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Objectives: Achieving optimal glycemic outcomes in young children with type 1 diabetes (T1D) is challenging. This study examined the durability of continuous glucose monitoring (CGM) coupled with a family behavioral intervention (FBI) to improve glycemia., Study Design: This one-year study included an initial 26-week randomized controlled trial of CGM with FBI ( CGM+FBI ) and CGM alone ( Standard-CGM ) compared with blood glucose monitoring (BGM), followed by a 26-week extension phase wherein the BGM Group received the CGM+FBI ( BGM-Crossover ) and both original CGM groups continued this technology., Results: Time in range (70-180 mg/dL) did not improve with CGM use (CGM+FBI: baseline 37%, 52 weeks 41%; Standard-CGM: baseline 41%, 52 weeks 44%; BGM-Crossover: 26 weeks 38%, 52 weeks 40%). All three groups sustained decreases in hypoglycemia (<70 mg/dL) with CGM use (CGM+FBI: baseline 3.4%, 52 weeks 2.0%; Standard-CGM: baseline 4.1%, 52 weeks 2.1%; BGM-Crossover: 26 weeks 4.5%, 52 weeks 1.7%, P -values <.001). Hemoglobin A1c was unchanged with CGM use (CGM+FBI: baseline 8.3%, 52 weeks 8.2%; Standard-CGM: baseline 8.2%, 52 weeks 8.0%; BGM-Crossover: 26 weeks 8.1%, 52 weeks 8.3%). Sensor use remained high (52-week study visit: CGM+FBI 91%, Standard-CGM 92%, BGM-Crossover 88%)., Conclusion: Over 12 months young children with T1D using newer CGM technology sustained reductions in hypoglycemia and, in contrast to prior studies, persistently wore CGM. However, pervasive hyperglycemia remained unmitigated. This indicates an urgent need for further advances in diabetes technology, behavioral support, and diabetes management educational approaches to optimize glycemia in young children.

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 ± 2.4 years. Moderate albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g and hyperfiltration as eGFR ≥ 135 mL/min/1.73 m 2 at two consecutive visits. Echocardiography (n = 256) and pulse wave velocity (n = 193) were evaluated twice, 5 years apart. Adjusted Cox proportional hazard models and logistic regression models were used to examine associations between biomarkers and outcomes., Results: At baseline, 35.7% were male, with a mean age 13.9 years, diabetes duration 7.8 months, and HbA1c 6.0%. Higher concentrations of E-selectin and proinsulin were associated with incident moderate albuminuria and hyperfiltration. Higher concentrations of FGF-23 were associated with lower risk of hyperfiltration and negatively correlated with eGFR. No candidate biomarkers predicted a decline in cardiac or vascular function., Conclusions: Circulating biomarkers of endothelial dysfunction and markers of β-cell dysfunction and insulin sensitivity could be used in a more personalized risk assessment of kidney disease in youth-onset type 2 diabetes. However, biomarkers studied have limited value in predicting cardiac dysfunction or vascular stiffness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Fear of hypoglycaemia (FOH) can contribute to impaired sleep for adults with type 1 diabetes (T1D) and parents of children with T1D, although it is unknown how FOH may affect sleep for adolescents with T1D. This study examines the relationship between adolescent FOH and sleep and assessed the influences of continuous glucose monitor (CGM) and insulin pump use., Methods: Adolescents ages 14-18 years with T1D completed questionnaires evaluating FOH (Child Hypoglycemia Fear Survey) and sleep (Pittsburgh Sleep Quality Index, PSQI). Analyses included linear and logistic regression, t-tests and Fisher's exact tests., Results: Participants included 95 adolescents (52 female) with a median (IQR) age of 16.5 (15.3-17.7) years and a T1D duration of 5.7 (2.5-9.6) years. Analyses showed increased FOH-Worry subscale scores were associated with reduced sleep duration (β = -0.03, p = 0.042, adjusting for BMI z-score, race and ethnicity) and increased sleep disturbances (OR = 1.1, p = 0.038, adjusting for race and ethnicity). Frequent CGM users had longer sleep duration (average 7.5 h) compared with infrequent or non-CGM users (average = 6.8 h; p = 0.029), and pump users had overall improved sleep health as determined by PSQI score (p = 0.019). Technology use did not have significant interactions in the relationships between FOH and sleep duration or sleep disturbances., Conclusions: Worrying about hypoglycaemia was associated with impaired sleep for adolescents with T1D. Diabetes technology users have some sleep improvements, but CGM and pump use do little to alter the relationship between FOH and sleep outcomes., (© 2023 Diabetes UK.)

