Double Intraperitoneal Artificial Pancreas
In patients with diabetes type 1 (DM 1), the body has partly or completely lost its ability to produce insulin. The first time insulin was administered to humans was in 1922, which stands as one of the great breakthroughs in the history of medicine. Patients with type 1 diabetes who had previously faced a certain death, could now live a long life. However, it was rapidly discovered that the new treatment revealed new challenges such as an oscillating glucose level with both too high and too low glucose. The largest challenge for DM1 patients is that a chronically elevated glucose level over many years will in many patients result in so-called diabetic long-term complications, such as kidney failure and damage to the retina of the eyes. Due to, among other things, changes in small and large vessels, this may result in blindsness, neuropathy (painful changes to the nervous system), heart attack, stroke and leg amputations. Despite the significant treatment improvements during the last years, long-term complications still give persons with DM1 from young age approximately a 10 year reduction in life expectancy. Good control of glucose levels is thus necessary for the best possible treatment of DM1. Ever since the 1970's, we have dreamed about offering DM1 patients such an artificial pancreas for automatic control of insulin infusion. Now we are approaching the technological solutions needed to achieve that.
Artificial pancreas – State of the art
In the year 2000, the first equipment for continuous glucose monitoring (CGM) came to the market, measuring glucose right under the skin (subcutaneously). Since then, the technology has been incrementally improved and there are now several companies and products to select from. In common for all of them is that the glucose level they measure is delayed compared to the glucose level in blood. This is due to a physiologic delay, since glucose uses time to move from blood to the subcutaneous site. The delay is at least 6–7 minutes, with a substantial variability between patients. Additionally, there is a delay in the sensor itself, and since the glucose value is offered usually every 5 minutes as an averaged value of the last five minutes, altogether this can result in a delay of more than 15 minutes compared to the glucose value in blood.
DM1 patients are today treated by either manual insulin injections, or by insulin pumps which are pre-programmed with a continuous insulin infusions and with additional meal doses or other corrections manually administered by the user. The main challenge of this is that even the most rapid acting insulin types will need 45 minutes to arrive in maximum concentration in blood, while the maximum glucose lowering effect is not seen until after 1.5–2 hours and the effect lasts for at least 5 hours in total. This means that it is hard to apply enough insulin to reduce the glucose excursion without at the same time achieving a low glucose level before the next meal. In practice, patients end up having chronically elevated glucose levels which increases the risk of developing long-term complications.
Many research groups all over the world are working towards an artificial pancreas. In common for most of these, is that they work on continued development of the technology described above. Since glucose is measured subcutaneously and insulin is infused in the same place, this approach (the double subcutaneous artificial pancreas) will never be able to achieve a really good glucose control. This can be illustrated by the fact that the patient himself/herself needs to dose the insulin ahead of meals, or tell the system how much food they will eat, so that the pump can calculate the meal dose needed for the specific meal. Without such manual adaptations, the artificial pancreas will have large variations in control of glucose levels.
Mathematical simulations of an artificial pancreas based on the double subcutaneous approach shows that you will have serious glucose excursions after a meal when trying to avoid low glucose ahead of next meal. By applying more insulin to reduce the glucose excursion, a too low glucose level will be ahieved after 3–4 hours, and one would need to eat more (and smaller) meals in order to avoid it.
Double intraperitoneal artificial pancreas
Our research group, Artificial Pancreas Trondheim (APT), was formally estabilished in August 2013, as a result of several years of engagement and research on sensor technology at the Norwegian University of Science and Tecnology (NTNU) and St Olav's Hospital in Trondheim. APT aims to develop an artificial pancreas able to normalise the glucose level in DM1 patients. We believe this is impossible by using today's state of the art glucose sensor technology and a double subcutaneous (SC) approach. This lead us into pursuing what we call the double intraperitoneal (IP) approach, where we will measure glucose levels in the fluid of the abdominal cavity. Our own experiements as well as other research shows a much more rapid response in changes to the glucose level when compared with existing subcutaneous technology. In addition, IP insulin will be absorbed much quicker than SC insulin. This means a shorter control loop and the mathematical models show that by our approach we can achieve a normalisation of glucose levels, i.e. the same glucose level as in non-diabetic people.
Thus, we explore the double IP approach, and the ultimate goal is to make a so small, robust and well functioning artificial pancreas that the patients can completely forget about their diabetes. They would just need to handle alarms every time insulin needs to be refilled, and when the battery needs to be recharged or replaced.
Challenges of the project
This is a very ambitious project which puts high demand of new technology to be developed. The largest challenge is to establish a solution for continuous IP glucose sensing. One cannot just use the well established technology for subcutaneous glucose sensing but will need to develop specific new sensor technology. By measuring IP glucose, some challenges of subcutaneous glucose sensing are reduced, but on the other hand several new challenges appear.
Another challenge is the development of an abdominal port, i.e. a small catheter to be installed through the peritoneal wall, which the insulin infusion and the glucose sensor will be introduced through. The port needs to be small, and the aim is to have an outer diameter smaller than 1 cm. This means that the sensor itself and the tubing for insulin need to be even smaller, probably below a diameter of 4–5 mm.
We also need to develop a mathematical model for control of insulin infusion based on the glucose level. In order to do that, we need to record sufficiently good data on the coherence between intraarterial and IP glucose, as well as the effect of IP insulin on the glucose level.
Areas of expertise involved in the project
The Double Intraperitoneal Artificial Pancreas is a highly transdisciplinary research project where so far the following areas of expertise at NTNU and St Olavs Hospital are involved:
Cybernetics (control engineering), mathematical modeling, biosensor technology, biochemistry, optical spectroscopy, veterinary medicine and the medical specialties of endocrinology, anaesthesia, intensive care and pharmacology. As the project develops, further areas of expertise will be involved.
The project has a formal collaboration with the Norwegian company Prediktor Medical AS which is also developing a glucose sensor.
Our research project Double Intraperitoneal Artificial Pancreas is a challenging and bold project addressing the challenges many other research groups try to avoid. The project has large challenges but has at the same time the potential to develop a robust artificial pancreas which can normalise or near normalise the blood glucose level in DM1 patients. We believe we will succeed, and if so we will not only simplify the daily life of DM1 patients, but also improve their quality of life, remove or reduce the tendency of diabetic long-term complications and normalise the life expectancy.