Severe obesity and global developmental delay in preschool children: Findings from a Canadian Paediatric Surveillance Program study.

Background: The co-presentation of severe obesity (SO) and global developmental delay (GDD) in Canadian preschool children has not been examined. However, SO and GDD may require syndromic diagnoses and unique management considerations. Objectives: To determine (1) minimum incidence; (2) age of onset and risk factors; and (3) health care utilization for co-presenting SO and GDD. Methods: Through the Canadian Paediatric Surveillance Program (CPSP), a monthly form was distributed to participants from February 2018 to January 2020 asking for reports of new cases of SO and GDD among children ≤5 years of age. We performed descriptive statistics for quantitative questions and qualitative content analysis for open-ended questions. Results: Forty-seven cases (64% male; 51% white; mean age: 3.5 ± 1.2 years) were included. Age of first weight concern was 2.5 ± 1.3 years and age of GDD diagnosis was 2.7 ± 1.4 years. Minimum incidence of SO and GDD was 3.3 cases per 100,000 for ≤5 years of age per year. Identified problems included school and/or behavioural problems (n = 17; 36%), snoring (n = 14; 30%), and asthma/recurrent wheeze (n = 10; 21%). Mothers of 32% of cases (n = 15) had obesity and 21% of cases (n = 10) received neonatal intensive care. Microarray was ordered for 57% (n = 27) of children. A variety of clinicians and services were accessed. As reported by CPSP participants, challenges faced by families and health service access were barriers to care. Conclusion: Children with SO and GDD have multiple comorbidities, and require early identification and referral to appropriate services. These cases may also benefit from additional testing to rule out known genetic obesity syndromes.

Individual and family characteristics associated with health indicators at entry into multidisciplinary pediatric weight management: findings from the CANadian Pediatric Weight management Registry (CANPWR).

OBJECTIVES: (1) To explore individual and family characteristics related to anthropometric and cardiometabolic health indicators and (2) examine whether characteristics that correlate with cardiometabolic health indicators differ across severity of obesity at time of entry to Canadian pediatric weight management clinics. METHODS: We conducted a cross-sectional analysis of 2-17 year olds with overweight or obesity who registered in the CANadian Pediatric Weight Management Registry (CANPWR) between May 2013 and October 2017 prior to their first clinic visit. Individual modifiable health behaviors included dietary intake, physical activity, screen time, and sleep. Family characteristics included parental BMI, family medical history, socioeconomic status and family structure. Linear mixed effects stepwise regression analysis was performed to determine which characteristics were related to each health indicator: BMI z-score; waist circumference; waist to height ratio; blood pressure; glycemia; HDL cholesterol; non-HDL cholesterol; triglycerides. RESULTS: This study included 1296 children (mean age ± standard deviation: 12.1 ± 3.5 years; BMI z-score: 3.55 ± 1.29; 95.3% with obesity). Hours spent sleeping (estimated ß = -0.10; 95% CI [-0.15, -0.05], p = 0.0001), hours per week of organized physical activity (estimated ß = -0.32; 95% CI [-0.53, -0.11], p = 0.0026), daily sugared drink intake (estimated ß = 0.06; 95% CI [0.01, 0.10], p = 0.0136) and maternal BMI (estimated ß = 0.03; 95% CI [0.02, 0.04], p < 0.0001) were associated with BMI z-score (adj. R2 = 0.2084), independent of other individual and family characteristics. Physical activity, total sugared drink intake and sleep duration were associated with glycemia and non-HDL cholesterol, independent of child BMI z-score. However, irrespective of obesity severity, little of the variance (0.86-11.1%) in cardiometabolic health indicators was explained by individual modifiable health behaviors. CONCLUSIONS: Physical activity, total sugared drink intake and hours spent sleeping were related to anthropometric and some cardiometabolic health indicators in children entering pediatric weight management programs. This highlights the importance of these modifiable health behaviors on multiple health indicators in children with obesity.

Nutrition and food literacy among young Canadian adults living with type 1 diabetes.

