Driving-Related Glucose Patterns Among Older Adults with Type 1 Diabetes.

Older adults with type 1 diabetes may face challenges driving safely. Glucose "above-5-to-drive" is often recommended for insulin-treated diabetes to minimize hypoglycemia while driving. However, the effectiveness of this recommendation among older adults has not been evaluated. Older drivers with type 1 diabetes were assessed while using sensor-augmented insulin pumps during a 2-week clinical trial run-in. Twenty-three drivers (median age 69 years [interquartile range; IQR 65-72]; diabetes duration 37 years [20-45]) undertook 618 trips (duration 10 min [5-21]). Most trips (n = 535; 87%) were <30 min duration; 9 trips (1.5%) exceeded 90 min and 3 trips (0.5%) exceeded 120 min. Pre-trip continuous glucose monitoring (CGM) was >5.0 mmol/L for 577 trips (93%) and none of these had CGM <3.9 mmol/L during driving (including 8 trips >90 min and 3 trips >120 min). During 41 trips with pre-trip CGM ≤5.0 mmol/L, 11 trips had CGM <3.9 mmol/L. Seventy-one CGM alerts occurred during 60 trips (10%), of which 54 of 71 alerts (76%) were unrelated to hypoglycemia. Our findings support a glucose "above-5-to-drive" recommendation to avoid CGM-detected hypoglycemia among older drivers, including for prolonged drives, and highlight the importance of active CGM low-glucose alerts to prevent hypoglycemia during driving. Driving-related CGM usability and alert functionality warrant investigation. Clinical trial ACTRN1261900515190.

The GLP-1 receptor is expressed in vivo by human metastatic prostate cancer.

Objectives: The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT. Materials and methods: Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression. Results: Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid. Conclusions: We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.

The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) Trial: A Randomized Controlled Trial of Early Intervention With an Electronic Specialist-Led Model of Diabetes Care.

OBJECTIVE: To investigate the effect of early intervention with an electronic specialist-led "proactive" model of care on glycemic and clinical outcomes. RESEARCH DESIGN AND METHODS: The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) randomized controlled trial was performed at the Royal Melbourne Hospital. Eligible participants were adults admitted to a surgical ward during the study with either known diabetes or newly detected hyperglycemia (at least one random blood glucose result ≥11.1 mmol/L). Participants were randomized 1:1 to standard diabetes care or the intervention consisting of an early consult by a specialist inpatient diabetes team using electronic tools for patient identification, communication of recommendations, and therapy intensification. The primary outcome was median patient-day mean glucose (PDMG). The key secondary outcome was incidence of healthcare-associated infection (HAI). RESULTS: Between 12 February 2021 and 17 December 2021, 1,371 admissions met inclusion criteria, with 680 assigned to early intervention and 691 to standard diabetes care. Baseline characteristics were similar between groups. The early intervention group achieved a lower median PDMG of 8.2 mmol/L (interquartile range [IQR] 6.9-10.0 mmol/L) compared with 8.6 mmol/L (IQR 7.2-10.3 mmol/L) in the control group for an estimated difference of -0.3 mmol/L (95% CI -0.4 to -0.2 mmol/L, P < 0.0001). The incidence of HAI was lower in the intervention group (77 [11%] vs. 110 [16%]), for an absolute risk difference of -4.6% (95% CI -8.2 to -1.0, P = 0.016). CONCLUSIONS: In surgical inpatients, early diabetes management intervention with an electronic specialist-led diabetes model of care reduces glucose and HAI.

Hyperglycemia in hospital: an independent marker of infection, acute kidney injury & stroke for hospital inpatients.

