used for a low-density lipoprotein cholesterol of ≥130 mg/dL. Upon reaching the primary outcome, insulin was started. Changes in lipids and inflammatory markers (slopes over time) were examined. Results Progression of dyslipidemia was related to glycemic control. In those with the primary outcome, insulin therapy impacted HbA1c modestly, and dampened the increase in total cholesterol, low-density lipoprotein cholesterol, and total apolipoprotein B, although statin use increased from 8.6% to 22% year after the primary outcome. The increase in triglycerides and plasma nonesterified fatty acids stabilized after insulin was started, independent of HbA1c. There was an increase in high-sensitivity C-reactive protein that continued after insulin initiation, related to HbA1c and percent overweight. Conclusions Worsening dyslipidemia and inflammation over time raise concern regarding premature development of atherosclerosis in youth with type 2 diabetes. Insulin therapy has a limited benefit in the absence of glycemic control. Strategies to achieve better glycemic control are needed. Trial registration ClinicalTrials.gov : NCT00081328 .

Context: Postprandial hypoglycemia (PPH) is a frequent complication of Nissen fundoplication in children. The mechanism responsible for the PPH is poorly understood, but involves an exaggerated insulin response to a meal and subsequent hypoglycemia. We hypothesize that increased glucagon-like peptide-1 (GLP-1) secretion contributes to the exaggerated insulin surge and plays a role in the pathophysiology of this disorder. Objective: The aim of the study was to characterize glucose, insulin, and GLP-1 response to an oral glucose load in children with symptoms of PPH after Nissen fundoplication. Design: Ten patients with suspected PPH and a history of Nissen fundoplication and eight control subjects underwent a standard oral glucose tolerance test at The Children’s Hospital of Philadelphia. Blood glucose (BG), insulin, and intact GLP-1 levels were obtained at various time points. Participants: Children ages 4 months to 13 years old were studied. Main Outcome Measures: Change scores for glucose, insulin, and intact GLP-1 were recorded after an oral glucose tolerance test. Results: All cases had hypoglycemia after the glucose load. Mean BG at nadir (± sd) was 46.7 ± 11 mg/dl for cases (vs. 85.9 ± 21.3 mg/dl; P < 0.0005). Mean change in BG from baseline to peak (± sd) was 179.3 ± 87.4 mg/dl for cases (vs. 57.8 ± 39.5 mg/dl; P = 0.003). Mean change in BG (± sd) from peak to nadir was 214.4 ± 85.9 mg/dl for cases (vs. 55.9 ± 41.1 mg/dl, P < 0.0005). Mean change in insulin (± sd) from baseline to peak was 224.3 ± 313.7 μIU/ml for cases (vs. 35.5 ± 22.2 μIU/ml; P = 0.012). Mean change in GLP-1 (± sd) from baseline to peak was 31.2 ± 24 pm (vs. 6.2 ± 9.5 pm; P = 0.014). Conclusions: Children with PPH after Nissen fundoplication have abnormally exaggerated secretion of GLP-1, which may contribute to the exaggerated insulin surge and resultant hypoglycemia.

Objective: We hypothesized that most patients with 22q11.2 deletion and a history of hypocalcemia have inadequate parathyroid function, manifested by intact parathyroid hormone levels below normal. We aimed to evaluate intact parathyroid hormone levels both during normocalcemia and at hypocalcemia, in this population. Study Design: Retrospective chart review of 103 patients with 22q11.2 deletion born since 1997 and cared for at the Children's Hospital of Philadelphia. Calcium and intact parathyroid hormone drawn simultaneously were recorded, along with clinical presentation at hypocalcemia. Results: Forty-seven simultaneous Ca/intact parathyroid hormone values were available. Seventy-nine percent of calcium levels and 81% of parathyroid hormone levels were within normal range. There were 19 patients with a history of symptomatic hypocalcemia, for whom any available simultaneous Ca/parathyroid hormone levels, before, during, or after hypocalcemia were analyzed. In this subgroup, 59% of calcium and 76% of parathyroid hormone levels were normal. None had an intact parathyroid hormone of >39.2 pg/mL at hypocalcemia. Seventy-three percent of hypocalcemic events had a precipitating stressor. Conclusions: Hypoparathyroidism in 22q11.2 deletion is mild, manifesting as a phenomenon of decreased parathyroid hormone reserve. Subjects are normocalcemic most of the time, but are unable to mount elevated intact parathyroid hormone levels, and therefore unable to correct hypocalcemia, in response to stressors.

Background Children with new onset diabetes (n = 175) were evaluated over 12-months. Patients were presumptively diagnosed with type 2 diabetes mellitus (T2DM) (n = 26) based on obesity, a relative with T2DM, the ability to wean from insulin, and absence of glutamic acid decarboxylase-65 (GAD-65) antibodies. We hypothesized that markers of insulinization at diagnosis, including fasting C-peptide and insulin-like growth factor-binding protein (IGFBP)-1, in addition to initial CO(2) levels and urine ketones, would help in distinguishing type 1 diabetes mellitus (T1DM) from T2DM. Results Children with T1DM (84 male, 65 female) had a mean age of 8.7 +/- 4.3 yr and a racial background of 78% white, 19% black, and 3% other. In contrast, children with T2DM (13 female, 13 male) had a mean age of 14.2 +/- 3.1 yr with a racial background of 58% black, 27% white, and 15% other. Fasting C-peptide level was 0.38 +/- 0.37 ng/mL in T1DM vs. 2.66 +/- 2.14 ng/mL in T2DM; a C-peptide of 0.85 ng/mL had 83% sensitivity in distinguishing T1DM from T2DM. Fasting IGFBP-1 level was 38.1 +/- 39.1 ng/mL (T1DM) vs. 3.6 +/- 4.5 ng/mL (T2DM); a value of 3.6 ng/dL could distinguish the two types of diabetes with 93% sensitivity. Urinary ketones were found in 79% of children with T1DM compared with 56% of those with T2DM, and the magnitude was associated with type of diabetes. Initial CO(2) level for T1DM was 17.9 +/- 6.9 mmol/L vs. 22.7 +/- 5.7 mmol/L for T2DM; a value of 21.5 mmol/L could distinguish the two types of diabetes with 83% sensitivity. Conclusions In addition to obesity, family history of T2DM, and absence of GAD-65 antibodies, children with new-onset T2DM may be distinguished from those with T1DM by a combination of biochemical parameters (C-peptide, IGFBP-1, CO(2), and urine ketones).