| Popis: |
Diabetes mellitus type 1 is an autoimmune disease that causes selective destruction of the insulin-producing β-cells in the pancreatic islet of Langerhans. Insulin induces glucose storage and reduces blood glucose concentrations. As it is essential for normal glucose regulation, patients with diabetes mellitus type 1 require lifelong treatment with exogenous insulin. The treatment of diabetes mellitus type 1 has evolved significantly since insulin was discovered in 1921. Modern treatment comprises continuous self-monitoring of glucose concentrations and self-administration of appropriate insulin dosages. Most patients cover their basal and prandial insulin needs through multiple manual injections or infusions via a pump into subcutaneous tissue. Hypoglycaemic episodes are a common side-effect of insulin treatment, and can be reversed with glucagon, which mobilises glucose from the liver and increases blood glucose concentrations. Lately, artificial pancreas technology has emerged as a promising new treatment option for patients with diabetes mellitus type 1. An artificial pancreas is a device that automatically calculates the demand for insulin based on continuous glucose feedback. Both unihormonal devices, delivering only insulin, and bihormonal devices, delivering insulin and glucagon, have been developed. However, only hybrid (partially automated), unihormonal devices that require meal announcements from the user are commercially available. Developing a fully automated subcutaneous artificial pancreas that can achieve excellent glucose control without meal announcements is challenging. One major barrier is the slow absorption rate of insulin from the subcutaneous tissue, which makes timing and adjustments of meal boluses of insulin difficult. As such, measures that can promote insulin absorption are needed. Alternatively, a more efficient route of insulin administration could be chosen. Intraperitoneal insulin administration mimics normal physiology and has a favourable pharmacokinetic profile compared to subcutaneous insulin administration. The first aim of this thesis was to investigate if the absorption, elimination, and utilisation of glucagon may also be improved with intraperitoneal drug delivery, as this could support developing a bihormonal intraperitoneal artificial pancreas, that would deliver both insulin and glucagon into the intraperitoneal space. The second aim was to investigate if subcutaneous insulin absorption may be accelerated by simultaneous subcutaneous glucagon administration, as glucagon is a potent vasodilator. This thesis demonstrates that intraperitoneal delivery of glucagon results in lower systemic glucagon concentrations than subcutaneous administration, probably because of a large first-pass metabolism of glucagon in the liver. However, the effects on glucose metabolism are equal after intraperitoneal and subcutaneous glucagon administration. Because of the increased risk of complications with intraperitoneal drug delivery, we conclude that the subcutaneous route for glucagon delivery is preferable for most patients. Simultaneous administration of glucagon did not accelerate subcutaneous insulin absorption. However, the total amount of insulin absorbed after a single bolus was significantly increased over an observation period of three hours. Clinical trials are needed to investigate if micro-doses of glucagon can be used to enhance insulin absorption and improve postprandial glucose control in subjects with diabetes mellitus type 1. |
