Multicenter Evaluation of Ultra-Rapid Lispro (URLi) Insulin with Control-IQ Technology in Adults, Adolescents and Children with Type 1 Diabetes.

OBJECTIVE: To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teens and adults living with type 1 diabetes (T1D). METHODS: At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology followed by a 13-week period in which URLi insulin was used in the pump. RESULTS: The trial included 179 individuals with type 1 diabetes (T1D) age 6 to 75 years. With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No DKA events occurred. Two participants stopped URLi use due to infusion site discomfort and one stopped after developing a rash. Mean time 70-180 mg/dL (TIR) increased from 65%±15% with lispro to 67%±13% with URLi (P=0.004). Mean insulin treatment satisfaction questionnaire (ITSQ) score improved from 75±13 at screening to 80±11 after 13 weeks of URLi use (mean difference = 6; 95% CI 4 to 8; P<0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment related impact measure-diabetes (TRIM-D) score improved from 74±12 to 80±12 (P<0.001), and mean TRIM-Diabetes Device (TRIM-DD) score improved from 82±11 to 86±12 (P<0.001). CONCLUSIONS: URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with type 1 diabetes, with quality of life benefits of URLi use perceived by the study participants.

Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at t-cell marker CD3, is the first medication approved by the FDA to delay progression from Stage 2 to Stage 3 type 1 diabetes (T1D). To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Islet autoantibodies as precision diagnostic tools to characterize heterogeneity in type 1 diabetes: a systematic review.

BACKGROUND: Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. METHODS: We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. RESULTS: Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. CONCLUSIONS: Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.

Islet autoantibodies are markers found in the blood when insulin-producing cells in the pancreas become damaged and can be used to predict future development of type 1 diabetes. We evaluated published literature to determine whether characteristics of islet antibodies (type, levels, numbers) could improve prediction and help understand differences in how individuals with type 1 diabetes respond to treatments. We found existing evidence shows that islet autoantibody type and number are most useful to predict disease progression before diagnosis. In addition, the age when islet autoantibodies first appear strongly influences rate of progression. These findings provide important information for patients and care providers on how islet autoantibodies can be used to understand future type 1 diabetes development and to identify individuals who have the potential to benefit from intervention or prevention therapy.

Cost-Effectiveness of Closed-Loop Automated Insulin Delivery Using the Cambridge Hybrid Algorithm in Children and Adolescents with Type 1 Diabetes: Results from a Multicenter 6-Month Randomized Trial.

BACKGROUND/OBJECTIVE: The main objective of this study is to evaluate the incremental cost-effectiveness (ICER) of the Cambridge hybrid closed-loop automated insulin delivery (AID) algorithm versus usual care for children and adolescents with type 1 diabetes (T1D). METHODS: This multicenter, binational, parallel-controlled trial randomized 133 insulin pump using participants aged 6 to 18 years to either AID (n = 65) or usual care (n = 68) for 6 months. Both within-trial and lifetime cost-effectiveness were analyzed. Analysis focused on the treatment subgroup (n = 21) who received the much more reliable CamAPS FX hardware iteration and their contemporaneous control group (n = 24). Lifetime complications and costs were simulated via an updated Sheffield T1D policy model. RESULTS: Within-trial, both groups had indistinguishable and statistically unchanged health-related quality of life, and statistically similar hypoglycemia, severe hypoglycemia, and diabetic ketoacidosis (DKA) event rates. Total health care utilization was higher in the treatment group. Both the overall treatment group and CamAPS FX subgroup exhibited improved HbA1C (-0.32%, 95% CI: -0.59 to -0.04; P = .02, and -1.05%, 95% CI: -1.43 to -0.67; P < .001, respectively). Modeling projected increased expected lifespan of 5.36 years and discounted quality-adjusted life years (QALYs) of 1.16 (U.K. tariffs) and 1.52 (U.S. tariffs) in the CamAPS FX subgroup. Estimated ICERs for the subgroup were £19 324/QALY (United Kingdom) and -$3917/QALY (United States). For subgroup patients already using continuous glucose monitors (CGM), ICERs were £10 096/QALY (United Kingdom) and -$33 616/QALY (United States). Probabilistic sensitivity analysis generated mean ICERs of £19 342/QALY (95% CI: £15 903/QALY to £22 929/QALY) (United Kingdom) and -$28 283/QALY (95% CI: -$59 607/QALY to $1858/QALY) (United States). CONCLUSIONS: For children and adolescents with T1D on insulin pump therapy, AID using the Cambridge algorithm appears cost-effective below a £20 000/QALY threshold (United Kingdom) and cost saving (United States).

