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BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

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BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.

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AIMS: To measure pancreatic area and exocrine function in young children with recent-onset Type 1 diabetes to determine whether the exocrine pancreas is also affected in the pathophysiology of early childhood diabetes. METHODS: Thirty-two children (14 boys) aged 5.5 (4.5, 7.3) median (IQR) years presenting with recent-onset Type 1 diabetes and 90 controls (44 boys) of similar age had ultrasound imaging of the pancreas. Children with Type 1 diabetes were receiving insulin and were without ketosis. Transverse and longitudinal areas of the pancreas were measured by digitalized outline. Pancreatic faecal elastase-1 was analysed using an enzyme-linked immunosorbent assay kit in recent-onset Type 1 diabetes and 38 first-degree relative control children. RESULTS: Pancreatic area and exocrine function were reduced in Type 1 diabetes. Mean transverse area (SD) in Type 1 diabetes was 6.82 cm2 (1.61) vs. 8.31 cm2 (1.74) in controls, adjusted estimate (95% CI) 1.45 (-2.12, -0.79), P < 0.001; longitudinal area was 1.28 cm2 (0.44) vs. 1.55 cm2 (0.43), adjusted estimate (95% CI) -0.27 (-0.45, -0.09), P = 0.003. Faecal elastase-1 levels in Type 1 diabetes were 455 (323, 833) ug/g, median (IQR) vs. 1408 µg/g (1031, 1989) in controls, P < 0.001. CONCLUSION: Pancreatic area and accompanying subclinical exocrine function were reduced in very young children with recent-onset Type 1 diabetes. This supports changes in the exocrine pancreas in the pathophysiology of Type 1 diabetes presenting in early life.

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The aim of this study was to assess prospectively changes in the health-related quality of life (HRQL) of children and adolescents with diabetes, asthma or cystic fibrosis (CF). One hundred and twenty-two parents of children aged 10-16 years with asthma, diabetes, or CF were recruited from specialist paediatric clinics. Parents described their children's HRQL using the Child Health Questionnaire (PF98) at baseline, 6, 12, 18 and 24 months post-baseline. They reported that the general health of children with CF was significantly worse than that of children with asthma and diabetes at baseline. In other domains there were few differences between the HRQL of children in the three groups. In several domains, the HRQL of children with asthma or diabetes improved over the 2 years of the study. This improvement was less evident for children with CF.

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OBJECTIVE: To assess longitudinal changes in folate status in South Australian children and adolescents during fortification of food with folic acid. METHODS: Sixty-nine children and adolescents (age 12.8 +/- 2.3 years), 47 with diabetes and 22 healthy controls, had their folate status assessed at the beginning of 1999 and again after a mean 1.1 +/- 0.23 years. Intake of folate at baseline was assessed with a quantitative food frequency questionnaire. RESULTS: Baseline red cell folate (mean +/- standard deviation (SD)) was 756 +/- 294.5 nmol/L and remained constant at follow up at 736 +/- 299 nmol/L (P = 0.55) in the whole group. Serum folate increased from 24.4 +/- 6.3 nmol/L to 27.2 +/- 8.8 nmol/L (P = 0.002). Children with diabetes showed a significant increase in serum folate (from 26.3 +/- 5.7-30.1 +/- 7.9, P < 0.001) and stable red cell folate (835.8 +/- 278.6 and 808.6 +/- 296.7, P = 0.51) between baseline and the second samples, while controls showed stable serum (20.4 +/- 5.7 and 21.1 +/- 7.7, P = 0.7) and red cell folate (586.6 +/- 255.9 and 579.8 +/- 240.1, P = 0.92). A third sample collected in 17 subjects after a further 9 +/- 1.3 months showed a further increase in serum and red cell folate. Mean folate intake at baseline was 301 +/- 129 micro g/day, below the mean recommended for prevention of neural tube defects. CONCLUSIONS: Voluntary fortification of food with folate is associated with improved folate status in South Australian children and adolescents, but may not be sufficient at current levels to provide maximal protection against neural tube defects at a population level.