AIM: Nutrition and food literacy encompasses knowledge, skills and confidence to prepare healthy meals. This project aimed to assess and compare the proportion of young Canadian adults (18-29 years old) living with type 1 diabetes and without diabetes (controls) who demonstrated adequate nutritional health literacy. METHODS: This cross-sectional study involved participants completing an online survey that included questions on socio-economic status, nutrition knowledge, confidence and skills in meal preparation and the Short Food Literacy Questionnaire (SFLQ). Proportion of participants with adequate SFLQ score (i.e. ≥34/52) was compared between the groups (two-sample t-test). RESULTS: Among the 236 people living with type 1 diabetes and 191 controls (81.5% women), mean age was 24 ± 3 years for people living with type 1 diabetes and 22 ± 3 years for controls (p < 0.001). More people living with type 1 diabetes reported adequate SFLQ score (people living with type 1 diabetes 88.0% vs. Controls 68.0%; p < 0.001). Similarly, majority of people living with type 1 diabetes prepared their own meals compared to the controls (74.5% vs. 47.6%; p < 0.001). Enhanced SFLQ score was associated with higher cooking skills (p = 0.02) and confidence (p < 0.01) in preparing healthy meals. CONCLUSIONS: Living with type 1 diabetes was associated with greater SFLQ scores among young Canadian adults. Having the independence, the confidence and skills in meal preparation were contributing factors.

Alleviating carbohydrate counting with a FiASP-plus-pramlintide closed-loop delivery system (artificial pancreas): Feasibility and pilot studies.

AIM: To assess whether a FiASP-and-pramlintide closed-loop system has the potential to replace carbohydrate counting with a simple meal announcement (SMA) strategy (meal priming bolus without carbohydrate counting) without degrading glycaemic control compared with a FiASP closed-loop system. MATERIALS AND METHODS: We conducted a 24-hour feasibility study comparing a FiASP system with full carbohydrate counting (FCC) with a FiASP-and-pramlintide system with SMA. We conducted a subsequent 12-day outpatient pilot study comparing a FiASP-and-placebo system with FCC, a FiASP-and-pramlintide system with SMA, and a FiASP-and-placebo system with SMA. Basal-bolus FiASP-and-pramlintide were delivered at a fixed ratio (1 U:10 µg). Glycaemic outcomes were measured, surveys evaluated gastrointestinal symptoms and diabetes distress, and participant interviews helped establish a preliminary coding framework to assess user experience. RESULTS: Seven participants were included in the feasibility analysis. Time spent in 3.9-10 mmol/L was similar between both interventions (81%-84%). Four participants were included in the pilot analysis. Time spent in 3.9-10 mmol/L was similar between the FiASP-and-placebo with FCC and FiASP-and-pramlintide with SMA interventions (70%), but was lower in the FiASP-and-placebo with SMA intervention (60%). Time less than 3.9 mmol/L and gastrointestinal symptoms were similar across all interventions. Emotional distress was moderate at baseline, after the FiASP-and-placebo with FCC and SMA interventions, and fell after the FiASP-and-pramlintide with SMA intervention. SMA reportedly afforded participants flexibility and reduced mealtime concerns. CONCLUSIONS: The FiASP-and-pramlintide system has the potential to substitute carbohydrate counting with SMA without degrading glucose control.

Perceptions and expectations of adults with type 1 diabetes for the use of artificial pancreas systems with and without glucagon addition: Results of an online survey.

BACKGROUND AND AIMS: The first hybrid artificial pancreas (AP) systems with insulin only (mono-hormonal) have recently reached the market while next generations systems are under development including those with glucagon addition (bi-hormonal). Understanding the expectations and impressions of future potential users about AP systems is important for optimal use of this clinically effective emerging technology. METHODS AND RESULTS: An online survey about AP systems which consisted of 50 questions was addressed to people with type 1 diabetes in the province of Quebec, Canada. Surveys were completed by 123 respondents with type 1 diabetes (54% women, mean (SD) age 40.2 (14.4) y.o., diabetes duration 23.7 (14.1) years, 58% insulin pump users and 43% glucose sensor users). Of the respondents, 91% understood how AP systems work, 79% trusted them with correct insulin dosing, 73% were willing to replace their current treatment with AP and 80% expected improvement in quality of life. Anxiety about letting an algorithm control their glucose levels was expressed by 18% while the option of ignoring or modifying AP instructions was favoured by 88%. As for bi-hormonal AP systems, 83% of respondents thought they would be useful to further reduce hypoglycemic risks. CONCLUSIONS: Overall, respondents expressed positive views about AP systems use and high expectations for a better quality of life, glycemic control and hypoglycemia reduction. Data from this survey could be useful to health care professionals and developers of AP systems.

