Hope for an ARTIFICIAL PANCREAS

Transcription

1 FEATURE Hope for an ARTIFICIAL PANCREAS By Dana VanBuecken Progress is being made to develop a continuous glucose monitor that works with an insulin pump to replace the body s insulin-producing cells. 1925: home testing for glucose in urine introduced 1921: discovery of Insulin by Frederick Banting and Charles Best 1936: first long acting insulin developed 1944: standard insulin syringe developed 1956: dip and read urine test to detect glucose levels introduced 1971: first portable blood glucose meter developed by Ames Diagnostics, primarily used in doctors offices 1976: HbA1c test developed to measure blood glucose control over a period of months 1979: first portable, commercial insulin pump made available 1983: first blood glucose meters made available for home use 2005: first continuous glucose monitors (CGMs) FDA approved for use in patients with diabetes 2008: FDA approves AP human clinical trials, trials begin Adapted from: JDRF Artificial Pancreas Project: Milestones [Interactive timeline illustration]. Available from artificialpancreasproject.com/milestones/default.html. Accessed April, 2013 Having diabetes is like driving in a car with your eyes closed; testing your blood sugar even 8 to 10 times in 24 hours is dangerous because you don t have your eyes open often enough or long enough for the best possible decision making, explained Dana Lewis, who has been living with Type 1 Diabetes (T1D) for over 10 years. Even with recent advances in technology that have allowed for the use of insulin pumps and continuous glucose monitors (CGMs) as alternatives to multiple, daily insulin injections and unremitting finger sticks, managing diabetes is an overwhelming responsibility. Fortunately, researchers and innovators around the globe are working to further ease glycemic management through the development of an artificial pancreas, a medical device that will regulate blood glucose automatically, requiring little to no input from the user. The artificial pancreas will not actually function as a surrogate for the entire pancreas as its name suggests. Instead, it will provide a replacement for the body s insulin-producing cells, the pancreatic beta cells. In T1D, these cells are destroyed by an autoimmune process that is not yet fully understood. Without sufficient insulin, the body is unable to transport glucose from the blood and into the body s cells, where it is needed as fuel for cellular activity. As a result, blood glucose levels escalate, while the body s cells are slowly energy starved. Without insulin, death is inevitable. Fortunately, since the 1920s, people with T1D have been able to compensate for inadequate beta-cell function with exogenous insulin. Now, almost 100 years after the discovery of the hormone, numerous medical devices exist to help those with T1D better manage their disease. Currently, insulin may be delivered via injection or an insulin pump, a device that delivers frequent small doses of basal insulin to manage the glucose produced by the liver and larger doses of bolus insulin to manage the glucose consumed in each meal. The pump wearer must carefully calculate the carbohydrate content of food to be consumed and then direct the device as to how much insulin to deliver before meals. The insulin is then administered through a small plastic cannula that inserts into the wearer s subcutaneous adipose tissue. Portable, commercial insulin pump technology was first made available for general use in More recently, in 2005, the FDA approved the first continuous glucose monitors (CGMs), devices that automatically take glucose measurements multiple times per hour and alert the wearer to the results via readings on a pump interface or external receiver JDRF Artificial Pancreas Project: Milestones. artificialpancreasproject.com/milestones/default.html. Accessed April JDRF Artificial Pancreas Project: Milestones.

