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Aims/hypothesis We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. Trial registration isrctn.org ISRCTN91419926. Graphical abstract

Identifying genetic determinants for longitudinal changes in albumin excretion in individuals with type 1 diabetes may help identify those that are predisposed to renal, retinal and cardiovascular complications. Most studies have focussed on genetic predisposition to diabetic kidney disease and used cross-sectional measurements of urinary albumin excretion, but with limited success. Here, we utilise the wealth of longitudinal data and bio-samples collected from cohorts of childhood-onset type 1 diabetes followed over the last 30 years to describe a novel trajectory phenotype quantifying urinary albumin excretion changes during childhood and adolescence. We conducted a genome-wide association study and fine-mapping analysis for albumin excretion in 1584 individuals, finding one signal for cross-sectional albumin excretion close toGALNTL6(rs150766792), which validated in a previous independent study, and a novel genome-wide significant signal for albumin excretion trajectory in theCDH18gene region (rs145715205). Our trajectory phenotype quantifies albumin progression and offers a complementary measure to an albumin excretion phenotype based on a single measurement (i.e. most recent data collection) or an average of repeated measurements in longitudinal studies. It can be used to identify genetic or other risk factors which predict better or worse prognosis, thus facilitating the development of new preventive and therapeutic approaches.

The Janus face metaphor approach highlights that a technology may simultaneously have two opposite faces or properties with unforeseen paradoxes within human-technology interaction. Suboptimal acceptance and clinical outcomes are sometimes seen in adolescents who use diabetes-related technologies. A traditional linear techno-determinist model of technology use would ascribe these unintended outcomes to suboptimal technology, suboptimal patient behavior, or suboptimal outcome measures. This paradigm has demonstratively not been successful at universally improving clinical outcomes over the last two decades. Alternatively, the Janus face metaphor moves away from a linear techno-determinist model and focuses on the dynamic interaction of the human condition and technology. Specifically, it can be used to understand variance in adoption or successful use of diabetes-related technology and to retrospectively understand suboptimal outcomes. The Janus face metaphor also allows for a prospective exploration of potential impacts of diabetes-related technology by patients, families, and their doctors so as to anticipate and minimize potential subsequent tensions.

HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8., Epitopes formed by fusion of more than one self peptide, such as proinsulin and other β cell proteins, can result in the formation of non-self hybrid peptides that can potentially trigger autoimmune responses. Here the authors show how TRBV5 + T cell receptors are geared towards recognition of HLA-DQ8 bound hybrid peptides in patients with type 1 diabetes.

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.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.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 was80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve.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.

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9]; P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4]; P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups; P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P >0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12]; P =0.001 and 0.5 m/s [0.4–0.6]; P Registration— URL: https://www.clinicaltrials.gov ; Unique identifier NCT01581476.

Context Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized. Objective The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk. Design Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019. Setting 15 tertiary care diabetes centers in the Australasian Diabetes Data Network. Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure. Main Outcome Measure Standardized systolic and diastolic blood pressure scores and non–high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. Results BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P Conclusions BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.

Introduction In 2017, the Australian Federal Government fully subsidized continuous glucose monitoring (CGM) devices for patients under 21 years of age with T1D with the aim of reducing rates of severe hypoglycaemia (SH) and improving metabolic control. The aim of this study was to reports on metabolic outcomes in youth from a single tertiary centre. Methods The study design was observational. Data were obtained on youth who commenced CGM between May 2017 and December 2019. Results Three hundred and forty one youth who commenced CGM and had clinical outcome data for a minimum of 4 months. 301, 261, 216, 172, and 125 had outcome data out to 8, 12, 16, 20, and 24 months, respectively. Cessation occurred between 27.9% and 32.8% of patients 12 to 24 months after CGM commencement. HbA1c did not change in patients who continued to use CGM. In the 12 months prior to starting CGM the rate of severe hypoglycaemia events were 5.0 per 100 patient years. The rates of severe hypoglycaemia in those continuing to use CGM at 4, 8, 12, 16, 20, and 24 months, were 5.2, 5.1, 1.6, 6.1, 2.4, and 0 per 100 patient years, respectively. Discussion Our experience of patients either ceasing or underusing CGM is less than reported in other cohorts but is nonetheless still high. There may have been a reduction in rates of severe hypoglycaemia over the 24 months follow up period; however, the absolute numbers of events were so low as to preclude meaningful statistical analysis.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D.METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource.RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR.CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis.Children newly diagnosed with type 1 diabetes aged15 years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis.Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4 year olds, the mean incidence was 75% higher in 5 to 9 year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4 year old boys and girls.This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.

