Predictive hyperglycemia and hypoglycemia minimization: In-home double-blind randomized controlled evaluation in children and young adolescents.

OBJECTIVE: The primary objective of this trial was to evaluate the feasibility, safety, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system vs predictive low glucose suspension (PLGS) alone in optimizing overnight glucose control in children 6 to 14 years old. RESEARCH DESIGN AND METHODS: Twenty-eight participants 6 to 14 years old with T1D duration ≥1 year with daily insulin therapy ≥12 months and on insulin pump therapy for ≥6 months were randomized per night into PHHM mode or PLGS-only mode for 42 nights. The primary outcome was percentage of time in sensor-measured range 70 to 180 mg/dL in the overnight period. RESULTS: The addition of automated insulin delivery with PHHM increased time in target range (70-180 mg/dL) from 66 ± 11% during PLGS nights to 76 ± 9% during PHHM nights (P<.001), without increasing hypoglycemia as measured by time below various thresholds. Average morning blood glucose improved from 176 ± 28 mg/dL following PLGS nights to 154 ± 19 mg/dL following PHHM nights (P<.001). CONCLUSIONS: The PHHM system was effective in optimizing overnight glycemic control, significantly increasing time in range, lowering mean glucose, and decreasing glycemic variability compared to PLGS alone in children 6 to 14 years old.

Diabetes technology and treatments in the paediatric age group.

Type 1 diabetes (T1D) is one of the most common chronic childhood diseases and its incidence has doubled during the last decade. The goals of intensive management of diabetes were established in 1993 by the Diabetes Control and Complications Trial (DCCT) (1). Children with T1D and their caregivers continue to face the challenge to maintain blood glucose levels in the near-normal range. It is important to prevent sustained hyperglycaemia which is associated with long-term microvascular and macrovascular complications and to avoid recurrent episodes of hypoglycaemia or hyperglycaemia, especially in young children, which may have adverse effects on cognitive function and impede efforts to achieve the recommended glycaemic targets. Advances in the use of technology that may help maintain the metabolic control goals for young people with T1D were centred on continuous subcutaneous insulin infusion (CSII) (2-4), continuous glucose monitoring (CGM) (5-7), and combining both technologies into a closed-loop system (8-10). The dilemma in paediatrics of patient selection for insulin pump therapy was found to be most successful in those with more frequent self-monitoring of blood glucose (SMBG) and younger age prior to pump initiation (2). Similarly, those who used a dual-wave bolus probably paid closer attention to their management and had lower HbA1c levels (3). The advantage of using a pre-meal bolus to improve postprandial glucose levels was shown to offer another potential method to improve glycaemic control (4). SMBG is an important component of therapy in patients with diabetes, especially in the paediatric age group. Standard use of glucose meters for SMBG provides only intermittent single blood glucose levels, without giving the 'whole picture' of glucose variability during the 24 h, and especially during the night, when blood glucose levels are seldom measured. Therefore, the use of a device such as real-time continuous glucose monitoring (RT-CGM) that provides continuous glucose measurements can help patients optimise glycaemic control. These devices may have the potential to increase the proportion of patients who are able to maintain target HbA1c values, to decrease glucose excursions and to decrease the risk of severe hypoglycaemia. Previous studies in paediatric T1D patients (11,12) have demonstrated that the frequency of CGM use was significantly associated with the effect of lowering HbA1c levels. The important STAR 3 study of 485 patients (156 children) with T1D showed the benefit of sensor-augmented pump therapy over remaining on multiple daily injections (MDI) (10). The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) studies were initially described in the 2009 Yearbook (13). Further reports of youths and adults in this study found that those with initial low HbA1c levels (< 7%) show a significant benefit from the use of CGM (5). Prolonged nocturnal hypoglycaemia was shown to continue to be a common occurrence in the entire cohort using CGM (7). Thus, there is an obvious need for closing the loop. Many patients with diabetes and especially parents of diabetic children dream about the invention of an 'artificial pancreas'. CSII and RT-CGM can be combined to form closed-loop systems. Insulin is then delivered according to RT-CGM data, as directed by a control algorithm, rather than at pre-programmed rates. Few closed-loop prototypes have been developed with advanced control algorithms, such as those that are based on model predictive control (14). The group at Cambridge studied 19 young people in closed-loop systems and was able to demonstrate that exercise and diet variations could be aptly managed (9). It is expected that closed-loop studies in young people will continue to multiply in future years. T1D is characterised by immune-mediated pancreatic ß-cell destruction. Thus, a major goal in the treatment of T1D in youth will be in the area of prevention. The identification of increased levels of inflammatory markers in the SEARCH study of young people with T1D may provide an important clue (15). Most of the studies countered the diabetes process by immunomodulation and/or enhancement of ß-cell proliferation and regeneration (16). An initial pilot trial of a tumour necrosis factor α (TNF-α) binding agent, Entanercept, showed benefit in preserving C-peptide production in 18 young people with newly diagnosed T1D. HbA1c levels were also lower in the treatment group (5.9% ± 0.5% vs. 6.98% ± 1.2%; p < 0.05) (17). Similarly, ß-cell function was shown to be preserved in children receiving the lower of two doses of ingested human recombinant interferon-α (hrINF-α) in comparison with subjects who received placebo (18). A future larger trial of both of these agents will be of interest. In this review of the literature we have tried to select recent publications that offer some insight into these issues in paediatric patients with T1D.

Use of insulin glargine in children under age 6 with type 1 diabetes.

AIM: Children under 6 yr have the highest incidence of severe hypoglycemia (SH) and the greatest likelihood of brain damage from SH. The purpose of this study is to evaluate the use of insulin glargine (Lantus in children under age 6 with type 1 diabetes (T1D). METHODS: The electronic medical records were reviewed for patients under age 6 during the first 6 months of insulin glargine therapy and compared with age, sex, and duration of diabetes for matched control patients on neutral protamine Hagedorn (NPH) insulin. Data from 128 subjects (32 male pairs and 32 female pairs) were collected relating to the incidence of severe and non-severe hypoglycemic events, hemoglobin A1c (HbA1c) values, body mass index (BMI), and daily insulin dose. Additionally, parents were asked to complete a diabetes Quality of Life (QoL) survey. RESULTS: In the 6 months before the study period, the glargine group had 16 SH events compared with three in the 6 months post-glargine. The comparison (NPH) group had seven and six SH events in their respective 6-month periods. Nighttime SH events in the glargine group decreased from 12 prestudy events to one during the study period. The average daily insulin dose in the glargine group was higher than that in the NPH group (0.8+/- 0.2 vs. 0.7+/- 0.2 U/kg/day; p=0.03). The HbA1c values, BMI, and QoL responses were not significantly different between the two groups. CONCLUSIONS: SH was decreased, particularly at night (from 12 episodes to one), after the introduction of glargine in young children with T1D.