CONTEXT: Hyperglycemia in hospital inpatients without pre-existing diabetes is associated with increased mortality. However, the independent contribution of hyperglycemia to healthcare-associated infection (HAI), acute kidney injury (AKI), and stroke is unclear. OBJECTIVE: To investigate the relationship between hyperglycemia and adverse clinical outcomes in hospital for patients with and without diabetes. DESIGN: Diabetes IN-hospital: Glucose and Outcomes (DINGO) was a 26-week (October 2019 - March 2020) prospective cohort study. Clinical and glucose data were collected up to the 14th day of admission. Primary stratification was by hyperglycemia, defined as ≥2 random capillary blood glucose (BG) measurements ≥11.1 mmol/L (≥200 mg/dL). Propensity weighting for nine clinical characteristics, was performed to allow interrogation of causality. To maintain the positivity assumption, patients with HbA1c > 12.0% were excluded and pre-hospital treatment not adjusted for. SETTING: The Royal Melbourne Hospital, a quaternary referral hospital in Melbourne, Australia. PATIENTS: Admissions with at least two capillary glucose values and length of stay >24 hours were eligible, with half randomly sampled. OUTCOME MEASURES: HAI, AKI, stroke, and mortality. RESULTS: Of 2,558 included admissions, 1,147 (45%) experienced hyperglycemia in hospital. Following propensity-weighting and adjustment, hyperglycemia in hospital was found to, independently of nine covariables, contribute an increased risk of in-hospital HAI (130 [11.3%] vs.100 [7.1%], adjusted odds ratio [aOR] 1.03, 95% confidence interval [95%CI] 1.01-1.05, p = 0.003), AKI (120 [10.5%] vs. 59 [4.2%], aOR 1.07, 95%CI 1.05-1.09, p < 0.001), and stroke (10 [0.9%] vs. 1 [0.1%], aOR 1.05, 95%CI 1.04-1.06, p < 0.001). CONCLUSIONS: In hospital inpatients (HbA1c ≤ 12.0%), irrespective of diabetes status and pre-hospital glycaemia, hyperglycemia increases the risk of in-hospital HAI, AKI, and stroke compared with those not experiencing hyperglycemia.

Real-world lived experience of older adults with type 1 diabetes after an automated insulin delivery trial.

AIMS: First-generation closed-loop automated insulin delivery improves glycaemia and psychosocial outcomes among older adults with type 1 diabetes in clinical trials. However, no study has previously assessed real-world lived experience of older adults using closed-loop therapy outside a trial environment. METHODS: Semi-structured interviews were conducted with older adults who were pre-existing insulin pump users and previously completed the OldeR Adult Closed-Loop (ORACL) randomised trial. Interviews focused on perceptions of diabetes technology use, and factors influencing decisions regarding continuation. RESULTS: Twenty-eight participants, mean age 70 years (SD 5), were interviewed at median 650 days (IQR 608-694) after their final ORACL trial visit. At interview, 23 participants (82%) were still using a commercial closed-loop system (requiring manual input for prandial insulin bolus doses). Themes discussed in interviews relating to closed-loop system use included sustained psychosocial benefits, cost and retirement considerations and usability frustrations relating to sensor accuracy and system alarms. Of the five participants who had discontinued, reasons included cost, continuous glucose monitoring-associated difficulties and usability frustrations. Cost was the largest consideration regarding continued use; most participants considered the increased ease of diabetes management to be worth the associated costs, though cost was prohibitive for some. CONCLUSIONS: Almost 2 years after completing a closed-loop clinical trial, closed-loop automated insulin delivery remains the preferred type 1 diabetes therapy for the majority of older adult participants. Chronological age is not a barrier to real-world successful use of diabetes technology. Identifying age-related barriers, and solutions, to diabetes technology use among older adults is warranted.

Feasibility and Validity of In-Home Self-Collected Capillary Blood Spot Screening for Type 1 Diabetes Risk.

Aims: Self-collection of a blood sample for autoantibody testing has potential to facilitate screening for type 1 diabetes risk. We sought to determine the feasibility and acceptability of this approach and the performance of downstream antibody assays. Methods: People living with type 1 diabetes and their family members (N = 97) provided paired capillary blood spot and serum samples collected, respectively, by themselves and a health worker. They provided feedback on the ease, convenience, and painfulness of blood spot collection. Islet antibodies were measured in blood spots by antibody detection by agglutination PCR (ADAP) or multiplex enzyme-linked immunoassay (ELISA), and in serum by radioimmunoassay (RIA) or ELISA. Results: Using serum RIA and ELISA to define antibody status, 50 antibody-negative (Abneg) and 47 antibody-positive (Abpos) participants enrolled, of whom 43 and 47, respectively, returned testable blood spot samples. The majority indicated that self-collection was easier, more convenient, and less painful than formal venesection. The sensitivity and specificity for detection of Abpos by blood spot were, respectively, 85% and 98% for ADAP and 87% and 100% for multiplex ELISA. The specificities by ADAP for each of the four antigen specificities ranged from 98% to 100% and areas under the receiver operator curve from 0.841 to 0.986. Conclusions: Self-collected blood spot sampling is preferred over venesection by research participants. ADAP and multiplex ELISA are highly specific assays for islet antibodies in blood spots with acceptable performance for use alone or in combination to facilitate screening for type 1 diabetes risk. Clinical Trial Registration number: ACTRN12620000510943.

