Despite the increasing number of effective treatment options and blood glucose monitoring methods, most people with type 1 diabetes still do not achieve the recommended glycemic control goals. Many experts believe that the most effective short-term treatment option for people with type 1 diabetes is a system that restores the balance between insulin and blood glucose.
According to Professor Aaron Kowalski, Vice President of the International Juvenile Diabetes Research Foundation (JDRF), “The artificial pancreas system will be the most revolutionary advance in diabetes treatment since the discovery of insulin.”
The artificial pancreas is based on a simple concept: an automated system for infusing insulin and other pancreatic hormones in response to real-time blood glucose changes. However, researchers face numerous challenges in translating this concept into reality.
According to Professor Frank Doyle, chair of the Department of Chemical Engineering at the University of California, Santa Barbara, “Some of us have been working in this field for more than 20 years, and at this point, most of us can proudly say that a truly fully automated device is on the verge of being used in the clinic during the next 3-5 years. However, just like any other technology, this one is in a process of constant development and continuous improvement.”
Stages of development of the artificial pancreas
According to the U.S. Food and Drug Administration (FDA), an artificial pancreas can be a fully mechanical therapy, a fully biological therapy (such as islet transplantation), or a mechanical-biological hybrid therapy. “I don’t think there is just one definition of an artificial pancreas, and some artificial pancreas products are already on the market today,” Professor Doyle noted. “
First-generation artificial pancreas systems are now in use in many countries. Last fall, the FDA approved the marketing of a new insulin infusion system developed by Medtronic Inc. With this new insulin infusion system, the insulin infusion system will automatically stop insulin infusion when the blood glucose value of the system’s receptors reaches a preset threshold, even if the patient has no warning symptoms of hypoglycemia.
Medtronic says the receptors of this insulin infusion device can detect up to 93% of hypoglycemic events when the pre-set threshold alarm system is in normal operation. However, the insulin infusion device does not yet mimic the full biological function of the pancreas, and it still requires patient manipulation, such as when a patient needs to eat to correct a hypoglycemia.
According to the artificial pancreas roadmap created by the JDRF, this Medtronic device is the first of six steps in the development of an artificial pancreas. Each step in the process represents a progressive advancement in technology, starting with a device that can automatically stop insulin infusions to prevent hypoglycemia, and eventually progressing to a fully automated system that may maintain blood glucose at target levels and does not require manual insulin infusions at mealtime. The first generation focused on preventing unsafe blood glucose levels, with the goal of maintaining blood glucose levels between 70 and 180 mg/dl.
The first of six steps in the artificial pancreas roadmap created by JDRF is a device such as Medtronic that can dynamically monitor blood glucose levels and suspend insulin infusion when blood glucose falls below a certain threshold.
The second step is a device that predicts when a user’s blood glucose level is about to reach a preset lower threshold and automatically stops or reduces insulin infusion before the user’s blood glucose level reaches the lower threshold. Such a device is called a hypoglycemic pause system with prediction and can be implemented by adding control software to currently available commercially available insulin pumps and glucose receptors.
A version has been developed by Medtronic and is expected to be approved first in Europe, Kowalski noted, “When device manufacturers plan to launch their products in a country, they must go through that country’s approval process. The time required for product approval varies from country to country, so it is often the case that the same product lags behind in one country’s launch in another.”
The third step, known as a hypoglycemia/hyperglycemia reduction system, is a system that prevents not only unsafe high blood sugar levels, but also unsafe low blood sugar levels.
The fourth step, called a closed-loop insulin infusion system, self-adjusts for high and low blood glucose thresholds and targets a specific blood glucose level rather than a blood glucose range.
Instead, in step five, there is no need for a pre-meal manual insulin infusion. Eventually, in the sixth step, the system will add the ability to infuse other hormone-like drugs that more closely mimic the way the body maintains blood glucose levels. For example, when blood glucose levels are too low, glucagon can be self-injected to counteract the effects of insulin and raise blood glucose levels. This feature is critical because hypoglycemia can lead to convulsions, coma, and even death, and because hypoglycemia can strike at night when patients are asleep, when they are unable to monitor their blood glucose levels.
The third-generation artificial pancreas system can also act on the gastrointestinal tract to slow the rate of carbohydrate absorption after a meal and infuse fast-acting insulin, which acts like the body’s intrinsic insulin for rapid hypoglycemic effects.