Comparison of two carbohydrate intake strategies to improve glucose control during exercise in adolescents and adults with type 1 diabetes.

BACKGROUND AND AIMS: During aerobic physical activity (PA), hypoglycemia is common in people with type 1 diabetes (T1D). Few studies have compared the effectiveness of different carbohydrate (CHO) intake strategies to prevent PA-induced hypoglycemia. Our objective was to compare the efficacy of two CHO intake strategies, same total amount but different CHO intake timing, to maintain glucose levels in the target range (4.0-10.0 mmol/L) during PA in people with T1D. METHODS AND RESULTS: An open-label, randomized, crossover study in 33 participants (21 adults; 12 adolescents). Participants practiced 60 min PA sessions (ergocyle) at 60% VO2peak 3.5 h after lunch comparing an intake of 0.5 g of CHO per kg of body weight applied in a pre-PA single CHO intake (SCI) or in a distributed CHO intake (DCI) before and during PA. The percentage of time spent in glucose level target range during PA was not different between the two strategies (SCI: 75 ± 35%; DCI: 87 ± 26%; P = 0.12). Hypoglycemia (<4.0 mmol/L) occurred in 4 participants (12%) with SCI compared to 6 participants (18%) with DCI (P = 0.42). The SCI strategy led to a higher increase (P = 0.01) and variability of glucose levels (P = 0.04) compared with DCI. CONCLUSIONS: In people living with T1D, for a 60 min moderate aerobic PA in the post-absorptive condition, a 0.5 g/kg CHO intake helped most participants maintain acceptable glycemic control with both strategies. No clinically significant difference was observed between the SCI and DCI strategies. ClinicalTrials.gov Identifier: NCT03214107 (July 11, 2017).

A single-blind, randomised, crossover study to reduce hypoglycaemia risk during postprandial exercise with closed-loop insulin delivery in adults with type 1 diabetes: announced (with or without bolus reduction) vs unannounced exercise strategies.

AIMS/HYPOTHESIS: For individuals living with type 1 diabetes, closed-loop insulin delivery improves glycaemic control. Nonetheless, maintenance of glycaemic control during exercise while a prandial insulin bolus remains active is a challenge even to closed-loop systems. We investigated the effect of exercise announcement on the efficacy of a closed-loop system, to reduce hypoglycaemia during postprandial exercise. METHODS: A single-blind randomised, crossover open-label trial was carried out to compare three strategies applied to a closed-loop system at mealtime in preparation for exercise taken 90 min after eating at a research testing centre: (1) announced exercise to the closed-loop system (increases target glucose levels) in addition to a 33% reduction in meal bolus (A-RB); (2) announced exercise to the closed-loop system and a full meal bolus (A-FB); (3) unannounced exercise and a full meal bolus (U-FB). Participants performed 60 min of exercise at 60% [Formula: see text] 90 min after eating breakfast. The investigators were not blinded to the interventions. However, the participants were blinded to the sensor glucose readings and to the insulin infusion rates throughout the intervention visits. RESULTS: The trial was completed by 37 adults with type 1 diabetes, all using insulin pumps: mean±SD, 40.0 ± 15.0 years of age, HbA1c 57.1 ± 10.8 mmol/mol (7.3 ± 1.0%). Reported results were based on plasma glucose values. During exercise and the following 1 h recovery period, time spent in hypoglycaemia (<3.9 mmol/l; primary outcome) was reduced with A-RB (mean ± SD; 2.0 ± 6.2%) and A-FB (7.0 ± 12.6%) vs U-FB (13.0 ± 19.0%; p < 0.0001 and p = 0.005, respectively). During exercise, A-RB had the least drop in plasma glucose levels: A-RB -0.3 ± 2.8 mmol/l, A-FB -2.6 ± 2.9 mmol/l vs U-FB -2.4 ± 2.7 mmol/l (p < 0.0001 and p = 0.5, respectively). Comparison of A-RB vs U-FB revealed a decrease in the time spent in target (3.9-10 mmol/l) by 12.7% (p = 0.05) and an increase in the time spent in hyperglycaemia (>10 mmol/l) by 21% (p = 0.001). No side effects were reported during the applied strategies. CONCLUSIONS/INTERPRETATION: Combining postprandial exercise announcement, which increases closed-loop system glucose target levels, with a 33% meal bolus reduction significantly reduced time spent in hypoglycaemia compared with the other two strategies, yet at the expense of more time spent in hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT0285530 FUNDING: JDRF (2-SRA-2016-210-A-N), the Canadian Institutes of Health Research (354024) and the Fondation J.-A. DeSève chair held by RR-L.

