Can insulin come in a pill? How an insulin-mimicking molecule could advance diabetes research

WEHI researchers in Melbourne have answered a 100-year-old question in diabetes research: could a different molecule than insulin have the same effect? The findings provide important information for the future development of an oral insulin pill.

The research team visualized how a non-insulin molecule could mimic the role of insulin, an important hormone needed to control blood sugar levels.

The WEHI-led work opens new avenues for the development of drugs that can replace daily insulin injections for people with type 1 diabetes.

at a glance

  • Researchers have visualized exactly how a molecule that mimics insulin reproduces insulin activity to regulate blood sugar levels.
  • Study answers the age-old question of whether it’s possible to replace insulin
  • The findings illuminate new opportunities for the development of oral insulin mimetics that could replace the daily injections of type 1 diabetes patients.

People with type 1 diabetes cannot produce insulin and need multiple injections of insulin per day to keep their blood sugar levels in check.

New research confirms that alternative molecules can be used to open up blood sugar intake, bypassing the need for insulin altogether.

published work, Nature CommunicationIt was led by Dr Nicholas Kirk of WEHI and Professor Mike Lawrence in collaboration with researchers from Lilly, an American-based pharmaceutical company.

Why is there no insulin pill?

Dr Kirk said scientists had a hard time making insulin as a pill because insulin is unstable and easily broken down by the body upon digestion.

“Since the discovery of insulin 100 years ago, the development of an insulin pill has been a dream come true for diabetes researchers, but after decades of experimentation there has been little success,” he said.

Research has been dramatically accelerated by the development of the cryo-electron microscope (cryo EM), a new technology that can visualize complex molecules in atomic detail and allows researchers to quickly create 3D images (“blueprints”) of the insulin receptor.

“With Kryo-EM we can now directly compare how different molecules, including insulin, change the shape of the insulin receptor,” said Dr Kirk.

“The insulin interaction turned out to be much more complex than anyone had anticipated, as both insulin and its receptor changed shape dramatically as they matched.”

Mimic insulin with simple molecules

New research shows how a molecule that mimics insulin acts on and activates the insulin receptor; it’s the first step in a pathway that prompts cells to absorb glucose when the body’s sugar levels are too high.

The team performed complex cryo-EM reconstructions to obtain blueprints of several molecules called “peptides” that are known to interact with the insulin receptor and keep it in an “active” state.

Cryo-EM experiments identified a peptide that can bind to and activate the receptor in a manner similar to insulin.

“Insulin has evolved to carefully grip the receptor, much like a hand holding a tongs together,” said Dr Kirk.

“The peptides we use work in pairs to activate the insulin receptor – just like two hands holding the tongs from the outside.”

While therapeutic results are distant, the team’s discovery could lead to a drug to replace insulin, reducing the need for injections for diabetics.

“Scientists have succeeded in replacing such mimetic molecules with drugs that can be taken as pills,” said Dr Kirk.

“It’s still a long way to go that will require more research, but it’s exciting to know that our discovery opens the door to oral treatments for type 1 diabetes.”

The study titled “Activation of the human insulin receptor by non-insulin-related peptides” was published in the USA. Nature Communication. The research was financially supported by Lilly.

WEHI authors: Nicholas Kirk, Mai Margetts and Mike Lawrence.

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