Pharmacodynamics and stability of subcutaneously infused glucagon in a type 1 diabetic swine model in vivo

Background: The objective of this study was to determine the in vivo pharmacodynamics of glucagon and to test its glycemic effect over days by assessing its time course of activity and potency in a type 1 diabetic swine model. Methods: Individual experiments were conducted in different pigs using glucagon preparations that were reconstituted on different days and stored at room temperature or near body temperature before usage. All experiments involved a subcutaneous bolus of glucagon to counter impending hypoglycemia induced by an earlier bolus of fast-acting insulin. Frequent blood-glucose measurements, using a standard in vitro hand-held meter, were taken during each experiment to track variations in blood-glucose concentration. Results: Significant glucagon action was observed as early as 5 min after administration, as evidenced by an effective halt to declining blood glucose and a subsequent twofold rise in blood glucose after similar to 20 min. Results also indicate that the consumption of glucagon from the subcutaneous depot is substantially faster than that of fast-acting insulin. Furthermore, no significant depreciation was observed in glucagon efficacy across aging preparations as old as 7 days. Conclusions: These results suggest profound utility of subcutaneous glucagon in a closed-loop glucose control system, especially since glucagon would provide an effective safeguarding measure to stave off impending hypoglycemia, an application where the rapid effect of subcutaneous glucagon is both serendipitous and essential. Despite the notion that the stability of glucagon in solution at room temperature is inferior to that of fast-acting insulin, its subcutaneous administration has promising prospects for long-term closed-loop ambulatory care.