JDRF Research

Glucagon May Add Another Dimension to Artificial Pancreas

As researchers work toward designing a closed-loop artificial pancreas, the assumption has been that the device would incorporate two elements: a glucose monitor and an insulin pump.

Insulin would be given only when needed to counteract rising glucose levels. But what would happen when glucose levels drop too low? The dangers from low blood glucose (hypoglycemia) are acute, resulting in unconsciousness, or even coma or death. Insulin won’t help in this situation.

One way to offset this danger is to equip the artificial pancreas with the means to raise blood glucose quickly by dispensing glucagon. This natural hormone spurs the liver to release glucose into the bloodstream and lift blood sugar levels back into normal
range. Many type 1 patients have lost the ability to make glucagon and need to inject it during hypoglycemic emergencies.

Now researchers at Boston University have shown that glucagon can be used effectively in tandem with insulin in a closed-loop setting. In studies using diabetic pigs, the insulin–glucagon combination quickly increased glucose levels and helped maintain normal-range levels without incidence of hypoglycemia. Results have been so encouraging that human tests could begin by the middle of this year.

“I think people will come to the conclusion that it makes sense to have glucagon in a closed-loop device not only from a safety standpoint, but also because it meets a physiological need,” said Ed Damiano, Ph.D., who led the study. Dr. Damiano conducted the tests at BU with one of his former Ph.D. students, Firas El-Khatib, Ph.D. (recipient of a two-year JDRF postdoctoral fellowship award), and laboratory manager, John Jiang, B.S.

In one study, published in the Journal of Diabetes Science and Technology, the researchers performed closed-loop experiments on four anesthetized pigs, simulating meals by infusing glucose into the animals. The scientists took regular readings of the animals’ blood-glucose levels, entered them into a computer, and then let their control algorithm (a mathematical formula) calculate how much insulin or glucagon should be given. The researchers then entered the computed control dose into the computer, which communicated wirelessly with two Deltec CoZmo pumps that were attached to the animals—one for each hormone.

Results showed that the insulin-glucagon complement provided tight control, bringing glucose levels into normal range within 80 to 120 minutes after each “meal,” with no incidence of hypoglycemia. The algorithm demonstrated great flexibility (the pigs’ weights varied as much as twofold in some cases) and stability (it ignored temporary, erratic fluctuations in glucose levels).

The BU researchers used single-point glucose measurements rather than readings from continuous glucose monitors because they wanted to take direct measurements from the blood. (CGMs take their readings from interstitial fluid found between the body’s cells, and the researchers were concerned that lag time or other variables might throw off the readings and confound the experiment.)

“I think we should address this problem in stages rather than jumping to the endgame right away,” Dr. Damiano said. The researchers also made another very important finding, which they will publish in Diabetes Technology and Therapeutics: glucagon remains stable and potent for up to seven days, even at room temperature. This contradicts conventional wisdom, which held that glucagon depreciates so rapidly once mixed in solution that it would be ineffective in closed-loop control—a notion that made many scientists reluctant to include it in an artificial pancreas.

The BU researchers followed the first study with similar closed-loop tests, in which the pigs were awake and allowed to walk around and eat three actual meals. The researchers hope to finish these subsequent experiments by June 2007.

“Despite their relatively small size, these pigs are capable of eating an enormous amount of carbohydrates in a very short time,” Dr. Damiano said. “It really challenges our control system.”

“Preliminary results of JDRF-funded closed-loop studies have proven to be extremely promising,” noted Dr. Aaron Kowalski, research director for the JDRF Artificial Pancreas Project. “Adding ‘counterregulation,’ the potential safeguard of glucagon to prevent lows, is very appealing and may be an important step as we drive towards an artificial pancreas.”

Dr. Damiano, whose 7-year-old son, David, has type 1 diabetes, thinks that with all the positive data from the pig studies and other human trials, most researchers will come around to seeing the benefits of incorporating glucagon into the artificial pancreas.

“You can certainly drive a car without using your seat belt, but it is not advisable,” he said. “In addition to the added safety benefits that glucagon offers, it also allows you to be slightly more aggressive in regulating your blood sugar.”