Danish scientists create ‘smart’ insulin with ‘on-off’ switch to target blood sugar highs & lows

Bengaluru: ‘Smart’ insulin that responds to rise and fall of blood sugar levels in real-time promises to revolutionise the treatment of all types of diabetes.

Bioengineers and scientists at Danish pharmaceutical company Novo Nordisk have synthesised an insulin molecule with an “on-and-off switch” that automatically responds to sugar levels in the blood. The research was published Wednesday in the journal Nature.

The synthesised modified molecule, called NNC2215, was tested in pigs and rats, and was discovered to be as good as natural insulin in humans. It is yet to be refined enough to be used in humans, but initial findings are promising enough to be extremely similar to the expected observations in humans already. The hope is that smart insulin will address the fluctuation of blood sugar levels and the challenge of matching insulin dosage to sugar levels.

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There have been previous attempts at engineering a smart molecule, but this is the first one that targets the sugar molecule glucose in the blood, instead of others like fructose.

The study is a successful demonstration of the molecule in action, described as a proof of principle, and further research is needed before it can be optimised for humans.

“This is a very good study that was well designed—they did all the necessary experiments to validate that this works,” said David Sacks, a clinical chemist unaffiliated with the study, in a statement accompanying the research.  “It certainly provides encouragement that this approach is worth pursuing.”

The engineering of this molecule is one among a series of studies targeting developing molecules that help regulate insulin automatically based on various sugar levels in the body.

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Need for glucose-sensitive insulin

Diabetes occurs when the pancreas does not produce enough insulin in the body to break down sugar in the blood (type 1), or the cells in the body develop resistance to insulin (type 2). One of the risks of insulin therapy in managing diabetes is the risk of low blood glucose, or too much insulin, which can become life-threatening.

Thus, there have been numerous efforts to develop and engineer a glucose-sensitive insulin molecule that can auto-adjust its bioactivity based on glucose levels in the blood, while lowering the risk of hypoglycemia. 

However, despite attempts since the 1970s, creating one successfully has been difficult so far because blood glucose fluctuations are difficult to predict. Sugar levels in blood depend on several parameters such as time from last meal, amount of exercise, health and infections, and more. 

As a result, patients with diabetes, who undergo insulin therapy, have to manually adjust their daily dose of insulin. These doses are slightly lower than required to lower the risk of hypoglycemia later.

Molecules that have been used in this kind of therapy so far in experiments have been polymer systems that aid in releasing insulin from pockets that the hormone tends to be stored in under the skin.

a) NNC2215 is an insulin molecule with a glucose-sensitive switch | b) 3D models of NNC2215 in the open and closed forms | Nature

Reversible insulin therapy

In the latest study, the insulin molecule itself has been made sensitive to glucose, so that it can reduce in levels when required, something that has been traditionally difficult to do.

The NNC2215 molecule consists of two major parts in its structure—a ring-shaped structure called a macrocycle, and a modified glucose molecule called glucoside. When glucose levels in the blood are low, the glucoside activates and binds to the macrocycle, keeping the insulin molecule ‘closed’ in an inactive state. But when the glucose levels go up, the sugar molecules in the blood displace the glucoside and change the shape of the synthetic insulin molecule. 

This causes the “switch” to turn on, triggering the release of insulin.

A major drawback at this stage of the experiment is that the glucose levels have to fluctuate to a very large degree and cause a steep rise for the molecule to activate. The team is now working on bringing these levels down to smaller increases in glucose.

The battle against diabetes

As of 2021, more than 10 percent of the world’s adult population has diabetes. According to the International Diabetes Federation, 537 million individuals live with the disease, and in 2019, it was the direct cause of the deaths of 1.5 million people worldwide.

Traditional therapies today use insulin replacement injections for type 1 diabetes, and blood glucose lowering medications, along with lifestyle management for type 2. Insulin triggers and releases are performed by glucose monitoring, and the amount of insulin released into the body depends on glucose levels in the blood at the time of the release. However, future levels of glucose after insulin has already been released are difficult to predict and adjust for, increasing the risk of hypoglycemia.

A number of revolutionary therapies to manage diabetes mellitus are underway across the globe today.

A molecule similar to NNC2215 was produced by a group of American researchers in 2021, but it targeted fructose in the blood instead of glucose. A Chinese team has also developed a similar glucose-sensitive molecule. 

Another set of Chinese researchers used stem cell therapy in different experiments to reverse both type 1 and type 2 diabetes.

Semaglutide, the molecule in the Ozempic drug, was also developed for diabetes management and is presently the active subject of several drug development trials. 

Semaglutide was used in combination with a procedure that increased the body’s sensitivity to insulin in groundbreaking results presented at a European conference earlier this year.

(Edited by Mannat Chugh)

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