Laurent Legault

Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial

BACKGROUND The artificial pancreas is an emerging technology for the treatment of type 1 diabetes and two configurations have been proposed: single-hormone (insulin alone) and dual-hormone (insulin and glucagon). We aimed to delineate the usefulness of glucagon in the artificial pancreas system. METHODS We did a randomised crossover trial of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy (continuous subcutaneous insulin infusion) in participants aged 12 years or older with type 1 diabetes. Participants were assigned in a 1:1:1:1:1:1 ratio with blocked randomisation to the three interventions and attended a research facility for three 24-h study visits. During visits when the patient used the single-hormone artificial pancreas, insulin was delivered based on glucose sensor readings and a predictive dosing algorithm. During dual-hormone artificial pancreas visits, glucagon was also delivered during low or falling glucose. During conventional insulin pump therapy visits, patients received continuous subcutaneous insulin infusion. The study was not masked. The primary outcome was the time for which plasma glucose concentrations were in the target range (4·0-10·0 mmol/L for 2 h postprandially and 4·0-8·0 mmol/L otherwise). Hypoglycaemic events were defined as plasma glucose concentration of less than 3·3 mmol/L with symptoms or less than 3·0 mmol/L irrespective of symptoms. Analysis was by modified intention to treat, in which we included data for all patients who completed at least two visits. A p value of less than 0·0167 (0·05/3) was regarded as significant. This trial is registered with ClinicalTrials.gov, number NCT01754337. FINDINGS The mean proportion of time spent in the plasma glucose target range over 24 h was 62% (SD 18), 63% (18), and 51% (19) with single-hormone artificial pancreas, dual-hormone artificial pancreas, and conventional insulin pump therapy, respectively. The mean difference in time spent in the target range between single-hormone artificial pancreas and conventional insulin pump therapy was 11% (17; p=0·002) and between dual-hormone artificial pancreas and conventional insulin pump therapy was 12% (21; p=0·00011). There was no difference (15; p=0·75) in the proportion of time spent in the target range between the single-hormone and dual-hormone artificial pancreas systems. There were 52 hypoglycaemic events with conventional insulin pump therapy (12 of which were symptomatic), 13 with the single-hormone artificial pancreas (five of which were symptomatic), and nine with the dual-hormone artificial pancreas (0 of which were symptomatic); the number of nocturnal hypoglycaemic events was 13 (0 symptomatic), 0, and 0, respectively. INTERPRETATION Single-hormone and dual-hormone artificial pancreas systems both provided better glycaemic control than did conventional insulin pump therapy. The single-hormone artificial pancreas might be sufficient for hypoglycaemia-free overnight glycaemic control. FUNDING Canadian Diabetes Association; Fondation J A De Sève; Juvenile Diabetes Research Foundation; and Medtronic.

Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency

Prednisolone has unknown growth-suppressing effects relative to other steroids. We retrospectively studied 9 children (6 with congenital adrenal hyperplasia, CAH) receiving hydrocortisone replacement after switching to prednisolone (dose ratio, 1:5). Growth velocity and, in patients with CAH, 17-OHP decreased significantly. Dose reduction reversed these effects. Roughly, growth suppression relative potency for prednisolone:hydrocortisone was 15:1.

Outpatient overnight glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or conventional insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, randomised controlled trial

