Abstract

1. Stopping Basal Insulin during Exercise Markedly Reduces the Risk of Hypoglycemia in Children with Type 1 Diabetes on Insulin Pump TherapySupported by NIH/NICHD Grants HD041919,HD041915,HD041890,HD041918,HD041908, HD041906; GCRC Grants RR00069,RR00059,RR06022,RR00070 Michael Tansey,1Eva Tsalikian,1 Roy W. Beck,2 Rosanna Fiallo-Scharer,3 Kathleen Janz,1 Larry Fox,4 Darrell Wilson,5 Stuart Weinzimer,6 William Tamborlane,6 Michael Steffes,7Dongyuan Xing,2 Katrina Ruedy2 and the Diabetes Research in Children Network (DirecNet) Study Group. 1Iowa City, IA; 2Tampa, FL; 3Denver, CO; 4Jacksonville, FL; 5Stanford, CA; 6New Haven, CT; 7Minneapolis, MN

2. Abstract Aerobic exercise is an important component of T1D management, but fear of hypoglycemia often deters children from getting the recommended amounts of exercise. Strategies for preventing hypoglycemia during exercise in children with T1D have not been well studied. To evaluate the effect of basal insulin on exercise induced hypoglycemia, DirecNet conducted a study of 49 children 8-17y with T1D on insulin pumps. Frequently sampled blood glucose (BG) concentrations (measured in the DirecNet Central Laboratory) were compared during exercise with and without basal insulin using a randomized, crossover design. Baseline BG concentrations were managed to remain within a target range of 120-200mg/dL. Each exercise session, performed from ~4-5 p.m., consisted of four 15min treadmill cycles at a target heart rate of 140 bpm interspersed with three 5min rest breaks over 75min. Hypoglycemia (≤70mg/dL) during exercise was significantly reduced when the basal insulin was discontinued. Hypoglycemia occurred only on the basal-continued visit in 15 subjects (31%), only on the basal-stopped visit in 2 (4%), on both visits in 6 (12%), and on neither visit in 26 (53%). Hyperglycemia (BG >200mg/dL) was present at the end of exercise in 1 subject (2%) on the basal-continued visit and in 6 (12%) on the basal-stopped visit (p=0.12). Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with T1D, but the risk of hyperglycemia may be increased.

3. Background • There are many benefits of exercise in patients with type 1 diabetes (T1DM) • Many children with T1DM participate in organized physical activity • Exercise is associated with an increased risk of hypoglycemia in patients with diabetes who take insulin • Patients using insulin pumps can alter their basal rates around periods of activity

4. Study Aims • Primary aim: • To determine the effects of continuing or discontinuing the basal rate upon the risk of hypoglycemia around structured exercise • Secondary aims: • Determine the effect of basal rate on or off upon the risk for hyperglycemia

5. Study Protocol • 2 CRC admissions (~7 hour stays) 1-4 weeks apart, crossover design • Conditions: • Both admissions with exercise sessions between 4-6PM • Same lunch meals and bolus insulin doses for both admissions • Basal insulin on (basal-continued)oroff (basal-stopped) during exercise • Baseline BG concentrations were managed to remain within a target range of 120-200 mg/dL prior to exercise. • Pump was turned off at the beginning of one of the exercise sessions and re-started 45 minutes post-exercise (off for approximately 2 hours) • Glucose measurements every 20 minutes during exercise and every 15 minutes for 45 minutes following exercise

6. Study Protocol • If during exercise the blood glucose dropped to ≤65 mg/dL, the subject was given 15-30g of carbohydrate and rechecked after 5 to 15 minutes • Exercise did not resume until the blood glucose was >70 mg/dL • Prior to starting and at the completion of the exercise session, urine ketones were checked and blood ketones were checked by fingerstick using a Precision XtraTM meter

7. Exercise Protocol Five minute rest periods Treadmill Exercise Exercise Exercise Exercise 0 15 20 35 40 55 60 75 90 105 120 TIME (minutes) ON or OFF basal insulin Exercise at ~55% maximum effort (VO2max): Target heart rate of 140 beats/minute

