Glomerular Filtration Rate Abnormalities in Children With Type 1 Diabetes.

OBJECTIVES: Type 1 diabetes (T1D) increases the risk of chronic kidney disease (CKD) development. The primary objective of this study was to assess the prevalence of abnormalities in estimated glomerular filtration rate (eGFR) in children with T1D. As a secondary objective, we sought to explore the relationship between clinical characteristics and abnormalities in eGFR. METHODS: This cross-sectional study involved children ≤18 years of age with T1D followed in the diabetes clinic at a pediatric tertiary care centre. Data were collected from health records between 2016 and 2020. Using the Bedside Schwartz, Chronic Kidney Disease in Children Under 25 (CKiD U25) and European Kidney Function Consortium (EKFC) equations, eGFR was categorized as CKD (<60 mL/min/1.73 m2), mildly decreased (60 to <90 mL/min/1.73 m2), normal (90 to <158 mL/min/1.73 m2) and hyperfiltration (≥158 mL/min/1.73 m2). Linear regression analysis was used to describe the relationship between eGFR and clinical characteristics. RESULTS: Of the 420 participants, 225 were male (54%); the median age at diagnosis and duration of T1D were 6.1 and 4.8 years, respectively. The proportion of participants with mildly decreased eGFR was similar regardless of eGFR equation, with 11% to 14% of participants with an eGFR <90 mL/min/1.73 m2. When analyzed as a function of duration of T1D, eGFR was 1.4 mL/min/1.73 m2 lower per year duration of T1D. CONCLUSIONS: A notable proportion of children with T1D demonstrates eGFR abnormalities early in their T1D course. This finding along with evidence of lower eGFR in adolescence is concerning for long-term risk of CKD and warrants systematic serum creatinine monitoring at diagnosis and regular intervals thereafter in children with T1D.

Perioperative Hypotensive Crisis in an Adolescent with a Pancreatic VIPoma and MEN1-Gene Variant.

BACKGROUND: Vasoactive intestinal peptide-secreting tumours (VIPomas) lead to high-volume secretory diarrhoea with hypokalaemia, as well as hyperglycaemia and hypercalcaemia. Diagnosis is often delayed. CASE DESCRIPTION: We present a 13-year-old girl with a distal pancreatic VIPoma diagnosed on her second hospital presentation who became severely hypotensive on anaesthetic induction prior to tumour removal, likely due to the vasodilatory effect of supraphysiological VIP levels. Prior to the second surgical attempt, an octreotide infusion was started preoperatively to suppress systemic VIP levels and counter the potential for VIP-induced hypotension upon tumour manipulation, and the tumour was successfully resected. Hyperparathyroidism and history of GI tumour resection were subsequently identified in the father, and the two members were found to have a heterozygous variant of uncertain significance in the multiple endocrine neoplasia type 1 (MEN1) gene. However, as this family meets the diagnostic criteria for MEN1 clinically, ongoing surveillance for MEN1 tumours and genetic counseling for at-risk family members are required despite the non-pathogenic genetic result. CONCLUSION: This case highlights the importance of screening for a VIPoma in patients with high-volume secretory diarrhoea and preventing cardiovascular complications with perioperative VIP suppression. Furthermore, careful interpretation of genetic results within the clinical context is required.

Risperidone But Not Quetiapine Treatment Is Associated With Increased Appetite But Not Satiety Hormones in Children During An Oral Glucose Tolerance Test: A Pilot Study.

BACKGROUND: Second-generation antipsychotics (SGAs) are commonly used to treat children with mental health conditions (MHCs) but are associated with adverse effects including obesity, hypertension, dyslipidemia, and type 2 diabetes. The mechanisms underlying these complications are unknown, but it has been suggested that SGAs increase appetite leading to weight gain. The present objective was to perform a pilot study to investigate appetite and satiety hormones in SGA-treated (risperidone or quetiapine) and SGA-naive children with similar mental health conditions. METHODS: Oral glucose tolerance tests (OGTTs) were conducted in SGA-naive (n = 18), risperidone-treated (n = 20), and quetiapine-treated (n = 16) children recruited from the British Columbia Children's Hospital Psychiatry Department. Over 5 time-points during the OGTT, appetite questionnaires using a visual analogue scale were administered, and blood was collected to measure ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, glucagon-like protein 1, leptin, and adiponectin. Mixed model analyses were conducted to examine between-group differences. RESULTS: The children were similar in age, psychiatric diagnosis, and global assessment of functioning scores. Body mass index z-scores were also similar between groups. Appetite was increased during the OGTT in the risperidone-treated compared with the SGA-naive group for 2 questions ("How strong is your desire to eat"; P = 0.003 and "How much food do you think you can eat"; P = 0.028). No differences in satiety hormones were observed between the 3 groups. CONCLUSIONS: Risperidone treatment in youth is associated with elevated appetite during an OGTT, with no differences in gut peptides or adipocytokines to explain risperidone's effect on appetite. Further research is needed to explore other mediators of weight gain and metabolic dysfunction in SGA-treated youth.