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Congenital and acquired forms of osteoporosis in childhood and adolescence can result in morbidity from fracture and pain in childhood, and place an individual at significant risk for problems in adult life. A range of therapies exist for the prevention and treatment of osteoporosis, including optimization of daily calcium intake, adequate vitamin D status, weight-bearing exercise, treatment with sex steroids where delayed puberty is a problem and, more recently, use of bisphosphonate therapy. Intravenous pamidronate therapy (a bisphosphonate) has been shown to reduce fractures and improve bone density in children with osteogenesis imperfecta, and might prove to be of benefit in other osteoporotic conditions in childhood. However, a number of issues regarding the optimal use of bisphosphonate therapy in children and adolescents remain to be resolved, including total annual dose and frequency and duration of administration. Bisphosphonate therapy should, therefore, be used only in the context of a well-run clinical programme with specialist knowledge in the management of osteopenic disorders in childhood.

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High risk HLA class II alleles account for 40% of the genetic susceptibility to type 1 diabetes in Caucasians, but the majority of the genetically predisposed do not develop the disease. This supports some environmental modification of the autoimmune destruction of beta cells that precedes type 1 diabetes. Identical twin studies and geographical variation in incidence also argue for a critical role of environmental factors. Attention has been directed to the possible harmful effect of cow's milk protein (or protective effect of breast-feeding) and enteric infections in early life. Natural history studies that follow children at increased risk of type 1 diabetes provide the best opportunity to study environmental triggers. The Australian Baby Diab Study has followed approximately 500 babies from birth who have a first-degree relative with type 1 diabetes. No prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity was found. The same Australian cohort demonstrated a relationship between rotavirus infection and the first appearance or increase in islet antibodies. Enteroviral infection is seen more frequently in prediabetic children and prior to the onset of islet autoimmunity in Finnish cohorts. Environmental factors may interact. Breast milk protects against enteric infections; enteric infections in turn could increase immunity to dietary antigens by increasing intestinal permeability. It is also possible that an alteration in gut mucosal immune function in genetically susceptible individuals underlies any effect of dietary or viral proteins on the development of islet autoimmunity in early life.

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Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.

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Studies of two post-mortem pancreata of children at the onset of type I diabetes have suggested activation and expansion of islet infiltrating T cells by a superantigen. We present the first reported case of a superantigen mediated disease, toxic shock syndrome (TSS), occurring at the diagnosis of type I diabetes. A 12-year-old girl presented with TSS and newly diagnosed diabetes with ketoacidosis. At presentation she was unconscious, febrile and hypotensive, with a desquamating erythematous rash and Kussmaul breathing. During resuscitation, her renal impairment, diarrhoea, thrombocytopaenia and ketoacidosis resolved. Vaginal discharge and blood cultures grew Staphylococcus aureus. T cell studies at 2 weeks after diagnosis detected a high level of spontaneous and islet antigen-specific proliferation with associated interleukin-10 production compared to human leucocyte antigen DR matched controls.

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AIMS/HYPOTHESIS: To determine the sequence of development of islet autoantibodies and their relation to HLA genes in infants at risk for Type I diabetes followed from birth. METHODS: We followed 357 (189 male, 168 female) infants, with a first degree relative with Type I diabetes for a mean of 3 years from birth. Human leukocyte antigen typing and assays for insulin autoantibodies (IAA), glutamic acid decarboxylase antibodies (GADAb) and tyrosine phosphatase IA2 (IA2Ab) antibodies were done on cord blood, and venous blood was sampled every 6 months for IAA, GADAb and IA2Ab. RESULTS: We did not find any antibodies in 263 (73%) infants; 50 (14%) were positive for a single antibody once, 19 (5%) for a single antibody more than once and 25 (7%) for two or more antibodies. Of the latter, 10 (2.8% overall) were persistently positive; they had higher frequencies of HLA DR4 (p < 0.01) and HLA DR3, 4 (p < 0.05). Of the group persistently positive for two or more antibodies four infants developed diabetes. Insulin autoantibodies were the first ones to develop in 64% of infants with two or more antibodies. CONCLUSION/INTERPRETATION: Infants with high risk HLA-DR alleles and multiple antibodies at high risk for diabetes were identified. A much larger group of infants had transient low level increases usually of a single antibody. Whereas transient low level positivity could be attributed to difficulties with assay technique and cut off levels for normality, the results overall support the phenomenon of transient 'self limited' islet autoimmunity in at risk infants.

