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

AIMS: Evaluate changes in circulating biomarkers as predictors of kidney disease, and cardiac/vascular dysfunction in participants from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Candidate biomarkers were assessed annually in 507 participants over a mean follow-up of 6.9 ± 2.4 years. Moderate albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g and hyperfiltration as eGFR ≥ 135 mL/min/1.73 m2 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 ß-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.

The impact of fear of hypoglycaemia on sleep in adolescents with type 1 diabetes.

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 (ß = -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.

Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial.

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; HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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.

Long-term Continuous Glucose Monitor Use in Very Young Children With Type 1 Diabetes: One-Year Results From the SENCE Study.

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.

Association between high levels of physical activity and improved glucose control on active days in youth with type 1 diabetes.

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.

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

BACKGROUND: Higher arterial stiffness may contribute to future alterations in left ventricular systolic and diastolic function. We tested this hypothesis in individuals with youth-onset type 2 diabetes from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Arterial stiffness (pulse wave velocity [carotid-femoral, femoral-foot, and carotid-radial], augmentation index, brachial distensibility) was measured in 388 participants with type 2 diabetes (mean age, 21 years; diabetes duration, 7.7 ± 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.

Genetic variations in adiponectin levels and dietary patterns on metabolic health among children with normal weight versus obesity: the BCAMS study.

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 (Pinteraction = 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 (Pinteraction = 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.

IL-6 receptor blockade does not slow ß cell loss in new-onset type 1 diabetes.

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 ß 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 ß 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.

"I Think Parents Shouldn't Be Too Pushy": A Qualitative Exploration of Parent and Youth Perspectives of Youth Decision-Making Involvement in Starting Continuous Glucose Monitoring.

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.

Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune-mediated destruction of ß 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 ß-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 ß-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.

Early Racial/Ethnic Disparities in Continuous Glucose Monitor Use in Pediatric Type 1 Diabetes.

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.

Racial disparities in treatment and outcomes of children with type 1 diabetes.

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.

Correlates of Continuous Glucose Monitoring Use Trajectories in Children and Adolescents with Type 1 Diabetes.

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.

Puberty Status Modifies the Effects of Genetic Variants, Lifestyle Factors and Their Interactions on Adiponectin: The BCAMS Study.

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 (Pinteraction = 0.022) and exercise (Pinteraction = 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.

Human plasma-derived alpha1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study.

BACKGROUND: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with ß-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) alpha1 -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 alpha1 -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 alpha1 -PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha1 -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.

Racial and Ethnic Disparities in Rates of Continuous Glucose Monitor Initiation and Continued Use in Children With Type 1 Diabetes.

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.

Insulin Pump Use in Children with Type 1 Diabetes: Over a Decade of Disparities.

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.

Youth Involvement in the Decision to Start CGM Predicts Subsequent CGM Use.

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.

Effect of Continuous Glucose Monitoring on Glycemic Control in Adolescents and Young Adults With Type 1 Diabetes: A Randomized Clinical Trial.

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.