2 Description of Artificial Pancreas 1. Blood glucose sensor 2. Receiver 3. Computer-controlled dosing algorithm 4. Insulin pump The CGM is worn on the body and measures interstitial glucose as compared to standard home glucose meters, which measure capillary glucose. With both insulin pumps and CGMs accessible, research teams began working to close the loop between these two devices, hoping to allow an insulin pump to receive glucose readings from a CGM and then automatically deliver appropriate insulin doses based on this data. Thus, the artificial pancreas was conceptualized. Several different combinations of CGMs and insulin pumps have been used in artificial pancreas clinical trials. In addition to these devices, most artificial pancreas systems utilize an external, computer-based dosing algorithm called the controller. Before a user may rely on the artificial pancreas for insulin dosing, the controller must be provided with information such as a participant s average total daily insulin dose, insulin sensitivity factor, and carbohydrate ratio. insulin to administer. Last, the controller communicates the recommended dose to the insulin pump, which delivers the insulin. Because this process repeats itself between 12 and 60 times per hour, it allows for frequent insulin dosing that is closely tailored to how a person s blood glucose is behaving at any given time. Once the artificial pancreas is activated, the CGM reads the interstitial glucose every one to five minutes, depending on the model, and transmits the reading to the computer, which then uses the dosing algorithm contained within the controller to decide how much JDRF, formerly known as the Juvenile Diabetes Research Foundation, asserts that a successful artificial pancreas device could dramatically improve the lives of millions of people living with diabetes; this belief is reflected in the nonprofit s $8 million investment in the technology.3,4 In 2006, JDRF established the Artificial Pancreas Project, aimed at funding doctors and researchers across the world to 3. JDRF Artificial Pancreas Project, The potential to be among the most revolutionary advancements in treating type 1 diabetes. artificialpancreasproject.com/about/default.html. Accessed April Health Media Ventures, Inc., Artificial pancreas prototype in development for type 1 diabetics. news.health.com/2010/01/14/artificialpancreas-prototype-development-type-1-diabetics/. Accessed April continues

3 ARTIFICIAL PANCREAS, CONT. advance artificial pancreas development. 5 Currently, this project is funding the work of numerous artificial pancreas clinical trials, one of which is being conducted by a small company called Dose Safety at Seattle s own Benaroya Research Institute (BRI). The Pacific Northwest offers a unique environment for artificial pancreas development, as it brings together Boeing s advanced aerospace technologies, BRI s internationally renowned diabetes-research program, and the nationwide increasing prevalence of T1D. 6 The Dose Safety team, composed of Boeing engineers Don Matheson and Robert Kircher and pediatric endocrinologist Richard Mauseth, is working to employ a technology called fuzzy logic to regulate blood glucose automatically via an artificial pancreas system. Fuzzy logic is commonly used to automate airplane flight, as it can direct an airplane s computer to make complex decisions about how to best fly at varying wind speeds, altitudes, temperatures, etc. Similarly, this technology allows for a dosing algorithm that can determine an insulin bolus at any given time based on numerous variables including current blood glucose (mg/dl), the glucose slope or rate of change (mg/dl/min), and the glucose acceleration (mg/dl/min/min). Employing fuzzy logic technology allows a controller to fully automate the dosing of insulin, both during fasting periods and post meal, Kircher said. Our vision is that the pump will be capable of operating safely without patient intervention, except in exceptional situations such as intense physical exercise, Kircher explained. In those situations, the patient may need to take over manual control of the pump for a while. In 2009, Dose Safety partnered with BRI to begin clinical trials with their device under the guidance of Dr. Carla Greenbaum, director of BRI s Diabetes Research Program. BRI has been a leader in immune system and autoimmune disease research since 1956 and has a very active and prolific diabetes program. The studies being done at BRI will help determine whether or not the artificial pancreas is safe and effective during two of the most difficult-to-manage situations for someone with T1D. First, BRI is testing the artificial pancreas s ability to regulate blood glucose after a participant consumes three slices of Ann Shultz, a participant in the artificial pancreas (AP) clinical research trial, smiles for the camera while the AP automatically manages her blood glucose levels. Ann wears two Dexcom continuous glucose monitors (CGMs) and an Omnipod insulin pump. Every five minutes, a blood glucose reading is transmitted from the CGM to a computer-contained dosing algorithm, which then directs the Omnipod pump to deliver an insulin dose based on the data received. pizza (120g carbohydrate and 60g fat). Blood-glucose management after high-fat, high-carbohydrate meals is notoriously complicated as the body s delayed metabolism of fat, coupled with the fact that fat slows the absorption of carbohydrate, tends to cause delayed or prolonged periods of hyperglycemia in many individuals with T1D. Second, BRI and Dose Safety researchers are trying to determine whether or not the artificial pancreas can perform adequately when a participant exercises on a recumbent 5. The potential to be among the most revolutionary advancements in treating type 1 diabetes. bicycle for 30 minutes and is later fed a 75g carbohydrate dinner and a 20g carbohydrate bedtime snack. The participant then stays at the research center overnight for monitoring. Aerobic exercise poses a challenge to the maintenance of in-range blood glucose levels because physical activity causes an increased uptake of glucose into skeletal muscle, which can lead to immediate or delayed hypoglycemia, a potentially dangerous situation. If the artificial pancreas, which is responsible for all insulin dosing during both of these study visits, can keep blood glucose levels American Diabetes Association, Diabetes rates increase significantly among American youth. sci-sessions-search.html. Accessed July 2013.