IMPORTANCE: Hybrid closed-loop (HCL) therapy has improved glycemic control in children and adolescents with type 1 diabetes; however, the efficacy of HCL on glycemic and psychosocial outcomes has not yet been established in a long-term randomized clinical trial. OBJECTIVE: To determine the percentage of time spent in the target glucose range using HCL vs current conventional therapies of continuous subcutaneous insulin infusion or multiple daily insulin injections with or without continuous glucose monitoring (CGM). DESIGN, SETTING, AND PARTICIPANTS: This 6-month, multicenter, randomized clinical trial included 172 children and adolescents with type 1 diabetes; patients were recruited between April 18, 2017, and October 4, 2019, in Australia. Data were analyzed from July 25, 2020, to February 26, 2021. INTERVENTIONS: Eligible participants were randomly assigned to either the control group for conventional therapy (continuous subcutaneous insulin infusion or multiple daily insulin injections with or without CGM) or the intervention group for HCL therapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the percentage of time in range (TIR) within a glucose range of 70 to 180 mg/dL, measured by 3-week masked CGM collected at the end of the study in both groups. Secondary outcomes included CGM metrics for hypoglycemia, hyperglycemia, and glycemic variability and psychosocial measures collected by validated questionnaires. RESULTS: A total of 135 patients (mean [SD] age, 15.3 [3.1] years; 76 girls [56%]) were included, with 68 randomized to the control group and 67 to the HCL group. Patients had a mean (SD) diabetes duration of 7.7 (4.3) years and mean hemoglobin A(1c) of 64 (11) mmol/mol, with 110 participants (81%) receiving continuous subcutaneous insulin infusion and 72 (53%) receiving CGM. In the intention-to-treat analyses, TIR increased from a mean (SD) of 53.1% (13.0%) at baseline to 62.5% (12.0%) at the end of the study in the HCL group and from 54.6% (12.5%) to 56.1% (12.2%) in the control group, with a mean adjusted difference between the 2 groups of 6.7% (95% CI, 2.7%-10.8%; P = .002). Hybrid closed-loop therapy also reduced the time that patients spent in a hypoglycemic (

Aims/hypothesis Type 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4+ T cells from a deceased organ donor who had type 1 diabetes. Methods Induced pluripotent stem cell (iPSC) lines derived from the above donor were differentiated into CD14+ macrophages and tested for their capacity to present antigen to T cell receptors (TCRs) derived from islet-infiltrating CD4+ T cells from the same donor. Results The iPSC macrophages displayed typical macrophage morphology, surface markers (CD14, CD86, CD16 and CD11b) and were phagocytic. In response to IFNγ treatment, iPSC macrophages upregulated expression of HLA class II, a characteristic that correlated with their capacity to present epitopes derived from proinsulin C-peptide to a T cell line expressing TCRs derived from islet-infiltrating CD4+ T cells of the original donor. T cell activation was specifically blocked by anti-HLA-DQ antibodies but not by antibodies directed against HLA-DR. Conclusions/interpretation This study provides a proof of principle for the use of iPSC-derived immune cells for modelling key cellular interactions in human type 1 diabetes.