BACKGROUND Additional benefits of the dual-hormone (insulin and glucagon) artificial pancreas compared with the single-hormone (insulin alone) artificial pancreas have not been assessed in young people in outpatient unrestricted conditions. We evaluated the efficacy of three systems for nocturnal glucose control in children and adolescents with type 1 diabetes. METHODS We did a randomised, three-way, crossover trial in children aged 9-17 years with type 1 diabetes attending a diabetes camp in Canada. With use of sealed envelopes, children were randomly assigned in a 1:1:1:1:1:1 ratio with blocks of six to different sequences of the three interventions (single-hormone artificial pancreas, dual-hormone artificial pancreas, and conventional continuous subcutaneous insulin pump therapy). Each intervention was applied for 3 consecutive nights. Participants, study staff, and endpoint assessors were not masked. The primary outcome was the percentage of time spent with glucose concentrations lower than 4·0 mmol/L from 2300 h to 0700 h. Analysis was by intention to treat. A p value of less than 0·0167 was regarded as significant. This study is registered with ClinicalTrials.gov, number NCT02189694. FINDINGS Between June 30, 2014, and Aug 9, 2014, we enrolled 33 children of mean age 13·3 years (SD 2·3; range 9-17). The time spent at a glucose concentration lower than 4·0 mmol/L was median 0% (IQR 0·0-2·4) during nights with the dual-hormone artificial pancreas, 3·1% (0·0-6·9) during nights with the single-hormone artificial pancreas (p=0·032), and 3·4% (0-11·0) during nights with conventional pump therapy (p=0·0048 compared with dual-hormone artificial pancreas and p=0·32 compared with single-hormone artificial pancreas). 15 hypoglycaemic events (<3·1 mmol/L for 20 min measured by sensor then confirmed with capillary glucose <4·0 mmol/L) were noted during nights with conventional pump therapy compared with four events with the single-hormone system and no events with the dual-hormone system. None of the assessed outcomes varied with the order in which children and young adults were assigned interventions. INTERPRETATION The dual-hormone artificial pancreas could improve nocturnal glucose control in children and adolescents with type 1 diabetes. Longer and larger outpatient studies are now needed. FUNDING Canadian Diabetes Association, Fondation J A De Sève.

Milk allergy and vitamin D deficiency rickets: a common disorder associated with an uncommon disease

BACKGROUND Cows milk allergy is one of the most common allergies in infancy. It has an excellent prognosis since most cases resolve by 4 years of age. The complications associated with milk allergy include delayed growth and atopic conditions, such as asthma, allergic rhinitis, atopic dermatitis, and other food allergies. OBJECTIVE To report a case of vitamin D deficiency rickets in a 2-year-old boy with cows milk allergy. METHODS We describe a patient with clinical and biochemical evidence of rickets, including decreased serum calcium, phosphate, and 25-hydroxy vitamin D levels and an elevated alkaline phosphatase level. A dietary history revealed the prolonged absence of dietary vitamin D because the child did not tolerate cows milk. Skin prick testing and measurement of specific IgE to cows milk were performed to determine whether there was an allergy to cows milk. RESULTS Results of skin prick testing and measurement of specific IgE to cows milk confirmed an IgE-mediated sensitivity to cows milk. Introduction of appropriate supplementation into the childs diet resulted in complete resolution of his symptoms. CONCLUSIONS This case emphasizes that the management of cows milk allergy involves strict avoidance of the allergenic food while also ensuring that essential dietary requirements are met. A dietary history is crucial at all pediatric visits, and inquiry about supplementation of vitamins and minerals is important, especially in children with food allergies.

Growth hormone deficiency in Costello syndrome

We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndrome and highlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.

Single- and Dual-Hormone Artificial Pancreas for Overnight Glucose Control in Type 1 Diabetes

CONTEXT The added benefit of glucagon in artificial pancreas systems for overnight glucose control in type 1 diabetes has not been fully explored. OBJECTIVE The objective of the study was to compare the efficacy of dual-hormone (insulin and glucagon) artificial pancreas, single-hormone (insulin alone) artificial pancreas, and conventional insulin pump therapy. DESIGN This study was a three-center, three-arm, open-label, randomized, crossover controlled trial involving three interventions, each applied over a night after a high carbohydrate/high fat meal and a second after exercise to mimic real-life glycemic excursions. SETTING The study was conducted in a home setting. PATIENTS Twenty-eight type 1 diabetes participants (21 adults and seven adolescents) participated in the study. INTERVENTIONS Dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional pump therapy was activated from 9:00 PM to 7:00 AM. MAIN OUTCOME The main outcome was a proportion of time in target (4-8 mmol/L) by continuous glucose monitoring from 11:00 PM to 7:00 AM. Analysis was by intention to treat. RESULTS The median (interquartile range) percentage of time-in-target glucose range was 47% (36%-71%) for conventional therapy, higher on both single-hormone (76% [65%-91%], P < .001) and dual-hormone artificial pancreas (81 [68%-93%], P < .001). The median (interquartile range) time spent below 4 mmol/L was 14% (4%-28%) for conventional therapy, lower on both single-hormone (5% [0%-13%], P = .004) and dual-hormone artificial pancreas (1% [0%-8%], P < .001). There were 14 hypoglycemic events on conventional therapy compared with six incidences on the single-hormone artificial pancreas (P = .059) and three incidences on the dual-hormone artificial pancreas (P = .017). None of these outcomes differed significantly between single- and dual-hormone configurations. CONCLUSIONS Single- and dual-hormone artificial pancreas systems both provided better glucose control than conventional therapy. Although the dual-hormone configuration did not increase overnight time-in-target glucose levels, an effect on lowering hypoglycemia risk cannot be ruled out.

