Molecule stays in the bloodstream and is turned on when blood sugar levels are too high.
Anne Trafton | MIT News Office
February 9, 2015
For patients with diabetes, insulin is critical to maintaining good health and normal blood-sugar levels. However, it’s not an ideal solution because it can be difficult for patients to determine exactly how much insulin they need to prevent their blood sugar from swinging too high or too low.
Patients with Type I diabetes lack insulin, which is normally produced by the 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, to ensure there is always some present when needed. Other patients calculate how much they should inject based on how many calories they consume or how much sugar is present in their blood.
The MIT team (Daniel Anderson and Robert Langer) set out to create a new form of insulin that would not only circulate for a long time, but 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 the insulin circulate in the bloodstream longer, although the researchers do not yet know exactly why that is. One theory is that the fatty tail may bind to albumin, a protein found in the bloodstream, sequestering the insulin and preventing it from latching onto sugar molecules.
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.