The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by dysglycaemia. Cardiovascular disease (CVD) is a major complication among T1DM patients and the leading cause of mortality later in life. METHODS: The study subjects consisted of T1DM children with poor glycemic control (HbA1c > 7.5%) and healthy age and gender matched controls. Venous blood samples were collected and tested by utilizing a novel immunoassay panel with 96 protein biomarkers. Data were analyzed using non-linear regression analysis and the expression of biomarkers was compared between T1DM and healthy control groups using an unpaired student's t-test. Dynamic principal component analysis (PCA) was operated based on the differentially expressed proteins. RESULTS: Ten T1DM children and 10 healthy controls were analyzed. Twelve CVD markers show significant differential expression between T1DM patients and healthy controls (p

Cortical neurospheres (NSPs) derived from human pluripotent stem cells (hPSC), have proven to be a successful platform to investigate human brain development and neuro-related diseases. Currently, many of the standard hPSC neural differentiation media, use concentrations of glucose (approximately 17.5-25 mM) and insulin (approximately 3.2 μM) that are much greater than the physiological concentrations found in the human brain. These culture conditions make it difficult to analyse perturbations of glucose or insulin on neuronal development and differentiation. We established a new hPSC neural differentiation medium that incorporated physiological brain concentrations of glucose (2.5 mM) and significantly reduced insulin levels (0.86 μM). This medium supported hPSC neural induction and formation of cortical NSPs. The revised hPSC neural differentiation medium, may provide an improved platform to model brain development and to investigate neural differentiation signalling pathways impacted by abnormal glucose and insulin levels.

OBJECTIVE: The purpose of this study was to estimate clinician qualities that influence metabolic outcomes in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data were gathered over two 3 month periods in a large tertiary diabetes center (1500 patients, 8 clinicians) from patients with type 1 diabetes who received continuous care from each clinician. Data included sex, age, diabetes duration, insulin regimen, body mass index (BMI), insulin dose and episodes of severe hypoglycemia. Clinician data included target blood glucose levels, target glycated hemoglobin (HbA1c), Diabetes Attitude Scale and Big 5 Personality Inventory Scale. Mean HbA1c per clinician was the primary outcome variable. RESULTS: The 8 clinicians saw a total of 464 patients during the first time period, and 603 in the second time period. Lowest to highest mean HbA1c per clinician varied by 0.7%. There were small but statistically significant differences between clinicians with their patients' age at diagnosis, duration of diabetes, age, gender, treatment type and BMI SD score. After controlling for these differences, the clinician characteristics that were associated with lower mean HbA1c were having no lower limit in target HbA1c and being self-reportedly "less agreeable." The impact of these clinician attitudinal traits was equivalent to the combined effects of patient characteristics and treatment type. CONCLUSIONS: There was a significant variation in metabolic outcomes between treating clinicians. After controlling for patient clinical differences, clinician mean HbA1c was associated with lower limit in target HbA1c and being "less agreeable." Clinicians who were more demanding and dogmatic appeared to have better outcomes.

BACKGROUND Few diabetes-specific quality of life (QOL) tools are available for young children. OBJECTIVES To design and evaluate, a new age-specific QOL questionnaire and its associations with treatment regimens and metabolic control. METHODS Clinical, demographic data and centrally analyzed HbA1c were collected on 1133 children

OBJECTIVE The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

OBJECTIVE To establish cut point(s) for the Problem Areas in Diabetes–teen version (PAID-T) scale to identify adolescents with clinically meaningful, elevated diabetes distress. RESEARCH DESIGN AND METHODS Data were available from the Diabetes Management and Impact for Long-term Empowerment and Success (MILES) Youth–Australia Study, a national survey assessing various psychosocial indicators among self-selected National Diabetes Services Scheme registrants. Participants in the current study (n = 537) were (mean ± SD) 16 ± 2 years old, had type 1 diabetes for 6 ± 4 years, and 62% (n = 334) were girls. They completed measures of diabetes distress (PAID-T) and depressive symptoms (Patient Health Questionnaire for Adolescents) and self-reported their most recent HbA1c and frequency of self-monitoring of blood glucose (SMBG). Relationships between the PAID-T and the psychological and clinical variables were examined to identify a clinically meaningful threshold for elevated diabetes distress. ANOVA was used to test whether these variables differed by levels of distress. RESULTS Two cut points distinguished none-to-mild (90) diabetes distress. Moderate distress was experienced by 18% of adolescents and high distress by 36%. Mean depressive symptoms, self-reported HbA1c, and SMBG differed significantly across the three levels of diabetes distress (all P < 0.001), with moderate-to-large effect sizes. CONCLUSIONS Using the PAID-T, this study defined two clinically meaningful cut points to distinguish none-to-mild, moderate, and high diabetes distress in adolescents (aged 13–19). Based on these cut points, most respondents experienced at least moderate diabetes distress, which was clinically significant. Establishing thresholds for elevated diabetes distress will aid clinicians and researchers to interpret PAID-T scores, prompt discussion and intervention for those with unmet needs, and enable the effectiveness of interventions to be evaluated.

