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Balancing Act
For people with diabetes, finding the equilibrium between sugar and insulin is a matter of survival—every day. A new “artificial pancreas,” still in the works, could change—even save—their lives.
March/April 2010
by Elizabeth Svoboda ’03
Elizabeth Svoboda ’03, a California-based science writer, also contributes to Fast Company, Popular Science, and Discover.
Ben Yarmis, 18 years old, is prostrate in a white-sheeted bed on the tenth floor of Yale–New Haven Hospital, hooked up to an IV and surrounded by doctors and technicians. You might assume he wishes he were outside on this glorious late-summer afternoon, but he’s thrilled to be just where he is right now. Yarmis, a George Washington University freshman who loves computer gaming and obscure rock bands, is participating in a trial of the first ambulatory automated insulin delivery system—a so-called artificial pancreas.
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The body responds differently to insulin at different times of the day.
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Whenever a healthy person so much as glimpses food or smells it cooking, the pancreas starts to churn out insulin, a hormone that stimulates the body’s cells to take up ingested sugars from the bloodstream for their energy supply. But because of Yarmis’s type 1 diabetes, a condition he was diagnosed with at age 11, his pancreas no longer produces insulin reliably. He has to give himself multiple insulin doses daily and monitor his blood sugar to prevent it from creeping too high or too low—dangerous conditions that, at extreme levels, could cause delirium or a diabetic coma. If his blood sugar levels stray too often, even moderately, over the long term they could cause damage leading to heart disease, blindness, or loss of limbs.
For the past seven years, Yarmis’s life has been punctuated with constant diabetes management. It’s not just a simple question of countering food with insulin. Blood sugar can go up or down dramatically and unpredictably because of an extra apple, a dash for the bus, a lost hour of sleep. Moreover, the body responds differently to insulin at different times of the day, and the liver can release glucose into the blood hours after a person has eaten. Slipups are inevitable. “I check my glucose number a lot,” Yarmis says, but “a lot of this is just controlling it by the seat of my pants.”
This clinical trial run by Yarmis’s doctor, Yale endocrinologist Stuart Weinzimer ’88, has granted him a short reprieve from his blood-sugar management regimen. For three days, he will eat, sleep, and exercise for carefully timed periods under the watchful eyes of a team of doctors, nurses, and researchers, all while wearing two electronic devices that together might make up for his lack of a functioning pancreas.
“This is the transmitter part that pops through his skin,” explains Weinzimer, pointing to a silver-dollar-sized gray circle taped to Yarmis’s abdomen. The sensor underneath continuously monitors his blood glucose levels and sends the data to a small blue computer on a belt clip, about the size of a Game Boy. “The transmitter beams data to this device,” Weinzimer says, “which signals the insulin pump.” Software developed by the manufacturer, Medtronic, directs an insulin reservoir to dispense doses appropriate for Yarmis’s current blood sugar levels. They enter his body via a narrow length of plastic tubing that feeds into a cannula inserted under his skin. Yarmis will wear the sensor and the pump throughout his three days in the hospital.
Continuous glucose monitors (CGMs) and insulin pumps aren’t new. Many diabetics already use them for checking their blood sugar and dosing themselves with the sugar-lowering hormone. But the artificial pancreas Weinzimer is testing, developed by the Minneapolis-based Medtronic, closes the loop—making an electronic connection between the CGM and the insulin pump, so that the wearer doesn’t need to determine when to take insulin or how much. Many different companies are working on versions of an artificial pancreas; Medtronic’s is the first in clinical trial. Its software allows the CGM to feed blood glucose readings to the insulin pump, which reacts by administering the amount of insulin needed to keep sugar levels within a normal range. “It automates the process so you don’t have to make adjustments all the time,” Weinzimer says. That means wearers like Yarmis can—in theory, anyway—go on complete diabetes autopilot. Better yet, if the device works as it should, they’ll be able to live their lives free of the fear of debilitating complications as they age.