4 * Top graph depicts blood glucose measurements taken by continuous glucose monitor. Bottom graph depicts corresponding insulin doses delivered by the artificial pancreas system. within an acceptable range during periods of pizza consumption and aerobic exercise, then it should also be able to function adequately under most other circumstances. To date, BRI has conducted 35 study visits using Dose Safety s artificial pancreas on 15 different participants. A person without diabetes will typically have blood glucose levels in the range of mg/dL at any given time, and the artificial pancreas aims to keep those with diabetes within a similar target range. In a successful visit, a participant s average blood glucose over the course of their time spent using the device has been under 160mg/dL and the blood glucose has never dropped below 60mg/dL. So far, the artificial pancreas has achieved this goal for several participants using the device in different scenarios. According to Aaron Kowalski, research director of the JDRF Artificial Pancreas Project, the need for an effective artificial pancreas is evidenced by the fact that, even with sophisticated blood glucose management equipment, those with T1D only spend 30 percent of the time in their blood sugar range, and it s often much less than that. 7 Sub-par glucose management can be attributed to the fact that it can be very difficult to determine the exact carbohydrate content of food, basal insulin requirements, etc., and the body s insulin sensitivity may vary from day to day, depending on factors such as exercise, illness, stress, and hormonal changes. Less than optimal blood glucose control is detrimental, as demonstrated by studies such as the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) which showed that poor glycemic control increases the risk of diabetes complications such as retinopathy, albuminuria, nephropathy, and neuropathy. Unfortunately, these studies also revealed that improved glycemic control correlates with an increased risk of severe hypoglycemia. 8,9 In light of these findings, the primary goal of an artificial pancreas is to provide the best glycemic control possible while still minimizing the risk for hypoglycemia. In Dose Safety s case, the artificial pancreas s target average blood glucose of 7. Health Media Ventures, Inc., Artificial pancreas prototype in development for type 1 diabetics. news.health.com/2010/01/14/artificialpancreas-prototype-development-type-1-diabetics/. Accessed April The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJMed, 1993; 329: UK Prospective Diabetes Study Group, Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 1998; 352: Nathan D, Kuenen J, Borg R, Zheng H, Schoenfeld D, and Heine R, Translating the A1c assay into estimated average glucose values. Diabetes Care, 2008; 31: mg/dL corresponds to an HbA1c of 7.0 percent and is thus consistent with the ADA s 2013 Clinical Practice Guidelines recommendation of an HbA1c of 7 percent for most non-pregnant adults. 10,11 In addition to improving glycemic control, the artificial pancreas could serve to alleviate some of the burden of diabetes management for those who are able to effectively control their blood glucose using a manually controlled insulin pump but would like relief. Artificial pancreas clinical trial participants Ted Bearor and Brandon Duffy echoed this sentiment. The artificial pancreas would enable [people with diabetes] to spend more time and attention dedicated to family, life, work, and the community, Bearor said. This technology would help diabetes to become more of an afterthought, Duffy said. I would hope to reduce the amount of work in my management and to effectively manage my care without much intervention other than the artificial pancreas. Researchers are implementing several new technologies and pump systems as they strive to create a successful artificial pancreas. One new technology, known as the low-glucose suspend (LGS) feature, may serve to protect those with T1D from hypoglycemia. LGS automatically prevents an artificial pancreas from dosing any insulin when the wearer s blood continues

5 ARTIFICIAL PANCREAS, CONT. glucose drops below a specific value. In the event that an artificial pancreas user does become hypoglycemic, the device will sound an alert to make the user aware of the outof-range glucose. Additionally, caregivers such as parents of children with T1D will be able to receive information about their child s glucose remotely through a cellular link. While not yet FDA approved in the United States, LGS technology is already available in other parts of the world. Medtronic s Paradigm Veo system, which is currently on the market in Europe, suspends insulin dosing for two hours if the glucose dips below a certain value. 