To evaluate the relationship between retinal vascular caliber and kidney function in a cohort of Australian children and adolescents with type 1 diabetes.This was a cross-sectional study of 483 children and adolescents with type 1 diabetes, aged 7-18 years. An audit of medical files of participants who attended the Royal Children's Hospital, Melbourne, between January 2009 and March 2014 was performed. Albumin to creatinine ratio (ACR) was acquired through spot urine samples and microalbuminuria was classified as ACR3.5 mg/mmol in females and2.5 mg/mmol in males. Retinal vascular caliber was measured using a standardized protocol and later summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE).CRAE was significantly narrower in participants with microalbuminuria compared to those with normo-albuminuria in crude analysis (mean ± standard deviation 159.07 ± 9.90µm vs 164.49 ± 12.45 µm; p = 0.006). After adjustment for key confounders and known or potential mediators of microalbuminuria (age, sex, ethnicity, hemoglobin A1c, systolic blood pressure, total cholesterol, body mass index, duration of diabetes and CRVE) the association between narrower CRAE and microalbuminuria was attenuated and was no longer significant (95% confidence interval 0.94-1.02, p = 0.222). No significant associations between CRVE or arteriole-to-venule ratio and microalbuminuria were observed in univariate or multivariate models.After adjustment for potential confounding variables, retinal vascular caliber was not significantly associated with microalbuminuria in this sample of children and adolescents with type 1 diabetes. Future prospective longitudinal research is warranted to further evaluate these findings.

Improved frequency of sensor use improves glycaemic control. Furthermore, there is no deterioration of glycaemic control with increased sensor use in individuals on Predictive Low Glucose Management (PLGM) system. Younger children are more likely to have better sensor uptake than older children.

Background: There has been a change in the management of type 1 diabetes (T1D) with the availability of continuous glucose monitoring (CGM) systems. In Australia, subsidized CGM is available to patients below the age of 21. A randomized controlled trial (RCT) evaluating hybrid closed loop therapy is currently underway and the baseline data provided an opportunity to analyze the glycemic patterns in patients on contemporary management. Methods: Adolescents and young adults with T1D and HbA1c Results: Data were analyzed from 100 participants (47M, 53F; pump 80, MDI 20) with (mean±SD) age 14.9±2.7 years, diabetes duration 7.6±0.9 years, HbA1c 7.9±0.9% of which 55% participants were on real-time CGM. The (mean±SD) SG was 9.6±1.6mmol/l with fasting SG of 8.8±1.9mmol/l. The SG coefficient of variation was 41.3±6.04%. The median [IQR] %time in range (3.9 to 10mmol/l) was 55.9 [44.1,62.3]. The %time in hypoglycemia (10 and >13.9mmol/l) were 35.5[24.7,45.7] and 14.1[8.1,18.8] respectively. Conclusion: Majority of adolescents in the trial were on insulin pump therapy with half of them on CGM. The baseline CGM data of these participants provide a snapshot of the glycemic management in patients with T1D on current therapy; especially highlighting the reduced time in hypoglycemia compared to earlier trials. The data can further inform the conduct of future trials. Disclosure M.B. Abraham: None. G.J. Smith: None. M. de Bock: None. B.R. King: None. J. Fairchild: None. G. Ambler: None. F. Cameron: None. E.A. Davis: None. D.N. ONeal: None. T. Jones: Research Support; Self; Dexcom, Inc., Medtronic MiniMed, Inc. Speaker's Bureau; Self; Eli Lilly and Company, Roche Diabetes Care.