Metabolic bone disease of prematurity screening and individualized enteral mineral supplementation in high-risk neonates: a quality improvement initiative.

OBJECTIVE: Prompted by an alarmingly low screening rate for metabolic bone disease of prematurity (MBDP), we aimed to increase MBDP screening with serum calcium, phosphorous, and alkaline phosphatase at four to six weeks of life in infants born at <1500 g and <32 gestational weeks from a baseline of 27.37% to 90% within one year. STUDY DESIGN: We used the Institute for Healthcare Improvement's Model for Improvement as a framework. A key driver diagram informed the interventions which were carried out through four Plan-Do-Study-Act cycles. RESULTS: There were 129 and 130 neonates in the pre-intervention baseline group and post-intervention MBDP bundle group, respectively. MBDP bundled primary screening rates increased from 27.37% to 95.56% (p < 0.001). Furthermore, 20% of infants had an individualized change in their enteral mineral supplementation after the initiative. CONCLUSIONS: An interdisciplinary team-based quality improvement approach was effective in altering clinical practice to improve screening and subsequent treatment for MBDP.

Invited Mini Review Metabolic Bone Disease of Prematurity: Overview and Practice Recommendations.

Metabolic bone disease of prematurity (MBDP) is defined by undermineralization of the preterm infant skeleton arising from inadequate prenatal and postnatal calcium (Ca) and phosphate (PO4) accretion. Severe MBDP can be associated with rickets and fractures. Despite advances in neonatal nutrition, MBDP remains prevalent in premature infants due to inadequate mineral accretion ex-utero. There also remain significant knowledge gaps regarding best practices for monitoring and treatment of MBDP among neonatologists and pediatric endocrinologists. Preventing and treating MBDP can prevent serious consequences including rickets or pathologic fractures. Postnatal monitoring to facilitate early recognition of MBDP is best done by first-tier laboratory screening by measuring serum calcium, phosphorus, and alkaline phosphatase to identify infants at risk. If these labs are abnormal, further studies including assessing parathyroid hormone and/or tubular resorption of phosphate can help differentiate between Ca and PO4 deficiency as primary etiologies to guide appropriate treatment with mineral supplements. Additional research into optimal mineral supplementation for the prevention and treatment of MBDP is needed to improve long-term bone health outcomes and provide a fuller evidence base for future treatment guidelines.

Gut microbial changes associated with obesity in youth with type 1 diabetes.

Obesity is increasingly prevalent in type 1 diabetes (T1D) and is associated with management problems and higher risk for diabetes complications. Gut microbiome changes have been described separately in each of T1D and obesity, however, it is unknown to what extent gut microbiome changes are seen when obesity and T1D concomitantly occur. OBJECTIVE: To describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized significant gut microbial and metabolite differences between T1D youth who are lean (BMI: 5-<85%) vs. those with obesity (BMI: ≥95%). METHODS: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) metabolite differences in lean (n=27) and obese (n=21) T1D youth. The mean±SD age was 15.3±2.2yrs, A1c 7.8±1.3%, diabetes duration 5.1±4.4yrs, 42.0% females, and 94.0% were White. Linear discriminant analysis (LDA) effect size (LEfSe) was used to identify taxa that best discriminated between the BMI groups. RESULTS: Bacterial community composition showed differences in species type (ß-diversity) by BMI group (p=0.013). At the genus level, there was a higher ratio of Prevotella to Bacteroides in the obese group (p=0.0058). LEfSe analysis showed a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance of Prevotella copri , among other taxa in the obese group. Functional profiling showed that pathways associated with decreased insulin sensitivity were upregulated in the obese group. Stool SCFAs (acetate, propionate and butyrate) were higher in the obese compared to the lean group (p<0.05 for all). CONCLUSIONS: Our findings identify gut microbiome, microbial metabolite and functional pathways differences associated with obesity in T1D. These findings could be helpful in identifying gut microbiome targeted therapies to manage obesity in T1D.

Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer.

Background: Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Methods: Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. Results: A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). Conclusion: GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.

Inhibition of polyamine biosynthesis preserves ß cell function in type 1 diabetes.