Background: The incidence of type 2 diabetes in young people is increasing, but treatments remain limited. We aimed to assess the efficacy and safety of an empagliflozin dosing regimen versus placebo and linagliptin versus placebo on glycaemic control in young people with type 2 diabetes., Methods: In this double-blind, placebo-controlled trial done in 108 centres in 15 countries, participants with type 2 diabetes (aged 10-17 years; HbA 1c 6·5-10·5% [48-91 mmol/mol]) who had been previously treated with metformin or insulin were randomly assigned (1:1:1) to oral empagliflozin 10 mg, oral linagliptin 5 mg, or placebo. Participants in the empagliflozin group who did not have HbA 1c below 7·0% (<53 mmol/mol) by week 12 underwent a second double-blinded randomisation (1:1) at week 14, either remaining on 10 mg or increasing to 25 mg. Participants in the placebo group were randomly reassigned (1:1:1) in a double-blinded manner at week 26 to linagliptin 5 mg or one of the empagliflozin doses (10 mg or 25 mg). Investigators were masked throughout the trial and received assignments of blinded medication kits through interactive response technology for all participants at the initial randomisation and for the re-randomisations at weeks 14 and 26. The primary outcome was change from baseline in HbA 1c at 26 weeks. For empagliflozin, results were based on a pooled analysis for all participants on empagliflozin. Safety was assessed until week 52. This trial is registered with ClinicalTrials.gov, NCT03429543., Findings: Between April 26, 2018, and May 26, 2022, of 262 screened participants, 158 (60%) were randomly assigned to treatment (53 [34%] to placebo, 52 [33%] to empagliflozin 10 mg, and 53 [34%] to linagliptin). For the primary outcome, the adjusted mean HbA 1c change from baseline at week 26 was -0·84% [-9·2 mmol/mol] in the empagliflozin pooled group versus placebo (95% CI -1·50 to -0·19 [-16·4 to -2·1]; p=0·012); the corresponding change from baseline for linagliptin versus placebo was -0·34% [-3·8 mmol/mol; 95% CI -0·99 to 0·30 [-10·8 to 3·3]; p=0·29). Adverse events occurred in 34 (64%) participants in the placebo group, 40 (77%) in the empagliflozin pooled group, and 37 (71%) in the linagliptin group, up to week 26. Of these, severe adverse events were reported in two (4%) participants in the placebo group, one (2%) in the empagliflozin pooled group, and one (2%) in the linagliptin group. Hypoglycaemia was the most frequently reported adverse event with higher rates for those on active drug treatment compared with placebo. No severe hypoglycaemia cases were reported., Interpretation: Empagliflozin provided clinically relevant placebo-corrected reductions in HbA 1c , whereas linagliptin did not, and might offer a new treatment option for young people with type 2 diabetes., Funding: The Boehringer Ingelheim and Eli Lilly and Company Alliance., Competing Interests: Declaration of interests LML has received consulting fees from Provention, Dompe, Medtronic, Roche, Janssen, Eli Lilly, Dexcom, Novo Nordisk, and Vertex. TD has received speaker, advisory panel, or research support from AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, Insulet, Lifescan, Medtronic, Novo Nordisk, Roche, and Sanofi; and is a shareholder of DreaMed Diabetes. WVT has received consulting fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Medtronic Diabetes. SW has served on a data safety monitoring board for the National Institute of Diabetes and Digestive and Kidney Diseases/US National Institutes of Health; and served on an advisory panel or board for Roche Diagnostics and Medtronic MiniMed. PZ has consulted for Boehringer Ingelheim, Merck, Eli Lilly, Janssen, I-ACT, and Novo Nordisk. DN and JM are employees of Boehringer Ingelheim. GJK declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Sixty minutes per day of at least moderate to vigorous physical activity (MVPA) is recommended for children for a variety of physical and psychological reasons. Adherence to these guidelines is confounded by challenges with glucose control during exercise in type 1 diabetes (T1D)., Objectives: This study examined the potential association between physical activity level on active days and glucose control in youth with T1D., Methods: Blinded continuous glucose monitors (CGM: Abbott Libre Pro) and physical activity data as measured from a body monitor patch (Metria IH1) were collected for up to 3 weeks in youth aged 9-17 years with T1D. The association between physical activity levels, expressed as mean active metabolic equivalent minutes (MET-minutes) per day, with CGM-based mean glucose, percent time in range (TIR: 70-180 mg/dl), % time above range (TAR) and % time below range (TBR) were assessed using a linear regression model adjusted for age, gender, and baseline HbA1c., Results: Study participants were deemed physically active, as defined by at least 10 min of continuous moderate-to-vigorous activity, on 5.2 ± 1.9 days per week, with a median accumulated physical activity time of 61 [IQR: 37-145] minutes per day. Higher physical activity levels were associated with lower mean glucose levels (r = -0.36; p = 0.02) and lower TAR (r = -0.45; p = 0.002) on active days. Higher activity levels were also associated with greater TIR (r = 0.54; p < 0.001) without being associated with more, or less, TBR., Conclusions: Higher amounts of physical activity are associated with improvements in TIR without significantly increasing TBR. These data suggest that youth ages 9-17 years with T1D can benefit from a high level of physical activity without undue fear of hypoglycemia., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 years). 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 or 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 among 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 a 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., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Adiponectin represents an important link between adipose tissue dysfunction and cardiometabolic risk in obesity; however, there is a lack of data on the effects of adiponectin-related genetic variations and gene-diet interactions on metabolic disorders in children. We aimed to investigate possible interactions between adiponectin-related genetic variants and habitual dietary patterns on metabolic health among children with normal weight versus overweight/obesity, and whether these effects in childhood longitudinally contribute to metabolic risk at follow-up., Subjects/methods: In total, 3,317 Chinese children aged 6-18 at baseline and 339 participants at 10-year follow-up from the Beijing Child and Adolescent Metabolic Syndrome study cohort were included. Baseline lifestyle factors, plasma adiponectin levels, and six adiponectin-related genetic variants resulting from GWAS in East Asians (loci in/near ADIPOQ, CDH13, WDR11FGF, CMIP, and PEPD) were assessed for their associations with the metabolic disorders. Being metabolically unhealthy was defined by exhibiting any metabolic syndrome component., Results: Among the six loci, ADIPOQ rs6773957 (OR 1.26, 95% CI:1.07-1.47, P = 0.004) and adiponectin receptor CDH13 rs4783244 (0.82, 0.69-0.96, P = 0.017) were correlated with metabolic risks independent of lifestyle factors in normal-weight children, but the associations were less obvious in those with overweight/obesity. A significant interaction between rs6773957 and diet (P interaction  = 0.004) for metabolic health was observed in normal-weight children. The adiponectin-decreasing allele of rs6773957 was associated with greater metabolic risks in individuals with unfavorable diet patterns (P < 0.001), but not in those with healthy patterns (P > 0.1). A similar interaction effect was observed using longitudinal data (P interaction  = 0.029)., Conclusions: These findings highlight a novel gene-diet interaction on the susceptibility to cardiometabolic disorders, which has a long-term impact from childhood onward, particularly in those with normal weight. Personalized dietary advice in these individuals may be recommended as an early possible therapeutic measure to improve metabolic health., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Hypoadiponectinemia has been associated with various cardiometabolic disease states. Previous studies in adults have shown that adiponectin levels were regulated by specific genetic and behavioral or lifestyle factors. However, little is known about the influence of these factors on adiponectin levels in children, particularly as mitigated by pubertal development., Methods: We performed a cross-sectional analysis of data from 3,402 children aged 6-18 years from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. Pubertal progress was classified as prepubertal, midpuberty, and postpuberty. Six relevant single nucleotide polymorphisms (SNPs) were selected from previous genome-wide association studies of adiponectin in East Asians. Individual SNPs and two weighted genetic predisposition scores, as well as their interactions with 14 lifestyle factors, were analyzed to investigate their influence on adiponectin levels across puberty. The effect of these factors on adiponectin was analyzed using general linear models adjusted for age, sex, and BMI., Results: After adjustment for age, sex, and BMI, the associations between adiponectin levels and diet items, and diet score were significant at prepuberty or postpuberty, while the effect of exercise on adiponectin levels was more prominent at mid- and postpuberty. Walking to school was found to be associated with increased adiponectin levels throughout puberty. Meanwhile, the effect of WDR11-FGFR2 -rs3943077 was stronger at midpuberty ( P = 0.002), and ADIPOQ -rs6773957 was more effective at postpuberty ( P = 0.005), while CDH13 -rs4783244 showed the strongest association with adiponectin levels at all pubertal stages (all P < 3.24 × 10 -15 ). We further found that effects of diet score ( P interaction = 0.022) and exercise ( P interaction = 0.049) were stronger in children with higher genetic risk of hypoadiponectinemia, while higher diet score and exercise frequency attenuated the differences in adiponectin levels among children with different genetic risks., Conclusions: Our study confirmed puberty modulates the associations between adiponectin, and genetic variants, lifestyle factors, and gene-by-lifestyle interactions. These findings provide new insight into puberty-specific lifestyle suggestions, especially in genetically susceptible individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Zhong, Li, Han, Fu, Li, Li, Zhang, Guo, Xiao, Qi, Li, Gao and Willi.)

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Racial-ethnic disparities in technology use have been described in children with type 1 diabetes (T1D). It is not known whether these emerge early in disease management. This single-center retrospective study examined disparities in continuous glucose monitor (CGM) initiation and durability in the first-year after diagnosis of T1D in children. Of 345 eligible children, 46% started CGM within their first year. In non-Hispanic white (NHW) children, 51% started using CGM versus 28% of non-Hispanic black (NHB) children ( P  = 0.006). After stratifying by commercial/government insurance, a proxy for socioeconomic status, this difference persisted among those with commercial insurance. One-year post-CGM initiation, 96% (125/130) of NHW children were using CGM versus 73% (11/15) of NHB children ( P  = 0.003). Disparities in CGM use emerge early in care of children with T1D, with lower rates of initiation and sustained use of CGM in NHB children. Strategies addressing causes of these disparities should begin early in T1D management.

Purpose: The purpose of this qualitative study was to explore parent and youth perspectives of the decision-making process to start continuous glucose monitoring (CGM)., Methods: Youth with type 1 diabetes and their parents were assessed with semistructured interviews before adding CGM to their regimen and 2 months after device initiation. Interviews focused on parent, youth, and provider decision-making roles and suggestions for enhancing youth decision-making involvement (DMI). Data were coded and analyzed using thematic analysis., Results: Youth (N = 41; 13.7 ± 2.9 years) were categorized into decision-making roles: (1) youth primary decision maker (54.8%), (2) youth primary decision maker with parental influence (14.3%), (3) parent primary decision maker with youth agreement (26.2%), and (4) parent primary decision maker without youth agreement (4.8%). Participants described that clinicians provided information, recommended CGM, and gave support. Recommendations to enhance youth DMI included that youth should ask questions, express opinions, and do their own research. Providers should give unbiased information and use visual aids (eg, show the device and videos) to engage youth., Conclusions: Participants agreed that whereas youth should have a primary role in the decision about CGM, parental and provider support is critical. Parents and providers can facilitate dialogue by directly engaging with youth about their thoughts, feelings, and concerns. Provider use of visual aids may enhance youth engagement and expectations.

