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.

The Need to Prioritize Education and Resources to Support Exercise in Type 1 Diabetes: Results of an Australian Survey of Adults With Type 1 Diabetes and Health Providers.

OBJECTIVES: Regular exercise is recommended for people with type 1 diabetes (PWD) to improve their health, but many do not meet recommended exercise targets. Educational resources supporting PWD to exercise exist, but their value is unclear. To determine the need for improved exercise resources in Australia, we surveyed adult PWD and health providers (HPs) about their confidence in managing type 1 diabetes (T1D) around exercise, barriers to exercise, and the adequacy of current resources. METHODS: Australian adult PWD and HPs completed surveys to rate the importance of exercise in T1D management, confidence in managing T1D around exercise, barriers to giving and receiving education, resources used, and what form new resources should take. RESULTS: Responses were received from 128 PWD and 122 HPs. Both groups considered exercise to be important for diabetes management. PWD cited time constraints (57%) and concern about dysglycemia (43%) as barriers to exercise, and many lacked confidence in managing T1D around exercise. HPs were more confident, but experienced barriers to providing advice, and PWD did not tend to rely on this advice. Instead, 72% of PWD found continuous glucose monitoring most helpful. Both groups desired better resources to support exercise in T1D, with PWD preferring to obtain information through a structured education program and HPs through eLearning. CONCLUSIONS: Australian HPs and PWD appreciate the importance of exercise in T1D management and express a clear desire for improved educational resources. Our findings provide a basis for developing a comprehensive package of resources for both adult PWD and HPs, to support exercise in PWD.

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.

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.

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.).

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.

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.

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.

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.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Long-term impact of weight loss for people with overweight but not obesity, and with type 2 diabetes: 10-year outcomes of a randomized trial of gastric band surgery.

AIM: Randomized trials reporting 5-year outcomes have shown bariatric surgery  to induce diabetes remission and improve cardiovascular risk. However, the longer-term effects of surgery are uncertain, with only one randomized trial reporting 10-year diabetes outcomes in people with obesity. We aimed to compare 10-year diabetes outcomes of people who are overweight but not obese, randomly assigned to receive either multidisciplinary diabetes care, or multidisciplinary diabetes care combined with gastric band (GB) surgery. METHODS: Between 2009 and 2011, 51 adults were randomized. After 5 years, they were discharged to receive community care and reassessed after 10 years. The primary outcome was diabetes remission, defined as glycated haemoglobin (HbA1c) <6.5% (48 mmol/mol) without glucose-lowering medication. RESULTS: Forty-one participants (20 medical and 21 GB) completed the 10-year assessment. The median (Q1, Q3) weight loss in the GB group was 9.8 (6.7, 16.3)% at 10 years compared with 5.6 (3.4, 7.6)% in the medical group (median difference 4.2%; p = .008). Diabetes remission occurred in five GB participants and no medical participants (relative risk 0.76, 95% CI: 0.55-0.93, p = .048). GB participants used fewer glucose-lowering medications at 10 years but HbA1c, fasting glucose, calculated cardiovascular risk, quality-of-life and incident diabetes complications did not differ significantly between the groups. CONCLUSION: When compared with medical care, GB surgery achieved greater weight loss and modestly increased the likelihood of diabetes remission. However, it did not improve HbA1c, cardiovascular risk or quality of life.

A Long-Term Evaluation of Facebook for Recruitment and Retention in the ENDIA Type 1 Diabetes Pregnancy-Birth Cohort Study.

BACKGROUND: The Environmental Determinants of Islet Autoimmunity (ENDIA) study is an Australia-wide pregnancy-birth cohort study following children who have a first-degree relative with type 1 diabetes (ACTRN1261300794707). A dedicated ENDIA Facebook page was established in 2013 with the aim of enhancing recruitment and supporting participant retention through dissemination of study information. To measure the impact of Facebook, we evaluated the sources of referral to the study, cohort demographics, and withdrawal rates. We also investigated whether engagement with Facebook content was associated with specific post themes. METHODS: Characteristics of Facebook versus conventional recruits were compared using linear, logistic, and multinomial logistic regression models. Logistic regression was used to determine the risk of study withdrawal. Data pertaining to 794 Facebook posts over 7.5 years were included in the analysis. RESULTS: Facebook was the third largest source of referral (300/1511; 19.9%). Facebook recruits were more frequently Australian-born (P < .001) enrolling postnatally (P = .01) and withdrew from the study at a significantly lower rate compared with conventional recruits (4.7% vs 12.3%; P < .001) after a median of follow-up of 3.3 years. Facebook content featuring stories and images of participants received the highest engagement even though <20% of the 2337 Facebook followers were enrolled in the study. CONCLUSIONS: Facebook was a valuable recruitment tool for ENDIA. Compared with conventional recruits, Facebook recruits were three times less likely to withdraw during long-term follow-up and had different sociodemographic characteristics. Facebook content featuring participants was the most engaging. These findings inform social media strategies for future cohort and type 1 diabetes studies. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN1261300794707.

Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand.

AIMS: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. METHODS: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. RESULTS: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. CONCLUSIONS: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.

Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective.

Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established.

Mental Health During Late Pregnancy and Postpartum in Mothers With and Without Type 1 Diabetes: The ENDIA Study.