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing ß cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with ß cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during ß cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve ß cell function in T1D through islet cell-autonomous effects.

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review.

BACKGROUND: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. METHODS: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. RESULTS: We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. CONCLUSIONS: While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.

Type 1 diabetes (T1D) is a condition that results from the destruction of a type of cell in the pancreas that produces the hormone insulin, leading to lifelong dependence on insulin injections. T1D prevention remains a challenging goal, largely due to the immense variability in disease processes and progression. Therapies tested to date in medical research settings (clinical trials) work only in a subset of individuals, highlighting the need for more tailored prevention approaches. We reviewed clinical trials of therapies targeting the disease process in T1D. While the overall quality of trials was high, studies testing individual features affecting responses to treatments were low. This review reveals an important need to carefully plan high-quality analyses of features that affect treatment response in T1D, to ensure that tailored approaches may one day be applied to clinical practice.

Hydroxychloroquine in Stage 1 Type 1 Diabetes.

OBJECTIVE: Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance). RESULTS: After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032). CONCLUSIONS: We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.

Evaluating the effect of prebiotics on the gut microbiome profile and ß cell function in youth with newly diagnosed type 1 diabetes: protocol of a pilot randomized controlled trial.

INTRODUCTION: Data show that disturbances in the gut microbiota play a role in glucose homeostasis, type 1 diabetes (T1D) risk and progression. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites favorably with an increase in bacteria producing short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity, and secretion in healthy non-diabetic adults. Additionally, a recent study testing an acetylated and butyrylated form of HAMS (HAMS-AB) that further increases SCFA production prevented T1D in a rodent model without adverse safety effects. The overall objective of this human study will be to assess how daily HAMS-AB consumption impacts the gut microbiome profile, SCFA production, ß cell heath, function, and glycemia as well as immune responses in newly diagnosed T1D youth. METHODS AND ANALYSIS: We hypothesize that HAMS-AB intake will improve the gut microbiome profile, increase SCFA production, improve ß cell health, function and glycemia as well as modulate the immune system. We describe here a pilot, randomized crossover trial of HAMS-AB in 12 newly diagnosed T1D youth, ages 11-17 years old, with residual ß cell function. In Aim 1, we will determine the effect of HAMS-AB on the gut microbiome profile and SCFA production; in Aim 2, we will determine the effect of HAMS-AB on ß cell health, function and glycemia; and in Aim 3, we will determine the peripheral blood effect of HAMS-AB on frequency, phenotype and function of specific T cell markers. Results will be used to determine the effect-size estimate of using HAMS-AB. We anticipate beneficial effects from a simple, inexpensive, and safe dietary approach. ETHICS AND DISSEMINATION: The Institutional Review Board at Indiana University approved the study protocol. The findings of this trial will be submitted to a peer-reviewed pediatric journal. Abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION: NCT04114357; Pre-results.

Interventions to address global inequity in diabetes: international progress.

Diabetes is a serious chronic disease with high associated burden and disproportionate costs to communities based on socioeconomic, gender, racial, and ethnic status. Addressing the complex challenges of global inequity in diabetes will require intentional efforts to focus on broader social contexts and systems that supersede individual-level interventions. We codify and highlight best practice approaches to achieve equity in diabetes care and outcomes on a global scale. We outline action plans to target diabetes equity on the basis of the recommendations established by The Lancet Commission on Diabetes, organising interventions by their effect on changing the ecosystem, building capacity, or improving the clinical practice environment. We present international examples of how to address diabetes inequity in the real world to show that approaches addressing the individual within a larger social context, in addition to addressing structural inequity, hold the greatest promise for creating sustainable and equitable change that curbs the global diabetes crisis.

Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response.

