Researchers Formulate Stable Liquid Glucagon

The search for a stable liquid formulation of glucagon has occupied many diabetes researchers for years. While currently the biosynthetic hormone is manufactured in dry form to ensure stability and shelf life, the delivery of glucagon in conjunction with insulin in standard diabetes pumps—a long-sought development—would require a viable liquid glucagon. Now, JDRF-funded scientists at Oregon Health & Science University (OHSU) and Legacy Health have developed such a formulation. Their work may not only make glucagon usable in standard diabetes pumps, but may also enable the operation of next-generation artificial pancreas systems that deliver both insulin and glucagon.

Glucagon is a naturally occurring hormone that responds to hypoglycemia (an extremely low blood-glucose level) by increasing the amount of glucose in the blood. It works in concert with insulin—which delivers glucose from the bloodstream to the cells—to maintain optimum blood-glucose balance. In type 1 diabetes (T1D), however, the regulation of insulin and the regulation of glucagon are impaired. Previous studies in people with T1D have shown that the addition of glucagon to regular insulin treatment reduces the frequency of hypoglycemic episodes, which can quickly become dangerous. However, currently available forms of glucagon cannot be kept for long periods of time in a portable pump.

W. Kenneth Ward, M.D., is an associate professor of medicine at OHSU School of Medicine and senior scientist at Legacy Health who worked on the liquid glucagon formulation. He has noted that while additional studies in animals and humans are necessary for the formulation before approval from the U.S. Food and Drug Administration (FDA) can be sought, the discovery is a significant step forward in improving treatment for people with T1D.

The challenge that Dr. Ward and his team faced was one of chemistry. Glucagon is a particularly unstable substance that cannot long maintain its molecular integrity after being dissolved in liquid, providing a short window of therapeutic viability. Dr. Ward and his team found that raising the pH of glucagon—rendering it more alkaline—enables the hormone to be maintained in a liquid form. The results were presented at the 72nd Scientific Sessions of the American Diabetes Association in Philadelphia in June. A stable formulation of liquid glucagon could not only improve both the ease and effectiveness of daily treatment regimens for people with T1D, it could also facilitate the development of bihormonal closed-loop artificial pancreas systems.

Artificial pancreas systems currently in development combine a continuous glucose monitor and an insulin pump via a computer algorithm that analyzes blood-glucose levels in real time and responds by administering the appropriate amount of insulin when needed. In March 2012, the FDA approved the first outpatient clinical trial of an artificial pancreas in the United States. Researchers are looking toward creating multihormonal systems, which in addition to insulin would administer glucagon and other treatments.

“Artificial pancreas systems represent an exciting new approach to the treatment of T1D, but we require highly sophisticated components to realize their development,” says Sanjoy Dutta, Ph.D., senior director of treat therapies at JDRF. “Dr. Ward’s innovative glucagon formulation provides one such component for a next-generation artificial pancreas system that has the potential to confer safer and better treatment for T1D individuals.”