Intraperitoneal insulin administration - superior choice for an artificial pancreas?

Abstract

The main focus of this thesis is to explore the intraperitoneal (IP) cavity as the location for insulin administration. We hypothesized that IP insulin administration is more physiologic as it mimics endogenous insulin secretion and theoretically should achieve superior glycaemic control compared to subcutaneous (SC) delivered insulin. An additional focus was on IP glucagon administration, as glucagon is administered in a case of severe hypoglycaemia and is explored for use in a bi-hormonal artificial pancreas (AP). We hypothesized that IP glucagon administration, as IP insulin administration, mimics endogenous glucagon secretion closer than SC glucagon administration. In the work of the thesis, we performed a systematic review where we explored a variety of physiological effects in a comparison between continuous IP insulin infusion (CIPII) and continuous SC insulin infusion (CSII) in patients with diabetes mellitus type 1 (Paper I). In the second paper, we contrasted the pharmacokinetics and pharmacodynamics of various IP insulin boluses in anaesthetised pigs to that of SC insulin (Paper II). In the third paper, we investigated pharmacodynamics of glucagon after IP and SC injection in rats (Paper III). The thesis involves the two most important pancreatic hormones affecting glucose homeostasis, insulin and glucagon. Therefore, in the chapter 2 ʻBackgroundʼ, endogenous insulin and glucagon synthesis, secretion and effects are described. Relevant available exogenous analogues are also described. Additionally, somatostatin is also mentioned as somatostatin analogues were used in the animal trials to supress endogenous insulin and glucagon secretion. The Artificial Pancreas Trondheim (APT) research group has its main focus towards the development of bi-hormonal AP system, i.e., a closed-loop IP insulin infusion system. In this thesis we obtained information of insulin pharmacodynamics and pharmacokinetics and glucagon pharmacodynamics that will be used to develop an algorithm for an IP AP. Therefore, chapter 2 includes an evaluation of potential benefits and disadvantages of CIPII compared to CSII. Also, available information on possible advantages and disadvantages of IP AP and bi-hormonal AP development are summarized. This thesis demonstrates the potential benefits of IP insulin and glucagon delivery as part of an AP. My hope is that this thesis will be one more step toward an AP that normalizes or close to normalizes glucose levels in patients with DM1.