Measurement of Pro-Islet Amyloid Polypeptide (1-48) in Diabetes and Islet Transplants.

Context: Islet amyloid is a feature of ß-cell failure in type 2 diabetes (T2D) and type 1 diabetes (T1D) recipients of islet transplants. Islet amyloid contains islet amyloid polypeptide (IAPP; amylin), a circulating peptide that is produced in ß cells by processing of its precursor, proIAPP1-67, via an intermediate form, proIAPP1-48. Elevated proinsulin to C-peptide ratios in the plasma of persons with diabetes suggest defects in ß-cell prohormone processing. Objective: Determine whether plasma levels of precursor forms of IAPP are elevated in diabetes. Design, Setting, and Patients: We developed an immunoassay to detect proIAPP1-48 in human plasma, and we determined the ratio of proIAPP1-48 to mature IAPP in subjects with T1D, T2D, recipients of islet transplants, and healthy controls. Results: The proIAPP1-48 immunoassay had a limit of detection of 0.18 ± 0.06 pM and cross-reactivity with intact proIAPP1-67 <15%. Healthy individuals had plasma concentrations of proIAPP1-48 immunoreactivity of 1.5 ± 0.2 pM and a proIAPP1-48 to total IAPP ratio of 0.28 ± 0.03. Plasma concentrations of proIAPP1-48 immunoreactivity were not significantly different in subjects with T2D but were markedly increased in T1D recipients of islet transplants. Children and adults with T1D had reduced mature IAPP levels relative to age-matched controls but an elevated ratio of proIAPP1-48 to total IAPP. Conclusion: The ß cells in T1D and islet transplants have impaired processing of the proIAPP1-48 intermediate. The ratio of proIAPP1-48-to-IAPP immunoreactivity may have value as a biomarker of ß-cell stress and dysfunction.

Does parental and adolescent participation in an e-health lifestyle modification intervention improves weight outcomes?

BACKGROUND: Few studies have evaluated the effect of adherence to a lifestyle intervention on adolescent health outcomes. The objective of this study was to determine whether adolescent and parental adherence to components of an e-health intervention resulted in change in adolescent body mass index (BMI) and waist circumference (WC) z-scores in a sample of overweight/obese adolescents. METHODS: In total, 159 overweight/obese adolescents and their parents participated in an 8-month e-health lifestyle intervention. Each week, adolescents and their parents were asked to login to their respective website and to monitor their dietary, physical activity, and sedentary behaviours. We examined participation (percentage of webpages viewed [adolescents]; number of weeks logged in [parents]) and self-monitoring (number of weeks behaviors were tracked) rates. Linear mixed models and multiple regressions were used to examine change in adolescent BMI and WC z-scores and predictors of adolescent participation and self-monitoring, respectively. RESULTS: Adolescents and parents completed 28% and 23%, respectively, of the online component of the intervention. Higher adolescent participation rate was associated with a decrease in the slope of BMI z-score but not with change in WC z-score. No association was found between self-monitoring rate and change in adolescent BMI or WC z-scores. Parent participation was not found to moderate the relationship between adolescent participation and weight outcomes. CONCLUSIONS: Developing strategies for engaging and promoting supportive interactions between adolescents and parents are needed in the e-health context. Findings demonstrate that improving adolescents' adherence to e-health lifestyle intervention can effectively alter the weight trajectory of overweight/obese adolescents.

Profiling of circulating microRNAs in children with recent onset of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of ß cells are destroyed. There is an unmet need for reliable and cost-effective biomarkers to predict and diagnose diabetes at an early stage. A number of stable microRNAs (miRNAs) have been reported in serum and plasma and are now being investigated as biomarkers of different diseases. We measured the levels of 745 miRNAs in sera of children with recent-onset T1D and age-matched controls using locked nucleic acid-enhanced (LNA-enhanced) quantitative PCR profiling. Thirty-five miRNAs were significantly different between the groups, and 27 miRNAs were elevated in T1D. Good discriminating power was obtained for 6 miRNAs (miR-454-3p, miR-222-3p, miR-144-5p, miR-345-5p, miR-24-3p, and miR-140-5p), which were not elevated at later stages of diabetes. In silico pathway analysis, based on inferred miRNA target genes, associated glycosaminoglycan biosynthesis as well as PI3K/Akt, MAPK, and Wnt signaling pathways with early stages of T1D. Among the 27 upregulated miRNAs in T1D, 2 miRNAs significantly correlated with hemoglobin A1c (HbA1c), as did 5 of 8 downregulated miRNAs. A total of 134 miRNAs significantly correlated with HbA1c when stratifying hyperglycemia-induced miRNAs from T1D-specific miRNAs. In conclusion, we have identified a serum miRNA pattern of recent-onset T1D and signaling pathways that may be involved in its pathogenesis.

