Intraperitoneal insulin administration in pigs: effect on circulating insulin and glucose levels

Abstract

Introduction: The effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses. There is a lack of studies comparing the insulin appearance in the systemic circulation after intraperitoneal compared with subcutaneous insulin delivery. Thus, we also aimed for a comparison with the subcutaneous route.

Research design and methods: Eight anesthetized, non-diabetic pigs were given three different intraperitoneal insulin boluses (2, 5 and 10 U). The order of boluses for the last six pigs was randomized. Endogenous insulin and glucagon release were suppressed by repeated somatostatin analog injections. The first pig was used to identify the infusion rate of glucose to maintain stable glucose values throughout the experiment. The estimated difference between insulin boluses was compared using two-way analysis of variance (GraphPad Prism V.8).In addition, a trial of three pigs which received subcutaneous insulin boluses was included for comparison with intraperitoneal insulin boluses.

Results: Decreased mean blood glucose levels were observed after 5 and 10 U intraperitoneal insulin boluses compared with the 2 U boluses. No changes in circulating insulin levels were observed after the 2 and 5 U intraperitoneal boluses, while increased circulating insulin levels were observed after the 10 U intraperitoneal boluses. Subcutaneously injected insulin resulted in higher values of circulating insulin compared with the corresponding intraperitoneal boluses.

Conclusions: Smaller intraperitoneal boluses of insulin have an effect on circulating glucose levels without increasing insulin levels in the systemic circulation. By increasing the insulin bolus, a major increase in circulating insulin was observed, with a minor additive effect on circulating glucose levels. This is compatible with a close to 100% first-pass effect in the liver after smaller intraperitoneal boluses. Subcutaneous insulin boluses markedly increased circulating insulin levels.

Keywords: animal experimentation; blood glucose; diabetes mellitus; insulin; type 1.

Figure 1

Glucose dynamics. Estimated blood glucose change for the 120 min after intraperitoneal insulin delivery in pigs (mean, SD). The 5 and 10 U intraperitoneal bolus gave significantly higher glucose elevations compared with 2 U intraperitoneal bolus. Insulin boluses: 2 U intraperitoneal insulin bolus (n=7, green line), 5 U intraperitoneal insulin bolus (n=7, blue line) and 10 U intraperitoneal insulin bolus (n=7, red line).

Figure 2

Insulin dynamics. Estimated insulin change for the 120 min after intraperitoneal insulin delivery in pigs (mean, SD). The 10 U intraperitoneal bolus gave significantly higher insulin elevation compared with 2 and 5 U intraperitoneal boluses. Insulin boluses: 2 U intraperitoneal insulin bolus (n=7, green line), 5 U intraperitoneal insulin bolus (n=7, blue line) and 10 U intraperitoneal insulin bolus (n=7, red line).

Figure 3

Insulin change after intraperitoneal and subcutaneous insulin boluses. Estimated insulin changes for the 120 min after intraperitoneal insulin delivery and for the 140 min after subcutaneous insulin delivery in pigs. Statistical testing was not provided based on limited number of included animals. Insulin boluses: 2 U intraperitoneal insulin bolus (n=7, green line), 5 U intraperitoneal insulin bolus (n=7, blue line), 10 U intraperitoneal insulin bolus (n=7, red line), 5 U subcutaneous insulin bolus (n=1, blue dashed line) and 10 U subcutaneous insulin bolus (n=2, red dashed line).