Background: Vitamin D deficiency is linked to adverse childhood health outcomes, yet data on the distribution and quantifiable determinants of neonatal 25-hydroxyvitamin D3 (25OHD) concentration, a vitamin D biomarker, are limited. Objective: Our aim was to identify determinants of neonatal 25OHD concentration, measured using neonatal dried blood spots (DBS). Methods: A total of 259 ethnically diverse children aged 0-16 years born in Victoria, Australia, were recruited. Data included maternal sun exposure, skin type, 25OHD concentration on stored neonatal DBS, and genotypes at the target genes. Associations were investigated using multiple linear regression models. Results: The median 25OHD concentration was 29.2 nmol/l (IQR 18.0-47.4). Measured 25OHD was GC (rs2282679), the gene encoding the vitamin D binding protein, and DHCR7 (rs12785878), a gene required for synthesis of 7-dehydrocholesterol, a precursor to 25OHD. DBS age explained 7%, and patterns of maternal sun exposure and clothing choices accounted for 4%. A child's skin colour was strongly associated with GC gene variants and not independent of these variants in predicting 25OHD. The final model explained 43% of the total variance in neonatal 25OHD concentration. Conclusion: Maternal lifestyle factors and infant genetic variants predict neonatal 25OHD levels; the importance of maternal UVR exposure in late pregnancy is highlighted.

Sensor-augmented pump therapy (SAPT) with a predictive algorithm to suspend insulin delivery has the potential to reduce hypoglycemia, a known obstacle in improving physical activity in patients with type 1 diabetes. The predictive low glucose management (PLGM) system employs a predictive algorithm that suspends basal insulin when hypoglycemia is predicted. The aim of this study was to determine the efficacy of this algorithm in the prevention of exercise-induced hypoglycemia under in-clinic conditions.This was a randomized, controlled cross-over study in which 25 participants performed 2 consecutive sessions of 30 min of moderate-intensity exercise while on basal continuous subcutaneous insulin infusion on 2 study days: a control day with SAPT alone and an intervention day with SAPT and PLGM. The predictive algorithm suspended basal insulin when sensor glucose was predicted to be below the preset hypoglycemic threshold in 30 min. We tested preset hypoglycemic thresholds of 70 and 80 mg/dL. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia with plasma glucose63 mg/dL or plasma glucose50 mg/dL) and was compared in both control and intervention arms.Results were analyzed in 19 participants. In the intervention arm with both thresholds, only 6 participants (32%) required treatment for hypoglycemia compared with 17 participants (89%) in the control arm (P = 0.003). In participants with a 2-h pump suspension on intervention days, the plasma glucose was 84 ± 12 and 99 ± 24 mg/dL at thresholds of 70 and 80 mg/dL, respectively.SAPT with PLGM reduced the need for hypoglycemia treatment after moderate-intensity exercise in an in-clinic setting.

Sensor-augmented pump therapy (SAPT) with algorithms to predict impending low blood glucose and suspend insulin delivery has the potential to reduce hypoglycemia exposure. The aim of this study was to determine whether predictive low glucose management (PLGM) system is effective in preventing insulin-induced hypoglycemia in controlled experiments.Two protocols were used to induce hypoglycemia in an in-clinic environment. (A) Insulin bolus: Insulin was administered as a manual bolus through the pump. (B) Increased basal insulin: Hypoglycemia was induced by increasing basal rates overnight to 180%. For both protocols, participants were randomized and studied on 2 separate days; a control day with SAPT alone and an intervention day with SAPT and PLGM activated. The predictive algorithm was programmed to suspend basal insulin infusion when sensor glucose was predicted to be80 mg/dL in 30 min. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia or plasma glucose50 mg/dL) and was compared in both control and intervention arms.With insulin bolus, 24/28 participants required hypoglycemia treatment with SAPT alone compared to 5/28 participants when PLGM was activated (P ≤ 0.001). With increased basal rates, all the eight SAPT-alone participants required treatment for hypoglycemia compared to only one with SAPT and PLGM. There was no post pump-suspend hyperglycemia with insulin bolus (P = 0.4) or increased basal rates (P = 0.69) in participants with 2-h pump suspension on intervention days.SAPT with PLGM reduced the requirement for hypoglycemia treatment following insulin-induced hypoglycemia in an in-clinic setting.

