Abstract Objective: Intensive insulin management (IIM) improves glycemic control, and lowers the risks of long-term microvascular complications. In children, the use of insulin Glargine for IIM has been limited by the shorter period of action (<24h), and the need for additional insulin injections. We determined the short term effects of mixing insulin Glargine with short acting insulin (SAI), and dividing the dose into twice daily, on glycemic control in children with type 1 diabetes (T1DM). Methods: Subjects with T1DM who were receiving glargine were studied on three different occasions. At baseline (Study B), subjects administered one dose of glargine and received 3 SAI injections. Subjects were then randomized to Study Mix and Study Separate (Sep). Study Mix:10 days of administration of a divided dose of Glargine into two halves given mixed with SAI twice daily and a lunch SAI. Study Sep was similar to Study Mix, except Glargine and SAI were given as separate injections. Glycemic control was evaluated using the CGMS® on final 3 days of each regimen. Results: 13 subjects (6M/7F, 13.5  0.5 y, 22.4  1.0 kg/m2, hemoglobinA1c of 7.7  0.2% and T1DM duration 44  8 mo) were studied. Mean 24h glucose was 9.3  1.3 mmol/l, 8.3  1.1 mmol/l and 9.3  1.3 mmol/l for study B, Mix, and Sep respectively (p <0.6). Conclusion: Mixing insulin Glargine with SAI does not affect glucose excursions. This will simplify the use of Glargine, decrease additional injections of insulin, and make IIM therapy in children more realistic.

Background Insulin Glargine is: A long acting, and “peakless” insulin. Cannot be mixed with other insulin analogs. Widely used in insulin intensive management (IIM). Major drawbacks to its use in pediatric patients are: Duration of effect < 24h. Requirement for multiple injections.

Background Mixing insulin Glargine with Regular insulin in healthy dogs did not affect the glucose lowering activity1. The effect of mixing insulin Glargine with short acting insulin analogs has not been evaluated in humans.

Objective Evaluate the effect of mixing insulin Glargine with short acting insulin analogs on glycemic control in adolescents with type 1 diabetes (T1D). Compare the glycemic control of insulin Glargine given twice a day versus once daily.

HYPOTHESIS In adolescents with T1D, mixing insulin Glargine with short acting insulin analogs, or dividing the dose to twice a day does not worsen glycemic control

Inclusion Criteria: 10-17 yr. Type I diabetes > 1yr. A1C < 9.0% Already on IIM therapy. No other chronic illnesses. No other medications.

Study Design Subjects were studied 1. At baseline, on their current insulin regimen (once a day Glargine). 2. Then in random order on: Mixing injection: insulin Glargine dose was divided into two halves and given before breakfast and before dinner, mixed in the same syringe with the short acting insulin. Separate injections: same as the mixing, except that Glargine and short acting insulin were administered separately. Glucose concentrations measured for 72h using the CGMS Medtronic MiniMed®.

STUDY DESIGN Enrollment Mixed injection Mixed injection 3 days 7 days Randomize Cross over Baseline Separate injection Separate injection Baseline : Glargine once daily, and (Lispro or Aspart) with meals. Mix & Separate : Glargine dose is divided into 2 equal doses, given before breakfast and before dinner, either mixed with the short acting insulin (Mix), or in separate syringes with separate injections (Separate).

DATA ANALYSIS Repeated measures ANOVA was used to determine the effects of treatment order of treatment and their interaction

Results: Subjects characteristics N 13 Age (yr)* 13.5 ± 1.6 Gender (M/F) 7/6 BMI (kg/m² )* 22.4 ± 1 Duration of DM (mo.)* 44 ± 28 A1C (%)* 7.7 ± 0.7 * (Mean ± SD)

Glucose concentrations* every 20 minutes Base Separate Mix 100 200 300 Glucose mg/dl P<0.6 24:00 06:00 12:00 18:00 24:00 * Mean ± SEM

Glucose concentration* for 24h and 72h P<0.6 200 200 150 150 mg/dl 100 100 50 50 72h 200 200 P<0.3 150 150 mg/dl 100 100 50 50 Base Separate Mix * Mean ± SEM

Pre-prandial and post-prandial glucose* Pre meals 100 200 mg/dl Base Mix Separate Post meals 100 200 Breakfast Lunch Dinner mg/dl * Mean ± SEM

Percentage of Hypoglycemic Episodes Baseline - 5% Mixing- 9% Separate injections-2% (p<0.8)

SUMMARY There was no difference among the three studies regarding: 24h or 72h average glucose concentrations. Number of hypoglycemic episodes. Pre-prandial or post-prandial glucose concentrations.

CONCLUSION Mixing insulin Glargine with short acting insulin analogs in adolescents with T1D: Does no compromise glycemic control Does not increase hypoglycemic episodes. Simplifies IIM therapy, which could result in improve compliance and control.

Reference 1: Werner U, Gerlach M, Hofmann M, et al. Mixture of regular human insulin and insulin glargine injected subcutaneously in healthy dogs does not increase risk of hypoglycemia. Diabetes 2002; 51(suppl 2):A296