Key components of the artificial pancreas
The key components of the artificial pancreas include a computer-programmed dynamic glucose monitoring system (CGM) and an insulin pump, which calculates the insulin dose based on blood glucose readings and directs the insulin pump to deliver insulin. Currently, approximately 9% of people with type 1 diabetes are using existing ambulatory glucose monitoring systems that measure blood glucose levels in pericellular tissue fluid.
Many experts believe that blood glucose readings in tissue fluid may lag behind actual blood glucose levels, which can be problematic when there are rapid changes in blood glucose concentrations, such as after a meal,” Kowalski noted. “However, it turns out that the ambulatory glucose monitoring system reads much more quickly than we expected, so this is not a problem. And, the study data also show that the dynamic glucose monitoring system works well in the artificial pancreas system.” However, more advanced glucose receptors are still needed, and the JDRF and other international organizations are working to improve existing ambulatory glucose monitoring systems.
A variety of algorithms have also been attempted to calculate the appropriate dose of insulin infusion. One algorithm, known as proportional-integral-differential control, is based on the calculation of blood glucose levels and the rate of change in blood glucose concentration. Another algorithm is called model predictive control (MPC) and is based on a model of human physiology and a specified probability to estimate possible future blood glucose values based on previous blood glucose values.
Professor Lutz Heinemann, scientific advisor at the Profil Institute for Metabolic Diseases in Germany, explains, “So if a patient’s blood glucose is elevated and his blood glucose level is likely to continue to rise, the system will infuse more insulin. However, if more insulin has just been infused and the rise in blood glucose slows down, this may signal a plateau and a possible subsequent drop in blood glucose, and the system will not continue to infuse more insulin at that point.”
A third commonly used algorithm is known as fuzzy logic, also known as expert rules. This algorithm is based on how an expert would handle the patient’s blood sugar at this point in time under specified conditions.
Professor Heinemann is the leader of an EU project called AP@home, which aims to improve home treatment for patients. The project is developing a new device that can both measure blood glucose and infuse insulin at the same site, in addition to testing existing instrumentation.
A recent clinical study conducted by AP@home project investigators found that 2 closed-loop algorithms provide safe glycemic control for patients. according to Prof. Heinemann, “In the first parallel controlled trial of these two control algorithms, there was no significant difference in glycemic control between the two. Both control algorithms maintained blood glucose levels in a desirable range with a low incidence of hypoglycemia compared to patient self-management of blood glucose.”
Meanwhile, Dr. Doyle and colleagues have developed a tool that is currently in clinical trials in a variety of different artificial pancreas systems.Dr. Doyle et al. used a computer platform to test combinations of different dynamic glucose monitoring systems, insulin pumps and algorithms. This tool provides a communication platform for a variety of different insulin pumps, glucose receptors and algorithms, allowing all three to work together as a closed-loop system.
According to Dr. Doyle, “We started our clinical studies on laptops, and now we are using micro-tablets on outpatients. Eventually, we will see this technology combined with insulin pumps and glucose receptors as a whole, but there will be all sorts of interesting user requirements and improvements needed in the user interface.”
From clinic to market
Since 2004, there have been more than 40 articles dealing with clinical trials of artificial pancreas systems, and the number of clinical trials of artificial pancreas systems published each year has steadily increased. It is difficult to compare clinical trials of artificial pancreas systems because of the wide variation in study design and protocols, but these studies can be summarized by saying that the efficacy of artificial pancreas in controlling blood glucose is similar to, or due to, conventional therapies.
In a recent study, the incidence of nocturnal hypoglycemia lasting more than 2 hours decreased by 74% when patients used a device that predicted hypoglycemia and stopped insulin infusion, the second step of the JDRF Artificial Pancreas Roadmap. In addition, the first use of the MPC algorithm produced satisfactory results after outpatients brought the artificial pancreas with them.
Although significant progress has been made with the artificial pancreas system, many challenges remain, Doyle noted, “Safety is key and longevity is important, but, in my opinion, one of the most important aspects of the artificial pancreas system is robustness. There is a lot of uncertainty about the artificial pancreas system: uncertainty about the patient and uncertainty about the patient’s daily activities, such as eating, exercise and disease.
A fully automated artificial pancreas may be available in a few years, but patients will continue to benefit as the artificial pancreas is developed.
According to Kowalski, “The process of developing a new treatment will continue to progress, gradually reducing daily burden, adverse effects and complications. Our ultimate goal is to restore the body’s glucose regulation under normal physiological function through a series of therapies.”