The Game Changer: Treating type 1 diabetes with glucose-responsive insulins

By Thania Benios

Since its discovery in 1921, insulin has been called one of the few miracle drugs, having saved countless lives from an otherwise incurable disease. Yet 90 years later, treating and managing type 1 diabetes (T1D) is still a tricky business.

Insulin, a hormone, is crucial to life. Without it, glucose cannot move from the bloodstream into the cells of the body to provide them with the energy they need to function. In T1D, which is an autoimmune disease, the immune system mistakenly attacks and destroys the beta cells in the pancreas that produce insulin. This immune attack leaves the body without the insulin that is needed to control blood sugar levels. As a result, the burden of managing blood sugar rests squarely on the shoulders of people with T1D, who must take multiple injections of insulin daily or infuse insulin through a pump.

But mimicking nature is a very time-consuming and difficult process. Exercise, meals and snacks—things that we all incorporate into daily life—require more than just a thought for people with T1D. Every decision means a recalibration of how much insulin to inject or infuse throughout the day, and when to inject it. And a miscalculation due to human error or guesswork can have dire and immediate consequences.

“Despite this round-the-clock vigilance, people with the disease still spend up to 70 percent of their day outside the normal blood sugar range,” says Aaron Kowalski, Ph.D., vice president of glucose control at JDRF. “So despite the effectiveness of current insulin treatments, they do not always prevent hypo- or hyperglycemic episodes, which in the short term can be very dangerous (hypoglycemia) and in the long term (hyperglycemia) cause the terrible complications of diabetes.”

The bottom line: type 1 diabetes is a difficult disease to manage.

In an effort to lift the overwhelming burden of living with T1D, JDRF is putting its resources, expertise, and academic and industry connections behind the development of a glucose-responsive insulin, a “designer” drug that could transform the lives of people with T1D, and any of those with type 2 diabetes who are insulin-dependent.

Unlike current insulin therapies, glucose-responsive insulins would act just like a surrogate pancreas, delivering insulin to the body’s tissues and organs precisely when and where it’s needed, in precisely the right amounts. The drug would only need to be taken once a day or less frequently, and wouldn’t have to be calibrated with carbohydrates, exercise, and blood glucose testing.

And since glucose-responsive insulins would be device-free—limiting finger sticks, replacing pumps, and reducing human intervention—it would drastically reduce the daily burden and cost of managing the disease (along with decreasing the risk of complications).

“Glucose-responsive insulins will be game-changers,” says Sanjoy Dutta, Ph.D., senior director of treatment therapies at JDRF. “When successful, they wouldn’t just be another incremental improvement in insulin therapy. They will provide a new way of life for people with the disease.”

The premise is simple enough: build a drug that can release insulin in the body, but designed to do so only when and where it is needed, and at exactly the right dose. Because they would be more complex than the average drug, these insulins wouldn’t release all their insulin at once, but instead would hold on to their stores until the next influx of sugar from a meal or snack. By minutely adjusting its output to the body’s needs, a glucose-responsive insulin would greatly reduce the human guesswork and human error that are inherently part of current insulin treatments.

However, a drug that can release its contents in response to cues from the body has never been developed, not for diabetes and not for any other disease. “There are implantable devices that can respond to a circulating metabolite,” explains Dr. Dutta. “But there are no drugs, either injectable or in pill form, that are capable of pulling off such a feat.”

To design a drug that can respond to minute changes in the body will require researchers to clear some pretty significant hurdles, both technical and regulatory. Scientists will not only have to design a drug that is capable of detecting a circulating metabolite (in the case of diabetes, the metabolite is glucose), but also formulate one that can safely release its contents, at any dose.

That is, glucose-responsive insulins by design will contain enough insulin to manage blood sugar for a day or potentially longer. This amount of insulin must be controlled and calibrated with the utmost precision, to ensure that a potentially dangerous amount would not be released. A successful drug will only release insulin when needed, only in the amount needed, and will have built-in safeguards to ensure that the insulin is always delivered safely and securely.

