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.

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.

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.

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.

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.

Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial.

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.

Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure.

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 ß-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and ß-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 ß-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. ß-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, ß-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.

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.

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.

A structured 1-year education program for children with newly diagnosed type 1 diabetes improves early glycemic control.

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.

Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial.

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 A1c 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/1.73m2) 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 A1c 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.

Childhood retinol-binding protein 4 (RBP4) levels predicting the 10-year risk of insulin resistance and metabolic syndrome: the BCAMS study.

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.

Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels.

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.

A cross-sectional view of the current state of treatment of youth with type 2 diabetes in the USA: enrollment data from the Pediatric Diabetes Consortium Type 2 Diabetes Registry.

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.

Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial.

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).

Effects of genetic severity on glucose homeostasis in Friedreich ataxia.

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.

Presentation of youth with type 2 diabetes in the Pediatric Diabetes Consortium.

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.

Effect of relative weight group change on nuclear magnetic resonance spectroscopy derived lipoprotein particle size and concentrations among adolescents.

OBJECTIVE: To examine whether longitudinal changes in relative weight category (as indicated by change in body mass index [BMI] classification group) were associated with changes in nuclear magnetic resonance (NMR)-derived lipoprotein particles among US youth. STUDY DESIGN: Secondary analysis of data from a clustered randomized controlled trial. BMI and fasting blood samples were obtained from 2069 participants at the start of the 6th grade and end of the 8th grade. BMI was categorized as normal weight, overweight, or obese at both time points. Lipoprotein particle profiles were measured with NMR spectroscopy at both time points. Regression models were used to examine changes in relative weight group and change in lipoprotein variables. RESULTS: A total of 38% of participants changed relative weight category (BMI group) during the 2.5-year study period. Low-density lipoprotein (LDL) cholesterol and non-high-density lipoprotein (HDL) cholesterol decreased almost universally, but more with improved BMI category. There were adverse effects on LDL size and total LDL particles, HDL size, and cholesterol for participants who remained obese or whose relative weight group worsened. Changes in relative category had no impact on HDL particles. CONCLUSION: Improvement in relative weight group from 6th to 8th grade was associated with favorable changes in non-HDL cholesterol, very low-density lipoprotein size, LDL size, HDL size, and LDL particles but had no effect on HDL particles. Findings indicate that an improvement in relative weight group between 6th and 8th grade had an effect on NMR-derived particles sizes and concentrations among a large group of adolescents, which overrepresented low-income minorities.

Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.

BACKGROUND: Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. METHODS: In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. RESULTS: At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. CONCLUSIONS: In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)