Stuart A. Weinzimer

Continuous glucose monitoring and intensive treatment of type 1 diabetes

BACKGROUND The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Persistence of Benefits of Continuous Subcutaneous Insulin Infusion in Very Young Children With Type 1 Diabetes: A Follow-up Report

Objective. Use of continuous subcutaneous insulin infusion (CSII) has increased dramatically in recent years, and pump therapy has been shown to be a safe and effective alternative to multiple daily injections in adults and older pediatric patients with type 1 diabetes. Its use in very young children, however, has been limited, although this group might be expected to benefit the most from CSII. The objective of this study was to analyze the CSII efficacy and safety data in very young children with type 1 diabetes from our Diabetes Clinic database. Methods. Glycosylated hemoglobin (HbA1c), severe hypoglycemia (SH), and ketoacidosis (DKA) in the year before CSII were compared with corresponding values during pump treatment in all children who started CSII before age 7. Results. Sixty-five children (mean age: 4.5 y at CSII initiation; range: 1.4–6.9 years; 28 girls; 3 black, 1 Hispanic) were analyzed for >162 patient-years of follow-up. Mean HbA1c (7.4 ± 1.0 prepump) decreased to 7.0 ± 0.9 after 12 months of CSII and continued to improve even after 4 years on CSII. The rate of SH was reduced by 53% (from 78 to 37/100 patient-years). Children who received daytime care from paid caregivers (n = 26) experienced significant reductions in HbA1c and hypoglycemia frequency. There were no episodes of DKA requiring emergency treatment in the year before CSII and 4 episodes (4 per 100 patient-years) after transition to pump. Conclusions. CSII is a durable and effective means of optimizing glycemic control in very young patients with type 1 diabetes and may be superior to multiple daily injections in minimizing the risk of severe hypoglycemia in this age group. Employment of paid caregivers does not preclude safe and effective use of CSII.

A Randomized Clinical Trial to Assess the Efficacy and Safety of Real-Time Continuous Glucose Monitoring in the Management of Type 1 Diabetes in Young Children Aged 4 to <10 Years

OBJECTIVE Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes. RESEARCH DESIGN AND METHODS After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 ± 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA1c at 26 weeks by ≥0.5% without the occurrence of severe hypoglycemia. RESULTS The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA1c was −0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA1c (rs = −0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced. CONCLUSIONS CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes.

Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes Closed-loopartificialpancreastechnologyusesacontrolalgorithm to automatically adjust insulin delivery based on subcutaneous sensor data to improve diabetes management. Currently available systems stop insulin in response to existing1 or predicted2 low sensor glucose values, whereas hybrid closed-loop systems combine user-delivered premeal boluses with automatic interprandial insulin delivery.3 This study investigated the safety of a hybrid closed-loop system in patients with type 1 diabetes.

Comparison of fingerstick hemoglobin A1c levels assayed by DCA 2000 with the DCCT/EDIC central laboratory assay: results of a Diabetes Research in Children Network (DirecNet) Study.

Abstract:  Background:  The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) high‐performance liquid chromatography (HPLC) method for measuring hemoglobin A1c (HbA1c) serves as a reference standard against which other assays are compared. The DCA 2000® + Analyzer (Bayer Inc., Tarrytown, NY, USA), which uses an immunoassay, is a very popular device for measuring HbA1c levels in pediatric diabetes practices.

Sustained benefit of continuous glucose monitoring on A1C, glucose profiles, and hypoglycemia in adults with type 1 diabetes

OBJECTIVE To evaluate long-term effects of continuous glucose monitoring (CGM) in intensively treated adults with type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 83 of 86 individuals ≥25 years of age with type 1 diabetes who used CGM as part of a 6-month randomized clinical trial in a subsequent 6-month extension study. RESULTS After 12 months, median CGM use was 6.8 days per week. Mean change in A1C level from baseline to 12 months was −0.4 ± 0.6% (P < 0.001) in subjects with baseline A1C ≥7.0%. A1C remained stable at 6.4% in those with baseline A1C <7.0%. The incidence rate of severe hypoglycemia was 21.8 and 7.1 events per 100 person-years in the first and last 6 months, respectively. Time per day with glucose levels in the range of 71–180 mg/dl increased significantly (P = 0.02) from baseline to 12 months. CONCLUSIONS In intensively treated adults with type 1 diabetes, CGM use and benefit can be sustained for 12 months.

Effect of Pramlintide on Prandial Glycemic Excursions During Closed-Loop Control in Adolescents and Young Adults With Type 1 Diabetes

OBJECTIVE Even under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions. RESEARCH DESIGN AND METHODS Eight subjects (4 female; age, 15–28 years; A1C, 7.5 ± 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-μg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal. RESULTS CLP was associated with overall delayed time to peak BG (2.5 ± 0.9 vs. 1.5 ± 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 ± 42 vs. 113 ± 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes. CONCLUSIONS Pramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast.

Human papillomavirus type 16 E7 oncoprotein binds and inactivates growth-inhibitory insulin-like growth factor binding protein 3.

ABSTRACT The E7 protein encoded by human papillomavirus type 16 is one of the few viral genes that can immortalize primary human cells and thereby override cellular senescence. While it is generally assumed that this property of E7 depends on its interaction with regulators of the cell cycle, we show here that E7 targets insulin-like growth factor binding protein 3 (IGFBP-3), the product of a p53-inducible gene that is overexpressed in senescent cells. IGFBP-3 can suppress cell proliferation and induce apoptosis; we show here that IGFBP-3-mediated apoptosis is inhibited by E7, which binds to IGFBP-3 and triggers its proteolytic cleavage. Two transformation-deficient mutants of E7 failed to inactivate IGFBP-3, suggesting that inactivation of IGFBP-3 may contribute to cell transformation.

Alterations in White Matter Structure in Young Children With Type 1 Diabetes

OBJECTIVE To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children. RESEARCH DESIGN AND METHODS Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition. RESULTS Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects. CONCLUSIONS These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.

Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study

Slover RH, Welsh JB, Criego A, Weinzimer SA, Willi SM, Wood MA, Tamborlane WV. Effectiveness of sensor‐augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study.