This research on a large cohort provides insight into epidemiologic characteristics of PREM in T1D defined by IDAA1c. As IDAA1c does not discriminate between insulin sensitivity and secretion, available data cannot resolve whether the sex-difference in PREM reflects innate higher insulin resistance in girls, or better beta-cell recovery in boys. Further research is needed to clarify the usefulness and performance of IDAA1c in clinical practice.

BackgroundDuchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology.Methodology/Principal FindingsTo address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged.Conclusions/SignificanceIon channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers.

We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1-7 years as well as evaluate the role of diluted insulin on glucose control. RESEARCH DESIGN AND METHODS In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3-6] and mean 6 SD HbA 1c 7.4 6 0.7% [57 6 8 mmol/mol] and total insulin 13.2 6 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closedloop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used. RESULTS The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean 6 SD 72 6 8% vs. 70 6 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; P = 0.16). There was no difference in mean glucose levels (8.0 6 0.8 vs. 8.2 6 0.6 mmol/L; P = 0.14), glucose variability (SD of sensor glucose 3.1 6 0.5 vs. 3.2 6 0.4 mmol/L; P = 0.16), or the proportion of time spent with sensor glucose <3.9 mmol/L (4.5 6 1.7% vs. 4.7 6 1.4%; P = 0.47) or <2.8 mmol/L (0.6 6 0.5% vs. 0.6 6 0.4%; P > 0.99). Total daily insulin delivery did not differ (17.3 6 5.6 vs. 18.9 6 6.9 units/day; P = 0.07). No closed-loop-related severe hypoglycemia or ketoacidosis occurred. CONCLUSIONS Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin. Despite advances in the management of type 1 diabetes and supporting technologies, the majority of children with type 1 diabetes are unable to achieve recommended treatment targets (1,2). Closed-loop systems (3) delivering insulin in glucose-responsive fashion may provide benefits compared with existing treatment modalities including

Objective To evaluate the experiences of families with very young children aged 1 to 7 years (inclusive) with type 1 diabetes using day‐and‐night hybrid closed‐loop insulin delivery. Methods Parents/caregivers of 20 children aged 1 to 7 years with type 1 diabetes completed a closed‐loop experience survey following two 3‐week periods of unrestricted day‐and‐night hybrid closed‐loop insulin therapy using Cambridge FlorenceM system at home. Benefits, limitations, and improvements of closed‐loop technology were explored. Results Responders reported reduced burden of diabetes management, less time spent managing diabetes, and improved quality of sleep with closed‐loop. Ninety percent of the responders felt less worried about their child's glucose control using closed‐loop. Size of study devices, battery performance and connectivity issues were identified as areas for improvement. Parents/caregivers wished for more options to input information to the system such as temporary glucose targets. Conclusions Parents/caregivers of very young children reported important quality of life benefits associated with using closed‐loop, supporting adoption of this technology in this population.

BACKGROUNDThe possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear. METHODSIn this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closedloop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, >180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, <70 mg per deciliter). Safety was assessed.

OBJECTIVE <p>This study aims to examine insulin delivery methods, glucose monitoring modalities and related outcomes in a large, international, diverse cohort of children and adolescents with type 1 diabetes from the SWEET-Registry</p> <p> </p> <p>RESEARCH DESIGN AND METHODS</p> <p>Participants with type 1 diabetes of <u>></u>1 year of duration, aged ≤18y and documented pump/sensor usage during the period August 2017-July 2019 were stratified into four categories: injections-no sensor (reference); injections+sensor; pump-no sensor; pump+sensor. HbA_1c and proportion of patients with DKA or SH were analyzed; linear and logistic regression models adjusted for demographics, region and gross-domestic-product (GDP)-per capita were applied.</p> <p> </p> <p>RESULTS</p> <p>Data of 25,654 subjects were analyzed. Injections-no sensor: 37.44% [adjusted-HbA_1c 8.72 (95%CI 8.68-8.75)]; injections+sensor: 14.98% [adjusted-HbA_1c 8.30 (8.25-8.35)]; pump-no sensor: 17.22% [adjusted-HbA_1c 8.07 (8.03-8.12)]; pump+sensor: 30.35% [adjusted-HbA_1c 7.81 (7.77-7.84)]. HbA_1c was lower in all categories of subjects using pump and/or sensor compared to injections-no sensor treatment method (p<0.001, respectively). Proportion of DKA episodes was lower in subjects with pump+sensor [1.98 (1.64-2.48); p<0.001] and pump-no sensor [2.02 (1.64-2.48); p<0.05)] when compared to injections-no sensor [2.91 (2.59-3.31)]. Proportion of SH was lower in pump-no sensor [1.10 (0.85-1.43); p<0.001] but higher in the injections+sensor [4.25 (3.65-4.95); p<0.001] compared to injections-no sensor [2.35 (2.04-2.71)].</p> <p> </p> <p>CONCLUSIONS</p> Lower HbA_1c and fewer DKA episodes were observed in subjects using either a pump, CGM or both. Pump use was associated with lower rate of SH. Across SWEET centers, use of pumps and CGM is increasing. The concomitant use of pump and CGM was found to be associated with an additive benefit.

OBJECTIVEThe risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control.RESEARCH DESIGN AND METHODSChildren (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated.RESULTSEPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A1c (HbA1c) was the strongest independent predictor of EPCs (β = −0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA1c changes of −4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA1c worsening during the time period.CONCLUSIONSThis is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.

To quantify age-related variability of insulin needs during day and night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS We retrospectively analyzed data from hybrid closed-loop studies involving young children (1-6 years old, n 5 20), children (7-12 years, n 5 21), adolescents (13-17 years, n 5 15), and adults (>18 years, n 5 58) with type 1 diabetes. The coefficient of variation quantified variability of insulin needs during 3 weeks of unrestrictedliving hybrid closed-loop use. RESULTS Data from 2,365 nights and 2,367 days in 114 participants were analyzed. The coefficient of variation of insulin delivery was higher in young children compared with adults (mean difference at nighttime 10.7 percentage points [95% CI 2.9-18.4], P 5 0.003; daytime 6.4 percentage points [95% CI 2.0-10.9], P 5 0.002) and compared with adolescents (mean difference at nighttime 10.2 percentage points [95% CI 0.0-20.4], P 5 0.049; daytime 7.0 percentage points [95% CI 1.1-12.8], P 5 0.014). CONCLUSIONS Diabetes management in young children is complicated by higher variability in insulin requirements, supporting fast-track clinical practice adoption of closed-loop in this vulnerable population. With increasing application of insulin pump therapy and continuous glucose monitors, hybrid closed-loop has become a feasible treatment modality for people with type 1 diabetes (1,2). Apart from manual mealtime boluses, insulin delivery is autonomously modulated by a control algorithm based on real-time sensor glucose values. Insulin delivery may vary considerably from day to day and night to night due to varying activity levels, insulin set-changes, meal timings and composition, and other factors (3,4). To date, the association between age and insulin variability has not been assessed. In the present analysis, we investigate whether insulin requirements may be more variable in younger age.