What’s the biggest issue for people taking insulin? Is it the difficulty of controlling your highs even when you’re conscientious about calculating your dose? Is it the fear of going way too low because you have too much insulin on board? Or is it the necessity of counting carbs, calculating a dose, and taking insulin practically every time food crosses your lips? All these issues have to do with the difficulty of coming up with a correct dose of insulin when you’re giving it from the outside, divorced from the body’s exquisitely precise system of doling out insulin when you eat.
JDRF, partnered with Sanofi, the company that manufactures Lantus among other insulins, recently pledged up to $4.6 million to support research into four different efforts to design a glucose-responsive insulin (GRI). The ultimate goal with a GRI is that someone could take insulin and then forget about it—no calculating, almost no testing, no worrying about highs or lows—because the insulin would only be activated when necessary. The program, which is still at a very early stage, is being overseen by Sanjoy Dutta, JDRF’s associate vice president of translational development. All four projects are approaching the problem of engineering a glucose-responsive insulin from different angles. Dutta explained that JDRF wants to have “multiple shots on goal” with this technology, because a successful glucose-responsive insulin would be a “game changer.” He commented, “I’m cautiously very optimistic. But I will not take the cautiously away until there’s human data.”
Dutta emphasized, though, that beyond the fact that only a small percentage of pharmaceutical products make it out of the pipeline, developing an insulin technology which essentially has a switch built in to turn the insulin on and off is a very challenging scientific problem. “There is no drug that I am aware of that works in response to an internal body signal. There’s no cardiac medicine that will work when you go into arrhythmia, no gastric medicine that responds to your PH level. There is no scientific or technical precedent for this. We are blazing the trail now as we speak, and I am sure we will see failure before successes.”
The first of the researchers, Alborz Mahdavi, was working in the field of chemical biology and developed novel concepts for a glucose-responsive insulin which led to winning the JDRF GRI Grand Challenge Prize—a competition designed to spark innovations in the field. Mahdavi now runs a biotechnology startup called Protomer Technologies in Pasadena, California, and his team there is working towards implementing and testing a variety of such insulin types.  Mahdavi has a PhD in bioengineering, and his research in chemical biology mainly focuses on chemical modifications to macromolecules such as proteins and polymers. In this case, he is trying to modify certain formulations of insulin to be able to sense glucose. As an analogy, Mahdavi describes how one’s taste buds sense glucose, and the body starts responding. “As soon as you eat something sweet, proteins in your tongue send signals to the brain. You could imagine developing a molecular sensor for sugar that would activate the same way. The whole system would be automatic.” This approach is often called biologically inspired design. “Getting an idea from nature is very helpful, because we see that it is possible,” says Mahdavi.
Similarly, Dr. Danny Chou’s lab is working on attaching a glucose-sensing particle to insulin, but his research involves altering the structure of the insulin molecule, depending on whether blood glucose is high or low, to create new analogues. “The three dimensional structure will be different in each case, and that structure will make the insulin active or inactive,” he explains. Dr. Christoph Hagemeyer of Monash University in Melbourne, Australia, is also working on developing glucose-sensing technology, in this case using enzymes to detect changes in glucose level.
These three projects would rely on existing methods for delivering insulin—injections or pumps. The last project that JDRF and Sanofi are funding, designed by Zhen Gu, a researcher at North Caroline State University and UNC Chapel Hill, would disperse insulin differently. As described in A Sweet Life last year, Zhen Gu and his research group have been working on an insulin patch with over a hundred tiny glucose-sensing, insulin-storing needles, each about the size of an eyelash. The patch that Gu has tested is penny-sized, can be placed anywhere on the body, and lasts for about nine hours.
Glucose-responsive insulin is not going to be the next big thing in diabetes management—the development of the technology is going to take a while. That distinction will belong to the artificial pancreas, with a few different companies set to release their versions over the next couple of years. The goal of the two technologies is similar: insulin dosing informed by your blood glucose level, so you don’t have to think about highs or lows and how to eat and dose to avoid them. Yet one of those tehnologies seeks to achieve that goal not by trying to recreate the pancreas outside the body, with circuits and electronics, but by essentially shrinking it to the size of a penny, or of a few droplets of smart insulin.
