New type of engineered insulin to treat diabetes

MIT scientists have engineered a new type of insulin that can circulate in the bloodstream for at least 10 hours and gets activated only when blood sugar levels are too high.
The advance could eliminate the need for diabetics to repeatedly monitor their blood sugar levels and inject insulin throughout the day, said researchers at Massachusetts Institute of Technology.
Patients with Type I diabetes lack insulin, which is produced by pancreas and regulates metabolism by stimulating muscle and fat tissue to absorb glucose from the bloodstream.
Insulin injections, which form the backbone of treatment for diabetes patients, 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.

Other patients calculate how much they should inject based on how many carbohydrates they consume or how much sugar is present in their blood.
The MIT team set out to create a new form of insulin that would circulate for a long time in the bloodstream and would be activated only when needed - that is, when blood-sugar levels are too high.

This would prevent patients' blood-sugar levels from becoming dangerously low, a condition known as hypoglycemia that can lead to shock and even death.
To create this glucose-responsive insulin, the researchers first added a hydrophobic molecule called an aliphatic domain, which is a long chain of fatty molecules dangling from the insulin molecule.

This helps insulin circulate in the bloodstream longer.
The researchers 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 research 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.
To compare each type of insulin, the researchers measured how the mice's blood-sugar levels responded to surges of glucose every few hours for 10 hours.

They found that the engineered insulin containing PBA with fluorine worked the best: Mice that received that form of insulin showed the fastest response to blood-glucose spikes.
Giving this type of insulin once a day instead of long-acting insulin could offer patients a better alternative that reduces their blood-sugar swings, which can cause health problems when they continue for years and decades, said Daniel Anderson in MIT's Department of Chemical Engineering.