For all people with type 1 diabetes, managing their disease is a daily challenge. As of 2000 an estimated 17.1 million people were afflicted with type 1 diabetes [4, 11], with a clear rising trend in the incidence of the disease [6]. The associated cost of the disease is staggering [1, 5]. Starting with the Diabetes Control and Complications Trial [3], the accumulated clinical evidence is that blood glucose levels must be normalized in order to prevent the complications associated with diabetes [2]. Maintaining normoglycemia entails frequent monitoring of blood glucose levels, together with frequent adjustments to the treatment strategy, including changing insulin dosing, meal composition, and exercise routines.

One of the components for normalizing blood glucose is determining and using the correct dosing of insulin to cover the carbohydrate content of meals. The insulin–to–carbohydrate ratio is not a fixed ratio; it depends on the time of day, and will change as the person’s insulin sensitivity changes due to myriad different factors, such as levels of physical activity and stress. We have previously tested a run–to–run control strategy to adjust this ratio based on post–meal blood glucose measurements [8, 12]. Based on the clinical trial results of this version, we have proposed an improved strategy [9].

The initial development was performed using a mathematical model of type 1 diabetes [7] to test the new run–to–run strategy [10]. The new algorithm calls for a pre–meal blood glucose test to serve as a heuristic screening that allows the algorithm to make an adjustment. If the blood glucose is outside a reasonable range, roughly 70-130 mg/dl, then the response to the meal bolus will be affected by other factors that cannot be measured, such as a hormonal counter–regulatory response to hypoglycemia. The performance measure was then calculated from two post–meal blood glucose measurements; the first one taken 60-90 minutes after the start of the meal, the second one 30-60 minutes after the first glucose measurement.

Preliminary clinical data were gathered in accordance with the proposed algorithm timing for several individuals. From an initial evaluation of a set of 35 meals from the subjects participating in the trial, it was clear that the new performance measure would not be the optimal solution. In some cases the correction the algorithm would take was not sufficient, in others it was too aggressive and even in a few cases headed in the wrong direction. The reason this did not show up in our simulation study was that the model describing the absorption of glucose from a mixed meal is not detailed enough, leading to a critical model mismatch.

The only way to guarantee good performance in the clinical trail was to define a new performance measure for the run–to–run algorithm. To this end, the preliminary clinical data was analyzed, and, with the clinical expertise in our group, a new performance measure was determined. The performance measure now uses the pre–meal blood glucose measurement in conjunction with the two post–meal determinations. From these, it estimates the blood glucose at 60 minutes after the start of the meal, as well as the deviation between the pre–meal and second post–meal measurements. Other possibilities were tested, but this one is the one that correlated the best with the clinical recommendations for dose adjustment. An added benefit of this new measure is that now the algorithm does not require any meal information for its calculations, which the original implementation did require.

As part of the clinical influence on the run–to–run algorithm implementation, further heuristics were incorporated. Under certain conditions, when an increase in the insulin dose could result in hypoglycemia, a reduction in the meal’s carbohydrate content is recommended instead of changing the dosing. Special handling of the correction is also taken when the post–meal measurements show hypoglycemia (defined as a blood glucose below 60 mg/dl for our purposes), thus adding a level of safety to the algorithm.

Our preliminary clinical trial results using this new measure for the run–to–run algorithm are quite satisfactory. In general convergence to a dose that results in clinically satisfactory post–meal blood glucose levels is achieved in three to four days. As part of the clinical trial protocol the physicians must approve the dosing recommended by the algorithm before the subjects make the change. In a few cases the physicians have overridden the algorithm; in several of the cases they did so for safety, the results the following day proved that the algorithm was right on target in its initial recommendation. Currently, the algorithm is undergoing further clinical testing.

This work was supported by the National Institutes of Health, grants R01-DK068706, R01-DK068663.

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