The Predictive Low-Glucose Management (PLGM) system suspends basal insulin when hypoglycemia is predicted and reduces hypoglycemia. The aim of this analysis was to explore the characteristics of automated insulin suspension and sensor glucose (SG) responses following PLGM-initiated pump suspension.Children and adolescents with type 1 diabetes used the Medtronic MiniMed™ 640G pump as part of a randomized controlled trial. Data collected on a subgroup of participants on PLGM (suspend before low enabled) from CareLinkThere were 20,183 suspend before low events in 8523 days (2.37 events/day). The mean suspend duration was 55.0 ± 32.7 min (day 50.0 ± 30.1, night 71.7 ± 35.1; P 0.001). Although a 2-h pump suspension was more frequent at night (day 5%, night 18%), a patient-initiated resumption occurred more during day (day 34%, night 12%). SG values did not reach3.5 and3 mmol/L in 79% and 91% of the events, respectively. The 2-h SG following pump resumption was higher following autoresumption during the day (day vs. night 9.3 mmol/L vs. 8.4 mmol/L; P 0.001).Longer suspends and fewer glycemic excursions occur at night compared with day. The higher glycemic daytime excursions could be due to carbohydrate consumption to increase glucose levels and highlights the need for health care professionals to educate patients about carbohydrate intake around pump suspension.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008–2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4(+) T cells recognize C-peptide–derived epitopes, we hypothesized that full-length C-peptide (PI(33–63)), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4(+) T cells in people with T1D. CD4(+) T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (

BACKGROUND. One in three adolescents and young adults with type 1 diabetes have at least one early diabetes-related complication/comorbidity. However, the prevalence, patterning, and risk factors for co-occurring complications in this population are not well understood. METHODS. The SEARCH for Diabetes in Youth observational cohort study includes 1327 individuals diagnosed with type 1 diabetes before 20 years of age from 5 United States locations. Sociodemographic and metabolic risk factors were assessed at baseline (mean diabetes duration = 0·8 years, mean age = 10·9 years) and follow-up (mean diabetes duration = 7.8 years, mean age = 18·0 years). Early diabetes complications (diabetic kidney disease, diabetic retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, and arterial stiffness) were assessed at follow-up. We aimed to describe co-occurrence of complications and examine differences in co-occurrence within demographic and metabolic risk factor clusters identified using cluster analysis. FINDINGS. Overall, co-occurrence of any ≥2 complications was observed in 5·9% of all participants, more frequently than expected by chance alone (4·4%, p=0·015). Specifically, retinopathy and diabetic kidney disease, retinopathy and arterial stiffness, and arterial stiffness and cardiac autonomic neuropathy all co-occurred more frequently than expected (all p

Families of children with diabetes increasingly obtain health information from a variety of sources. Doctor-patient relationships have accordingly become more fluid and dynamic with input from other parties. These outside parties include representatives from the diabetes health care industry-industry third parties (ITPs). This review is an exploration of the ethical principles and cognitive processes involved when doctors and patients negotiate around health care practices and the role of ITPs in that dialogue. Ethical principles of conflicts of interest, beneficence (act in the best interests of the patient), non-maleficence (act so as to do no harm) and justice (act so as to allocate resources fairly or justly) are relevant considerations. Reflexive and analytic thinking and various cognitive biases also play a significant part in clinical decision making. A complex case example is analyzed to highlight a process of ethical cognition in decision making to ensure high-value care and optimal patient outcomes.