Yarmis will remain hooked up to the artificial pancreas for about 72 hours straight. On the first day, he’ll have to stay quiet and still—“like a couch potato,” Weinzimer says. On the second day, things will start ramping up. For instance, he’ll run on a treadmill in the corner of the room for about an hour to make sure the “pancreas” adapts properly to the body’s insulin needs when he’s exercising. Yarmis knows malfunctions are a possibility, but when I ask him how he feels about that, he says he’s not nervous. More than anything, he says, “I feel lucky.”
Stuart Weinzimer majored in molecular biophysics and biochemistry as a Yale undergraduate and attended the Albert Einstein College of Medicine in New York. In 1995 he accepted a fellowship in pediatric endocrinology—the study of the body’s hormone-secreting glands—at the Children’s Hospital of Philadelphia. “I liked the science of endocrinology,” he says. “It’s beautiful and mathematical and makes perfect sense.”
But at the University of Pennsylvania School of Medicine, where he spent several years doing research after the Philadelphia fellowship, Weinzimer found himself intrigued by juvenile diabetes (now called type 1 diabetes) precisely because, as he says, it “makes no sense. You can’t reduce it to easily digested treatments.” The more insoluble the problem of insulin management seemed, the more Weinzimer wanted to crack it. When he treated young patients in the clinic, he saw firsthand the outsized impact the disease had on their day-to-day existence. What if, he mused, someone could come up with a reliable way to automate diabetes management—to free up patients’ time and energy for the business of living life?
Yale has a long record in diabetes research. The first insulin pumps for children were tested in the late 1970s at the Yale School of Medicine by William Tamborlane and Robert Sherwin. In 2002, Weinzimer joined Yale as an assistant professor of pediatrics in the medical school and began working with Tamborlane. (Weinzimer is now an associate professor.) Around that same time, he heard that Medtronic, which manufactured the first commercial insulin pump, was developing a closed-loop artificial pancreas device for adults. His brain started to race. Could the device work for his under-30 patients?
The closed-loop system didn’t work very quickly, and Weinzimer worried that time lags in the absorption of insulin could put his young patients in danger. “One of the technical problems with the first generation” of the device, he explains, “is that because you’re delivering medicine subcutaneously, you’re always going to be a little behind.” Insulin delivered through the skin takes longer to absorb than insulin delivered directly into the bloodstream, and the resulting delay—as much as an hour—could potentially affect children and teenagers differently from adults. But Weinzimer thought he could address the problem by allowing patients to give themselves small “priming” doses manually, using a button on the insulin pump, just before eating. The closed-loop system would manage the rest.
Working with Garry Steil, a Medtronic engineer now at Boston Children’s Hospital, Weinzimer designed a clinical trial, and in 2008, they published data from the first 17 participants in the journal Diabetes Care. (The trials are funded by the Juvenile Diabetes Research Foundation and the National Institutes of Health and conducted in partnership with Medtronic.) Teenagers and young adults who wore the artificial pancreas achieved better control over their blood glucose levels than they’d had before trying the device. Some participants’ glucose levels fluctuated after they ate, but in the trial group that received doses before meals, the fluctuations were smaller.
Media outlets all over the world showered Weinzimer with attention after the data appeared. But he knew he still had to deal with the problem of exercise. The artificial pancreas is programmed to cut back on its normal background rate of insulin delivery whenever a patient’s glucose levels fall below a predetermined level. This helps ensure that wearers’ blood sugar never falls dangerously low during sleep, for instance—when one in three diabetes patients suffer from low blood sugar. But type 1 diabetics’ blood sugar often plummets after exercise, and the plunge can take place just 15 minutes after the start of biking, swimming, running, or other intense activity. Weinzimer was concerned that the detection mechanism might not work quickly enough to compensate. He designed a second trial to find out—the trial that had brought Ben Yarmis to Yale–New Haven. This study, which includes adults up to age 30, is still under way.