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing ß-cells. Insufficient control of autoreactive T cells by regulatory T cells (Tregs) is believed to contribute to disease pathogenesis, but changes in Treg function are difficult to quantify because of the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We established a new way to track Tregs by using a gene signature that discriminates between Tregs and conventional T cells regardless of their activation states. The resulting 31-gene panel was validated with the NanoString nCounter platform and then measured in sorted CD4(+)CD25(hi)CD127(lo) Tregs from children with T1D and age-matched control subjects. By using biomarker discovery analysis, we found that expression of a combination of six genes, including TNFRSF1B (CD120b) and FOXP3, was significantly different between Tregs from subjects with new-onset T1D and control subjects, resulting in a sensitive (mean ± SD 0.86 ± 0.14) and specific (0.78 ± 0.18) biomarker algorithm. Thus, although the proportion of Tregs in peripheral blood is similar between children with T1D and control subjects, significant changes in gene expression can be detected early in disease process. These findings provide new insight into the mechanisms underlying the failure to control autoimmunity in T1D and might lead to a biomarker test to monitor Tregs throughout disease progression.

Waist circumference is a sensitive screening tool for assessment of metabolic syndrome risk in children treated with second-generation antipsychotics.

OBJECTIVE: To compare the prevalence of metabolic syndrome (MetS) and its components in second-generation antipsychotic (SGA)-treated and SGA-naive children; and to explore the utility of clinical markers, such as waist circumference (WC) and body mass index (BMI), as screening tools for MetS. METHODS: Subjects were prospectively recruited from the Psychiatry Emergency Unit at British Columbia Children's Hospital. As part of a quality-assurance project, a metabolic monitoring protocol was implemented, including collection of anthropomorphic and laboratory data. RESULTS: From January 2008 to February 2010, there were 117 SGA-treated and 217 SGA-naive children recruited. The overall prevalence of MetS was 19.0% (16/84; median treatment duration = 14 months) in SGA-treated and 0.8% (1/127) in SGA-naive children (OR 29.7; 95% CI 3.85 to 228.40, P < 0.001), with an increased prevalence of all components except high-density lipoprotein cholesterol (HDL-C), respectively: elevated WC (40.7% and 10.1%; P < 0.001); hypertriglyceridemia (33.7% and 18.8%; P = 0.01); impaired fasting glucose (12.5% and 0.7%; P = 0.005); and elevated blood pressure (41.2% and 16.5%; P < 0.001). SGA treatment was the strongest predictor of MetS (OR 19.2; 95% CI 2.30 to 160.44, P = 0.006) followed by male sex (OR 5.7; 95% CI 1.08 to 30.62, P = 0.04). Presence of abdominal obesity was more sensitive (92.9%) than BMI (68.8%), while fasting glucose of 5.6 mmol/L or more and HDL-C of 1.03 mmol/L or less were most specific (94.1%) in correctly identifying MetS. CONCLUSIONS: SGA treatment confers a significantly increased risk for MetS over the long term. WC measurement is a simple and sensitive screening tool for determining MetS risk in SGA-treated children. These data highlight the dangers of SGA treatment and the importance of standardized metabolic monitoring using sex- and age-adjusted tables in this population.

Implementing a whole school physical activity and healthy eating model in rural and remote first nations schools: a process evaluation of action schools! BC.

