Simulation environment to evaluate closed-loop insulin delivery systems in type 1 diabetes

Abstract

Background: Closed-loop insulin delivery systems linking subcutaneous insulin infusion to real-time continuous glucose monitoring need to be evaluated in humans, but progress can be accelerated with the use of in silico testing. We present a simulation environment designed to support the development and testing of closed-loop insulin delivery systems in type 1 diabetes mellitus (T1DM).

Methods: The principal components of the simulation environment include a mathematical model of glucose regulation representing a virtual population with T1DM, the glucose measurement model, and the insulin delivery model. The simulation environment is highly flexible. The user can specify an experimental protocol, define a population of virtual subjects, choose glucose measurement and insulin delivery models, and specify outcome measures. The environment provides graphical as well as numerical outputs to enable a comprehensive analysis of in silico study results. The simulation environment is validated by comparing its predictions against a clinical study evaluating overnight closed-loop insulin delivery in young people with T1DM using a model predictive controller.

Results: The simulation model of glucose regulation is described, and population values of 18 synthetic subjects are provided. The validation study demonstrated that the simulation environment was able to reproduce the population results of the clinical study conducted in young people with T1DM.

Conclusions: Closed-loop trials in humans should be preceded and concurrently guided by highly efficient and resource-saving computer-based simulations. We demonstrate validity of population-based predictions obtained with our simulation environment.

Figure 1.

An overview of the simulation environment, which consists of a set of virtual subjects with T1DM, a glucose measurement model, and an insulin delivery model. The control algorithm resides outside the simulation environment but interacts with it.

Figure 2.

Schematic representation of the virtual population of 18 subjects with T1DM.

Figure 3.

Example of an in silico study protocol. The protocol is subdivided into sections. The first section, basic information, contains the duration and starting time of the in silico experiment, the time steps, and frequencies of various tasks such as sampling, closed-loop cycle, or logging the events. The meal section contains meal details, their timing, size (CHO contents), and whether the meal bolus should be advised by the controller. The third section, called other inputs, contains information about intravenous glucose bolus and infusion, enteral glucose infusion, and the details of rescue CHO treatment. The disturbances section provides information about any unannounced insulin bolus or meals. The system failures section includes the characteristics of system failure such as pump occlusion and the loss of sensor signal. In the starting glucose section, the user is able to specify plasma glucose at the start of the simulated experiment, while in the past insulin infusion section, insulin infusion rate prior to the start can be specified. The final two sections deal with the timing of sensor calibration and the sensor error characteristics.

Figure 4.

Sample simulated closed-loop study using a generic glucose measurement model (panel A) and experimentally derived CGM model (panel B). The red continuous curve represents simulated plasma glucose, the green squares represent simulated CGM glucose, the blue piecewise constant curve represents the insulin infusion rate, the green horizontal lines indicate the target glucose range from 3.9 to 8.0 mmol/liter, the magenta and light blue horizontal lines mark mild at 3.5 mmol/liter and significant at 2.8 mmol/liter (panel A) or severe at 2.0 mmol/liter (panel B) hypoglycemia, respectively, the magenta and blue down arrows indicate the meal and prandial insulin bolus, and the red crosses indicate the CGM calibration points.

Figure 5.

An overview of the simulation model of glucose regulation in T1DM. Model inputs include the meal intake and sc insulin delivery. Model outputs include plasma glucose and sc glucose.

Figure 6.

Protocol of simulated overnight closed-loop study.

Figure 7.

Continuous glucose monitoring glucose during simulated experiments (orange curve, N = 18) and the APCam01 clinical study (grey curve, N = 12). The horizontal dashed lines represent the target glucose range from 3.9 to 8.0 mmol/liter. Median (interquartile range) is shown.