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OBJECTIVE: To determine whether a 6-month home-based intervention program in adolescents with poorly controlled diabetes improves metabolic control and whether benefits are maintained after the intervention. RESEARCH DESIGN AND METHODS: Adolescents with a mean HbA1c of > 9.0% over the preceding 12 months received either routine care in a diabetes clinic and an ambulatory intervention for 6 months (n = 37) or routine care only (n = 32). A diabetes educator provided monthly home visits and weekly phone contact to educate and support the adolescents in setting goals for insulin adjustment, blood glucose monitoring, and target blood glucose range. There was no systematic change in the frequency of insulin injections. After the intervention, there was a 12-month follow-up when the intervention and control groups both received only routine care. Outcome measures were HbA1c and Diabetes Knowledge Assessment (DKN). RESULTS: During the intervention, mean HbA1c fell (baseline: 11.1 +/- 1.3%, 6 months: 9.7 +/- 1.6%; P = 0.0001) and mean knowledge scores increased (P = 0.0001) in the intervention group but not in control subjects. However, this improvement in HbA1c and increase in knowledge was not maintained in the intervention group at 12- and 18-month follow-up assessments. Parents' knowledge scores also improved significantly from baseline levels in the intervention group at 6 and 12 months (P = 0.001, P = 0.005, respectively). CONCLUSIONS: An ambulatory program improves metabolic control and knowledge in adolescents with poorly controlled type 1 diabetes; however, it is effective only while the intervention is maintained.

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The hypothesis that early exposure to cow's milk or lack of breast-feeding predisposes to type 1 diabetes remains controversial. We aimed to determine prospectively the relationship of, first, duration of exclusive breast-feeding and total duration of breast-feeding, and second, introduction of cow's milk protein as infant formula, cow's milk, or dairy products, to the development of islet antibodies in early life. Some 317 children with a first-degree relative with type 1 diabetes were followed prospectively from birth for 29 months (4-73). Mothers kept a home diary and answered infant feeding questionnaires at 6-month intervals. No systematic feeding advice was given. Insulin autoantibodies (normal range <5.5%), anti-GAD antibodies (<5.0 U), and anti-IA2 antibodies (<3.0 U) were measured at 6-month intervals. Cox proportional hazards model of survival analysis detected no significant difference between children who did not develop islet antibodies (225 of 317 [71%]), children with one islet antibody raised once (52 of 317 [16.4%]), children with one antibody raised repeatedly (18 of 317 [5.7%]), or children with two or more antibodies raised (22 of 317 [6.9%]), in terms of duration of exclusive breast-feeding, total duration of breast-feeding, or introduction of cow's milk-based infant formulas, cow's milk, or dairy products (relative risk: 0.91-1.09). Four of the children with two or more islet antibodies developed type 1 diabetes. We conclude that there is no prospective association between duration of breast-feeding or introduction of cow's milk and the development of islet autoimmunity in high-risk children.

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In this study we have investigated both the expression of c-met in cultured human mesangial cells and the proliferative effect of HGF on these cells. RNAse protection analysis using a c-met riboprobe showed c-met to be expressed and further that this expression was unaffected by the glucose concentration or osmolality of the media. Immunofluorescence studies performed using anti-HGF or anti-c-met antibodies clearly showed that both proteins are localised to human mesangial cells. Proliferation of human mesangial cells after 24-h treatment with HGF was also examined. HGF 10 ng/ml and 100 ng/ml stimulated 3-H-Thymidine incorporation 1.35-fold (P = 0.001) and 1.6-fold (P<0.00001) respectively in cells made quiescent for 24 h. A similar dose-dependent stimulation of proliferation was observed in cells made quiescent for 48 h. Finally, using RNAse protection analysis we have shown that HGF (10 ng/ml, 100 ng/ml) induces the expression of c-met in these cells in a dose-dependent manner. Together these results indicate for the first time a potential autocrine role for HGF in the human mesangium.