Postprandial hyperglycaemia following insulin suspensions by the artificial pancreas: Implications for bolus calculators.

Conventional bolus calculators apply negative prandial corrections when premeal glucose levels are low. However, no study has evaluated the need for this negative correction with closed-loop systems. We analysed data retrospectively from a cohort study evaluating a closed-loop artificial pancreas system conducted in a diabetes camp over a period of 11 days. Meal boluses with negative correction (n = 98) of 47 participants aged 8 to 22 years were examined. If there was no insulin-on-board from previous boluses at mealtime, the postprandial hyperglycaemia rate increased with increased duration of insulin suspension (P = .03), with odds ratios being exaggerated by 17% per 10 minutes of suspension. However, if there was insulin-on-board from previous boluses, the hyperglycaemia rate did not change with increased duration of insulin suspension (P = .24). When there was no insulin-on-board, the rate of hyperglycaemia after meals preceded by no suspension was 21% (3/14), compared with 52% (12/23) and 64% (9/14) after meals preceded by suspensions of ≥50 and ≥70 minutes, respectively. Meal size did not influence these results. We conclude that, in the absence of insulin-on-board, negative prandial corrections may not be necessary following long insulin suspensions.

A pilot non-inferiority randomized controlled trial to assess automatic adjustments of insulin doses in adolescents with type 1 diabetes on multiple daily injections therapy.

BACKGROUND: Multiple daily injections (MDI) therapy for type 1 diabetes involves basal and bolus insulin doses. Non-optimal insulin doses contribute to the lack of satisfactory glycemic control. We aimed to evaluate the feasibility of an algorithm that optimizes daily basal and bolus doses using glucose monitoring systems for MDI therapy users. METHODS: We performed a pilot, non-inferiority, randomized, parallel study at a diabetes camp comparing basal-bolus insulin dose adjustments made by camp physicians (PA) and a learning algorithm (LA), in children and adolescents on MDI therapy. Participants wore a glucose sensor and underwent 11 days of daily dose adjustments in either arm. Algorithm adjustments were reviewed and approved by a physician. The last 7 days were examined for outcomes. RESULTS: Twenty-one youths (age 13.3 [SD, 3.7] years; 13 females; HbA1c 8.6% [SD, 1.8]) were randomized to either group (LA [n = 10] or PA [n = 11]). The algorithm made 293 adjustments with a 92% acceptance rate from the camp physicians. In the last 7 days, the time in target glucose (3.9-10 mmol/L) in LA (39.5%, SD, 20.7) was similar to PA (38.4%, SD, 15.6) (P = .89). The number of hypoglycemic events per day in LA (0.3, IQR, [0.1-0.6]) was similar to PA (0.2, IQR, [0.0-0.4]) (P = .42). There was no incidence of severe hypoglycemia nor ketoacidosis. CONCLUSIONS: In this pilot study, glycemic outcomes in the LA group were similar to the PA group. This algorithm has the potential to facilitate MDI therapy, and longer and larger studies are warranted.

Pathways to eating in children and adolescents with obesity.

