Model-based sensor-augmented pump therapy.

BACKGROUND: In insulin pump therapy, optimization of bolus and basal insulin dose settings is a challenge. We introduce a new algorithm that provides individualized basal rates and new carbohydrate ratio and correction factor recommendations. The algorithm utilizes a mathematical model of blood glucose (BG) as a function of carbohydrate intake and delivered insulin, which includes individualized parameters derived from sensor BG and insulin delivery data downloaded from a patient's pump. METHODS: A mathematical model of BG as a function of carbohydrate intake and delivered insulin was developed. The model includes fixed parameters and several individualized parameters derived from the subject's BG measurements and pump data. Performance of the new algorithm was assessed using n = 4 diabetic canine experiments over a 32 h duration. In addition, 10 in silico adults from the University of Virginia/Padova type 1 diabetes mellitus metabolic simulator were tested. RESULTS: The percentage of time in glucose range 80-180 mg/dl was 86%, 85%, 61%, and 30% using model-based therapy and [78%, 100%] (brackets denote multiple experiments conducted under the same therapy and animal model), [75%, 67%], 47%, and 86% for the control experiments for dogs 1 to 4, respectively. The BG measurements obtained in the simulation using our individualized algorithm were in 61-231 mg/dl min-max envelope, whereas use of the simulator's default treatment resulted in BG measurements 90-210 mg/dl min-max envelope. CONCLUSIONS: The study results demonstrate the potential of this method, which could serve as a platform for improving, facilitating, and standardizing insulin pump therapy based on a single download of data.

Closed-loop insulin delivery utilizing pole placement to compensate for delays in subcutaneous insulin delivery.

BACKGROUND: We have previously used insulin feedback (IFB) as a component of a closed-loop algorithm emulating the ß cell. This was based on the observation that insulin secretion is inhibited by insulin concentration. We show here that the effect of IFB is to make a closed-loop system behave as if delays in the insulin pharmacokinetic (PK)/pharmacodynamic (PD) response are reduced. We examine whether the mechanism can be used to compensate for delays in the subcutaneous PK/PD insulin response. METHOD: Closed-loop insulin delivery was performed in seven diabetic dogs using a proportional-integral-derivative model of the ß cell modified by model-predicted IFB. The level of IFB was set using pole placement. Meal responses were obtained on three occasions: without IFB (NONE), reference IFB (REF), and 2xREF, with experiments performed in random order. The ability of the insulin model to predict insulin concentration was evaluated by correlation with the measured profile and results reported as R(2). The ability of IFB to improve the meal response was evaluated by comparing peak and nadir postprandial glucose and area under the curve (AUC; repeated measures analysis of variance with post hoc test for linear trend). RESULTS: Insulin concentration was well predicted by the model (median R(2) = 0.87, 0.79, and 0.90 for NONE, REF, and 2xREF, respectively). Peak postprandial glucose (294 ± 15, 243 ± 21, and 247 ± 16 mg/dl) and AUC (518.2 ± 36.13, 353.5 ± 45.04, and 280.3 ± 39.37 mg/dl · min) decreased with increasing IFB (p < .05, linear trend). Nadir glucose was not affected by IFB (76 ± 5.4, 68 ± 7.3, and 72 ± 4.3 mg/dl; p = .63). CONCLUSIONS: Insulin feedback provides an effective mechanism to compensate for delay in the insulin PK/PD profile.

Evaluation of the effect of gain on the meal response of an automated closed-loop insulin delivery system.

A continuous closed-loop insulin delivery system using subcutaneous insulin delivery was evaluated in eight diabetic canines. Continuous glucose profiles were obtained by extrapolation of blood glucose measurements. Insulin delivery rate was calculated, using a model of beta-cell insulin secretion, and delivered with a Medtronic MiniMed subcutaneous infusion pump. The model acts like a classic proportional-integral-derivative controller, delivering insulin in proportion to glucose above target, history of past glucose values, and glucose rate of change. For each dog, a proportional gain was set relative to the open-loop total daily dose (TDD) of insulin. Additional gains based on 0.5 x TDD and 1.5 x TDD were also evaluated (gain dose response). Control was initiated 4 h before the meal with a target of 6.7 mmol/l. At the time of the meal, glucose was similar for all three gains (6.0 +/- 0.3, 5.2 +/- 0.3, and 4.9 +/- 0.5 mmol/l for 0.5 x TDD, TDD, and 1.5 x TDD, respectively; P > 0.05) with near-target values restored at the end of experiments (8.2 +/- 0.9, 6.0 +/- 0.6, and 6.0 +/- 0.5, respectively). The peak postprandial glucose level decreased significantly with increasing gain (12.1 +/- 0.6, 9.6 +/- 1.0, and 8.5 +/- 0.6 mmol/l, respectively; P < 0.05). The data demonstrate that closed-loop insulin delivery using the subcutaneous site can provide stable glycemic control within a range of gain.