Kim C Donaghue's research while affiliated with The University of Sydney and other places

Objective. Microvascular complications increase the risk of cardiovascular disease and premature death in adults with type 1 diabetes. We examined the association between microvascular complications during adolescence, including cardiac autonomic nerve dysfunction and subsequent mortality. Research Design and Methods. We undertook data linkage with the Australian National Death Index in a cohort of 409 adolescents (diagnosed between 1973 and 1993), 48% male, median age at final complications assessment 17.4 years (interquartile range: 16.0–18.9), followed longitudinally for median 22.3 years (21.0–23.4) from diagnosis. Generalized estimating equations (GEE) were used to examine associations between mortality and adolescent complications. Mortality risk was calculated as standardized mortality ratio (SMR). Results. At final adolescent visit, 20% had CAN abnormality, 30% abnormal pupillary response, 20% albuminuria, 40% early elevation of albumin excretion rate (AER) and 45% retinopathy. Data linkage 8–13 years later showed 14 were deceased (3% of cohort), 57% male, median age 28.3 years (24.8–32.9). Acute or chronic diabetes complications accounted for 25% of deaths. In multivariable GEE, elevated AER (OR 4.54, 1.23–16.80, p=0.030), pupillary abnormality (OR 4.27, 1.20–15.22, p=0.023), systolic blood pressure SDS (OR 2.17, 1.26–3.74, p=0.005) and CAN (OR 4.65, 1.03–21.0, p=0.045) predicted mortality. HbA1c was not significant. SMR was 2.5 (1.4–4.2) and was higher in females (SMR 3.5, 1.3–7.8) but not in males (SMR 2.1, 0.9–4.0). Conclusion. Mortality in young adults with type 1 diabetes is predicted by subclinical markers of autonomic neuropathy and elevated AER during adolescence, but not glycemia. Mortality was over twice that of the background population in females but not in males.

Objective. Evaluate the mortality risk of childhood-onset type 1 diabetes compared to the general population. Research Design and Methods. The study population, identified from the Australasian Paediatric Endocrinology Group diabetes register, was diagnosed with type 1 diabetes at age < 16 in New South Wales (NSW), Australia, from 1990 to 2010. The register was linked to National Death Index registrations to ascertain timing and cause of death up to 31/12/2022. Risk factors for mortality were assessed using multivariable Cox regression models and observed mortality rate compared to “expected” rates in the Australian general population using indirect-standardized mortality ratios (SMR), overall and by sex and age at diagnosis. Diabetes-related cause of death categories were identified. Results. Of 5,417 children diagnosed with type 1 diabetes, 157 subsequently died, with all-cause mortality of 1.37/1,000 person years. Increased mortality risk was associated with living in most disadvantaged areas (aHR 1.81 (1.05, 3.11)) but not living in a rural area. Overall SMR was 2.83 (95% CI 2.40, 3.33) with females having higher SMR than males (4.18 vs. 2.19). Most common causes of death recorded were acute diabetes complications (26%), including diabetes ketoacidosis, accident/misadventure (21%), and chronic diabetes complications (15%). Alcohol and/or drug use contributed to 17% of deaths. Conclusion. Compared to the general population, higher risk of mortality in people with type 1 diabetes was associated with female sex and living in area of socioeconomic disadvantage. Education about minimizing risk-taking behaviors should be communicated to young adults with type 1 diabetes.

Background Familial non-autoimmune hyperthyroidism is a rare disorder characterized by the absence of thyroid autoimmunity, particularly TSH receptor antibody [TRAb]. Objective The aim of this study was to describe a novel TSHR mutation identified in a family of two siblings and their father. Methods Two siblings presented for endocrine assessment at ages 7 and 14 years with mild T3 toxicosis, and the father presented at 30 years of age with non-autoimmune thyrotoxicosis. Both siblings were treated with oral antithyroid therapy to achieve reasonable symptom control and thyroid function normalization. The father was treated with oral antithyroid therapy, radioactive iodine, thyroidectomy, and thyroid replacement therapy. Peripheral blood DNA was extracted from both affected siblings and father. Mutation analysis of TSHR was carried out by PCR and Sanger sequencing of both strands of the extracted DNA. Results Both siblings and their father were heterozygous for the missense TSHR variant c.1855G>C, p.[Asp619His], in exon 10. Conclusions This novel TSHR variant is associated with T3 toxicosis during childhood. Therefore, early identification and treatment may improve patient outcomes.

Background Given limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations. Methods Retrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort’s distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial’s intervention was targeted (national). Results Recruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001). Conclusions Significant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials. Trial registration NCT01581476. Registered on 20 April 2012.

Introduction: Childhood-onset type 1 diabetes (T1D) is associated with an increased risk of premature cardiovascular mortality. Objectives: This study aimed to assess the evolution of subclinical vascular damage in young people with T1D as they transitioned through adolescence. Methods: Repeated vascular phenotyping was performed in early adolescence (age 13), late adolescence (age 17), and young adulthood (age 23) in 288 adolescents with T1D (52% male) recruited to the Adolescent Type 1 Diabetes Intervention Trial Follow-Up Study (AdDIT Follow-Up). Carotid remodelling was assessed via measures of lumen diameter, intima-media thickness (IMT), and beta stiffness index; aortic stiffness via carotid-femoral pulse wave velocity (PWV); and endothelial function via flow-mediated dilation (FMD). Repeated measures ANOVA were used to assess vascular changes over time, and unpaired t-tests used to compare vascular phenotypes measured in young adulthood to an age- and sex-matched group without T1D (n = 292; 49% male). Results: In individuals with T1D, progressive stiffening of both the carotid artery and aorta was observed across the 9-year follow-up (e.g. PWV mean [95%CI] change = 1.1 [0.9, 1.3] m/s). In the transition from late adolescence to young adulthood, IMT also increased (+0.04 [0.03, 0.06] mm) and FMD decreased (-1.0 [-0.8, -1.2] %). As a result, young adults with T1D had carotid arteries that were narrower, thicker (IMT = +0.3 [0.2, 0.4] mm), and stiffer (beta stiffness index = +0.3 [0.1, 0.5]) than those without T1D. Aortic stiffness was also higher (PWV = +0.8 [0.6, 0.9] m/s) in T1D, while a compromised FMD (-2.8 [-2.0, -3.6]%) indicated the presence of systemic endothelial dysfunction. Conclusions: Young people with T1D demonstrate accelerated arterial ageing as they transition adolescence. As a result, these individuals enter young adulthood with arteries that are already smaller, thicker, stiffer, and with evidence of profound endothelial dysfunction when compared to young adults without T1D.