Automated insulin delivery among adults with type 1 diabetes for up to 2 years: a real-world, multicentre study.

BACKGROUND AND AIMS: Automated insulin delivery (AID) improves glycaemia among people with type 1 diabetes in clinical trials and overseas real-world studies. Whether improvements are sustained beyond 12 months in the real world, and whether they occur in the Australian context, has not yet been established. We aimed to observe, up to 2 years, the effectiveness of initiating first-generation AID for type 1 diabetes management. METHODS: Retrospective, real-world, observational study using medical records, conducted across five sites in Australia. Adults with type 1 diabetes, who had AID initiated between February 2019 and December 2021, were observed for 6-24 months after initiation (until June 2022). Outcomes examined included glucose metrics assessed by glycated haemoglobin (HbA1c ) and continuous glucose monitoring (CGM), safety and therapy continuation. RESULTS: Ninety-four adults were studied (median age 39 years (interquartile range, IQR: 31-51); pre-initiation HbA1c 7.8% (7.2-8.6)). After AID initiation, HbA1c decreased by mean 0.5 percentage points (95% confidence interval (CI): -0.7 to -0.2) at 3 months (P < 0.001); CGM time in range 3.9-10.0 mmol/L increased by 11 percentage points (9-14) at 1 month (P < 0.001); these improvements were maintained up to 24 months (all P < 0.02). Median CGM time below 3.9 mmol/L was <1.5% pre- and post-AID initiation. The subgroup with pre-initiation HbA1c above 8.5% had the greatest HbA1c improvement (-1.4 percentage points (-1.8 to -1.1) at 3 months). Twelve individuals (13%) discontinued AID, predominantly citing difficulties with CGM. During the 150 person-years observed, four diabetes-related emergencies were documented: three severe hypoglycaemic events and one hyperglycaemic event without ketoacidosis. CONCLUSIONS: Early glucose improvements were observed after real-world AID initiation, sustained up to 2 years, without excess adverse events. The greatest benefits were observed among individuals with highest glycaemia before initiation. Future-generation systems with increased user-friendliness may enhance therapy continuation.

The diabetes management experiences questionnaire: Psychometric validation among adults with type 1 diabetes.

AIMS: To examine the psychometric properties of the Diabetes Management Experiences Questionnaire (DME-Q). Adapted from the validated Glucose Monitoring Experiences Questionnaire, the DME-Q captures satisfaction with diabetes management irrespective of treatment modalities. METHODS: The DME-Q was completed by adults with type 1 diabetes as part of a randomized controlled trial comparing hybrid closed loop (HCL) to standard therapy. Most psychometric properties were examined with pre-randomization data (n = 149); responsiveness was examined using baseline and 26-week follow-up data (n = 120). RESULTS: Pre-randomization, participants' mean age was 44 ± 12 years, 52% were women. HbA1c was 61 ± 11 mmol/mol (7.8 ± 1.0%), diabetes duration was 24 ± 12 years and 47% used an insulin pump prior to the trial. A forced three-factor analysis revealed three expected domains, that is, 'Convenience', 'Effectiveness' and 'Intrusiveness', and a forced one-factor solution was also satisfactory. Internal consistency reliability was strong for the three subscales ( α range = 0.74-0.84) and 'Total satisfaction' ( α = 0.85). Convergent validity was demonstrated with moderate correlations between DME-Q 'Total satisfaction' and diabetes distress (PAID: rs = -0.57) and treatment satisfaction (DTSQ; rs = 0.58). Divergent validity was demonstrated with a weak correlation with prospective/retrospective memory (PRMQ: rs = -0.16 and - 0.13 respectively). Responsiveness was demonstrated, as participants randomized to HCL had higher 'Effectiveness' and 'Total satisfaction' scores than those randomized to standard therapy. CONCLUSIONS: The 22-item DME-Q is a brief, acceptable, reliable measure with satisfactory structural and construct validity, which is responsive to intervention. The DME-Q is likely to be useful for evaluation of new pharmaceutical agents and technologies in research and clinical settings.

Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids.