BACKGROUND: Paediatric obesity management remains generalised to dietary and exercise modifications with an underappreciation for the contributions of eating behaviours and appetitive traits in the development of obesity. OBJECTIVES: To determine whether treatment-seeking children and adolescents with obesity cluster into phenotypes based on known eating behaviours and appetitive traits ("eating correlates") and how socio-demographic and clinical characteristics associate with different phenotypes. METHODS: A cross-sectional, multi-centre questionnaire was administered between November 2015 and March 2017 examining correlates of eating in children and adolescents attending weight-management programmes in Canada. Latent profile analysis was used to cluster participants based on seven eating correlate scores obtained from questionnaires. Analysis of variance (ANOVA) was used to determine phenotype differences on socio-demographic and clinical characteristics. Multinomial logistic regression models assessed relative risk of specific characteristics associating with a disordered eating phenotype. RESULTS: Participants were 247 children and adolescents (45.3% male, mean BMI z-score = 3.4 ± 1.0 kg/m2) from six paediatric weight management centres in Canada. Seven eating correlates clustered into three distinct phenotypes: (1) loss of control eating, emotional eating, external eating, hyperphagia, impulsivity ("Mixed-Severe"; n = 42, 17%), (2) loss of control eating, emotional eating, external eating, hyperphagia ("Mixed-Moderate"; n = 138, 55.9%), and (3) impulsivity ("Impulsive"; n = 67; 27.1%). Social functioning scores and body esteem were significantly different across groups, with the Mixed-Severe participants having the poorest social functioning and lowest body esteem. Low body esteem indicated a greater risk of being in a multi-correlate group compared to the Impulsive group, while poor social function had a greater risk of clustering in the Mixed-Severe than Impulsive phenotype. CONCLUSIONS: Distinct eating phenotypes were found in treatment-seeking children and adolescents with obesity. Empirical evidence is needed, but these data suggest that tailored treatment approaches could be informed by these classifications to improve weight-management outcomes.

Parent Recommendations to Enhance Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management.

OBJECTIVE: To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity. STUDY DESIGN: Data for this interpretative description study were collected through individual, semistructured interviews that were audiorecorded, transcribed verbatim, and analyzed thematically. Parents (n = 79) were recruited from 4 multidisciplinary weight management clinics in Canada located in Edmonton, Hamilton, Montreal, and Vancouver. RESULTS: Most interviewed parents had children with obesity (body mass index ≥95th percentile; 84.2%), were female (87.3%), had postsecondary education (69.6%), and were white (75.9%). Parents' recommendations referred to enrollment opportunities, information about obesity services, motivation for treatment, and accessibility to obesity services. Specifically, parents recommended to increase referral options and follow-up contacts with families during the enrollment process, inform referring physicians and families about the availability and characteristics of obesity services, enhance families' motivation for treatment, prevent families from getting discouraged, make services more appealing to families, and address accessibility issues (eg, offering multiple options for appointment times, providing support for transportation). CONCLUSIONS: Parents' recommendations support the need for family-centered approaches to enhance enrollment; however, their feasibility, acceptability, and effectiveness remain to be tested empirically.

The challenges of achieving postprandial glucose control using closed-loop systems in patients with type 1 diabetes.

For patients with type 1 diabetes, closed-loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal-time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post-meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate-matched bolus in the post-meal period. The latter strategy has been efficient in controlling post-meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal-priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag-time. New and upcoming faster acting insulins could provide important benefits. Multi-hormone CLS (eg, dual-hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP-1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined.

Risk of ketoacidosis in children at the time of diabetes mellitus diagnosis by primary caregiver status: a population-based retrospective cohort study.

BACKGROUND: Diabetic ketoacidosis is the leading cause of death among children with type 1 diabetes mellitus, and is an avoidable complication at first-time diagnosis of diabetes. Because having a usual provider of primary care is important in improving health outcomes for children, we tested the association between having a usual provider of care and risk of diabetic ketoacidosis at onset of diabetes. METHODS: Using linked health administrative data for the province of Quebec, we conducted a population-based retrospective cohort study of children aged 1-17 years in whom diabetes was diagnosed from 2006 to 2015. We estimated adjusted risk ratios (RRs) for an episode of diabetic ketoacidosis at the time of diabetes diagnosis in relation to usual provider of care (family physician, pediatrician or none) using Poisson regression models with robust error variance. RESULTS: We identified 3704 new cases of diabetes in Quebec children from 2006 to 2015. Of these, 996 (26.9%) presented with diabetic ketoacidosis. A decreased risk of this complication was associated with having a usual provider of care; the association was stronger with increasing age, reaching statistical significance among those aged 12-17 years. Within this age group, those who had a family physician or a pediatrician were 31% less likely (adjusted RR 0.69, 95% confidence interval [CI] 0.56-0.85) or 38% less likely (adjusted RR 0.62, 95% CI 0.45-0.86), respectively, to present with diabetic ketoacidosis, relative to those without a usual provider of care. INTERPRETATION: For children with newly diagnosed diabetes, having a usual provider of care appears to be important in decreasing the risk of diabetic ketoacidosis at the time of diabetes diagnosis. Our results provide further evidence concerning the need for initiatives that promote access to primary care for children.

