Autonomous and continuous adaptation of a bihormonal bionic pancreas in adults and adolescents with type 1 diabetes

Abstract

Context: A challenge for automated glycemic control in type 1 diabetes (T1D) is the large variation in insulin needs between individuals and within individuals at different times in their lives.

Objectives: The objectives of the study was to test the ability of a third-generation bihormonal bionic pancreas algorithm, initialized with only subject weight; to adapt automatically to the different insulin needs of adults and adolescents; and to evaluate the impact of optional, automatically adaptive meal-priming boluses.

Design: This was a randomized controlled trial.

Setting: The study was conducted at an inpatient clinical research center.

Patients: Twelve adults and 12 adolescents with T1D participated in the study.

Interventions: Subjects in each age group were randomized to automated glycemic control for 48 hours with or without automatically adaptive meal-priming boluses.

Main outcome measures: Mean plasma glucose (PG), time with PG less than 60 mg/dL, and insulin total daily dose were measured.

Results: The 48-hour mean PG values with and without adaptive meal-priming boluses were 132 ± 9 vs 146 ± 9 mg/dL (P = .03) in adults and 162 ± 6 vs 175 ± 9 mg/dL (P = .01) in adolescents. Adaptive meal-priming boluses improved mean PG without increasing time spent with PG less than 60 mg/dL: 1.4% vs 2.3% (P = .6) in adults and 0.1% vs 0.1% (P = 1.0) in adolescents. Large increases in adaptive meal-priming boluses and shifts in the timing and size of automatic insulin doses occurred in adolescents. Much less adaptation occurred in adults. There was nearly a 4-fold variation in the total daily insulin dose across all cohorts (0.36-1.41 U/kg · d).

Conclusions: A single control algorithm, initialized only with subject weight, can quickly adapt to regulate glycemia in patients with TID and highly variable insulin requirements.

Figures

Figure 1.

Each panel shows cumulative plots of 48-hour and night PG and 48-hour and night CGMG. A, Cumulative plots for adults with AMB, in which 4.8% of the 48-hour PG was 70 mg/dL or less, 80.1% within 70–80 mg/dL (1.2% and 88.4% for CGMG), and 7.1% of night PG was 70 mg/dL or less, 92.1% within 70–80 mg/dL (0.9% and 96.7% for CGMG). B, Cumulative plots for adolescent subjects with AMB, in which 0.3% of the 48-hour PG was 70 mg/dL or less, 68.4% within 70–80 mg/dL (0.2% and 70.7% for CGMG), and 0.5% 0% of night PG 70 mg/dL or less, 95.2% within 70–80 mg/dL (0% and 95.7% for CGMG). C, Cumulative plots for adults with NMB, in which 4% of the 48-hour PG was 70 mg/dL or less, 69.1% within 70–80 mg/dL (2% and 76.1% for CGMG), and 5.8% of night PG 70 mg/dL or less, 93.9% within 70–80 mg/dL (2% and 97.9% for CGMG). D, Cumulative plots for adolescent subjects with NMB, in which 0.4% of the 48-hour PG was 70 mg/dL or less, 59.6% within 70–80 mg/dL (0.3%, 62.7% for CGMG), and 0.3% of night PG 70 mg/dL or less, 93.9% within 70–80 mg/dL (0.3% and 95.2% for CGMG).

Figure 2.

A, Forty-eight-hour mean PG trace (PG sampled every 15 min) for adults with AMB (solid line) superimposed on a trace for adolescent subjects with AMB (dashed line). The six meals are indicated by black triangles. B, Forty-eight -hour mean CGMG trace (CGMG sampled every 5 min) that provided the input for the closed-loop control algorithm. C, Superposition of the means of sc insulin-glucagon doses (including priming insulin doses, indicated by downward arrows) administered by the closed-loop system in response to CGMG in panel B. D and E, Superposition of mean plasma insulin and glucagon levels, respectively. Notice the higher PG and CGMG for adolescent subjects relative to adults in both panels A and B, despite a higher insulin dosing (C) and corresponding higher plasma insulin levels (D) as well as lower glucagon dosing (C) and corresponding lower plasma glucagon levels (E). Although the system's dosing per kilogram of body mass was the same at initialization, it automatically increased its insulin dosing more for adolescent subjects than adults (B) and achieved better control by the second day in both cases. These plots broken out across the adult and adolescent AMB subgroups are shown are Supplemental Figures 26 and 28.

Figure 3.

A, Forty-eight -hour mean PG trace (PG sampled every 15 min) for adults with NMB (solid line) superimposed on a trace for adolescent subjects with NMB (dashed line). The six meals are indicated by black triangles. B, Forty-eight -hour mean CGMG trace (CGMG sampled every 5 min) that provided the input for the closed-loop control algorithm. C, Superposition of the means of sc insulin-glucagon doses (including priming insulin doses, indicated by downward arrows) administered by the closed-loop system in response to CGMG in panel B. D and E, Superposition of mean plasma insulin and glucagon levels, respectively. Notice the higher PG and CGMG for adolescent subjects relative to adults in both panels A and B, despite higher insulin dosing (C) and corresponding higher plasma insulin levels (D) as well as lower glucagon dosing (C) and corresponding lower plasma glucagon levels (E). Although the system's dosing per kilogram of body mass was the same at initialization, it automatically increased its insulin dosing more for adolescent subjects than adults (B) and achieved better control by the second day in both cases. These plots broken out across the adult and adolescent NMB subgroups are shown are Supplemental Figures 27 and 29. Note that subject 283 (Supplemental Figure 8) has very high antiinsulin antibody levels, which appear to interfere with the insulin immunoassay. This results in extremely high measured insulin levels and shifts the overall mean for the adult NMB group upward, explaining why the mean insulin levels in the adult NMB cohort are higher than in the adolescent NMB cohort despite higher dosing in the adolescent cohort.

Figure 4.

Glycemic control quantities relating to the times around the six meals, ordered as first dinner (D1), first breakfast (B1), first lunch (L1), second dinner (D2), second breakfast (B2), and second lunch (L2). For each meal, the bar on the left relates to adults and the one on the right relates to adolescent subjects. Each of the six meals is assigned a reference symbol: †, D1; *, B1; $, L1; ‡, to D2; **, B2; and $$, L2. The appearance of any meal symbol above a bar pertaining to any of the other five meals for the same age group indicates a statistically significant difference (P < .5) in the values of the represented quantity for those two meals. The appearance of a square brace above any pair of bars indicates a statistically significant difference in the values of the represented quantities for that meal between the adult and adolescent cohorts. A, Average size of adaptive meal boluses. B and E, Four-hour postprandial insulin with AMB and NMB, respectively. C and F, Four-hour CGMG postprandial AUC with AMB and NMB, respectively. D and G, Peak postprandial PG with AMB and NMB, respectively.