8. Patient Demographics

9. Results • Baseline plasma glucose concentrations prior to the start of the exercise measured at the central laboratory ranged from 115 to 230 mg/dL (all but one of the Freestyle values were within the specified range of 120 to 200 mg/dL). • Baseline values were similar on basal-continued and basal-stopped visits (mean ± SD = 156 ± 27 vs. 161 ± 24 mg/dL; P=0.30). • Blood and urine ketone levels remained suppressed during and after exercise • None of the subjects during the basal-stopped study required more than one carbohydrate snack vs. one-third of the subjects during the basal-continued study

10. Treatment for Hypoglycemia

11. Reductions in Glucose and hypoglycemia during/following Exercise (mg/dL;N (%) ormean ± SD) a – Baseline glucose minus nadir b – Glucose Drop divided by baseline glucose (expressed as a percentage) c – Glucose ≤70 mg/dL d – Includes 2 visits (1 basal-stopped and 1 basal-continued) where treatment was given for hypoglycemia based on a meter glucose value, but the central laboratory value was >70 mg/dL (85 and 71 mg/dL) P=0.001 for analysis restricted to laboratory confirmed cases e –Glucose ≥200 mg/dL and ≥20% increase from baseline

12. Glucose during Exercise (mg/dL) Baseline Rest #1 Rest #2 Rest #3 End Post 15 Post 30 Post 45 Figure 1. Median Glucose Concentrations during/following Exercise (N=98 visits from 49 subjects) Black dots denote mean values and boxes denote median, 25th and 75th percentiles.

13. Figure 2A. Glucose Concentrations at Baseline Level vs Nadir Glucose During Exercise (N=98 visits from 49 subjects) The nadir glucose concentration during exercise (A) and glucose concentration 45 minutes after completion of exercise (B) are shown by baseline level. Dashed lines denote the hypo- and hyperglycemia thresholds of 70 and 200 mg/dL, respectively. Note different scales on the horizontal and vertical axes.

14. Figure 2B. Glucose Concentrations by Baseline Level vs 45 minute Post-Exercise (N=98 visits from 49 subjects) The nadir glucose concentration during exercise (A) and glucose concentration 45 minutes after completion of exercise (B) are shown by baseline level. Dashed lines denote the hypo- and hyperglycemia thresholds of 70 and 200 mg/dL, respectively. Note different scales on the horizontal and vertical axes.

15. Conclusions • The risk of hypoglycemia occurring during the exercise period is reduced by stopping the basal insulin infusion at the start of exercise. However, this did not completely eliminate the risk of hypoglycemia in the basal-stopped group. • Treatment for hypoglycemia was rarely required if the pre-exercise plasma glucose level was >130 mg/dL • The response to treatment of hypoglycemia was more effective under basal-stopped conditions

16. Conclusions (cont’d) • Stopping the basal insulin infusion just prior to starting a prolonged period of moderate aerobic exercise is a safe and effective means of markedly reducing the risk of hypoglycemia, especially if pre-exercise glucose levels are >130 mg/dl. • The risk of becoming hyperglycemic may increase when suspension of the basal insulin infusion rate extends beyond 75 minutes.

17. Therapeutic Implications • Check glucose pre-exercise and: • Take 15-30 gms of CHO if glucose is <130 mg/dl • Take small correction dose if glucose is >200 mg/dl • Suspend or disconnect pump during exercise • Recheck glucose after 60-90 min and reconnect or give bolus if glucose levels have increased above pre-exercise values

18. Stanford University • Bruce Buckingham • Darrell Wilson • Jennifer Block • Paula Clinton • Yale University • William Tamborlane • Stuart Weinzimer • Elizabeth Doyle • Kristen Sikes • Amy Steffen • Jaeb Center for Health Research • Roy Beck • Katrina Ruedy • Craig Kollman • Dongyuan Xing • Cynthia Stocldale • Barbara Davis Center • H. Peter Chase • Rosanna Fiallo-Scharer • Laurel Messer • Barbara Tallant • University of Iowa • Eva Tsalikian • Michael Tansey • Kathleen Janz • Linda Larson • Julie Coffey • Joanne Cabbage • Nemours Children’s Clinic • Tim Wysocki • Nelly Mauras • Larry Fox • Keisha Bird • Kim Englert

19. Jaeb Center for Health Research