Background: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention. Methods: To understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results: We identified 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss in individuals at disease onset. Seventeen agents tested, mostly immunotherapies, showed benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employed precision analyses to assess features linked to treatment response. Age, measures of beta cell function and immune phenotypes were most frequently tested. However, analyses were typically not prespecified, with inconsistent methods reporting, and tended to report positive findings. Conclusions: While the quality of prevention and intervention trials was overall high, low quality of precision analyses made it difficult to draw meaningful conclusions that inform clinical practice. Thus, prespecified precision analyses should be incorporated into the design of future studies and reported in full to facilitate precision medicine approaches to T1D prevention. Plain Language Summary: Type 1 diabetes (T1D) results from the destruction of insulin-producing cells in the pancreas, necessitating lifelong insulin dependence. T1D prevention remains an elusive goal, largely due to immense variability in disease progression. Agents tested to date in clinical trials work in a subset of individuals, highlighting the need for precision medicine approaches to prevention. We systematically reviewed clinical trials of disease-modifying therapy in T1D. While age, measures of beta cell function, and immune phenotypes were most commonly identified as factors that influenced treatment response, the overall quality of these studies was low. This review reveals an important need to proactively design clinical trials with well-defined analyses to ensure that results can be interpreted and applied to clinical practice.

Twelve-month psychosocial outcomes of continuous glucose monitoring with behavioural support in parents of young children with type 1 diabetes.

AIM: Managing type 1 diabetes in young children can cause significant stress for parents. Continuous glucose monitoring (CGM) may reduce parental burden. The Strategies to Enhance CGM Use in Early Childhood (SENCE) trial randomized parents of children (ages 2 to <8 years) with type 1 diabetes to CGM with family behavioural intervention (CGM + FBI), CGM alone (Standard-CGM) or blood glucose monitoring for 26 weeks before receiving CGM + FBI (BGM-Crossover). This report assesses changes in psychosocial outcomes for all groups over 52 weeks. METHODS: CGM + FBI (n = 45), Standard-CGM (n = 42) and BGM-Crossover (n = 44) participants completed psychosocial assessments at baseline, 26 weeks and 52 weeks. Repeated measures linear regression models evaluated change within and between treatment groups. RESULTS: The BGM-Crossover group reported improved diabetes burden (Δ -6.9, 95% CI [-11.3, -2.6], p = 0.003), fear of hypoglycaemia (Δ -6.4, CI [-10.1, -2.6], p = 0.002) and technology satisfaction (Δ 7.3, CI [2.4, 12.2], p = 0.005) from 26 to 52 weeks, similar to published findings in the CGM + FBI group over the first 26 weeks. The Standard-CGM group reported increased technology satisfaction (Δ 7.3, CI [0.6, 14.0], p = 0.027) from baseline to 52 weeks. The CGM + FBI group reported less diabetes burden and fear of hypoglycaemia from baseline to 52 weeks, but changes were not statistically significant. Scores from 26 to 52 weeks did not deteriorate. CONCLUSIONS: Parents demonstrated psychosocial benefits following FBI that appeared to maintain without additional intervention. CGM-focused education with behavioural support likely helps parents of young children with type 1 diabetes reduce burden and worry in the short- and long-term.

Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials.

Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown. Objective: To identify factors associated with screening for T1D prevention trials. Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22). Univariate and multivariate logistic regression models were used to examine participant, site, and study factors at the time of prevention trial accrual. Results: Screening rates for trials were: 50% for TN-07 (584 screened/1172 eligible), 9% for TN-10 (106/1249), 24% for TN-18 (313/1285), 17% for TN-20 (113/667), and 28% for TN-22 (371/1336). Younger age and male sex were associated with higher screening rates for prevention trials overall and for oral therapies. Participants with an offspring with T1D showed lower rates of screening for all trials and oral drug trials compared with participants with other first-degree relatives as probands. Site factors, including larger monitoring volume and US site vs international site, were associated with higher prevention trial screening rates. Conclusions: Clear differences exist between participants who screen for prevention trials and those who do not screen and between the research sites involved in prevention trial screening. Participant age, sex, and relationship to proband are significantly associated with prevention trial screening in addition to key site factors. Identifying these factors can facilitate strategic recruitment planning to support rapid and successful enrollment into prevention trials.

Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals. Objective: To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years. Interventions: Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo. Main Outcomes and Measures: The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis. Results: Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group. Conclusions and Relevance: In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial.

Importance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, Setting, and Participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main Outcomes and Measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and Relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT04233034.

Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes.

AIMS: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready-to-use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). MATERIALS AND METHODS: An integrated analysis of dasiglucagon safety was conducted on data from two placebo-controlled trials (placebo-controlled pool) and two placebo-controlled and four non-placebo-controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo-controlled and two non-placebo-controlled trials in adults with T1D. RESULTS: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo-controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin-induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo-controlled trial subgroups. CONCLUSIONS: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin-induced SH in people with T1D.