The goal of this study was to characterize trajectories of continuous glucose monitoring (CGM) use in youth 5-12 weeks after starting CGM and examine what factors differentiate between the trajectory groups. Parent-youth dyads completed assessments before starting CGM. Days of CGM use between weeks 5 and 12 were accessed through cloud-based data repository. Three patterns of use were observed among 96 youth (mean age 13.4 ± 2.75 years; 75% white): sustained high, declining, and sustained low. Youth in the sustained low and declining groups were more likely than those in the sustained high group to use a receiver (versus smart phone). There were no differences between the trajectory groups with respect to age, race, ethnicity, income, or insulin regimen. Future research should examine trajectory groups for a longer follow-up period and identify baseline factors that reliably predict which youth will have low or declining CGM use over time.

Background: Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes., Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (<100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol L -1 on a mixed meal tolerance test (MMTT) were enrolled from nine medical centres in the USA (n=8) and Australia (n=1). Participants were randomly assigned (2:1) to receive either 400 mg imatinib mesylate (4 × 100 mg film-coated tablets per day) or matching placebo for 26 weeks via a computer-generated blocked randomisation scheme stratified by centre. Treatment assignments were masked for all participants and study personnel except pharmacists at each clinical site. The primary endpoint was the difference in the area under the curve (AUC) mean for C-peptide response in the first 2 h of an MMTT at 12 months in the imatinib group versus the placebo group, with use of an ANCOVA model adjusting for sex, baseline age, and baseline C-peptide, with further observation up to 24 months. The primary analysis was by intention to treat (ITT). Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, NCT01781975 (completed)., Findings: Patients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events., Interpretation: A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required., Funding: Juvenile Research Diabetes Foundation., Competing Interests: Declaration of interests SEG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Caladrius, Intrexon, Janssen, Provention Bio, and Tolerion. JLG has consulted for Vertex Pharmaceuticals and Regeneron Pharmaceuticals, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PAG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk, and Pfizer, and is co-founder and chief medical officer for ImmunoMolecular Therapeutics. RGM has a patent application for DNA methylation in inflammatory disease. SMW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals and Medtronic, and a data and safety monitoring board for the US National Institutes of Health (NIH). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While circulating levels of alpha 1 -proteinase inhibitor (alpha 1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha 1 -PI [human] (alpha 1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with β-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha 1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients., Participants: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis., Methods: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha 1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables., Results: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha 1 -PI treatment groups but not the placebo group., Conclusion: Pharmacologic therapy with alpha 1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive., (© 2020 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to assess racial disparities in treatments and outcomes between Non-Hispanic black (NHB), Hispanic and Non-Hispanic white (NHW) children with type 1 diabetes (T1D)., Methods: We reviewed electronic health records of children (<18 years) attending a large, pediatric tertiary care diabetes center in the United States between October 1, 2018, and December 31, 2019. Health care utilization (appointment attendance, ED visits, hospitalizations), technology use (insulin pumps, continuous glucose monitors [CGM]) and hemoglobin A1c (HbA1c) were examined for each race/ethnicity and stratified by insurance type (private/government) as a proxy for socioeconomic status (SES)., Results: Of 1331 children (47% female) with a median (IQR) age of 14.2 (11.5, 16.3) years and T1D duration of 5.8 (3.8, 9) years; 1026 (77%) were NHW, 198 (15%) NHB, and 107 (8%) Hispanic. Government insurance was used by 358 (27%) children, representing 60% of NHB and 53% of Hispanic, but only 18% of NHW children. NHB children had higher HbA1c, more ED visits and hospitalizations, and were less likely to be treated with insulin pumps or CGM than NHW children (P < .001 for all). There were no racial disparities with regard to the number of appointments attended., Conclusions: Racial disparities in technology use and diabetes outcomes persist in children with T1D, regardless of insurance status. To ensure equitable care, pediatric healthcare providers should remain cognizant of racial disparities in diabetes treatment. The impact of provider and patient factors should be explored when studying the etiology of these health disparities., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Racial/ethnic disparities in continuous glucose monitor (CGM) use exist among children with type 1 diabetes. It is not known whether differential rates of device initiation or sustained use are the cause of this disparity. Our objective was to compare CGM initiation rates and continued use among non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic children., Research Design and Methods: We conducted a retrospective review including children with type 1 diabetes attending the Children's Hospital of Philadelphia between 1 January 2015 and 31 December 2018., Results: Of 1,509 eligible children, 726 (48%) started CGM during the study period. More NHW (54%) than NHB (31%) and Hispanic (33%) children started CGM ( P < 0.001). One year after starting, fewer NHB (61%) than NHW (86%) and Hispanic (85%) children were using CGM ( P < 0.001)., Conclusions: Lower CGM use in NHB children was due to lower rates of device initiation and higher rates of discontinuation. Interventions to address both of these barriers are needed to reduce disparities in CGM use., (© 2020 by the American Diabetes Association.)

Purpose: Racial disparities have been shown in outcomes and treatment of children with type 1 diabetes (T1D). The purpose of this study was to examine temporal trends in insulin pump use among non-Hispanic white (NHW), non-Hispanic black (NHB) and Hispanic children attending a large urban diabetes center. . This study was a retrospective chart review of insulin pump usage by race (NHW/ NHB) in 2005, and race/ethnicity (NHW/NHB/Hispanic) in 2011-2019. Demographic data (age, sex, diabetes duration, SES) and most recent hemoglobin A1c were also abstracted in 2011-2019., Results: In 2005, NHW children were twice as likely to use an insulin pump as NHB children. From 2011 to 2019, the odds ratio increased to 2.5 for NHW compared to NHB children. The odds of Hispanic children using insulin pumps were also higher than NHB. Insurance status (government versus private), a surrogate for SES, had very little influence on these trends, with NHW children consistently more likely than NHB children to be treated with insulin pumps in 2011, 2013, 2017, 2019 (p < 0.001)., Conclusions: We have demonstrated that racial disparities in insulin pump use have persisted over the past 15 years, and are not determined by SES. This inequity in diabetes treatment may be playing a role in the poorer glycemic control and higher rates of diabetes complications in NHB children., Practice Implications: Healthcare providers should be cognizant of racial and ethnic disparities in the treatment of children with T1D. Standardized treatment protocols may reduce unconscious bias in prescribing., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The ability of continuous glucose monitoring (CGM) to improve diabetes outcomes depends upon consistent use. To identify factors that facilitate long-term use of CGM, this study tested the hypothesis that youth involvement in the decision to initiate this therapy would influence subsequent CGM use and that CGM self-efficacy and satisfaction mediate this relationship., Research Design and Methods: Before initiating CGM, parent-youth dyads (i.e., pairs) from an academic endocrinology clinic completed assessments, including a measure of the child's involvement in the decision to start CGM. Two months into CGM use, youth completed measures of CGM self-efficacy and satisfaction. Fidelity of CGM use between weeks 5 and 12 was accessed via a cloud-based data repository. Hypotheses were tested with linear mixed-effects models, accounting for patients clustered within provider and repeated measures within patients., Results: CGM use in 108 dyads (youth mean age 13.4 ± 2.7 years; 73% White) was positively predicted by baseline parent report of youth involvement in the CGM decision ( P < 0.0001), and this relationship was mediated by youth's perceptions of CGM self-efficacy ( P < 0.0001) and hassle ( P = 0.014). So, when the youth shared their opinions about CGM with parents and participated in the decision to start, they perceived higher self-efficacy and lower hassle at 2-month follow-up, which predicted more days of use. This pattern held in models adjusting for youth race and sex and family income., Conclusions: To achieve maximum clinical benefit from CGM use, providers should facilitate youth involvement in the decision to initiate the device., (© 2020 by the American Diabetes Association.)