The CANadian Pediatric Weight management Registry (CANPWR): lessons learned from developing and initiating a national, multi-centre study embedded in pediatric clinical practice.

BACKGROUND: There is increasing recognition of the value of "real-world evidence" in evaluating health care services. Registry-based, observational studies conducted in clinical settings represent a relevant model to achieve this directive. Starting in 2010, we undertook a longitudinal, observational study (the CANadian Pediatric Weight management Registry [CANPWR]), which is embedded in 10 multidisciplinary, pediatric weight management clinics across Canada. The objective of this paper was to share the lessons our team learned from this multi-centre project. METHODS: Data sources included a retrospective review of minutes from 120 teleconferences with research staff and investigators, notes taken during clinical site visits made by project leaders, information from quality control processes to ensure data accuracy and completeness, and a study-specific survey that was sent to all sites to solicit feedback from research team members (n = 9). Through an iterative process, the writing group identified key themes that surfaced during review of these information sources and final lessons learned were developed. RESULTS: Several key lessons emerged from our research, including the (1) value of pilot studies and central research coordination, (2) need for effective and regular communication, (3) importance of consensus on determining outcome measures, (4) challenge of embedding research within clinical practice, and (5) difficulty in recruiting and retaining participants. The sites were, in spite of these challenges, enthusiastic about the benefits of participating in multi-centre collaborative studies. CONCLUSION: Despite some challenges, multi-centre observational studies embedded in pediatric weight management clinics are feasible and can contribute important, practical insights into the effectiveness of health services for managing pediatric obesity in real-world settings.

Genetic variations at the human growth hormone receptor (GHR) gene locus are associated with idiopathic short stature.

GH plays an essential role in the growing child by binding to the growth hormone receptor (GHR) on target cells and regulating multiple growth promoting and metabolic effects. Mutations in the GHR gene coding regions result in GH insensitivity (dwarfism) due to a dysfunctional receptor protein. However, children with idiopathic short stature (ISS) show growth impairment without GH or GHR defects. We hypothesized that decreased expression of the GHR gene may be involved. To test this, we investigated whether common genetic variants (microsatellites, SNPs) in regulatory regions of the GHR gene region were associated with the ISS phenotype. Genotyping of a GT-repeat microsatellite in the GHR 5'UTR in a Montreal ISS cohort (n = 37 ISS, n = 105 controls) revealed that the incidence of the long/short (L/S) genotype was 3.3× higher in ISS children than controls (P = 0.04, OR = 3.85). In an Italian replication cohort (n = 143 ISS, n = 282 controls), the medium/short (M/S) genotype was 1.9× more frequent in the male ISS than controls (P = 0.017, OR = 2.26). In both ISS cohorts, logistic regression analysis of 27 SNPs showed an association of ISS with rs4292454, while haplotype analysis revealed specific risk haplotypes in the 3' haploblocks. In contrast, there were no differences in GT genotype frequencies in a cohort of short stature (SS) adults versus controls (CARTaGENE: n = 168 SS, n = 207 controls) and the risk haplotype in the SS cohort was located in the most 5' haploblock. These data suggest that the variants identified are potentially genetic markers specifically associated with the ISS phenotype.

Outpatient 60-hour day-and-night glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or sensor-augmented pump therapy in adults with type 1 diabetes: An open-label, randomised, crossover, controlled trial.

AIMS: To assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared to the single-hormone (insulin alone) artificial pancreas in outpatient settings during the day and night. MATERIAL AND METHODS: In a randomized, three-way, crossover trial we compared the dual-hormone artificial pancreas, the single-hormone artificial pancreas and sensor-augmented pump therapy (control) in 23 adults with type 1 diabetes. Each intervention was applied from 8 AM Day 1 to 8 PM Day 3 (60 hours) in outpatient free-living conditions. The primary outcome was time spent with sensor glucose levels below 4.0 mmol/L. A P value of less than .017 was regarded as significant. RESULTS: The median difference between the dual-hormone system and the single-hormone system was -2.3% (P = .072) for time spent below 4.0 mmol/L, -1.3% (P = .017) for time below 3.5 mmol/L, and -0.7% (P = .031) for time below 3.3 mmol/L. Both systems reduced (P < .017) hypoglycaemia below 4.0, 3.5 and 3.3 mmol/L compared to control therapy, but reductions were larger with the dual-hormone system than with the single-hormone system (medians -4.0% vs -3.4% for 4.0 mmol/L; -2.7% vs -2.2% for 3.5 mmol/L; and -2.2% vs -1.2% for 3.3 mmol/L). There were 34 hypoglycaemic events (<3.0 mmol/L for 20 minutes) with control therapy, 14 with the single-hormone system and 6 with the dual-hormone system. These differences in hypoglycaemia were observed while mean glucose level was low and comparable in all interventions (P = NS). CONCLUSIONS: The dual-hormone artificial pancreas had the lowest risk of hypoglycaemia, but the differences were not statistically significant. Larger studies are needed.

