Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in a pig model

Abstract

Introduction There is increasing scientific evidence to substantiate using low‐dose glucagon as a supplement to insulin therapy in artificial pancreata for diabetes mellitus type 1. The delivery of both these hormones intraperitoneally would mimic normal physiology. However, our knowledge of the pharmacological properties of glucagon after intraperitoneal administration is limited. This study compared the pharmacokinetics of glucagon after intraperitoneal, subcutaneous and intravenous administration and the pharmacodynamic effects of glucagon on glucose metabolism after intraperitoneal and subcutaneous administration in a pig model. Materials and methods Twelve pigs were included. Glucagon was administered intraperitoneally, subcutaneously and intravenously in a randomised order. Arterial samples were collected every 2–10 min for 150 min to determine plasma glucagon and blood glucose concentrations. Results The bioavailability of glucagon was significantly lower after intraperitoneal compared with subcutaneous administration with a median difference (95% confidence interval) of 13% (4–22). The effect of glucagon on glucose metabolism was equal after intraperitoneal and subcutaneous administration. Conclusions Intraperitoneal glucagon administration resulted in lower systemic glucagon exposure than subcutaneous administration without loss of efficiency. We interpret this as evidence of a major first‐pass metabolism of glucagon in the liver.

Vasodilatory effects of glucagon: A possible new approach to enhanced subcutaneous insulin absorption in artificial pancreas devices

“…Unlike insulin, glucagon is absorbed rapidly after SC administration, reaching maximum plasma concentrations in humans at approximately 10-20 min (Simmons and Williams, 1992;Graf et al, 1999;El-Khatib et al, 2010;El Youssef et al, 2014;Blauw et al, 2016;Castle et al, 2016;Ranjan et al, 2016;Hövelmann et al, 2018;Hövelmann et al, 2019). Previous animal trials conducted by our research group demonstrated no significant difference in the absorption speed or glucose elevating effect of glucagon after SC compared to intraperitoneal administration (Dirnena-Fusini et al, 2018;Åm et al, 2020;Teigen et al, 2022). This observation contrasts with the major delay in insulin absorption and effect after SC administration compared to intraperitoneal administration (Christiansen et al, 2017).…”

“…This observation contrasts with the major delay in insulin absorption and effect after SC administration compared to intraperitoneal administration ( Christiansen et al, 2017 ). Therefore, we hypothesise that the local vasodilatory effect of glucagon promotes its absorption from the SC space, as this would explain why there is no significant difference in absorption or the time to onset and maximum effect of SC versus intraperitoneally delivered glucagon ( Teigen et al, 2022 ).…”

Effects of Low-Dose Glucagon on Subcutaneous Insulin Absorption in Pigs

“…The values of T max and T 1/2 of glucagon were comparable to observations in a previous pig study we have performed that investigated glucagon pharmacokinetics. 15 As such, the absorption and elimination time of glucagon did not seem to be influenced by insulin being deposited at the same subcutaneous site. No local adverse reactions on the skin were observed during the insulin and glucagon infusions.…”

“…It is therefore not surprising that there seems to be a considerable first-pass metabolism of glucagon in the liver; that is, that a large proportion of glucagon is extracted (and utilized) upon passing the liver and that only a small fraction reaches systemic circulation. 15 If this first-pass effect is saturable, as we have previously hypothesized, 16 microdoses of glucagon administered with mealtime insulin are probably less likely to cause postprandial glucose excursions because the liver will already be saturated with glucagon. This would have to be investigated in patients with DM1.…”