Factors affecting the success of glucagon delivered during an automated closed-loop system in type 1 diabetes

Abstract

Background In bi-hormonal closed-loop systems for treatment of diabetes, glucagon sometimes fails to prevent hypoglycemia. We evaluated glucagon responses during several closed-loop studies to determine factors, such as gain factors, responsible for glucagon success and failure. Methods We extracted data from four closed-loop studies, examining blood glucose excursions over the 50 minutes after each glucagon dose and defining hypoglycemic failure as glucose values < 60 mg/dl. Secondly, we evaluated hyperglycemic excursions within the same period, where glucose was > 180 mg/dl. We evaluated several factors for association with rates of hypoglycemic failure or hyperglycemic excursion. These factors included age, weight, HbA1c, duration of diabetes, gender, automation of glucagon delivery, glucagon dose, proportional and derivative errors (PE and DE), insulin on board (IOB), night vs. day delivery, and point sensor accuracy. Results We analyzed a total of 251 glucagon deliveries during 59 closed-loop experiments performed on 48 subjects. Glucagon successfully maintained glucose within target (60 – 180 mg/dl) in 195 (78%) of instances with 40 (16%) hypoglycemic failures and 16 (6%) hyperglycemic excursions. A multivariate logistic regression model identified PE (p<0.001), DE (p<0.001), and IOB (p<0.001) as significant determinants of success in terms of avoiding hypoglycemia. Using a model of glucagon absorption and action, simulations suggested that the success rate for glucagon would be improved by giving an additional 0.8 mcg/kg. Conclusion We conclude that glucagon fails to prevent hypoglycemia when it is given at a low glucose threshold and when glucose is falling steeply. We also confirm that high IOB significantly increases the risk for glucagon failures. Tuning of glucagon subsystem parameters may help reduce this risk.

Closed loop insulin delivery in diabetes

“…Despite the clear theoretical advantage of having the possibility of preventing imminent hypoglycaemia with a glucagon bolus, dual-hormone closed loop does not completely eliminate the need of rescue carbohydrates administered by the patients upon a closed loop triggered alarm [51,64]. Additionally, the stability [65] and consequences of long-term subcutaneous glucagon administration are not resolved.…”

Pathway to Artificial Pancreas Systems Revisited: Moving Downstream

“…However, more research will be needed to address significant questions regarding the consequences of glucagon infusion set failure and failure of the liver to respond to glucagon. Bakhtiani et al (10) found that glucagon failed to prevent hypoglycemia and that these failures occurred more frequently when glucagon is delivered while glucose is falling rapidly, at a lower glucose threshold, and when there are high levels of insulin on board. El Youssef et al (34) demonstrated that glucagon failed to prevent hypoglycemia ;20% of the time in their initial studies.…”

“…The core elements of these AP systems will be an insulin infusion pump, a continuous glucose monitor, a control algorithm, and rapid-acting insulin analogs (in some cases, there may be a handheld control device). Reports in the literature use a wide variety of terminology (artificial pancreas, bionic pancreas, closed loop, automated insulin delivery device, and treat-to-range system [7][8][9][10][11]) because there is no, nor will there ever be, a singular AP. Rather, these systems will evolve over time to increase in automation, increase in sophistication, and increase in their ability to normalize blood glucose levels.…”

A Review of Safety and Design Requirements of the Artificial Pancreas

“…To further mimic physiologic glucose control and mitigate the risk of hypoglycemia, the use of glucagon may become an important safety measure,4,63,76 especially for fully automated systems for day and night closed-loop glucose control. For successful glucagon action, the insulin-on-board should be taken into account, as high insulin levels at the time of glucagon delivery limits the effect of glucagon 3,13. Moreover, it should not be possible that control algorithms deliver both insulin and glucagon at the same time 78.…”