Context: Minority young adults (YA) currently represent the largest growing population with type 1 diabetes (T1D) and experience very poor outcomes. Modifiable drivers of disparities need to be identified, but are not well-studied., Objective: To describe racial-ethnic disparities among YA with T1D and identify drivers of glycemic disparity other than socioeconomic status (SES)., Design: Cross-sectional multicenter collection of patient and chart-reported variables, including SES, social determinants of health, and diabetes-specific factors, with comparison between non-Hispanic White, non-Hispanic Black, and Hispanic YA and multilevel modeling to identify variables that account for glycemic disparity apart from SES., Setting: Six diabetes centers across the United States., Participants: A total of 300 YA with T1D (18-28 years: 33% non-Hispanic White, 32% non-Hispanic Black, and 34% Hispanic)., Main Outcome: Racial-ethnic disparity in HbA1c levels., Results: Non-Hispanic Black and Hispanic YA had lower SES, higher HbA1c levels, and much lower diabetes technology use than non-Hispanic White YA (P < 0.001). Non-Hispanic Black YA differed from Hispanic, reporting higher diabetes distress and lower self-management (P < 0.001). After accounting for SES, differences in HbA1c levels disappeared between non-Hispanic White and Hispanic YA, whereas they remained for non-Hispanic Black YA (+ 2.26% [24 mmol/mol], P < 0.001). Diabetes technology use, diabetes distress, and disease self-management accounted for a significant portion of the remaining non-Hispanic Black-White glycemic disparity., Conclusion: This study demonstrated large racial-ethnic inequity in YA with T1D, especially among non-Hispanic Black participants. Our findings reveal key opportunities for clinicians to potentially mitigate glycemic disparity in minority YA by promoting diabetes technology use, connecting with social programs, and tailoring support for disease self-management and diabetes distress to account for social contextual factors., (© Endocrine Society 2020.)

Importance: Adolescents and young adults with type 1 diabetes exhibit the worst glycemic control among individuals with type 1 diabetes across the lifespan. Although continuous glucose monitoring (CGM) has been shown to improve glycemic control in adults, its benefit in adolescents and young adults has not been demonstrated., Objective: To determine the effect of CGM on glycemic control in adolescents and young adults with type 1 diabetes., Design, Setting, and Participants: Randomized clinical trial conducted between January 2018 and May 2019 at 14 endocrinology practices in the US including 153 individuals aged 14 to 24 years with type 1 diabetes and screening hemoglobin A1c (HbA1c) of 7.5% to 10.9%., Interventions: Participants were randomized 1:1 to undergo CGM (CGM group; n = 74) or usual care using a blood glucose meter for glucose monitoring (blood glucose monitoring [BGM] group; n = 79)., Main Outcomes and Measures: The primary outcome was change in HbA1c from baseline to 26 weeks. There were 20 secondary outcomes, including additional HbA1c outcomes, CGM glucose metrics, and patient-reported outcomes with adjustment for multiple comparisons to control for the false discovery rate., Results: Among the 153 participants (mean [SD] age, 17 [3] years; 76 [50%] were female; mean [SD] diabetes duration, 9 [5] years), 142 (93%) completed the study. In the CGM group, 68% of participants used CGM at least 5 days per week in month 6. Mean HbA1c was 8.9% at baseline and 8.5% at 26 weeks in the CGM group and 8.9% at both baseline and 26 weeks in the BGM group (adjusted between-group difference, -0.37% [95% CI, -0.66% to -0.08%]; P = .01). Of 20 prespecified secondary outcomes, there were statistically significant differences in 3 of 7 binary HbA1c outcomes, 8 of 9 CGM metrics, and 1 of 4 patient-reported outcomes. The most commonly reported adverse events in the CGM and BGM groups were severe hypoglycemia (3 participants with an event in the CGM group and 2 in the BGM group), hyperglycemia/ketosis (1 participant with an event in CGM group and 4 in the BGM group), and diabetic ketoacidosis (3 participants with an event in the CGM group and 1 in the BGM group)., Conclusions and Relevance: Among adolescents and young adults with type 1 diabetes, continuous glucose monitoring compared with standard blood glucose monitoring resulted in a small but statistically significant improvement in glycemic control over 26 weeks. Further research is needed to understand the clinical importance of the findings., Trial Registration: ClinicalTrials.gov Identifier: NCT03263494.

Objective: In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and β-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and β-cell function in MODY vs. non-MODY obese youth at randomization and over time., Methods: Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and β-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA)., Results: At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. β-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth., Conclusions: In TODAY, β-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: A subset of normal-weight individuals appears predisposed to obesity-related cardiometabolic abnormalities. Studies of this metabolically obese, normal weight (MONW) phenotype in youth are scarce. We aimed to identify early environmental and genetic factors associated with MONW in children., Methods: Overall, 1475 normal-weight Chinese children aged 6-18 were recruited from the Beijing Children and Adolescents Metabolic Syndrome study cohort. Birthweight, childhood lifestyle, socio-economic factors, and 20 genetic variants previously shown to be associated with BMI or glucose metabolism in East Asian adults were examined for their association with the MONW phenotype. MONW was defined by exhibiting any metabolic syndrome component., Results: After adjusting for covariates including BMI, low birthweight and low levels of physical activity, fruit consumption, parental education and household income, as well as CDKAL1 rs2206734 genotype were independent predictors of the MONW phenotype (all P < 0.05). Moreover, rs2206734 interacted with birthweight to predict the MONW phenotype (Pinteraction = 0.0008). Among high (>75th percentile) birthweight individuals, each C allele at this locus was associated with a 62% reduced risk of MONW (OR = 0.38; 95% CI = 0.26-0.58; P = 5.71 × 10-6), while no such genetic associations were found in intermediate or low birthweight individuals (P > 0.1). This CDKAL1-MONW relationship in high birthweight individuals was especially strong in the presence of favorable childhood environmental factors (high levels of physical activity, fruit consumption, parental education and household income) (Pinteraction = 0.013)., Conclusions: Our findings provided the novel evidence that early environment (especially birthweight) and genetics, along with their interaction with one another, play important roles in predicting the MONW phenotype among children.

Background: Individual health behaviors (ie, eating habits and sedentary lifestyle) are associated with type 2 diabetes (T2D). Health behavior profiles specific to adolescents with T2D have not been described., Objective: To identify health behavior profiles in adolescents with T2D and examine how these profiles change over time., Methods: Diet (via food frequency questionnaire) and activity behaviors (via 3-day physical activity recall) examined at baseline, 6 months, and 24 months from participants in the the Treatment Options for T2D in Adolescents and Youth (TODAY) study were used for this analysis. Latent profile analysis identified profiles of health behaviors within three time points, and latent transition probabilities were estimated to examine the change from baseline to 6 months (n = 450) and baseline to 24 months (n = 415). Multinomial logistic regressions were used to examine if the assigned TODAY treatment group (Metformin [Met], Met + Rosiglitazone [Rosi], or Met + Lifestyle) predicted change in health behavior profiles., Results: Three profiles emerged: "most sedentary," "healthy eaters," and "active and eat most." At 6 months, 50% of males and 29% of females in the Met + Lifestyle treatment group improved in their health behavior profile. Among males only, the Met + Lifestyle treatment group were more likely to improve their profiles from baseline to 6 months (P = .01)., Conclusions: Three health behavior profiles emerged and shifted over time. A high quality, lifestyle intervention had little effect on improving health behavior profiles. Optimizing outcomes in youth with T2D might require more robust and multifaceted interventions beyond family-level lifestyle, including more extensive psychosocial intervention, novel medication regimen, or bariatric surgery., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: BMI fluctuations during puberty are common. Data on individual change in BMI from childhood to young adulthood are limited in youth with type 1 diabetes., Objectives: To compare longitudinal trajectories of body mass index z score (BMIz) from childhood to adolescence across three registries spanning five countries., Methods: Data sources: T1DX (USA), DPV (Germany/Austria/Luxembourg) and ADDN (Australia). The analysis included 11,513 youth with type 1 diabetes, duration >1 year, at least one BMI measure at baseline (age 8-10 years) and >5 aggregated BMI measures by year of age during follow-up until age 17 years. BMIz was calculated based on WHO charts. Latent class growth modelling was used to identify subgroups following a similar trajectory of BMIz over time., Results: Five distinct trajectories of BMIz were present in the T1DX and ADDN cohorts, while six trajectories were identified in the DPV cohort. Boys followed more often a low/near-normal pattern while elevated BMIz curves were more likely in girls (ADDN; DPV). For T1DX cohort, no sex differences were observed. Comparing the reference group (BMIz ~0) with the other groups during puberty, higher BMIz was significantly associated with older age at T1D onset, racial/ethnic minority and elevated HbA1c (all p<0.05)., Conclusion: This multinational study presents unique BMIz trajectories in youth with T1D across three continents. The prevalence of overweight and the longitudinal persistence of overweight support the need for close monitoring of weight and nutrition in this population. The international and individual differences likely result from diverse genetic, environmental and therapeutic factors., (© 2019 World Obesity Federation.)

