Novel use of glucagon in a closed-loop system for prevention of hypoglycemia in type 1 diabetes

Abstract

Objective: To minimize hypoglycemia in subjects with type 1 diabetes by automated glucagon delivery in a closed-loop insulin delivery system.

Research design and methods: Adult subjects with type 1 diabetes underwent one closed-loop study with insulin plus placebo and one study with insulin plus glucagon, given at times of impending hypoglycemia. Seven subjects received glucagon using high-gain parameters, and six subjects received glucagon in a more prolonged manner using low-gain parameters. Blood glucose levels were measured every 10 min and insulin and glucagon infusions were adjusted every 5 min. All subjects received a portion of their usual premeal insulin after meal announcement.

Results: Automated glucagon plus insulin delivery, compared with placebo plus insulin, significantly reduced time spent in the hypoglycemic range (15 +/- 6 vs. 40 +/- 10 min/day, P = 0.04). Compared with placebo, high-gain glucagon delivery reduced the frequency of hypoglycemic events (1.0 +/- 0.6 vs. 2.1 +/- 0.6 events/day, P = 0.01) and the need for carbohydrate treatment (1.4 +/- 0.8 vs. 4.0 +/- 1.4 treatments/day, P = 0.01). Glucagon given with low-gain parameters did not significantly reduce hypoglycemic event frequency (P = NS) but did reduce frequency of carbohydrate treatment (P = 0.05).

Conclusions: During closed-loop treatment in subjects with type 1 diabetes, high-gain pulses of glucagon decreased the frequency of hypoglycemia. Larger and longer-term studies will be required to assess the effect of ongoing glucagon treatment on overall glycemic control.

Figure 1

Study diagram depicting the number of subjects studied under each condition and the study lengths.

Figure 2

Example of data taken from a closed-loop study. Venous blood glucose is noted by black diamonds, insulin delivery rate by a gray line, and glucagon delivery rate by rectangles. Note that glucagon is delivered by algorithm in the late postprandial period at times of impending hypoglycemia. Overt hypoglycemia is avoided without the use of carbohydrate supplementation.

Figure 3

Summary of glucose levels (means ± SE), insulin delivery rate, and, for glucagon studies, the glucagon delivery rate. Venous blood glucose is noted by gray diamonds, insulin delivery rate by a black line, glucagon delivery rate by a light gray line, and meals by black triangles. A: Composite of eight insulin plus placebo studies. B: Composite of seven insulin plus high-gain glucagon studies. Insulin delivery and overall glycemic control were similar in both conditions.