IntroductionManual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months’ closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes.Methods and analysisThis open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged ≥25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9–10.0 mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA1c, severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users.Ethics and disseminationThe study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications.Trial registration numberNCT12617000520336.

To understand what children with type 1 diabetes in a representative tertiary hospital clinic are eating compared to their peers and explore dietary intake impact on HbA1c outcome. An open cross-sectional dietary audit of children and adolescents with diabetes aged 2–17 years attending the Royal Children’s Hospital, Melbourne was conducted using an age-appropriate validated Food Frequency Questionnaire. Total energy, macronutrient intake and diet quality were calculated and compared to dietary advice provided and national intake data. Body weight, and dietary intake influences on glycaemic control were investigated. Overall, 785 patients were recruited, from which 429 dietary surveys were completed. Dietary intakes were overall nutritionally adequate with macronutrient distribution (% total energy intake) being lower carbohydrate (48.6%), higher total sugars (22.4%), fat (32.9%), saturated fat (14.9%) and protein intake (19.1%) than recommendations, but similar to their peers. Energy intakes were excessive compared to their peers in the 4–13 year olds. Rates of overweight (30%) were significantly higher than national data (18%). Overall, 43% achieved optimal glycaemic control (HbA1c

Aim: Hearing loss (as reflected by abnormal sound detection) is a frequently reported consequence of Type 1 diabetes mellitus. We sought to evaluate sound detection, auditory neural function and binaural processing ability in a group of school-aged participants with Type 1 diabetes and to assess their functional hearing and general communication ability. Methods: A range of electroacoustic, electrophysiological and behavioural test techniques were used to evaluate both cochlear and auditory neural function in 19 affected children. A cohort of matched controls was also assessed. Results: Although all of the participants with Type 1 diabetes enjoyed normal sound detection, 9 of the 19 (47%) showed evidence of auditory pathway abnormality with evoked potential latencies and/or amplitudes beyond age-related norms. Auditory brainstem response interpeak latencies (wave I-V) were longer than in matched controls [ 95% confidence interval (95% CI); 0.10, 0.28 ms: P

A constant supply of glucose to the brain is critical for normal cerebral metabolism. The dysglycemia of type 1 diabetes (T1D) can affect activity, survival, and function of neural cells. Clinical studies in T1D have shown impairments in brain morphology and function. The most neurotoxic milieu seems to be young age and/or diabetic ketoacidosis at onset, severe hypoglycemia under the age of 6 years followed by chronic hyperglycemia. Adverse cognitive outcomes seem to be associated with poorer mental health outcomes. It is imperative to improve outcomes by investigating the mechanisms of injury so that neuroprotective strategies independent of glycemia can be identified.

Objective: To document electroencephalogram (EEG) changes and their correlation with clinical parameters in a newly diagnosed pediatric cohort of type 1 diabetes mellitus (T1DM) patients with and without diabetic ketoacidosis (DKA) and to define their medium term utility and significance. Research design and methods: Prospective longitudinal study of children presenting with T1DM. EEGs were performed within 24 h of diagnosis, day 5, and at 6 months post-diagnosis and reviewed by a neurologist blinded to clinical status. Severity of encephalopathy was graded from 1 to 5 using the Aoki and Lombroso encephalopathy scale. Cognitive abilities were assessed using standardized tests of attention, memory, and intelligence. Results: Eighty eight children were recruited; 34 presented with DKA. Abnormal background slowing was more often observed in the first 24 h in children with DKA (p = 0.01). Encephalopathy scores on day 1 correlated with initial pH, CO2, HCO3, base excess, respiratory rate, heart rate, diastolic blood pressure, and IV fluid intake (all parameters p < 0.05). EEG scores at day 1 did not correlate with contemporaneous mental state or cognition in the medium term. Conclusions: DKA was associated with significant clinical and neurophysiologic signs of brain dysfunction at presentation. While EEG is sensitive to the detection of encephalopathy in newly diagnosed T1DM, it has limited use in identifying children at risk of later cognitive deficits.