Control to range for diabetes: functionality and modular architecture

Abstract

Background: Closed-loop control of type 1 diabetes is receiving increasing attention due to advancement in glucose sensor and insulin pump technology. Here the function and structure of a class of control algorithms designed to exert control to range, defined as insulin treatment optimizing glycemia within a predefined target range by preventing extreme glucose fluctuations, are studied.

Methods: The main contribution of the article is definition of a modular architecture for control to range. Emphasis is on system specifications rather than algorithmic realization. The key system architecture elements are two interacting modules: range correction module, which assesses the risk for incipient hyper- or hypoglycemia and adjusts insulin rate accordingly, and safety supervision module, which assesses the risk for hypoglycemia and attenuates or discontinues insulin delivery when necessary. The novel engineering concept of range correction module is that algorithm action is relative to a nominal open-loop strategy-a predefined combination of basal rate and boluses believed to be optimal under nominal conditions.

Results: A proof of concept of the feasibility of our control-to-range strategy is illustrated by using a prototypal implementation tested in silico on patient use cases. These functional and architectural distinctions provide several advantages, including (i) significant insulin delivery corrections are only made if relevant risks are detected; (ii) drawbacks of integral action are avoided, e.g., undershoots with consequent hypoglycemic risks; (iii) a simple linear model is sufficient and complex algorithmic constraints are replaced by safety supervision; and (iv) the nominal profile provides straightforward individualization for each patient.

Conclusions: We believe that the modular control-to-range system is the best approach to incremental development, regulatory approval, industrial deployment, and clinical acceptance of closed-loop control for diabetes.

Figure 1.

Modular architecture of control to range. The real-time layer corresponds to the RCM, and the continuous time layer corresponds to the SSM.

Figure 2.

Open-loop glycemic regulation in nominal conditions. Open-loop therapy consisting of basal insulin and premeal boluses proportional to meal amounts was optimized via trial-and-error experiments on the virtual patient. Regulation is satisfactory as it maintains glycemia within the range.

Figure 3.

Control-to-range vs open-loop glycemic regulation under perturbed meals. Closed-loop control starts at 13:00. Actual meals (blue dots) differ from nominal ones so that the open-loop therapy is no more optimal. Then, the RCM applies corrections in order to achieve a faster recovery of glycemic regulation within the range. The first two meals are greater than nominal, leading to administration of additional insulin. Because the control to range relies on nominal open-loop therapy, after the first two meals the initial rise of glycemia is similar to that observed in open loop. However, the RCM reacts and gives supplementary insulin so that recovery of within-range glycemia is faster than in open loop. This faster recovery is less evident after the first meal because closed-loop regulation is initiated at 13:00, when the glycemic peak has already been reached. The second meal is entirely under closed-loop regulation, and recovery within the range is therefore faster. The third meal is smaller than the nominal one and is delayed by 30 minutes. To cope with this perturbation, the RCM decreases the insulin basal value temporarily. On two occasions, a risk for hypoglycemia is detected and the SSM enforces attenuation of insulin delivery (red line, bottom).

Figure 4.

Control-to-range vs open-loop glycemic regulation under nominal meals and perturbed insulin sensitivity. Closed-loop control starts at 13:00. Insulin sensitivity is 25% higher than nominal; consequently the open loop fails to prevent hypoglycemia. RCM and SSM act to maintain glycemic regulation within the range. On three occasions, risks for hypoglycemia are detected and the SSM further enforces attenuation of insulin delivery (red line, bottom). Between 20:00 and 22:30 insulin delivery is decreased compared to the nominal open-loop basal one. This explains the glucose peak around midnight and, as a consequence, the higher glucose profile during all night leading to the 125-mg/dl fasting glucose, even if nocturnal closed-loop insulin delivery does not differ from the open-loop basal.

Figure 5.

Control-to-range vs open-loop glycemic regulation under perturbed meals and perturbed insulin sensitivity. Closed-loop control starts at 13:00. Insulin sensitivity is 25% higher than nominal. The first two meals are greater than nominal, which counterbalances the reduction in insulin sensitivity and helps open-loop control maintain glycemia within the range. Nevertheless, it cannot avoid a severe hypoglycemia after the third meal, which is smaller than nominal and delayed by 30 minutes. The joint action of the RCM and SSM achieves effective glycemic regulation. In particular, when risk for hypoglycemia is detected on three occasions, the SSM prevents possible hypoglycemia.