One of the first patients to sign up for the exercise study was Tyler Wolf, a 27-year-old financial analyst at Google. Diagnosed with diabetes as a young teen, Wolf initially rebelled against the regimen the disease imposed on him. “I was very stubborn. I would even deny friends when they told me, ‘You should check your blood sugar,’” he says. “There were a few instances when I was out of body, almost delusional, especially when I was under a lot of stress at school. One instance, I was driving home and got pulled over two blocks from my house. The police thought I was intoxicated.”
Wolf took part in Weinzimer’s second trial in the spring of 2009. Like Yarmis, he made two visits to Yale–New Haven. On the first, he followed his usual maintenance routine so the doctors could get an idea of his typical glucose levels. On the second, he wore the artificial pancreas for three days, exercising intensely for brief periods. The effortlessness of his 72 hours with the device thrilled Wolf. “It was an amazing respite from all of the day-to-day things I have to deal with,” he says. “The control during the night was excellent. I woke up feeling perfect.”
The morning after his first full night with the artificial pancreas, Ben Yarmis is sitting up in his hospital bed and smiling. He feels pretty good, he says. There was a glitch during the night—one of the glucose sensors moved out of place as he tossed and turned in his sleep—but attending staff were able to resolve the issue quickly. “It’s odd getting accustomed to it,” he reflects. “I don’t have to do something I’ve been doing for the past however-many years. I can’t wait for it to be released.”
In his most optimistic moments, Weinzimer predicts that an artificial pancreas might hit the medical marketplace within five years. But he knows that’s an aggressive estimate. One reason is that the U.S. Food and Drug Administration will be vetting the device with extreme scrutiny. Automated devices carry a high risk of liability; if a patient died while wearing the mechanism, the manufacturer could be in for years of costly lawsuits. Weinzimer thinks the FDA will look more favorably on the artificial pancreas if devices for partial automation of insulin delivery—which are already on the market—gain wide acceptance. “In terms of a product,” he says, “we’re not going to have a home run. It’s going to be a series of singles and doubles.”
The Paradigm Veo, which Medtronic launched last fall in over 50 countries (not including the United States), represents the first step in this progression. The Veo includes both an insulin pump and a continuous glucose monitor, and it will withhold insulin if the patient’s glucose levels drop too far. But patients must program the insulin pump themselves. And they still have to check their own blood sugar regularly.
So far, diabetics have given the Veo good reviews. But the artificial pancreas is not ready to follow it into mass production. One hurdle is the problem Yarmis experienced with a sensor that shifted at night; in most trials, patients’ sensors fell out at least once.
Medtronic’s technicians plan to address the issue in future prototypes. “The best fail-safe is to have some redundancy,” says Cesar C. Palerm, a Medtronic principal scientist who came to Yale–New Haven to observe Yarmis’s trial. That might involve multiple sensors; if one sensor showed glucose levels rising and others did not, the system could be programmed to disregard the first sensor’s input. Alternatively, a differently designed sensor might be less likely to pull free from the patient’s skin.
Weinzimer is still reviewing the exercise trial and hasn’t finalized his conclusions. Still, he’s optimistic: “Preliminary data suggest this device can really help reduce the risk of low blood sugar reactions that frequently accompany exercise,” he says. He’s now planning another critical step toward taking the artificial pancreas live: a trial to establish whether patients can safely use it outside the hospital.
As the trials progress, Weinzimer and Medtronic expect to make an assortment of tweaks to the device. They’re considering adding a function that will let users lower their insulin dosage before they start exercising, as well as warning alarms that will alert users if the glucose sensors stop functioning accurately.
For Yarmis—who is now mulling medical sensor development as a future career option—the day when Weinzimer and Medtronic have the device ready for production can’t come too soon. Wolf feels the same way. “To say the artificial pancreas is a step up is an extreme understatement,” he says. “The idea of never having to worry about monitoring—that’s close to a cure.”  |
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