One of the biggest reasons diabetes management remains such a challenge is the struggle of regulating insulin dosages. Too much insulin, and BGs drop. Too little, and they rise. Even more frustrating–you can eat the exact same thing and take the exact same amount of insulin 2 days in a row and get completely different results. Attempting to mimic the precise mechanisms of a pancreas with functioning beta cells is truly exhausting.
Many diabetes innovations focus on making this regulation of insulin doses better. Closed-loop insulin pump systems that communicate with CGMs, for example, automate part of this process. While this is welcome progress, scientists have been starting to wonder: what if the insulin itself responded to blood glucose levels? Then the insulin could do the work, instead of the person with diabetes or their pump.
Glucose-responsive insulin (aka “smart insulin”) is designed only to function when it is needed in the body. It is in an inactive form when BGs are low or in-range, and becomes active when BGs rise. The idea is that it would be delivered one time daily and then work throughout the day as needed (1). Benefits of this strategy are that the insulin would already be circulating in the body when it is needed, allowing it to act quickly. Its inability to function when BG levels are low would also protect against hypoglycemia!
There have been a couple different approaches used to pursue glucose-responsive insulin. In 2015, a group at MIT modified insulin to be able to circulate in the body for longer and be activated by glucose. The modification utilized phenylboronic acid, which is a common glucose sensing tool (2). Promisingly, their system was able to restore BG levels after a meal faster than standard insulins in mice. More recently, a team at the Indiana University School of Medicine inserted a molecular switch into the insulin molecule which stabilizes insulin in its closed state until a sugar binds to it. With this system, the binding of fructose was able to initiate insulin signaling in human cells (3, 4).
Another smart insulin called MK-2640 was developed to mitigate hypoglycemia. When glucose levels are low, MK-2640 binds to a cell receptor allowing it to be degraded. This is one of the only glucose-responsive insulins to have made it to clinical trials, but unfortunately the trial was not successful.
Progress from small-scale experiments to actual clinical use can be quite slow. However, there are significant strides being made in the glucose-responsive insulin space so it is definitely worth keeping an eye on! Though not the traditional biological cure we often think about, smart insulin has the potential to really improve life with diabetes. It’s amazing to think that more than 100 years after insulin was first developed, there are still potential improvements on the horizon.
References
- JDRF. Glucose Responsive Insulin. https://www.jdrf.org/mountainwest/wp-content/uploads/sites/95/2013/06/Glucose-Responsive-Insulin.pdf
- Chou, D. H.-C., et al. (2015). “Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates.” Proceedings of the National Academy of Sciences 112(8): 2401-2406.
- Chen, Y.-S., et al. (2021). “Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone receptor activation.” Proceedings of the National Academy of Sciences 118(30): e2103518118.
- IU School of Medicine. Newsroom. July 29, 2021. Synthetic hinge could hold key to revolutionary “smart” insulin therapy.” https://medicine.iu.edu/news/2021/07/synthetic-hinge-could-hold-key-to-revolutionary-smart-insulin-therapy