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Pancreatic islet beta cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is believed to be mediated by a T-helper 1 (T(H)1) lymphocyte response to islet antigens. In the mouse, T(H)1 (IL-2, IFN-gamma) and T(H)2 (IL-4, -5, -6, -10) responses are associated with the generation of IgG2a and IgG1 subclasses, respectively. The equivalent human subclasses have not been defined. Because the IgG subclass response to an antigen may be a potentially useful marker of T(H)1/T(H)2 immune balance we measured IgG subclass antibodies to glutamic acid decarboxylase (GAD), a major islet autoantigen in IDDM, in 34 newly-diagnosed IDDM patients and in 28 at-risk, first-degree relatives of people with IDDM. In the newly-diagnosed patients, total IgG antibodies to GAD were detected in 74% (25/34); IgG1 and/or IgG3 were significantly more frequent than IgG4 or IgG4/IgG2 (14/34 versus 5/34, p = 0.01). GAD antibody-negative patients were significantly younger (p = 0.01). In 15 at-risk relatives who had not progressed to clinical diabetes after a median of 4.5 years, 10 had IgG2 and/or IgG4 antibodies compared to only 3/13 progressors (p = 0.02). Total IgG and IgG2 antibodies were higher in non-progressors. Non-progressors were older than progressors (p = 0.01), and relatives with IgG2 and/or IgG4 responses were also older (p = 0.01). These results suggest that IgG subclass antibodies to GAD may contribute to diabetes risk assessment in islet antibody relatives.

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OBJECTIVE: To investigate power spectral analysis (PSA) of heart rate variability (HRV) in children and adolescents with IDDM, its relationship with other measures of HRV and standard cardiovascular responses, and factors associated with reduced HVR. RESEARCH DESIGN AND METHODS: A total of 130 subjects with IDDM aged 12.8 +/- 3.2 years and 108 healthy control subjects were studied. Power spectra were analyzed from supine electrocardiograph (ECG) recordings by processing into consecutive R-R intervals and analysis using fast Fourier transformation. Standard cardiovascular responses to deep breathing and standing were performed. RESULTS: IDDM subjects had a reduction in total power including both low-frequency (0.05-0.14 Hz; P = 0.0001) and high-frequency (0.14-0.40 Hz; P = 0.0002) components. These changes were seen from diagnosis. Other measures of HRV, coefficient of variation (CV) and standard deviation (SD) of mean resting heart rate, were also significantly lower in IDDM. All 20 (15%) of the 130 IDDM subjects with total power less than the 5th percentile in control subjects also had reduced HRV when measured by CV of heart rate. There was an independent relationship between age and the high-frequency component in IDDM subjects and control subjects. Total power correlated with mean heart rate (r = -0.56; P < 0.0001), CV of heart rate (r = 0.90; P < 0.00001), SD of heart rate (r = 0.91; P < 0.00001), heart rate response to deep breathing (r = 0.45; P < 0.0001), and duration in IDDM subjects. There was no correlation with short-term or long-term metabolic control. Retesting of 27 subjects showed a variability in total power and its components comparable to other measures of HRV and standard heart rate responses. CONCLUSIONS: Changes in HRV are a sensitive and reproducible measure of early autonomic dysfunction in childhood. In this age-group, PSA appears no more sensitive a measure of reduced HRV than other closely correlated measures of HRV.