Oxidative stress and cystic fibrosis-related diabetes: a pilot study in children.

BACKGROUND Cystic fibrosis (CF) is characterized by chronic inflammation with increased oxidative stress. We evaluated the relationship between glucose tolerance and oxidative stress in CF children. METHODS Patients 10-18 years old underwent oral glucose tolerance testing (n=31). At 2-h, we assessed blood glutathione and 4-hydroxynonenal-protein adducts (HNE-P), and urine 1,4-dihydroxynonane-mercapturic acid conjugate (DHN-MA). Plasma fatty acid (FA) profile was performed. Patients with impaired glucose tolerance (IGT) were retested 6 to 24 months later and received additional nutritional recommendations (NR) when possible. RESULTS Fifty-two percent of patients had normal glucose tolerance (NGT), 42% IGT and 6% cystic fibrosis-related diabetes (CFRD). HNE-P concentrations significantly increased with diabetes (109%). Two-h BG correlated positively with HNE-P and negatively with DHN-MA. FA profile was modified with IGT. Of retested IGT patients, 25% received no NR; they remained IGT at 6 months and progressed to CFRD. Of those who received NR, 67% normalized, 11% remained intolerant and 22% developed CFRD. HNE-P levels dropped (88%) in IGT patients reverting to NGT, increased (94%) in the IGT patients with NR developing CFRD, decreased (90%) with persistent IGT. CONCLUSION CF children showed evidence of increased oxidative stress with worsening of glucose metabolism. NR may delay the appearance of CFRD.

Should I stay or should I go? Understanding families' decisions regarding initiating, continuing, and terminating health services for managing pediatric obesity: the protocol for a multi-center, qualitative study.

BackgroundAt least two million Canadian children meet established criteria for weight management. Due to the adverse health consequences of obesity, most pediatric weight management research has examined the efficacy and effectiveness of interventions to improve lifestyle behaviors, reduce co-morbidities, and enable weight management. However, little information is available on families’ decisions to initiate, continue, and terminate weight management care. This is an important knowledge gap since a substantial number of families fail to initiate care after being referred for weight management while many families who initiate care discontinue it after a brief period of time. This research aims to understand the interplay between individual, family, environmental, and systemic factors that influence families’ decisions regarding the management of pediatric obesity.Methods/DesignIndividual interviews will be conducted with children and youth with obesity (n = 100) and their parents (n = 100) for a total number of 200 interviews with 100 families. Families will be recruited from four Canadian multi-disciplinary pediatric weight management centers in Vancouver, Edmonton, Hamilton, and Montreal. Participants will be purposefully-sampled into the following groups: (i) Non-Initiators (5 families/site): referred for weight management within the past 6 months and did not follow-up the referral; (ii) Initiators (10 families/site): referred for weight management within the past 6 months and did follow-up the referral with at least one clinic appointment; and (iii) Continuers (10 families/site): participated in a formal weight management intervention within the past 12 months and did continue with follow-up care for at least 6 months. Interviews will be digitally recorded and analyzed using an ecological framework, which will enable a multi-level evaluation of proximal and distal factors that underlie families’ decisions regarding initiation, continuation, and termination of care. Demographic and anthropometric/clinical data will also be collected.DiscussionA better understanding of family involvement in pediatric weight management care will help to improve existing health services in this area. Study data will be used in future research to develop a validated survey that clinicians working in pediatric obesity management can use to understand and enhance their own health services delivery.

Glucagon in the 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.

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.

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.