Objective: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) may convey disparate risks of metabolic consequences. Fasting plasma glucose (FPG), while an expedient screening procedure, may not adequately assess metabolic risk, particularly among youths. In order to inform a strategy for screening Chinese youth for pre-diabetes, we examined the relative value of IFG versus IGT to define metabolic risk by assessing their association with insulin resistance, beta-cell dysfunction, adverse adipokine profiles and other cardiometabolic risk factors., Research Design and Methods: We recruited 542 subjects (age 14-28 years) from the Beijing Child and Adolescent Metabolic Syndrome study for an in-depth assessment of cardiometabolic risk factors, including a 2-hour oral glucose tolerance test, liver ultrasound and serum levels of four adipokines., Results: FPG failed to identify nearly all (32/33) youths with IGT, whereas 2-hour plasma glucose (2 h PG) missed 80.8% (21/26) of subjects with IFG. Impaired beta-cell function was evident from decreased oral disposition indices in those with isolated impaired fasting glucose (iIFG) or isolated impaired glucose tolerance (iIGT) versus normal glucose tolerance (NGT) (all p<0.001), whereas reduced insulin sensitivity (Matsuda) index was most pronounced in the iIGT group (p<0.01). Moreover, alterations in adipokine levels (fibroblast growth factor 21, adiponectin and leptin/adiponectin ratio) were associated with iIGT (p<0.05) but not iIFG. Youths with iIGT had a 2-fold to 32-fold increased incidence of hypertriglyceridemia, hypertension and metabolic syndrome (MetS) compared with those with NGT. In addition, subgroup analyses of participants with normal FPG revealed that the odds of having IGT increased 3-fold to 18-fold among those with elevated TGs, hypertension, moderate-to-severe non-alcoholic fatty liver disease or MetS., Conclusions: Chinese youth with iIGT exhibit a higher cardiometabolic risk profile than those with iIFG. Thus, 2 h PG is preferred over FPG to identify the pre-diabetes phenotype at greatest risk of subsequent development of cardiovascular disease., Trial Registration Number: NCT03421444., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Type 1 diabetes (T1D) is associated with an increased fracture risk across the life course. The effects on bone accrual early in the disease are unknown., Objective: To characterize changes in bone density and structure over the year following diagnosis of T1D and to identify contributors to impaired bone accrual., Design: Prospective cohort study., Setting: Academic children's hospital., Participants: Thirty-six children, ages 7 to 17 years, enrolled at diagnosis of T1D., Outcomes: Whole body and regional dual-energy X-ray absorptiometry and tibia peripheral quantitative computed tomography obtained at baseline and 12 months. The primary outcome was bone accrual assessed by bone mineral content (BMC) and areal bone mineral density (aBMD) velocity z score., Results: Participants had low total body less head (TBLH) BMC (z = -0.46 ± 0.76), femoral neck aBMD (z = -0.57 ± 0.99), and tibia cortical volumetric BMD (z = -0.44 ± 1.11) at diagnosis, compared with reference data, P < 0.05. TBLH BMC velocity in the year following diagnosis was lower in participants with poor (hemoglobin A1c ≥7.5%) vs good (hemoglobin A1c <7.5%) glycemic control at 12 months, z = -0.36 ± 0.84 vs 0.58 ± 0.71, P = 0.003. TBLH BMC velocity was correlated with gains in tibia cortical area (R = 0.71, P = 0.003) and periosteal circumference (R = 0.67, P = 0.007) z scores in participants with good, but not poor control., Conclusions: Our results suggest that the adverse effects of T1D on BMD develop early in the disease. Bone accrual following diagnosis was impaired in participants with poor glycemic control and appeared to be mediated by diminished bone formation on the periosteal surface., (Copyright © 2019 Endocrine Society.)

Background and Aims: The relationship between vitamin D deficiency and metabolic syndrome (MS) remains controversial with relatively sparse data among youth. Therefore, we attempted to explicate the association of 25-hydroxyvitamin D [25(OH)D] levels with MS in Chinese adolescents and young adults., Methods: A cohort of 559 subjects at elevated risk of MS were recruited at 14-28 years of age as a follow-up to the Beijing Child and Adolescent Metabolic Syndrome Study. Subjects underwent clinical assessment including a 2h-oral glucose tolerance test. The concentrations of 25(OH)D, glucose, insulin and lipids were determined. MS was defined using the 2009 harmonized definition., Results: The prevalence of vitamin D deficiency (< 20 ng/ml) was 78.3%. After adjusting for age, gender and season, 25(OH)D concentrations were negatively correlated with neck circumference, percent body fat, LDL cholesterol, fasting and 2h-glucose levels (all P < 0.05). 25(OH)D levels were significantly lower in participants with obesity, high triglycerides, type 2 diabetes, or MS, compared to their respective counterparts (all P < 0.05). After adjusting for potential confounders (e.g., body mass index), participants in the lowest 25(OH)D tertile were 2.5 times more likely to exhibit MS than were those in the highest tertile (Odds Ratio: 2.48; 95% CI: 1.13-5.45, P < 0.05)., Conclusions: Vitamin D deficiency was very common in this young Chinese population at risk for MS. Given this association between low vitamin D levels and MS, the role of vitamin D supplementation in Chinese youths needs further examination, particular in those at risk for MS., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims: Diabetic kidney disease (DKD) is a major complication of type 1 diabetes (T1D). To better understand the development of DKD in modern clinical practice, we evaluated risk factors in participants from the T1D Exchange Registry who completed 5-years of longitudinal follow-up., Methods: Participants had T1D duration ≥ 1 year, age ≥ 10 years, eGFR ≥ 60 ml/min and no albuminuria at enrollment, and at least two serum creatinine and urine albumin measurements recorded during follow-up. Adverse kidney outcomes were defined as eGFR ≪ 60 ml/min and/or albuminuria (ALB) defined by as two consecutive albumin/creatinine ratios or two out of the past three measurements ≫ 30 μg/mg at any follow-up data collection. Associations of baseline characteristics with adverse kidney outcomes were assessed., Results: Among 3940 participants (mean age 41 ± 15 yrs, T1D duration 21 ± 13 yrs), 653 (16.6%) experienced an adverse kidney outcome: 268 (6.8%) experienced incident ALB only, 322 (8.2%) had eGFR decline to ≪60 ml/min without ALB, and 63 (1.6%) experienced eGFR ≪ 60 ml/min with ALB. In a multivariable analysis, higher HbA1c, higher SBP, lower DBP, older age and lower education level were associated with the development of adverse kidney outcomes (all p values ≤ 0.03)., Conclusions: Improving modifiable risk factors, including glucose and blood pressure control, remain important to reduce the risk of DKD in T1D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The diagnosis of type 1 diabetes (T1D) brings significant medical, psychosocial, and educational challenges for the child, family, and medical team. We developed a structured certified diabetes educator (CDE) led program spanning the year after diagnosis with the goal of supporting families as their understanding of this chronic disease and its management evolves., Objective: The aim of this study was to determine the effect of this program upon hemoglobin A1c (HbA1c), and how this effect is mitigated by socioeconomic status (SES)., Methods: Patients enrolled in the type 1 year 1 (T1Y1) program were assigned a CDE who provided intensive coaching, tailored to family lifestyle, and readiness to assume independence. We identified all patients diagnosed with T1D in the 2 years before (controls) and after (T1Y1 group) the start of the T1Y1 program on January 7, 2014., Results: There were 675 patients diagnosed with T1D between July 2012 and June 2016 (284 controls, 391 T1Y1). HbA1c was significantly lower in the T1Y1 group at 6 (6.7% vs. 7.1%, P < 0.001), 12 (7.3% vs. 7.8%, P < 0.001) and 18 (7.6% vs. 7.9%, P = 0.01) months, but not 24 (7.8% vs. 8%, P = 0.14) months after diagnosis. This effect was not observed in patients with lower SES., Conclusion: Additional structured education and support in the year after diagnosis can improve short-term outcomes in children with T1D, but this effect may not persist after discontinuing intensive coaching. Families of lower SES did not benefit from this approach., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This study aimed to examine the associations between low birth weight (LBW) versus high birth weight (HBW) and dysglycemia, including insulin resistance (IR) and impaired fasting glucose (IFG) in children, and aimed to explore the role of adipose tissue in these relationships., Methods: A total of 2,935 subjects aged 6 to 18 years were recruited to examine the relationship between birth weight and IR (defined as homeostasis model assessment of IR > 2.3) and IFG. Mediation analyses were conducted to examine the roles of various adipokines and anthropometrics in these relationships., Results: Children with LBW had a nearly twofold increased risk of IR and IFG compared with children with normal birth weight, even after adjusting for BMI. Decreased circulating adiponectin levels contributed to 21.2% of the LBW-IR relationship, whereas none of the selected adipose markers mediated the LBW-IFG relationship. In contrast, after controlling for current BMI or waist circumference, HBW reduced the risk of IR by 34%, but it was not associated with IFG. The HBW-IR relationship was significantly mediated by reduced leptin levels (21.4%) and fat mass percentage (8.8%), after controlling for BMI., Conclusions: These findings suggest the potential role of adipose tissue dysfunction as an underlying mechanism for the birth weight-type 2 diabetes relationship., (© 2019 The Obesity Society.)