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We aimed to determine the natural history of borderline increases in albuminuria in adolescents with insulin-dependent (Type 1) diabetes mellitus (IDDM) and factors which are associated with progression to persistent microalbuminura. Fifty-five normotensive adolescents with IDDM and intermittent microalbuminura (overnight albumin excretion ratte of 20-200 micrograms min-1 on one of three consecutive timed collections, n = 29) or borderline albuminura (mean overnight albumin excretion rate of 7.2-20 micrograms min-1 on one of three consecutive timed collections, n = 30) were followed prospectively at 3 monthly intervals. The endpoint was persistent microalbuminuria defined as a minimum of three of four consecutive overnight albumin excretion rates of greater than 20 micrograms min-1. One hundred and forty-two adolescents with IDDM and normoalbuminura were also followed prospectively. Fifteen of the 59 patients (25.4%) with intermittent (9/29) or borderline (6/30) albuminura progressed to persistent microalbuminura (progressors) over 28 (15-50) months [median (range)] in comparison with two of the 142 patients with normoalbuminuria at entry (relative risk = 12.6; p = 0.001). Progressors to persistent microalbuminura were pubertal and had higher systolic (p = 0.02) and diastolic (p = 0.02) blood pressure, and HbA1c (p = 0.004) than non-progressors. All patients remained normotensive. Glomerular filtration rate, apolipoproteins, dietary phosphorus, protein and sodium intakes, and prevalence of smoking did not differ between progressors and non-progressors. Total renin was higher in the diabetic patients without a difference between progressors and non-progressors. In conclusion there is a relatively high rate of progression to persistent microalbuminuria in pubertal adolescents with borderline increases in albuminura and duration greater than 3 years. These patients require attention to minimize associated factors of poor metabolic control and higher blood pressure in the development of incipient nephropathy.

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The study aimed to determine the prevalence of impaired nocturnal BP fall in adolescents with Type 1 diabetes. Thirty-six normoalbuminuric normotensive adolescents with Type 1 diabetes (19 males, 17 females) aged 14.4 +/- 2.1 years (mean +/- SD) with duration of 4.0 (2.6-7.5) years (median (25-75th percentile)) and 23 controls (11 males, 12 females) aged 15.0 +/- 1.6 years were studied. Day/night BP variation was examined using Ambulatory Accutracker II Monitor (Raleigh, NC). Recordings were made at 30 min intervals during the day and 60 min intervals during the night. Time records were set according to individual diaries. There was no significant difference in day and night systolic or diastolic BP or in mean day/night BP variability between patients with Type 1 diabetes and control subjects. 15/36 patients compared to 3/23 controls (chi squared = 5.43, p < 0.02) were non-dippers defined as a nocturnal fall in either systolic (13/36) or diastolic (6/36) BP or both (4/36) of less than 10%. These non-dippers had normal day-night ratio of heart rate when compared with the remainder of the patients or controls. In conclusion a significant number of young normotensive normoalbuminuric patients with Type 1 diabetes show an impaired fall in blood pressure at night, predominantly in systolic BP. These changes may be relevant to the long-term development of macrovascular or microvascular disease.

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We aimed to examine the longitudinal relationship between lipoprotein(a) and haemoglobin A1c, albumin excretion rate, and puberty in peripubertal children with insulin-dependent diabetes. A total of 114 patients aged 11.5 +/- 3.6 years (mean (SD)) were followed prospectively for 15.2 +/- 2.8 months. Lipoprotein(a), apolipoproteinB-100, haemoglobin A1c, mean overnight albumin excretion rate and Tanner stage were determined at the beginning and end of the study period. Lipoprotein(a) and apolipoproteinB-100 were measured using nephelometry. This method was correlated with radioimmunoassay and there was no significant change in mean bias during the study. Lipoprotein(a) fell significantly over time (214, (152, 276); 160 (84, 236) mg l-1 geometric mean (0.95 confidence intervals), p < 0.001); apolipoproteinB-100 did not change. Lipoprotein(a) and apolipoproteinB-100 did not differ in 233 cross-sectional controls of similar age. The change in lipoprotein(a) did not correlate with a small fall in haemoglobin A1c or with overnight albumin excretion rate, Tanner stage or insulin dose. Separate analysis of male and female patients and prepubertal and pubertal patients continued to show a significant fall in lipoprotein(a) independent of change in haemoglobin A1c or albumin excretion rate. Likewise, 53 patients with a change in haemoglobin A1c of greater than 1%, and 20 patients who progressed from normal albumin excretion rate to albumin excretion rate above the 95th centile, showed no relationship between lipoprotein(a) and haemoglobin A1c or albumin excretion rate. In conclusion, longitudinal changes in lipoprotein(a) do not relate to metabolic control or early changes in albuminuria in young patients with insulin-dependent diabetes.

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