OBJECTIVE: Pregnancy and type 1 diabetes are each associated with increased anxiety and depression, but the combined impact on well-being is unresolved. We compared the mental health of women with and without type 1 diabetes during pregnancy and postpartum and examined the relationship between mental health and glycemic control. RESEARCH DESIGN AND METHODS: Participants were women enrolled from 2016 to 2020 in the Environmental Determinants of Islet Autoimmunity (ENDIA) study, a pregnancy to birth prospective cohort following children with a first-degree relative with type 1 diabetes. Edinburgh Postnatal Depression Scale (EPDS) and Perceived Stress Scale (PSS) were completed during the third trimester (T3) (median [interquartile range] 34 [32, 36] weeks) and postpartum (14 [13, 16] weeks) by 737 women (800 pregnancies) with (n = 518) and without (n = 282) type 1 diabetes. RESULTS: EPDS and PSS scores did not differ between women with and without type 1 diabetes during T3 and postpartum. EPDS scores were marginally higher in T3: predicted mean (95% CI) 5.7 (5.4, 6.1) than postpartum: 5.3 (5.0, 5.6), independent of type 1 diabetes status (P = 0.01). HbA1c levels in type 1 diabetes were 6.3% [5.8, 6.9%] in T3 and did not correlate with EPDS or PSS scores. Reported use of psychotropic medications was similar in women with (n = 44 of 518 [8%]) and without type 1 diabetes (n = 17 of 282 [6%]), as was their amount of physical activity. CONCLUSIONS: Overall, mental health in late pregnancy and postpartum did not differ between women with and without type 1 diabetes, and mental health scores were not correlated with glycemic control.

Women with type 1 diabetes exhibit a progressive increase in gut Saccharomyces cerevisiae in pregnancy associated with evidence of gut inflammation.

AIMS: Studies of the gut microbiome have focused on its bacterial composition. We aimed to characterize the gut fungal microbiome (mycobiome) across pregnancy in women with and without type 1 diabetes. METHODS: Faecal samples (n = 162) were collected from 70 pregnant women (45 with and 25 without type 1 diabetes) across all trimesters. Fungi were analysed by internal transcribed spacer 1 amplicon sequencing. Markers of intestinal inflammation (faecal calprotectin) and intestinal epithelial integrity (serum intestinal fatty acid binding protein; I-FABP), and serum antibodies to Saccharomyces cerevisiae (ASCA) were measured. RESULTS: Women with type 1 diabetes had decreased fungal alpha diversity by the third trimester, associated with an increased abundance of Saccharomyces cerevisiae that was inversely related to the abundance of the anti-inflammatory butyrate-producing bacterium Faecalibacterium prausnitzii. Women with type 1 diabetes had higher concentrations of calprotectin, I-FABP and ASCA. CONCLUSIONS: Women with type 1 diabetes exhibit a shift in the gut mycobiome across pregnancy associated with evidence of gut inflammation and impaired intestinal barrier function. The relevance of these findings to the higher rate of pregnancy complications in type 1 diabetes warrants further study.

Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells That Mark Progression to Type 1 Diabetes.

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ("progressors") compared with five children matched for sex, age, and HLA-DR who had not progressed ("nonprogressors"). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.

Characterising the age-dependent effects of risk factors on type 1 diabetes progression.

AIMS/HYPOTHESIS: Age is known to be one of the most important stratifiers of disease progression in type 1 diabetes. However, what drives the difference in rate of progression between adults and children is poorly understood. Evidence suggests that many type 1 diabetes disease predictors do not have the same effect across the age spectrum. Without a comprehensive analysis describing the varying risk profiles of predictors over the age continuum, researchers and clinicians are susceptible to inappropriate assessment of risk when examining populations of differing ages. We aimed to systematically assess and characterise how the effect of key type 1 diabetes risk predictors changes with age. METHODS: Using longitudinal data from single- and multiple-autoantibody-positive at-risk individuals recruited between the ages of 1 and 45 years in TrialNet's Pathway to Prevention Study, we assessed and visually characterised the age-varying effect of key demographic, immune and metabolic predictors of type 1 diabetes by employing a flexible spline model. Two progression outcomes were defined: participants with single autoantibodies (n=4893) were analysed for progression to multiple autoantibodies or type 1 diabetes, and participants with multiple autoantibodies were analysed (n=3856) for progression to type 1 diabetes. RESULTS: Several predictors exhibited significant age-varying effects on disease progression. Amongst single-autoantibody participants, HLA-DR3 (p=0.007), GAD65 autoantibody positivity (p=0.008), elevated BMI (p=0.007) and HOMA-IR (p=0.002) showed a significant increase in effect on disease progression with increasing age. Insulin autoantibody positivity had a diminishing effect with older age in single-autoantibody-positive participants (p<0.001). Amongst multiple-autoantibody-positive participants, male sex (p=0.002) was associated with an increase in risk for progression, and HLA DR3/4 (p=0.05) showed a decreased effect on disease progression with older age. In both single- and multiple-autoantibody-positive individuals, significant changes in HR with age were seen for multiple measures of islet function. Risk estimation using prediction risk score Index60 was found to be better at a younger age for both single- and multiple-autoantibody-positive individuals (p=0.007 and p<0.001, respectively). No age-varying effect was seen for prediction risk score DPTRS (p=0.861 and p=0.178, respectively). Multivariable analyses suggested that incorporating the age-varying effect of the individual components of these validated risk scores has the potential to enhance the risk estimate. CONCLUSIONS/INTERPRETATION: Analysing the age-varying effect of disease predictors improves understanding and prediction of type 1 diabetes disease progression, and should be leveraged to refine prediction models and guide mechanistic studies.