Intraperitoneal and subcutaneous glucagon delivery in anaesthetized pigs: effects on circulating glucagon and glucose levels

Abstract

Glucagon is a pancreatic hormone and increases the blood glucose levels. It may be incorporated in a dual hormone artificial pancreas, a device to automatically and continuously control blood glucose levels of individuals with diabetes. Artificial pancreas systems have been developed for use in the subcutaneous tissue; however, the systems are not fully automated due to slow dynamics. The intraperitoneal space is therefore investigated as an alternative location for an artificial pancreas. Glucose dynamics after subcutaneous and intraperitoneal glucagon delivery in ten anaesthetized pigs were investigated. The pigs received intraperitoneal boluses of 0.3 µg/kg and 0.6 µg/kg and a subcutaneous bolus of 0.6 µg/kg in randomized order. They also received an intraperitoneal bolus of 1 mg given at the end of the experiments to test the remaining capacity of rapid glucose release. Six pigs were included in the statistical analysis. The intraperitoneal glucagon bolus of 0.6 µg/kg gave a significantly higher glucose response from 14 to 30 min compared with the subcutaneous bolus. The results indicate that glucagon induces a larger glucose response after intraperitoneal delivery compared with subcutaneous delivery and is encouraging for the incorporation of glucagon in an intraperitoneal artificial pancreas.

Figure 1

Glucose dynamics. Estimated glucose changes for the full 80 min (a) and for the first 15 min (b) after glucagon delivery in pigs, which responded with a BG rise after the 1 mg IP bolus. The 0.6 µg/kg IP bolus gave significantly higher glucose elevations compared with the 0.6 µg/kg SC bolus from time points 14–30 min (marked with *). 1 mg IP bolus gave significantly higher glucose elevations compared with all other boluses from 4 to 20 min, except at 20 min compared to the 0.6 µg/kg IP bolus (not marked in the graph).

Figure 2

Glucose dynamics for the 0.6 µg/kg IP and 0.6 µg/kg SC bolus. Estimated glucose changes and 95% confidence intervals for the full 80 min after glucagon delivery in pigs, which responded with a BG rise after the 1 mg IP bolus. The 0.6 µg/kg IP bolus gave significantly higher glucose elevations compared with the 0.6 µg/kg SC bolus from time points 14–30 min (marked with *). The p-values for these time points were 0.033, 0.022, 0.042, 0.027, 0.023, 0.009, and 0.037, respectively.

Figure 3

Glucose, insulin, and glucagon profiles from two full experiments. Glucagon boluses are marked with triangles and vertical dashed lines. The top graph shows pig no. 10, which responded with a rise in BG values after every glucagon bolus (a), while the bottom graph shows pig no. 11, which only responded to the first glucagon bolus although high levels of glucagon were detected in peripheral blood after all boluses (b). Only the first octreotide and pasireotide treatments are marked as vertical solid bars around 9 o’clock. Please see the methods section for full description.