Background The role of adipokine dysregulation in determining the metabolic fate of obesity is not well studied. We aimed to examine whether the matricellular protein osteonectin and the profiles of certain adipokines could differentiate metabolically healthy obese ( MHO ) versus metabolically unhealthy obese phenotypes in childhood. Methods and Results This study included 1137 obese children and 982 normal-weight healthy ( NWH ) controls recruited from the BCAMS (Beijing Child and Adolescent Metabolic Syndrome) study. MHO was defined by the absence of insulin resistance and/or any metabolic syndrome components. Six adipokines-osteonectin, leptin, adiponectin, resistin, FGF21 (fibroblast growth factor 21), and RBP-4 (retinol binding protein 4)-were assessed. Approximately 20% of obese children displayed the MHO phenotype. MHO children had a more favorable adipokine profile than metabolically unhealthy obese children, with lower osteonectin, leptin, and RBP -4 and higher adiponectin (all P<0.05). Compared with normal-weight healthy controls, MHO children displayed increased leptin, resistin, and RBP -4 levels and reduced adiponectin concentrations (all P<0.05) but similar osteonectin and FGF 21 levels. Among obese subjects, decreased osteonectin (odds ratio [OR]: 0.82; 95% confidence interval [CI] per standard deviation, 0.70-0.97), RBP -4 (OR: 0.77; 95% CI per standard deviation, 0.64-0.93), and leptin/adiponectin ratio (OR: 0.58; 95% CI per standard deviation, 0.43-0.77) were independent predictors of MHO . In addition, compared with children without abnormalities, those with any 3 adipokine abnormalities were 80% less likely to exhibit the MHO phenotype ( OR : 0.20; 95% CI , 0.10-0.43) and 3 times more likely to have metabolic syndrome ( OR : 2.77; 95% CI , 1.52-5.03). Conclusions These findings suggest that dysregulation of adipokines might govern the metabolic consequences of obesity in children. Low osteonectin levels, along with a healthy adipokine profile, might be used as an early marker of the MHO phenotype.

Background/objective: Restrictive eligibility criteria have hampered enrollment into trials for new drugs for youth with type 2 diabetes (T2D). We utilized Pediatric Diabetes Consortium (PDC) T2D Registry enrollment data to estimate the percentage of patients who would be excluded from current T2D trials based on out-of-range HbA1c levels. We also examined whether well-controlled patients could be included because baseline HbA1c would rise during a 6 to 12-month study if assigned to control group., Methods: Clinical characteristics and HbA1c levels were collected from 956 T2D patients aged 10 to <18 years upon Registry enrollment. HbA1c levels were also analyzed in 6-month intervals during the first 30 months of T2D duration., Results: There was an approximately 2:1 ratio of females to males; the majority were obese and from economically disadvantaged minority families. On enrollment in the Registry, 53% of patients would be excluded from current trials because HbA1c levels were either <6.5% (<48 mmol/mol) (37%) or >10.5% (>91 mmol/mol) (16%). Furthermore, in patients with HbA1c levels <6.5% (<48 mmol/mol) and T2D duration between 6 and 30 months, mean HbA1c levels increased by 0.6% (6 mmol/mol) and 0.9% (10 mmol/mol) over the subsequent 6 and 12 months, respectively., Conclusions: Eligibility criteria for current clinical trials still exclude a large proportion of pediatric T2D patients because of HbA1c levels. Including patients with HbA1c <6.5% (<48 mmol/mol) would enhance recruitment and allow comparisons of the investigational treatment with placebo-assigned subjects in whom HbA1c levels would on average increase during the 6 to 12 months of the trial., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We aimed to assess haemoglobin A1c (HbA1c) for the diagnosis of pre-diabetes and diabetes in a population of Chinese youths at risk of metabolic syndrome., Setting: Beijing, China., Participants: A total of 581 subjects aged 14-28 years underwent evaluation including an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell function and a number of cardiovascular disease risk factors were evaluated. Receiver operating characteristic (ROC) curves were used to assess the screening efficacy of HbA1c., Results: Using OGTT data as a standard, the majority (70.0%, 7/10) of subjects with diabetes would have been diagnosed with HbA1c ≥6.5%. In contrast, only 28.1% (16/57) of subjects with pre-diabetes possessed elevated HbA1cs, while the majority (68.4%) had normal HbA1cs. On the contrary, a total of 8.1% (39/479) of youths in the normal HbA1c category (<5.7%) and 21.3% in the pre-diabetes category had pre-diabetes. In the ROC analysis, the area under the curve (AUC) for HbA1c identifying pre-diabetes was 0.680(95% CI 0.640 to 0.719); the optimal threshold was 5.5%, with a sensitivity of 61.4% and specificity of 68.5%. For type 2 diabetes mellitus, the AUC for HbA1c was 0.970 (0.952 to 0.982), and the optimal threshold was 6.1%, with a sensitivity of 90.0% and a specificity of 98.7%. Applying these new cut-offs, pre-diabetic participants (HbA1c 5.5%-6.1%) had lower disposition index and higher risk of dyslipidaemia (OR=1.61,95% CI 1.10 to 2.37) and metabolic syndrome (OR=2.09, 1.27 to 3.45) than those with normal HbA1c (<5.5%)., Conclusion: The American Diabetes Association's established HbA1c criteria for pre-diabetes and diabetes (5.7% and 6.5%) may not be appropriately applied to adolescents and young adults in China. Our findings suggest that those with HbA1c of 5.5%-6.1% already exhibit impaired β-cell function and increased cardiometabolic risk factors which may warrant intervention., Trial Registration Number: NCT03421444., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Elevated retinol-binding protein 4 (RBP4) levels may contribute to the development of metabolic abnormalities, but prospective studies evaluating the association between childhood RBP4 levels and metabolic syndrome (MS) in adulthood are lacking. We investigated whether RBP4 levels during childhood predict cardiometabolic risk at 10-year follow-up., Methods: The relationships between RBP4 levels, the established adipokines (leptin and adiponectin) and the components of MS were examined in 3445 school-aged children recruited in 2004 for the Beijing Child and Adolescent Metabolic Syndrome study. In 2015, 352 of these individuals completed an in-depth follow-up examination., Results: Participants with higher childhood RBP4 levels had adverse cardiometabolic profiles at follow-up. Those with incident or persistent MS had higher baseline RBP4 levels than those who never exhibited the elements of MS. Moreover, baseline RBP4 predicted hyperglycemia (OR per SD increase = 1.48, P = 0.009), elevated triglyceride (OR = 1.54, P < 0.001), elevated blood pressures (OR = 1.46, P = 0.015), MS (OR = 1.68, P = 0.002) and insulin resistance (OR = 1.44, P = 0.015) in the 10-year follow-up phase, independent of baseline BMI. Significant improvements were seen for the net reclassification improvement and integrated discrimination index after adding childhood RBP4 levels into the risk models using conventional cardiometabolic risk factors in predicting MS at follow-up (P < 0.05). Leptin and adiponectin demonstrated the expected associations with metabolic disorders., Conclusions: Childhood RBP4 serves as a risk factor for subsequent development of MS and its components, independent of pediatric obesity. Incorporating childhood RBP4 into conventional cardiometabolic risk assessment models significantly improves the prediction of MS.

