1. Mealtime Glycemic Excursions in Pediatric Subjects with Type 1 Diabetes: Results of the Diabetes Research in Children (DirecNet) Accuracy Study Study Group

2. Background The Diabetes Research in Children Network (DirecNet) is a multi-center group whose aim is to study the accuracy and practicability of glucose sensor systems in children with type 1 diabetes (T1DM) Meal-related hyperglycemic excursions contribute greatly to difficulty in optimal diabetes control Continuous glucose monitoring systems provide the opportunity to study meal-related glucose excursions

3. Objectives To describe meal-related glycemic excursions in children and adolescents with T1DM To determine the accuracy of the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Inc.) and the GlucoWatch ® G2™ Biographer (GW2B, Cygnus, Inc.) under rapidly changing glucose levels

4. Methods 82 children with T1DM admitted to 5 CRCs CGMS, GW2B, blood-drawing IV inserted Short-acting or meal-related bolus insulin omitted Standard liquid carbohydrate meal administered, 1.75 gm/kg (max 75 gm) Reference venous blood glucose (BG) measured at baseline and every 5 min for up to 60 min Sensor glucose (SG) levels compared to reference BG

5. Subject Demographics Gender F / M41 / 41 Age mean ± SD (y)10.4 ± 4.1 Race / Ethnicity N(%) White73 (89) Hispanic or Latino4 (5) African-American3 (4) Other2 (2) BMI percentile mean ± SD (%)67 ± 23

6. Clinical Characteristics Duration of T1DM mean ± SD (y) All ages4.9 ± 3.3 1 - < 7 (n = 23)3.2 ± 1.0 7 - < 12 (n = 27)3.8 ± 2.4 12 - < 18 (n = 32)7.0 ± 3.9 Insulin Route N (%) Pump38 (46) Multiple daily injection44 (54) HbA1c mean ± SD (%)7.7 ± 1.1

7. BG Distribution at each 5-minute interval during meal-induced Hyperglycemia test Time since start of test (min) 0 100 200 300 400 500 Glucose (mg/dL) 0 5 10 15 20 25 30 35 40 45 50 55

8. Baseline and Peak Glucose Levels by Age and Treatment Modality* 0 50 100 150 200 250 300 350 400 Overall1 - < 77 - < 1212- < 18CSIIMDI Blood Glucose (mg/dL) BaselinePeak *Height of bar = mean Whisker = mean + 1 SD

9. Time to peak BG (min) 30 40 50 60 70 Overall1 - < 77 - < 1212- < 18CSIIMDI 2 2.5 3 3.5 4 4.5 5 5.5 6 Rate of Change (mg/dL-min) Time Course of Glucose Excursion by Age and Treatment Modality* Restricted to n=62 subjects in whom hyperglycemia was successfully induced (increase of 100 mg/dL or doubling from baseline) *Height of bar = mean Whisker = mean + 1 SD

10. Sensor Accuracy According to Rate of Glucose Change During Test Median Relative Absolute Deviation Rate of Change* (mg/dL per min) Accuracy did not vary by rate of change. *Calculated from the previous reference glucose value (drop in BG divided by minutes between values)

11. Fulfillment of ISO Criteria* According to Rate of Glucose Change During Test Accuracy did not vary by rate of change *ISO criteria: for reference BG ≤75 mg/dL, SG within ±15 mg/dL for reference BG >75 mg/dL, SG value within ±20% % Meeting ISO Criteria Rate of Change (mg/dL per min)

12. Conclusions Magnitude, timing, and rate of meal-related hyperglycemic excursions were consistent across all age groups Sensor accuracy was not affected by rapid increases in BG levels Sensor performance during rapid glucose changes met ISO criteria for 51-72% of SG readings

13. Barbara Davis Center –H. Peter Chase –Rosanna Fiallo-Scharer –Jennifer Fisher University of Iowa –Eva Tsalikian –Michael Tansey –Linda Larson Nemours Children’s Clinic –Tim Wysocki –Nelly Mauras –Kristen Gagnon Stanford University –Bruce Buckingham –Darrell Wilson –Jennifer Block Yale University –William Tamborlane –Stuart Weinzimer –Elizabeth Boland Jaeb Center for Health Research –Roy Beck –Katrina Ruedy –Craig Kollman –Andrea Booth –Gladys Bernett

14. Abstract Mealtime Glycemic Excursions in Pediatric Subjects with Type 1 Diabetes Mellitus (T1DM): the DirecNet Experience Stuart Weinzimer 1, Roy Beck 2, Katrina Ruedy 2, Andrea Booth 2, Elizabeth Boland 1, and the Diabetes Research in Children Network (DirecNet) Study Group. 1 Department of Pediatrics, Yale University School of Medicine, New Haven, CT and 2 Jaeb Center for Health Research, Tampa, FL. Background: DirecNet is a multi-center network whose aim is to study glucose sensing systems in children with T1DM. A meal protocol, in which a standard carbohydrate load was administered to test the accuracy of these sensors during changing blood glucose (BG) conditions, provided the opportunity to study the magnitude and timing of hyperglycemic excursions in children with T1DM. Objective: To describe the BG excursions in children with T1DM after a standard meal challenge and determine their relationship to patient factors. Design/Methods: 82 subjects with T1DM (41F, 41M, mean age 10  4 y [range 3-17 y]) were admitted to the CRC for metabolic monitoring. After oral ingestion of a standard liquid simple carbohydrate meal (1.75 gm/kg, maximum 75 gm), venous BG measurements were obtained at baseline and every 5 minutes for up to 60 minutes. Subjects using multiple daily injections (MDI) delayed their insulin injection, and pump subjects continued basal insulin delivery but delayed bolus insulin, until meal test completion. Results: BG increased from a mean baseline of 148  65 mg/dL to a peak of 283  78 mg/dL. Mean time to peak BG was 56  9 min. Among subjects who increased at least 100 mg/dL or 100% from baseline (N=62), mean rate of rise of BG was 3.4  1.1 mg/dL-min from start of increase to peak glucose. Magnitude of time to glucose peak, and rate of change of blood glucose were similar comparing the MDI and insulin pump-treated subjects. Conclusions: This standardized carbohydrate load induced a large hyperglycemic excursion, which was relatively consistent across all age groups and treatment modalities. Notably, the timing of BG rise was slower than anticipated, particularly in the first 15 minutes, which has important therapeutic implications regarding conventional treatment of hypoglycemia in T1DM with oral carbohydrates.