INTRODUCTION: Aboriginal people who reside in rural and remote areas of Canada often have poorer health than other Canadians. For instance, the prevalence rate of type 2 diabetes is 3 to 5 times higher than for the general population. Chronic disease risk factors such as obesity are also more prevalent. Overweight and obesity have become major health challenges for all Canadian children, but for Aboriginal children, the numbers are 2 to 3 times higher. 'Action Schools! BC' (AS! BC) is a whole-school framework designed as a positive approach to addressing childhood inactivity and unhealthy eating patterns during the school day that was effective for children in a large urban center. The purpose of this study was to explore the feasibility and implementation of AS! BC in 3 remote Aboriginal communities in northern British Columbia. METHODS: The AS! BC model provided tools for schools and teachers to create individualized 'action plans' to increase the opportunities for physical activity (PA) and healthy eating (HE) across 6 'action zones'. These zones included: (1) school environment; (2) scheduled physical education; (3) classroom action; (4) family and community; (5) extra-curricular; and (6) school spirit. Teachers (primarily generalists) were provided with the training and resources necessary to implement their action plan for their class. Schools had three visits from the AS! BC support team. Teachers received specialized training and support, a 'planning guide' and classroom-based resources. Gender- and skill-level-inclusive activities were prioritized. Although the model emphasized choice using a whole-school framework, 'classroom action' was a flagship component. Teachers were asked to provide students with a minimum of 15 additional minutes of PA each school day and at least one HE activity per month in the 'classroom action zone'. Information about implementation was gathered from weekly 'classroom logs' completed by teachers and focus groups with school staff. RESULTS: The logs showed that all 3 schools implemented physical activities (mean = 140 min/week, range = 7-360 min/week) and HE activities (mean = 2.3 times/week, range = 0-10 times/week) but this varied by school and teacher. Adherence to logging was low (34% of eligible weeks). Focus group data showed that the program was well received and that support from the AS! BC master trainer and support team was crucial to delivery of the program. Staff highlighted challenges (eg time, high staff turnover at the schools and lack of financial resources), but felt that with continued support and cultural adaptations they would continue to implement AS! BC in their schools. CONCLUSIONS: The evaluation demonstrated that AS! BC was appropriate and feasible for use in the First Nations schools in these rural and remote communities with some cultural adaptations and ongoing support. Rural and remote locations have very specific challenges that need to be considered in broader dissemination strategies.

Identification of Novel HLA-A*0201-restricted epitopes in recent-onset type 1 diabetic subjects and antibody-positive relatives.

Cytotoxic T-lymphocytes (CTLs) are considered to be essential for beta-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B-secreting cells in response to at least one putative epitope compared with healthy control subjects. The most prevalent responses in antibody-positive and type 1 diabetic subjects were to ppIAPP(9-17). Other peptides recognized by type 1 diabetic or antibody-positive subjects included GFAP(143-151), IGRP(152-160), and GFAP(214-222). These data implicate peptides of ppIAPP, GFAP, and IGRP as CTL epitopes for a heterogenous CD8(+) T-cell response in type 1 subjects and antibody-positive relatives.

Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes.

Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic beta-cells by cytotoxic T-lymphocytes (CTLs). In humans, few beta-cell epitopes have been reported, thereby limiting the study of beta-cell-specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the beta-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for gamma-interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201-restricted T-cell epitopes in type 1 diabetic patients. Interestingly, we observed a strong inverse correlation between the binding affinity of beta-cell peptides to HLA-A*0201 and CTL responses against those peptides in recent-onset type 1 diabetic patients. In addition, we found that self-reactive CTLs with specificity for an insulin peptide are frequently present in healthy individuals. These data suggest that many beta-cell epitopes are recognized by CTLs in recent-onset type 1 diabetic patients. These epitopes may be important in the pathogenesis of type 1 diabetes.

Identification of a beta-cell-specific HLA class I restricted epitope in type 1 diabetes.

Type 1 diabetes is an autoimmune disease in which pancreatic beta-cells are destroyed by cytotoxic T-cells that recognize peptide epitopes presented by HLA class I molecules. The identification of human beta-cell epitopes may significantly improve the prospects for immunodiagnosis and immunotherapy in type 1 diabetes. Using algorithms to predict nonameric beta-cell peptides that would bind to the common HLA allele, HLA-A*0201, we identified a potential epitope from the leader sequence of islet amyloid polypeptide (human islet amyloid polypeptide [IAPP] precursor protein [preproIAPP] 5-13: KLQVFLIVL). Peripheral blood mononuclear cells (PBMCs) were isolated from 18 HLA-A*0201 patients with type 1 diabetes (9 with recent-onset [<180 days; range, 1-120 days] and 9 with long-standing diabetes [>180 days; range, 183-3,273 days]) and 9 healthy, nondiabetic control subjects. PBMCs were screened for peptide recognition using interferon-gamma enzyme-linked immunospot (ELISpot) assays. Of the nine patients with recent-onset type 1 diabetes, six had ELISpot responses to preproIAPP 5-13 that were >3 SDs above the mean of the nondiabetic control subjects (P = 0.002). In contrast, no patients with type 1 diabetes for >180 days had a response above this threshold. In summary, preproIAPP 5-13 is a novel HLA class I epitope recognized by a significant proportion of cytotoxic T-cells from HLA-A*0201 patients with recent-onset type 1 diabetes and may prove to be a useful tool for the prediction and/or prevention of this disease.