Objective: To determine the minimum sample of continuous glucose monitoring (CGM) data needed to accurately reflect 3 months of glycemic control., Research Design and Methods: Three months of CGM data were collected on 257 individuals (age 10-78 years) with type 1 diabetes in two studies (one using the Abbott FreeStyle Libre Pro™ and the other using the Dexcom™ G4). Correlations were calculated between the full 3 months and incremental sampling periods of CGM data., Results: Correlation to the full 3 months of data improved with an increasing number of days of data collection, plateauing by about 14 days, with an R 2 value of 0.84-0.86 for mean glucose, time at 70-180 mg/dL, and time >180 mg/dL, with lower values for time <70 mg/dL (0.76) and coefficient of variation (0.70)., Conclusions: Fourteen days of CGM data provide a good estimation of glucose metrics for a 3-month period.

Background: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM., Study Design: Observational prospective cohort study., Setting & Participants: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control., Predictors: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A 1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension., Outcomes: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m 2 ) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30μg/mg at 3 consecutive annual visits., Results: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A 1c concentration, but not estimated insulin sensitivity., Limitations: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM., Conclusions: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Glycemic control often deteriorates during adolescence and the transition to young adulthood for patients with type 1 diabetes. The inability to manage type 1 diabetes effectively during these years is associated with poor glycemic control and complications from diabetes in adult life., Objective: To determine the effect of daily financial incentives on glucose monitoring adherence and glycemic control in adolescents and young adults with type 1 diabetes., Design, Setting, and Participants: The Behavioral Economic Incentives to Improve Glycemic Control Among Adolescents and Young Adults With Type 1 Diabetes (BE IN CONTROL) study was an investigator-blinded, 6-month, 2-arm randomized clinical trial conducted between January 22 and November 2, 2016, with 3-month intervention and follow-up periods. Ninety participants (aged 14-20) with suboptimally controlled type 1 diabetes (hemoglobin A1c [HbA1c] >8.0%) were recruited from the Diabetes Center for Children at the Children's Hospital of Philadelphia., Interventions: All participants were given daily blood glucose monitoring goals of 4 or more checks per day with 1 or more level within the goal range (70-180 mg/dL) collected with a wireless glucometer. The 3-month intervention consisted of a $60 monthly incentive in a virtual account, from which $2 was subtracted for every day of nonadherence to the monitoring goals. During a 3-month follow-up period, the intervention was discontinued., Main Outcomes and Measures: The primary outcome was change in HbA1c levels at 3 months. Secondary outcomes included adherence to glucose monitoring and change in HbA1c levels at 6 months. All analyses were by intention to treat., Results: Of the 181 participants screened, 90 (52 [57.8%] girls) were randomized to the intervention (n = 45) or control (n = 45) arms. The mean (SD) age was 16.3 (1.9) years. The intervention group had significantly greater adherence to glucose monitoring goals in the incentive period (50.0% vs 18.9%; adjusted difference, 27.2%; 95% CI, 9.5% to 45.0%; P = .003) but not in the follow-up period (15.3% vs 8.7%; adjusted difference, 3.9%; 95% CI, -2.0% to 9.9%; P = .20). The change in HbA1c levels from baseline did not differ significantly between groups at 3 months (adjusted difference, -0.08%; 95% CI, -0.69% to 0.54%; P = .80) or 6 months (adjusted difference, 0.03%; 95% CI, -0.55% to 0.60%; P = .93)., Conclusions and Relevance: Among adolescents and young adults with type 1 diabetes, daily financial incentives improved glucose monitoring adherence during the incentive period but did not significantly improve glycemic control., Trial Registration: clinicaltrials.gov Identifier: NCT02568501.

Objectives: Sleep has physiological and behavioral impacts on diabetes outcomes, yet little is known about the impact of sleep disturbances in children with type 1 diabetes. The current study sought to characterize sleep in children with type 1 diabetes and in their parents and to examine the associations between child sleep, glycemic control and adherence, parent sleep and well-being, parental fear of hypoglycemia, and nocturnal caregiving behavior., Methods: Surveys were emailed to parents of 2- to 12-year-old participants in the Type 1 Diabetes (T1D) Exchange clinic registry. Clinical data were obtained from the registry for the 515 respondents., Results: In our sample, 67% of children met criteria for poor sleep quality. Child sleep quality was related to glycemic control (HbA1c of 7.9% [63 mmol/mol] in children with poor sleep quality vs 7.6% [60 mmol/mol] in children with non-poor sleep quality; P < 0.001) but not mean frequency of blood glucose monitoring (BGM) (7.6 times/day vs 7.4 in poor/non-poor quality; P = 0.56). Associations were similar for sleep duration. Children with poor sleep quality were more likely to experience severe hypoglycemia (4% in children with poor sleep quality vs 1% in children with non-poor sleep quality; P = 0.05) and more likely to experience DKA (7% vs 4%, respectively; P < 0.001). Poorer child sleep quality was associated with poorer parental sleep quality, parental well-being, and fear of hypoglycemia (P < 0.001 for all). Child sleep was not related to the use of diabetes-related technology (CGM, insulin pump)., Conclusions: Sleep may be a modifiable factor to improve glycemic control and reduce parental distress., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin., Objective: To determine whether a racial difference exists in the relationship of mean glucose and HbA1c., Design: Prospective, 12-week observational study., Setting: 10 diabetes centers in the United States., Participants: 104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%., Measurements: Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values., Results: The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons)., Limitation: There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals., Conclusion: On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes., Primary Funding Source: Helmsley Charitable Trust.