12 A recent study showed that the use of this device was associated with reduced nocturnal hypoglycemia in those at greatest risk. 13 As most episodes of hypoglycemia occur at night, this safety feature could prove to be very useful. Additionally, several research teams are employing dual-hormone pumps in their artificial pancreas systems. A dual-hormone pump doses insulin in conjunction with another hormone to regulate blood glucose. Examples include a pump capable of administering both insulin to lower blood glucose and glucagon to raise blood glucose and a pump containing both insulin and pramlintide, an amylin analog, to regulate glycemia. 14,15 In healthy individuals, amylin is co-secreted with insulin from beta cells, slowing digestion, slowing the rate of glucose entering the bloodstream, and temporarily suppressing the release of glucagon. Other teams are developing artificial pancreas systems that employ meal announcement technology. This feature requires the artificial pancreas user to alert the device when a meal is about to be consumed. With the push of a button, the user signals the artificial pancreas to begin dosing more aggressively in anticipation of a rapid rise in blood glucose. Obviously, artificial pancreas systems employing this technology are not completely automated as they necessitate input from the user to make dosing decisions. Future iterations of the artificial pancreas may also employ implantable pumps or CGMs that do not break the skin. It is difficult to predict when an artificial pancreas device might become available to those with insulin-dependent diabetes. All teams are working diligently to move an artificial pancreas from the clinical trial stage to having an FDA-approved device, Kircher said. On November 9, 2012, the FDA released its guidance for the regulatory approval of an artificial pancreas device. Safety remains a prime concern and the FDA 11. American Diabetes Association, Standards of medical care in diabetes. Diabetes Care, 2013; 36:(Suppl.1), S11-S Gebel E, The artificial pancreas. Diabetes Forecast, 2010; 63. forecast.diabetes.org/magazine/features/artificial-pancreas 13. Choudhary P, Shin J, Wang Y, Evans M, Hammond P, Kerr D, Shaw J, Pickup J, Amiel S, Insulin pump therapy with automated insulin suspension in response to hypoglycemia: reduction in nocturnal hypoglycemia in those at greatest risk. Diabetes Care, 2011; 34: Haidar A, Legault L, Dallaire M, Alkhateeb A, Coriati A, Messier V, Cheng P, Millette M, Boulet B, Huang C, Rabasa-Lhoret R, Glucoseresponsive insulin and glucagon delivery (dual-hormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover controlled trial. Canadian Medical Association Journal 185: , Weinzimer S, Sherr J, Cengiz E, Kim G, Ruiz J, Carria L, Voskanyan G, Roy A, Tamborlane W, Effect of pramlintide on prandial glycemic excursions during closed-loop control in adolescents and young adults with type 1 diabetes. Diabetes Care, 2012; 35: Boyne M, Silver D, Kaplan J, Suadek C, Timing changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes, 2003; 52: also works diligently to ensure that an artificial pancreas is safe and has been thoroughly tested in a wide range of situations. Because of the testing requirements, it is not possible to predict when a device will be available. After an artificial pancreas device proves safe and effective in the carefully controlled lab environment, it will have to be tested in outpatient settings, where participants diets and activities will be less regulated. Several challenges remain before widespread use of an artificial pancreas can be implemented. First, the equipment that comprises the artificial pancreas system is far from perfect. Unlike blood glucose meters, CGMs measure interstitial glucose, and interstitial glucose readings generally lag behind whole blood glucose levels by 4 to 10 minutes. 16 Next, there is a delay from the time that insulin is delivered into the subcutaneous tissue to the time it enters the bloodstream, where it may take effect. Also, because meals vary in content and time of consumption, they are particularly challenging for an artificial pancreas to manage. Because an artificial pancreas cannot dose in anticipation of a meal without intervention from the wearer, many trials have shown postprandial hyperglycemia with use of the device. As clinical trials progress and research teams work to perfect their controllers dosing algorithms, those living with T1D eagerly await this technology. Fifty years from now, I hope there s a true cure, diabetes patient Lewis said. On the road to a cure, though, I see software like the artificial pancreas making the biggest difference in diabetes care, syncing CGMs with insulin pumps to create a better decision making and loop system that more closely mimics our body s innate systems. About the Authors Dana VanBuecken received her Master of Nursing degree from the University of Washington in After becoming certified as an ARNP, she joined the Benaroya Research Institute (BRI), where she works as a research nurse practitioner within the Diabetes Clinical Research Program. Dana has type 1 diabetes herself, which fuels her passion for improving diabetes management options and her desire to contribute to finding a cure.