Mitigating Reductions in Glucose During Exercise on Closed-Loop Insulin Delivery: The Ex-Snacks Study.

OBJECTIVE: To assess whether snacking could be used with closed-loop (CL) insulin delivery to avoid exercise-induced reductions in plasma glucose (PG), as well as elevations in PG at the end of exercise. RESEARCH DESIGN AND METHODS: Twelve type 1 diabetes (T1D) subjects (age 13-36 years, duration 10.7 ± 8.4 years, A1c 7.4% ± 0.8% [57 ± 8.7 mmol/mol]) underwent two 105-min exercise studies while under CL control: CL alone and CL+snack. Exercise, commenced at 3 PM, consisted of four 15-min periods of brisk treadmill walking to 65%-70% HRmax (separated by three 5-min rest periods), followed by a 30-min recovery period. Fifteen to 30 g carbohydrate (Gatorade) was provided on snacking visits just before and midway through the exercise period. PG and insulin were measured every 15-20 min during the exercise studies. RESULTS: Baseline PG levels were similar for CL alone (164 ± 16 mg/dL) versus CL+snack (172 ± 11 mg/dL). During exercise, PG levels fell by 53 ± 10 mg/dL without snacking versus a modest 10 ± 13 mg/dL increase in PG with snacking (P = 0.0005); similar differences in the change in PG levels were observed at the end of recovery period. Hypoglycemia requiring rescue treatment (PG ≤60 mg/dL) during exercise occurred in three nonsnacking visits versus none with snacking. During the 75-min exercise period, insulin delivered was 1.8 ± 0.4 U for the CL+snack admission compared to 0.7 ± 0.1 U during CL alone (P = 0.002). CONCLUSION: These results support the use of a simple snacking strategy to avoid exercise-induced lowering of PG while on CL insulin delivery. Persistent insulin infusion during exercise with snacking also appears to be effective in limiting increases in PG at the end of exercise.

Mitigating Meal-Related Glycemic Excursions in an Insulin-Sparing Manner During Closed-Loop Insulin Delivery: The Beneficial Effects of Adjunctive Pramlintide and Liraglutide.

OBJECTIVE: Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-µg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration. RESEARCH DESIGN AND METHODS: Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7.2 ± 0.6% [55 ± 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-µg pramlintide (CL + P), after a 3-4-week outpatient dose escalation. Eleven subjects (age 18-27 years; A1C 7.5 ± 0.9% [58 ± 9.8 mmol/mol]) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3-4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced. RESULTS: Pramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose. CONCLUSIONS: Adjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed.

Faster in and faster out: accelerating insulin absorption and action by insulin infusion site warming.

OBJECTIVE: This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch(40)(™) (IP(40)) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes. SUBJECTS AND METHODS: Seventeen subjects with type 1 diabetes (age, 15±1 years; hemoglobin A1c, 7.5±0.2% [58±2.2 mmol/mol]) underwent two euglycemic clamps performed on separate mornings with and without IP(40) activation with warming temperature at 40°C. On both days, the basal infusion was suspended, and glucose levels were maintained between 90 and 100 mg/dL by a variable rate dextrose infusion for up to 5 h after a 0.2 U/kg bolus of insulin aspart. RESULTS: Time to peak insulin action and time to half-maximal action occurred earlier with a greater early glucodynamic effect (area under the curve [AUC] for glucose infusion rate from 0 to 30 min) with IP(40) than without the IP(40), whereas the AUC for the time-action profile and the peak action did not differ with and without infusion site warming. PK parameters were in agreement with PD parameters, namely, a significantly earlier time to reach the maximum increment in insulin concentrations and greater early bioavailability (AUC for the change in insulin concentration from 0 to 30 min) with the IP(40). The tail of the plasma insulin response curve was also shortened with infusion site warming, with the time to reach baseline insulin concentration occurring significantly earlier (P=0.04). CONCLUSIONS: Our data demonstrate that skin warming around the infusion site to 40°C with the IP(40) is an effective means to accelerate absorption and action of rapid-acting insulin. These improvements in time-action responses have the potential to enhance the performance of open- and closed-loop insulin delivery systems.