Effect of Repeated Glucagon Doses on Hepatic Glycogen in Type 1 Diabetes: Implications for a Bihormonal Closed-Loop System

Abstract

Objective: To evaluate subjects with type 1 diabetes for hepatic glycogen depletion after repeated doses of glucagon, simulating delivery in a bihormonal closed-loop system.

Research design and methods: Eleven adult subjects with type 1 diabetes participated. Subjects underwent estimation of hepatic glycogen using (13)C MRS. MRS was performed at the following four time points: fasting and after a meal at baseline, and fasting and after a meal after eight doses of subcutaneously administered glucagon at a dose of 2 µg/kg, for a total mean dose of 1,126 µg over 16 h. The primary and secondary end points were, respectively, estimated hepatic glycogen by MRS and incremental area under the glucose curve for a 90-min interval after glucagon administration.

Results: In the eight subjects with complete data sets, estimated glycogen stores were similar at baseline and after repeated glucagon doses. In the fasting state, glycogen averaged 21 ± 3 g/L before glucagon administration and 25 ± 4 g/L after glucagon administration (mean ± SEM) (P = NS). In the fed state, glycogen averaged 40 ± 2 g/L before glucagon administration and 34 ± 4 g/L after glucagon administration (P = NS). With the use of an insulin action model, the rise in glucose after the last dose of glucagon was comparable to the rise after the first dose, as measured by the 90-min incremental area under the glucose curve.

Conclusions: In adult subjects with well-controlled type 1 diabetes (mean A1C 7.2%), glycogen stores and the hyperglycemic response to glucagon administration are maintained even after receiving multiple doses of glucagon. This finding supports the safety of repeated glucagon delivery in the setting of a bihormonal closed-loop system.

Trial registration: ClinicalTrials.gov NCT01986231.

Figure 1

Median venous blood glucose values in milligrams per deciliter (top graph) and median insulin infusion rates in units per hour (bottom graph). The interquartile range is shown in gray. Meals (white squares) and glucagon doses (black triangles) are also shown. Note that glucose levels consistently rose after each glucagon dose. The insulin infusion rate was fixed after the first and last glucagon dose, but was otherwise adjusted to bring the glucose concentration into the target range.

Figure 2

Estimated individual and group mean glycogen stores with SEM before (white squares) and after (black circles) glucagon administration in subjects with type 1 diabetes, under fed and fasting conditions (n = 8). Liver glycogen stores after eight doses of glucagon were similar to baseline levels.

Figure 3

Mean incremental glucose AUC with SEM after each of eight doses of glucagon. The modeled AUC accounting for the effects of meals, dextrose, and insulin was subtracted from the observed AUC to isolate the effect of each glucagon dose.