The B-cell lymphoma 2 (BCL2) family members, BCL2-associated protein X (BAX) and BCL2 homologous antagonist killer (BAK), are required for programmed cell death via the mitochondrial pathway. When cells are stressed, damaged or redundant, the balance of power between the BCL2 family of proteins shifts towards BAX and BAK, allowing their transition from an inactive, monomeric state to a membrane-active oligomeric form that releases cytochrome c from the mitochondrial intermembrane space. That oligomeric state has an essential intermediate, a symmetric homodimer of BAX or BAK. Here we describe crystal structures of dimers of the core domain of BAX, comprising its helices α2-α5. These structures provide an atomic resolution description of the interactions that drive BAX homo-dimerisation and insights into potential interaction between core domain dimers and membrane lipids. The previously identified BAK lipid-interacting sites are not conserved with BAX and are likely to determine the differences between them in their interactions with lipids. We also describe structures of heterodimers of BAK/BAX core domains, yielding further insight into the differences in lipid binding between BAX and BAK.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Introduction: Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. Methods: This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. Results: There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Conclusion: Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

What difference does sleep make? Continuous glucose monitoring metrics during fixed-overnight time versus sleep periods among older adults with type 1 diabetes.

Hypoglycaemia during sleep is a common and clinically important issue for people living with insulin-treated diabetes. Continuous glucose monitoring devices can help to identify nocturnal hypoglycaemia and inform treatment strategies. However, sleep is generally inferred, with diabetes researchers and physicians using a fixed-overnight period as a proxy for sleep-wake status when analysing and interpretating continuous glucose monitoring data. No study to date has validated such an approach with established sleep measures. Continuous glucose monitoring and research-grade actigraphy devices were worn and sleep diaries completed for 2 weeks by 28 older adults (mean age 67 years [SD 5]; 17 (59%) women) with type 1 diabetes. Using continuous glucose monitoring data from a total of 356 nights, fixed-overnight (using the recommended period of 00:00 hours-06:00 hours) and objectively-measured sleep periods were compared. The fixed-overnight period approach missed a median 57 min per night (interquartile range: 49-64) of sleep for each participant, including five continuous glucose monitoring-detected hypoglycaemia episodes during objectively-measured sleep. Twenty-seven participants (96%) had at least 1 night with continuous glucose monitoring time-in-range and time-above-range discrepancies both ≥ 10 percentage points, a clinically significant discrepancy. The utility of fixed-overnight time continuous glucose monitoring as a proxy for sleep-awake continuous glucose monitoring is inadequate as it consistently excludes actual sleep time, obscures glycaemic patterns, and misses sensor hypoglycaemia episodes during sleep. The use of validated measures of sleep to aid interpretation of continuous glucose monitoring data is encouraged.

Baricitinib and ß-Cell Function in Patients with New-Onset Type 1 Diabetes.

BACKGROUND: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves ß-cell function in type 1 diabetes is unclear. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring. RESULTS: A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo. CONCLUSIONS: In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve ß-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).

No relationship between socioeconomic status, education level and development and progression of diabetic retinopathy in type 2 diabetes: a FIELD trial substudy.

In 6002 Australian adults with type 2 diabetes and a median 5-year follow-up in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, baseline socioeconomic status (SES) and self-reported education level were not related to development of on-trial sight-threatening diabetic retinopathy. Similarly, in a retinal photography substudy (n = 549), two-step diabetic retinopathy progression was not related to SES or education.

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Experiences of Caregivers and At-Risk Children Enrolled in a Prospective Pregnancy-Birth Cohort Study into the Causes of Type 1 Diabetes: The ENDIA Study.

BACKGROUND: We sought research experiences of caregivers and their children were enrolled in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. METHODS: ENDIA is a pregnancy-birth cohort investigating early-life causes of type 1 diabetes (T1D). Surveys were sent to 1090 families between June 2021 and March 2022 with a median participation of >5 years. Caregivers completed a 12-item survey. Children ≥ 3 years completed a four-item survey. RESULTS: The surveys were completed by 550/1090 families (50.5%) and 324/847 children (38.3%). The research experience was rated as either "excellent" or "good" by 95% of caregivers, and 81% of children were either "ok", "happy" or "very happy". The caregivers were motivated by contributing to research and monitoring their children for T1D. Relationships with the research staff influenced the experience. The children most liked virtual reality headsets, toys, and "helping". Blood tests were least liked by the children and were the foremost reason that 23.4% of the caregivers considered withdrawing. The children valued gifts more than their caregivers. Only 5.9% of responses indicated dissatisfaction with some aspects of the protocol. The self-collection of samples in regional areas, or during the COVID-19 pandemic restrictions, were accepted. CONCLUSIONS: This evaluation identified modifiable protocol elements and was conducted to further improve satisfaction. What was important to the children was distinct from their caregivers.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort.