Objective: To describe the clinical characteristics, treatment approaches, clinical outcomes, and co-morbidities of youth with type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium (PDC) T2D Registry., Methods: PDC enrolled 598 youth <21 yr of age with T2D from February 2012 to July 2015 at eight centers. Data were collected from medical records and interviews with participants and/or parents and included glycated hemoglobin (HbA1c), diabetes treatments, prevalence of diabetes comorbidities (hypertension (HTN), dyslipidemia (DL), microalbuminuria (MA), and nonalcoholic fatty liver disease (NAFLD)., Results: Insulin use was observed in 45% of those with T2D duration <1 yr, 44% for 1-<2 yr, 55% for 2-3 yr and 60% for ≥4 yr. Median HbA1c was 6.7% (50 mmol/mol), 8.5% (69 mmol/mol), 9.6% (81 mmol/mol), and 9.7% (82 mmol/mol) in those with disease duration <1, 1-<2, 2-3 and ≥4 yr, respectively. Only 33 and 11% of those with HTN and DL respectively, were being treated. MA and NAFLD were observed in 5-6% of the participants. Prevalence of HTN was associated with higher BMI (p < 0.001), DL with higher HbA1c (p < 0.001), and MA with longer diabetes duration (p = 0.001)., Conclusions: Frequency of insulin therapy in youth with T2D was associated with increased disease duration and those with longer duration rarely achieve target HbA1c level. This highlights the aggressive course of T2D in youth and adolescents. Additionally, co-morbidities are not being adequately treated. Follow up data from the PDC will provide additional important information about the natural history of T2D and patterns of gaps in treatment., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated that glycemic failure rates in the three treatments combined-metformin plus rosiglitazone, metformin alone, and metformin plus lifestyle-were higher in non-Hispanic blacks (NHB; 52.8%) versus non-Hispanic whites (NHW; 36.6%) and Hispanics (H; 45.0%). Moreover, metformin alone was less effective in NHB versus NHW versus H youth. This study describes treatment-associated changes in adiponectin, insulin sensitivity, and β-cell function over time among the three racial/ethnic groups to understand potential mechanism(s) responsible for this racial/ethnic disparity., Research Design and Methods: TODAY participants underwent periodic oral glucose tolerance tests to determine insulin sensitivity, C-peptide index, and oral disposition index (oDI), with measurements of total and high-molecular-weight adiponectin (HMWA)., Results: At baseline NHB had significantly lower HMWA than NHW and H and exhibited a significantly smaller increase (17.3% vs. 33.7% vs. 29.9%, respectively) during the first 6 months overall. Increases in HMWA were associated with reductions in glycemic failure in the three racial/ethnic groups combined (hazard ratio 0.61, P < 0.0001) and in each race/ethnicity separately. Over time, HMWA was significantly lower in those who failed versus did not fail treatment, irrespective of race/ethnicity. There were no differences in treatment-associated temporal changes in insulin sensitivity, C-peptide index, and oDI among the three racial/ethnic groups., Conclusions: HMWA is a reliable biomarker of treatment response in youth with type 2 diabetes. The diminutive treatment-associated increase in HMWA in NHB (∼50% lower) compared with NHW and H may explain the observed racial/ethnic disparity with higher therapeutic failure rates in NHB in TODAY., (© 2017 by the American Diabetes Association.)

Objective: To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels., Methods: 25-hydroxy vitamin D (25OHD) levels were measured in 215 youth with T1D and 326 youth with T2D enrolled in the Pediatric Diabetes Consortium (PDC). These levels were compared with those of youth of the same age without diabetes from the 2005-2006 NHANES Survey., Results: Vitamin D deficiency (<21 ng/mL) was present in 36% of PDC participants, and insufficiency (21-29 ng/mL) was present in an additional 34%. About 36% of age-matched youth in the NHANES Survey were vitamin D deficient and an additional 41% were insufficient. Deficiency or insufficiency varied by race/ethnicity, being highest in African-Americans (86%), intermediate in Hispanics (77%), and lowest in non-Hispanic whites (47%). Lower 25OHD levels were observed in African-American and Hispanic youth, during fall and winter, and at sites in the northern United States (all p-values < 0.001). Youth with T2D had significantly lower 25OHD levels than youth with T1D (p < 0.001), but this difference was largely eliminated after adjusting for race/ethnicity and socio-economic status., Conclusions: Vitamin D deficiency/insufficiency is present in a substantial proportion of youth with diabetes, particularly minorities, but the prevalence appears similar to that in youth without diabetes. Further studies are needed to examine whether youth with diabetes would benefit from vitamin D supplementation., Competing Interests: J. Wood, K. Ruedy, R. Beck, F. Bacha, C. Connor, E. Cengiz, B. Gregg, S. Willi, D. Schatz, and P. Cheng report no conflict of interest., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction., Methods: To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA., Results: Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanine-adenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and intravenous glucose loads., Conclusions: FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient to patient. Muscle Nerve 54: 887-894, 2016., (© 2016 Wiley Periodicals, Inc.)

Aims/hypothesis: Type 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2 years., Methods: A multicentre, randomised, double-blind, placebo-controlled trial of 6.5 mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100 days from diagnosis. Subjects were randomised to 6.5 mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24 months included meal-stimulated C-peptide AUC, safety and immunological responses., Results: Fifty-eight patients were enrolled; at 2 years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35 years) in the ATG group had significantly greater C-peptide AUCs at 24 months than placebo patients. Using complete preservation of baseline C-peptide at 24 months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24 months. Beta cell autoantibodies did not change over the 24 months in the ATG-treated or placebo participants. At 12 months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections., Conclusions/interpretation: A brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24 months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study., Trial Registration: ClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.org, Funding: National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN).

Objective: Type 2 diabetes (T2D) in youth is recognized as a pediatric disease, but few reports describe the characteristics during diagnosis. We describe the clinical presentation of 503 youth with T2D., Methods: The Pediatric Diabetes Consortium (PDC) T2D Clinic Registry enrolled T2D participants from eight pediatric diabetes centers in the USA. Clinical and laboratory characteristics at the time of diagnosis were analyzed., Results: In total 67% presented with symptoms of diabetes and confirming laboratory data, but 33% were identified by testing at risk children, 11% presented with diabetic ketoacidosis (DKA), and 2% with hyperglycemic hyperosmolar state (HHS). The mean age was 13.1 ± 2.3 yr (range, 4.6-19.8 yr) with 38 (8%) less than 10 yr of age at diagnosis. The majority was female (65%), Hispanic (54%) and had a family history of T2D (92%). The median body mass index (BMI) z-score was 2.3 (interquartile range 2.0-2.6). Fewer than half (46%) lived with both parents, only 30% had parents with education beyond high school, and 43% lived in a household with an income of <$25 000 per year. In the initial month after diagnosis, almost all (92%) were treated with insulin (30%), metformin (31%), or a combination of insulin and metformin (32%); 7% were treated with lifestyle modification alone., Conclusions: The demographics of T2D in youth indicate significant social vulnerability which may affect outcomes. Metformin and insulin were the initial treatment in most youth. Importantly, T2D may occur at younger ages than previously thought and should be considered in all high-risk children presenting with diabetes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount.

Objective: We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study., Research Design and Methods: The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother's prenatal care and delivery and the infant's health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed., Results: Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly., Conclusions: Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To evaluate the frequency of depressive symptoms and the diagnosis and management of depression in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium T1D and T2D registries., Research Design and Methods: The Children's Depression Inventory (CDI) 2 Self-Report (Short) version was completed by 261 T1D and 339 T2D youth aged 10-17 years., Results: Symptoms of depression were identified in 13% of T1D and 22% of T2D (P = 0.007) participants; of these, only 4% of T1D and 9% of T2D youth were treated by a therapist within the prior 12 months. Depressive symptoms were associated with lower family income (P = 0.006) and obesity (P = 0.002) in T1D but not T2D youth., Conclusions: Depressive symptoms are more frequent than diagnosed depression in youth with T1D or T2D. These results underscore the need for regular depression screening and appropriate referral for youth with diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)