Glucagon in artificial pancreas systems: Potential benefits and safety profile of future chronic use.

The role of glucagon in the pathophysiology of diabetes has long been recognized, although its approved clinical use has so far been limited to the emergency treatment of severe hypoglycaemia. A novel use of glucagon as intermittent mini-boluses is proposed in the dual-hormone version (insulin and glucagon) of the external artificial pancreas. Short-term studies suggest that the incorporation of glucagon into artificial pancreas systems has the potential to further decrease hypoglycaemic risk and improve overall glucose control; however, the potential long-term safety and benefits also need to be investigated given the recognized systemic effects of glucagon. In the present report, we review the available animal and human data on the physiological functions of glucagon, as well as its pharmacological use, according to dosing and duration (acute and chronic). Along with its main role in hepatic glucose metabolism, glucagon affects the cardiovascular, renal, pulmonary and gastrointestinal systems. It has a potential role in weight reduction through its central satiety function and its role in increasing energy expenditure. Most of the pharmacological studies investigating the effects of glucagon have used doses exceeding 1 mg, in contrast to the mini-boluses used in the artificial pancreas. The available data are reassuring but comprehensive human studies using small but chronic glucagon doses that are close to the physiological ranges are lacking. We propose a list of variables that could be monitored during long-term trials of the artificial pancreas. Such trials should address the questions about the risk-benefit ratio of chronic glucagon use.

Efficacy of single-hormone and dual-hormone artificial pancreas during continuous and interval exercise in adult patients with type 1 diabetes: randomised controlled crossover trial.

AIMS/HYPOTHESIS: The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise. METHODS: An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6 years; HbA1c, 8.0 ± 1.0% [63.9 ± 10.2 mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60 min) and interval (2 min alternating periods at 85% and 50% [Formula: see text] for 40 min, with two 10 min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30 hours until 19:30 hours; exercise was started at 18:00 hours and announced 20 min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal. RESULTS: During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3 mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0 mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0 mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057 mg) than during interval exercise (0.093 ± 0.068 mg) (p = 0.03), with no reported side-effects in all interventions. CONCLUSIONS/INTERPRETATION: The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.

Bacillus Calmette-Guérin (BCG) Vaccination in Infancy and Risk of Childhood Diabetes.

BACKGROUND: A narrow time window in infancy may be relevant for the aetiology of immune-mediated type 1 diabetes. We investigated whether a non-specific immune stimulation in the first year of life, as resulting from Bacillus Calmette-Guérin (BCG) vaccination, was associated with childhood diabetes. METHODS: Using data from a birth cohort assembled through linkage of administrative databases, 78,492 subjects born in 1974 were the object of the present analysis. Information was extracted from the birth, death, and BCG vaccination registries. Diabetes-related health services were obtained from administrative health databases (physician billing claims and hospitalisation data) until 1994. Subjects were classified as having diabetes according to two validated definitions: (1) ≥2 diabetes-related medical visits within 2 years or ≥1 hospitalisation for diabetes; and 2) ≥4 diabetes-related medical visits within 2 years. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI), adjusted for potential confounders. RESULTS: Forty-four per cent of subjects were BCG vaccinated in the first year of life. According to the first and second definition, respectively, 293 (0.37%) and 230 (0.29%) subjects were classified as having diabetes. There was no association between BCG vaccination in the first year of life and risk of diabetes with either definition (HR(def1) = 0.92, 95% CI 0.73, 1.17; HR(def2) = 1.04, 95% CI 0.80, 1.37), and results did not differ by sex. CONCLUSIONS: Given the potentially critical importance of the exposure window and paucity of studies addressing BCG vaccination timing in relation to diabetes risk, this question deserves further investigation.