Glucose-responsive insulin to better control diabetes

Researchers from Massachusetts Institute of Technology (MIT) have developed a new type of insulin which activates in the bloodstream only when it is needed. The development could make everyday life much easier for type 1 diabetes patients, who lack the ability to generate their own insulin and must therefore take daily injections of the hormone in response to their changing blood-sugar levels.

Insulin injections can be deployed in different ways: some people take a modified form called long-acting insulin, which stays in the bloodstream for up to 24 hours to ensure there is always some present when needed; while others calculate how much they should inject based on how many carbohydrates they consume or how much sugar is present in their blood. MIT’s Associate Professor Daniel Anderson explained that a big challenge for diabetes sufferers is “getting the right amount of insulin available when you need it”.

“If you have too little insulin your blood sugar goes up, and if you have too much, it can go dangerously low,” Associate Professor Anderson said. “Currently available insulins act independent of the sugar levels in the patient.”

Writing in the Proceedings of the National Academy of Sciences, Associate Professor Anderson and his colleagues said their derivative of insulin contains a “molecular switch to provide glucose-mediated activation of the insulin molecule”. The insulin can circulate in the bloodstream for at least 10 hours and responds to changes in blood-sugar levels only when they are too high. This prevents patients’ blood-sugar levels from becoming dangerously low - a condition known as hypoglycaemia, which can lead to shock and even death.

To create the insulin, the researchers added a hydrophobic molecule called an aliphatic domain, which is a long chain of fatty molecules dangling from the insulin molecule. This helps the insulin circulate in the bloodstream longer. They also attached a chemical group called PBA, which can reversibly bind to glucose. When blood-glucose levels are high, the sugar binds to insulin and activates it, allowing the insulin to stimulate cells to absorb the excess sugar.

The team created four variants of the engineered molecule, each of which contained a PBA molecule with a different chemical modification, such as an atom of fluorine and nitrogen. They then tested these variants, along with regular insulin and long-acting insulin, in mice engineered to have an insulin deficiency. The engineered insulin containing PBA with fluorine worked the best, with its test subjects showing the fastest response to blood-glucose spikes.

“The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative,” the authors wrote. “Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas.”

The researchers now plan to test this type of insulin in other animal models and are also working on tweaking the chemical composition of the insulin to make it even more responsive to blood-glucose levels. Anderson said, “We’re continuing to think about how we might further tune this to give improved performance so it’s even safer and more efficacious.”

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