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Blood pressure in adolescents and young adults with type 1 diabetes: data from the Australasian Diabetes Data Network registry.

AIM: Hypertension increases complication risk in type 1 diabetes (T1D). We examined blood pressure (BP) in adolescents and young adults with T1D from the Australasian Diabetes Data Network, a prospective clinical diabetes registry in Australia and New Zealand. METHODS: This was a longitudinal study of prospectively collected registry data. INCLUSION CRITERIA: T1D (duration ≥ 1 year) and age 16-25 years at last visit (2011-2020). Hypertension was defined as (on ≥ 3 occasions) systolic BP and/or diastolic BP > 95th percentile for age < 18 years, and systolic BP > 130 and/or diastolic BP > 80 mmHg for age ≥ 18 years. Multivariable Generalised Estimating Equations were used to examine demographic and clinical factors associated with BP in the hypertensive range across all visits. RESULTS: Data from 6338 young people (male 52.6%) attending 24 participating centres across 36,655 T1D healthcare visits were included; 2812 (44.4%) had BP recorded at last visit. Across all visits, 19.4% of youth aged < 18 years and 21.7% of those aged ≥ 18 years met criteria for hypertension. In both age groups, BP in the hypertensive range was associated with male sex, injection (vs. pump) therapy, higher HbA1c, and higher body mass index. CONCLUSIONS: There is a high proportion of adolescents and young adults reported with BP persistently in hypertensive ranges. Findings flag the additive contribution of hypertension to the well-established body of evidence indicating a need to review healthcare models for adolescents and young adults with T1D.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Early intervention model of inpatient diabetes care improves glycemia following hospitalization.

Admission to hospital provides an opportunity to optimize long-term diabetes management, but clinical inertia is common. We previously reported the randomized study of a proactive inpatient diabetes service (RAPIDS), investigating an early intervention model of care and demonstrated improved in-hospital glycemia and clinical outcomes. This follow-up study assessed whether proactive care in hospital improved postdischarge HbA1c. In a subgroup of 298 RAPIDS trial participants with type 2 diabetes, age <80 years, and admission HbA1c ≥ 7.0%, diabetes treatment intensification occurred more often in early intervention versus usual care groups (37% vs. 19% [p = .001]), adjusted odds ratio 3.2 (95% confidence interval [CI]: 1.7-6.0). There was a greater change in HbA1c in the early intervention group (mean -0.9% [95% CI -1.3 to -0.4]) versus the usual care group (-0.3% [-0.6 to -0.1]), p = .029. The value of acute care by dedicated inpatient diabetes teams can extend beyond improving inpatient clinical outcomes and can lead to sustained improvement in glycemia.

Lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery in a randomised trial.

AIM: To explore the lived experience of older adults with type 1 diabetes using closed-loop automated insulin delivery, an area previously receiving minimal attention. METHODS: Semi-structured interviews were conducted with adults aged 60 years or older with long-duration type 1 diabetes who participated in a randomised, open-label, two-stage crossover trial comparing first-generation closed-loop therapy (MiniMed 670G) versus sensor-augmented pump therapy. Interview recordings were transcribed, thematically analysed and assessed. RESULTS: Twenty-one older adults participated in interviews after using closed-loop therapy. Twenty were functionally independent, without frailty or major cognitive impairment; one was dependent on caregiver assistance, including for diabetes management. Quality of life benefits were identified, including improved sleep and reduced diabetes-related psychological burden, in the context of experiencing improved glucose levels. Gaps between expectations and reality of closed-loop therapy were also experienced, encountering disappointment amongst some participants. The cost was perceived as a barrier to continued closed-loop access post-trial. Usability issues were identified, such as disruptive overnight alarms and sensor inaccuracy. CONCLUSIONS: The lived experience of older adults without frailty or major cognitive impairment using first-generation closed-loop therapy was mainly positive and concordant with glycaemic benefits found in the trial. Older adults' lived experience using automated insulin delivery beyond trial environments requires exploration; moreover, the usability needs of older adults should be considered during future device development.