Modified insulin prevents sudden drops in blood sugar

Scientists have engineered a chemical switch into the insulin used to treat people with diabetes. This enables the hormone to sense the blood sugar level and turn off the insulin signal if blood glucose drops too low. It could work as a way to prevent life-threatening “hypos” that diabetics run the risk of developing if they inject too much insulin or don’t consume enough sugar. To find out more, we put in a call to David Sacks, from the National Institutes of Health. David has just written a news and views piece on this topic for the journal Nature, where the research is also published…

David - People who inject themselves with insulin to treat their diabetes often develop very low glucose called hypoglycaemia. And this is a potentially life-threatening problem. Parents, if you have a child who has Type 1 diabetes and they inject themselves with insulin. Glucose goes too low, the child loses consciousness and has seizures. The parents are devastated and so they tend not to try to get tight glucose control, which is necessary to prevent the long-term complications of diabetes, which include blindness, kidney failure, and heart attacks and strokes. The novelty of this paper is that the authors developed a special insulin molecule that responds to the glucose level in the blood. When the glucose is high, the molecule is switched on and when it is low, the molecule switches itself off because it detects the low glucose in the blood.

Chris - When you say a molecule can turn itself on and off, how on earth does it do that?

David - They took the insulin and they added, stuck onto it, a ring-shaped structure called a macrocycle. And this binds glucose at a different part of the insulin. They stuck on another molecule, which is similar to glucose. And normally when the glucose is low in the blood, this insulin is switched off because the glucose-like molecule called a glucoside is stuck in the ring. When glucose goes high, it replaces the glucoside in the ring shape molecule and the insulin then is switched on.

Chris - So basically the molecule warps the insulin according to how much glucose there is, and that affects whether it can lock onto the cells that would normally see the insulin. And that affects its ability to be an insulin signal or not?

David - That's exactly correct. So what happens normally is that insulin binds to a special molecule inside the lining of the cell, the membrane, and then it signals to the inside of the cell. So the cell then knows that insulin's there and it produces effects inside the cell.

Chris - And I suppose that the benefit here is if you did over inject yourself with this, as soon as your glucose level falls below a limit that we'd define as a safe threshold, that signalling would stop. And so your body would stop lowering your blood sugar and you wouldn't end up going into a coma.

David - That's absolutely correct, because in people without diabetes, when you eat glucose, in your blood goes up, insulin is released, and then it lowers the glucose in your blood and then it stops being released and is eliminated from the body. When you inject normal insulin, which patients do, they've injected under their skin, it can stay in the body for up to 40 hours and it continues working. It doesn't get switched off. So even when the glucose is lowered, the insulin continues lowering it more, causing this dangerous condition of low blood glucose. Now this modified insulin molecule that is described in the paper, when the blood glucose goes low, it stops working, switches itself off.

Chris - How have they tested this? Have they proved it does actually do that?

David - They did studies in rats and pigs to show that the molecule is effective. And in a pig model of diabetes, they demonstrated very clearly and nicely that the glucose does not go very low when they use this modified insulin. And they demonstrated that using standard insulin, human insulin that is injected by people with Type 1 diabetes, the glucose did go low. So it appears to protect against the development of low blood glucose.

Chris - Could it be used then in a sort of depot way where a person could just give themselves a massive injection of this which would last them all week and their sugar would refuse to budge and go too low, but wouldn't go too high either?

David - Most people who inject themselves with insulin do multiple injections every day. They use a long acting insulin and they also use short acting insulins that they inject with meals. You need both of them because they have slightly different effects in the body in terms of controlling your blood glucose concentration. So it could, if effective, replace the current long-acting insulins that most people with diabetes use.