And since this will be the first drug that responds to a circulating metabolite, explains Dr. Dutta, the unprecedented regulatory path to approval will need to be determined.

Here’s the hitch: this is an area well-suited for researchers beyond those traditionally focused exclusively on T1D. Chemists, biochemical engineers and pharmacologists, who have the know-how of designing and formulating drugs, will need to be onboard, among other experts. But these researchers are neither thinking about nor working on the problem. Bringing these fields of expertise to work in a coherent team will be a key to success in this area—and JDRF is leveraging its leadership position to bring these investigators together.

To attract new investigators from all corners of the world to the area of glucose-responsive insulins, JDRF has partnered with InnoCentive to create the JDRF Glucose-Responsive Insulin Grand Challenge Prize, and catalyze truly innovating thinking. Rather than use traditional funding mechanisms such as grants or fellowship awards to attract interest, JDRF has sponsored a prize to jumpstart the development of these drugs. Open to the public globally, the prize, which is promoted as a challenge, aims to bring in talent and new ideas from experts in fields not normally associated with T1D research.

“Anyone anywhere in the world and from any professional, scientific, or academic background may submit an idea,” says Julie Yu, Ph.D., director of project management in treatment therapies research. “We want to attract not only the usual suspects, but many of the unusual suspects, too.”

This approach is called crowdsourcing, in which a problem is broadcast to a large number of people with varying forms of expertise and which allows multiple solutions to be explored in a relatively short period of time. Any individual motivated by the challenge can apply their talents toward creating a solution.

“We are tremendously excited about this novel approach—one that crowdsources—reaching outside of the traditional diabetes space for new ideas,” says Darlene Deecher, Ph.D., senior vice president of research at JDRF. “JDRF has never before attempted such a unique funding mechanism and our optimism reflects our expectations that working with InnoCentive will bring innovation to the design of glucose-responsive insulins in a phased approach.”

The approach to the JDRF Glucose-Responsive Insulin Grand Challenge Prize is divided into three phases:

  • Phase 1: Ideation Phase
  • Phase 2: Validation Phase for Preclinical Proof of Principle
  • Phase 3: Translation Phase for Clinical Proof of Concept

The glucose-responsive insulin initiative builds off of previous support that JDRF provided for a start-up biotechnology company in 2008 called Smart Cells Inc., which was recently acquired by the pharmaceutical giant Merck. The progress that Smart Cells had made in developing a glucose-responsive insulin is substantial, but JDRF realizes that a single path toward developing glucose-responsive insulins might not provide the only answer. That’s because it is likely that not all people with insulin-dependent diabetes would respond the same way to a single type of glucose-responsive insulin drug.

Designing glucose-responsive insulins will require a large-scale and concerted effort, but JDRF is confident that the ideas and expertise needed to build a drug like this are out there. By casting a wide net, JDRF will bring the most innovative minds and the best ideas into the field of T1D research.

“The sky’s the limit,” says Dr. Dutta. “And we plan to solicit and nourish the best ideas until they are found.”


An eye on the prize

JDRF’s goal is to ease the burden of managing T1D while we work toward a cure. To make this a reality, JDRF has partnered with InnoCentive, the pioneer in open innovation in crowdsourcing, to formulate and broadcast a challenge to its global network of more than 250,000 “solvers” to develop a new type of insulin that can be a “transformer” in the treatment of diabetes. “From the very first meeting, our colleagues at JDRF have impressed me with their genuine passion for the people suffering with type 1 diabetes—and with their deep understanding of the complex medical and economic issues that we, as a society, must face when dealing with this debilitating disease,” says Eugene Ivanov, Ph.D., innovation program manager of client services at InnoCentive. “I applaud their decision to post a challenge and create a prize that goes to the very core of the problem: finding novel approaches to designing glucose-responsive insulins.”