Insulin is a hormone that plays a critical role in the regulation of glucose (sugar) levels in the blood. It is produced by the pancreas and assists the body in storing glucose as energy. In individuals with diabetes, the body is either not producing enough insulin or is ineffective in storing it effectively. This results in high blood glucose levels.
Researchers at WEHI have discovered that a different substance from insulin may have the same effect. This information is crucial for the future development of an oral insulin tablet.
Researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne have finally answered a question that has puzzled diabetes researchers for a century: can a substance other than insulin have the same effect? The findings provide crucial information on the development of an oral insulin tablet.
They have successfully demonstrated how a non-insulin molecule may imitate insulin, which is critical for maintaining blood sugar levels.
The WEHI-led research opens up new avenues for the discovery of medications that might substitute daily insulin injections for people with type 1 diabetes.
Professor Mike Lawrence, Dr. Nicholas Kirk, and Mai Margetts have produced the first 3D images of an insulin-mimicking protein that is in sync with the insulin receptor. Credit: WEHI
- Researchers have visualized precisely how an insulin-mimicking molecule reproduces the activity of insulin to regulate blood glucose levels
- The study answers a century-old question of whether it is possible to replace insulin
- Findings illuminate new opportunities for the development of oral insulin mimetics that may replace daily injections by type 1 diabetics
- People with type 1 diabetes cannot produce insulin and require multiple daily insulin injections to keep their blood glucose levels in check.
The new study demonstrates that alternative substances may be employed to slash the amount of insulin required in the blood.
Dr. Nicholas Kirk and Professor Mike Lawrence of WEHI collaborated with researchers from Lilly, an American pharmaceutical company.
A 3D representation of how an insulin-improving substance (purple) interacts with a part of the insulin receptor (grey) to turn on. Once activated, the receptor instructs cells to soak up glucose when the body's sugar levels are too high. Credit: WEHI
Scientists have hampered in developing insulin as a tablet because insulin is unstable and easily degraded by the body upon digestion.
The development of an insulin tablet has been a dream for diabetes researchers since the discovery of insulin 100 years ago, but after decades of effort, there has been little success, according to the inventor.
With the development of cryo-electron microscopy (cryo-EM), a new technique that can visualize complicated molecules in atomic detail, researchers may now create 3D models of the insulin receptor in record time.
"With cryo-EM, we may now directly compare how different substances, such as insulin, alter the shape of the insulin receptor," said Dr. Kirk.
"Insulin's interaction turns out to be considerably more complicated than anyone anticipated, with both insulin and its receptor changing dramatically as they partner up."
The new study examines how an insulin-imicking substance works on the insulin receptor and turns it on, the first step in a pathway that guides cells to absorb glucose when sugar levels are too low.
The group performed intricate cryo-EM reconstructions to uncover blueprints for several molecules called "peptides" known to interact with the insulin receptor and maintain its "active" position.
The cryo-EM investigations identified a single protein that may be able to attach to and activate the receptor in a manner similar to insulin.
"Insulin has evolved to hold the receptor tightly, as if carrying a pair of tongs together," Dr. Kirk said.
"The peptides we used work in pairs to activate the insulin receptor — just like two hands grabbing the pair of tongs around the outside."
The team's discovery may lead to a medication that can replace insulin, reducing the need for injections by diabetics.
Dr. Kirk believes that scientists have had great success in substituting these kinds of mimetic molecules with medicines that can be taken as tablets.
"It's still a long journey that will require further investigation, but it's rewarding to know that our discovery opens the door to oral therapies for type 1 diabetes."
Nicholas S. Kirk, Qi Chen, Haitao Hu, Juan F. Espinosa, Faiz A. Mohammed, Vladislav V. Kiselyov, Michael C. Lawrence, Nature Communications, 28 September 2022. DOI: 10.1038/s41467-022-33315-8
Lilly provided funding for the research.